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Raynaud's phenomenon, anticentromere antibodies, and digital necrosis without sclerodactyly: An entity independent of scleroderma?
Raynaud’s phenomenon, anticentromere antibodies, and digital necrosis without sclerodactyly: An entity independent of scleroderma? Evelyn M. Sachsenberg-Studer, MD,a Christa Prins, MD,b Jean-Hilaire Saurat, MD,b and Denis Salomon, MDb Frankfurt, Germany, and Geneva, Switzerland We describe 4 women of 43, 73, 84, and 86 years with Raynaud’s phenomenon, severe digital necrosis, and high serum levels of anticentromere antibodies without skin thickening or internal organ sclerosis. Investigations revealed no diabetes or arterial vascular disease leading to arterial obstruction. Histologic examination did not show any dermal sclerosis or calcinosis. The intravenous infusions of prostaglandin reversed the ischemic lesions in 3 patients. These cases suggest that the triad Raynaud’s phenomenon, anticentromere antibodies and necrosis of digits without sclerodactyly and sclerosis of internal organ should be considered as an entity distinct from scleroderma with sclerosis. For this entity we propose the name RACAND syndrome. (J Am Acad Dermatol 2000;43:631-4.)
A
nticentromere antibodies (ACA) directed against a 19-kd nuclear protein (CR-19) are present in 35% to 96% of cases of limited systemic sclerosis (lSSc), in fewer than 10% of cases of diffuse systemic sclerosis (dSSc) and infrequently in systemic lupus erythematosus, primary Sjögren’s syndrome, primary biliary cirrhosis, rheumatoid arthritis, immune thrombocytopenic purpura, Graves’ disease, immune hemolytic anemia, vitiligo, and Raynaud’s syndrome.1 The clinical significance of ACA is widely discussed. It has been suggested that the association of ACA and Raynaud’s phenomenon (RP) could be the earliest sign of SSc preceding other manifestations by several years. In a study of 77 patients with RP, the presence of ACA was associated with a 163-fold increased risk of a connective tissue disease.2 The patients with ACA but without a definitive diagnosis of connective tissue disease presented a risk to develop a limited scleroderma, which has been evaluated with a sensitivity of 60% and a specificity of
Abbreviations used: ACA: CT: dSSc: lSSc: RP: SSc:
anticentromere antibodies computed tomography diffuse systemic sclerosis limited systemic sclerosis Raynaud’s phenomenon systemic sclerosis
98%.3 In patients with SSc, ACA seem to be associated with an increased risk of major peripheral vascular occlusive disease and could be a predictor of digital ischemic loss.4 We describe 4 patients with ACA and RP, without any skin thickening or internal organ sclerosis, who experienced severe digital necrosis. To our knowledge, only two reports have described similar cases so far, and this subject has not been highlighted in the dermatologic literature.
CASE REPORTS From the Department of Dermatology, J-W Goethe University Hospital, Frankfurt,a and the Clinic of Dermatology, University Hospital DHURDV, Geneva.b Accepted for publication March 28, 2000. Reprint requests: E. M. Sachsenberg-Studer, MD, Department of Dermatology, J-W Goethe University Hospital,Theodor-Stern-Kai 7, 60590 Frankfurt a.M., Germany. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/107499 doi:10.1067/mjd.2000.107499
Case 1 A 43-year-old woman, an occasional smoker without diabetes or hypertension, had suffered from RP and fluctuating digital edema for 2 years. She consulted us for painful finger necrosis of 1 week’s duration. We observed digital edema and important necrosis of the third left and second right fingertips without any sclerodactyly, telangiectases, or cutaneous calcinosis. A capillaroscopy revealed giant cap631
632 Sachsenberg-Studer et al
J AM ACAD DERMATOL OCTOBER 2000
Fig 1. Histologic examination of amputated digit. Photomicrograph shows luminal arterial narrowing from thrombosis and thickening of the media without any cutaneous sclerosis.
Fig 2. Severe necrosis of third and fourth left, and second and third right fingers.
illaries of the right finger 2-5 but no pathology of the left fingers. Investigations showed ACA at the dilution of 1:20,000, but no antibodies directed against Scl-70, Ro, La, Sm, RNP, or antiphospholipids. Investigations for pulmonary, esophageal, and renal involvement including pulmonary function tests, chest x-ray, high-resolution computed tomographic (CT) scan of the lungs, esophageal radionuclide transit, and creatinine clearance remained negative. We started a treatment with intravenous iloprost, 2 ng/kg per minute, over 7 days. Two weeks later the necrotic lesions had disappeared and the RP became less important. After a follow-up of 2 years no sclerodactyly or internal organ sclerosis has been observed.
globulins, antiphospholipid antibodies, or antibodies against Scl-70, Ro, La, Sm, or RNP. We started a treatment with intravenous alprostadil 40 µg/day for 18 days and observed a progressive improvement of digital perfusion and digital necrosis.
Case 2 A 73-year-old woman was hospitalized with necrotic lesions of the second right and the second and third left fingers that had appeared 6 weeks earlier and progressively worsened. She was a nonsmoker and without diabetes, but she had hypertension treated by enalapril and clonidine. She had suffered with RP for the past 12 years. We observed no cutaneous sclerosis, telangiectases, or calcinosis cutis. Esophageal and pulmonary fibrosis was excluded by means of esophageal radionuclide transit, esophageal manometry, pulmonary function tests, chest x-ray examination, and high-resolution CT scan. Creatinine clearance was within the normal range. A capillaroscopy showed no dilated capillary loops, but several loop dropouts of the right finger 2 and left fingers 2 and 3 were noted. An arteriography revealed a reduced perfusion of all digital arteries, especially of right and left digits 2 and 5. ACAs were detected at a titer of 1:20,000. There were no cryo-
Case 3 In February 1994, an 84-year-old woman, a nonsmoker and without diabetes but with a long-standing hypertension treated by enalapril, presented with dry necrosis of the second right and left fingers of 1 week’s duration. Clinical and serologic examination, pulmonary function tests, chest x-ray, CT scan, and barium meal showed no evidence of sclerodactyly, telangiectases, calcinosis cutis, or renal, pulmonary, or esophageal sclerosis. A cold test for RP was positive. A capillaroscopy showed a mild degree of loop dropout, but no dilated capillary loops. ACAs were detected at a titer of 1:10,000. No antibodies directed against Scl-70, Ro, La, Sm, RNP, antiphospholipids, or cryoglobulins were detected. A treatment with anticalcic drugs (nifedipine 20 mg twice a day) was initiated without improvement. In May 1994, transmetacarpal amputation of the second left finger was necessary. Histologic examination of the amputated digit showed luminal arterial narrowing caused by thrombosis and thickening of the media without any dermal sclerosis (Fig 1). A treatment with pentoxifylline (800 to 1200 mg/day) was started. One year later, necrosis of the third and fourth left fingers, second and third right fingers, and first left and second right toes was observed (Fig 2). The first left toe had to be amputated, and infusions of iloprost 2 ng/kg per minute over 7 days were started. Initially, this treatment limited the extension of digital necrosis. However, a few months later, new digi-
Sachsenberg-Studer et al 633
J AM ACAD DERMATOL VOLUME 43, NUMBER 4
Table I. Patients with RP and severe digital ischemic lesions without sclerodactyly associated with an increased level of ACA Patient No.
Sex
Age (y)
RP
1
F
43
+
2 3 4 5 6 7 8
F F F F F F M
73 84 86 60 74 79 67
+ + + + + + +
Interval between RP and digital necrosis
2 y (fingers) 1 y (toes) 12 y RP clinically silent RP clinically silent 0.3 y 54 y 30 y ?
Amputation
Sclerodactyly
Systemic involvement
1:20,000
-
-
-
1:20,000 1:10-20,000 1:10,000 + 1:640 + 1:1280
+ + -
-
-
ACA
ACA, Anticentromere antibodies; RP, Raynaud’s phenomenon. 1-4: our cases; 5-7: cases of Takahashi, Okada, and Kondo6; 8: case of Barr and Robinson.5
tal necrosis appeared and ACA was measured at a titer of 1:20,000. The left fingers 4 and 5 had to be amputated distally. Histologic investigation showed severe subocclusive endofibrosis of the digital arteries without any calcification or thrombosis. We introduced prednisone at 10 mg/day together with aspirin without any success. One month later, the patient died of severe bronchopneumonia. Case 4 An 86-year-old woman, nonsmoker without diabetes or hypertension, was hospitalized with severe necrotic lesions of the second and third right fingers and the right big toe of 2 months’ duration. There was no cutaneous sclerosis, digital telangiectases, or calcinosis. A cold test for RP was positive. Laboratory investigations showed ACA at a titer of 1:10,000. Extractable nuclear antigens, antiphospholipids, and cryoglobulins were not detected. Vascular investigations did not show any signs of macroangiopathy. Capillaroscopy was normal as were findings of chest x-ray, arterial gases, pulmonary function tests, barium meal, and creatinine clearance. We started a treatment with prednisone without any significant success. Under a therapy with iloprost infusions, 2 ng/kg per minute, over 7 days with subsequent anticalcic drugs, we observed a disappearance of the toe necrosis and subsequently a disappearance of the necrosis of the right index and middle fingers. After a follow-up of 1 year, no relapse has been observed.
DISCUSSION We report 4 cases demonstrating that severe digital necrosis may occur in ACA-positive patients without any skin or internal organ sclerosis. These 4 female patients with RP and severe digital ischemic lesions presented with a very high level of ACA with-
out diabetes or chronic arteriopathy (Table I). None of them showed any skin or visceral involvement that suggested the diagnosis of systemic scleroderma. Histopathologic examination did not reveal any dermal sclerosis or specific signs of arterial disease. In 2 cases, the interval between the appearance of RP and the onset of digital ischemia ranged between 1 and 12 years. In 2 cases RP was clinically silent and diagnosed by a cold test when the patients were admitted for vascular problems. The onset of skin thickening in SSc has been suggested to be associated with vascular damage.7 Sclerodactyly with ischemic digital lesions is seen predominantly in patients with the limited form of scleroderma. In this subset, ACAs are found in 35% to 96% of patients and seem to be a risk factor for losing 1 or more digits because of major peripheral vascular occlusive disease independent of age, race, smoking status, and duration of RP and SSc disease.4 The characteristics common to our 4 patients were that all had RP and ACA, but although severe vascular damage of the skin was present, skin or internal organ sclerosis, telangiectases, and calcinosis cutis were absent. In contrast to the patients with severe digital ischemic lesions reported by other authors,4,8 they did not seem to have lSSc respectively dSS as defined by the American Rheumatism Association in 1980.9 In this classification, fibrosis was the only definitive diagnostic criterion for SSc. However, recent studies showed that RP may predate systemic illness with sclerosis by up to 2 decades in patients testing positive for ACA.2 These antibodies in association with RP seem to be a predictor of SSc. Therefore, in that our patients had a relatively short follow-up, the possibility is not excluded that some cases might develop into SSc at a later stage.
634 Sachsenberg-Studer et al
For different authors, such as LeRoy et al,10 patients presenting with such features as RP with either abnormal capillaroscopy or ACA, but without cutaneous sclerosis, should be considered as having “scleroderma sine sclerosis” and therefore as lSSc. For them, these features are part of the pathobiologic continuum of SSc. The purpose of our report is not to enter into the semantic controversy of “scleroderma sine sclerosis,” but rather to focus on the fact that ACAs are a factor of risk for severe digital necrosis with loss of one or more digits even without sclerosis detectable, especially in elderly and female patients. To our knowledge, this fact has been pointed out only twice so far (Table I).5,6 In other reports skin thickening remained unclear.11 The mechanism of vascular damage in our patients remains to be elucidated. ACA could be related to the factors supposed to be responsible for arterial occlusion in patients with SSc, such as enhanced platelet activation,12-14 endothelial damage,15 increased levels of soluble mediators of vasoconstriction,12 or a hypercoagulation state.16,17 It is also possible that they are directly toxic to endothelial cells, as suggested by Takahashi, Okada, and Kondo.6 With regard to therapeutic, in particular prophylactic interventions, it seems important to think over the pathologic significance of ACA. Treatments like anticalcic drugs, phenoxybenzamine, pentoxifylline, and systemic steroids either alone or in combination did not have any significant effect on our patients. However, we observed a major improvement of digital ischemia after intravenous prostaglandin (iloprost in 3 cases and alprostadil in 1 case). This treatment has been described for RP or ischemic ulcers in SSc.18,19 In our patients it prevented the progression of necrosis in 3 patients without recurrence after 1 and 2 years of follow-up. Nevertheless, in the most severe case, it could not prevent the occurrence of new episodes of digital necrosis. Therefore it seems important to start prostaglandins early. In conclusion, our observations demonstrate that vasculopathy and skin thickening are not necessarily related and suggest that ACA are a risk factor for digital necrosis independent of the presence of cutaneous sclerosis. Therefore the triad RP, ACA, and necrosis of digits without sclerodactyly should be identified as an entity distinct from the various subsets of systemic scleroderma with established sclerosis. To coin a name for this entity, we propose the acronym “RACAND syndrome.” REFERENCES 1. Chan HL, Lee YS, Hong HS, Kuo TT. Anticentromere antibodies ACA: clinical distribution and disease specificity. Clin Exp Dermatol 1994;19:298-302.
J AM ACAD DERMATOL OCTOBER 2000
2. Weiner ES, Hildebrandt S, Senécal JL, Daniels L, Noell S, Joyal F, et al. Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud’s disease. Arthritis Rheum 1991;34:68-77. 3. Kallenberg CGM, Wouda AA, Hoet MH, Van Venrooij ANW. Development of connective tissue disease in patients presenting with Raynaud’s phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis 1988;47:634-41. 4. Wigley FM, Wise RA, Miller R, Needlema BW, Spence RJ. Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis. Arthritis Rheum 1992;35: 688-93. 5. Barr WG, Robinson JA. Systemic sclerosis and digital gangrene without scleroderma. J Rheumatol 1988;15:875-7. 6. Takahashi M, Okada J, Kondo H. Six cases positive for anti-centromere antibodies with ulcer and gangrene in the extremities. Br J Rheumatol 1997;36:889-93. 7. Rodnan GP, Myerowitz RL, Justh GO. Morphologic changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynaud phenomenon. Medicine 1982; 59:393-408. 8. Herrick AL, Heaney M, Hollis S, Jayson MIV. Anticardiolipin, anticentromere and anti-Scl-70 antibodies in patients with systemic sclerosis and severe digital ischemia. Ann Rheum Dis 1994;53:540-2. 9. Subcommittee of the American Rheumatism Association: Preliminary criteria for the classification of systemic sclerosis (scleroderma): Arthritis Rheum 1980;23:581-90. 10. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202-5. 11. Oddis CV, Eisenbeis CHJ, Reidbord HE, Steen VD, Medsger TJ. Vasculitis in systemic sclerosis: association with Sjögren’s syndrome and the CREST syndrome variant. J Rheumatol 1987;14: 942-8. 12. Reilly IAG, Roy L, Fitzgerald GA. Biosynthesis of thromboxane in patients with systemic sclerosis and Raynaud’s phenomenon. Br Med J 1986;292:1057-9. 13. Seibold JR, Harris JN. Plasma beta-thromboglobulin in the differential diagnosis of Raynaud’s phenomenon. J Rheumatol 1985;12:99-103. 14. Wigley FM, Wise RA, Malamet R, Scott TE. Nicardipine in the treatment of Raynaud’s phenomenon: dissociation of platelet activation from vasospasm. Arthritis Rheum 1987;30:281-6. 15. Kaheleh MB.Vascular disease in scleroderma: endothelial T lymphocyte-fibroblast interactions. Rheum Dis Clin North Am 1990;16:53-73. 16. Fritzler MJ, Hart DA. Prolonged improvement of Raynaud’s phenomenon and scleroderma after recombinant tissue plasminogen activator therapy. Arthritis Rheum 1990;33:274-6. 17. Jarrett PEM, Morland M, Browse NL. Treatment of Raynaud’s phenomenon by fibrinolytic enhancement. Br Med J 1978;2: 523-5. 18. Bartolone S, Trifiletti A, De Nuzzo G, Scamardi R, Larosa D, Sottilotta G, et al. Efficacy evaluation of prostaglandin E1 against placebo in patients with progressive systemic sclerosis and significant Raynaud’s phenomenon. Minerva Cardioangiol 1999;47:137-43. 19. Black CM, Halkier-Sorensen L, Belch JJ, Ullman S, Madhok R, Smit AJ, et al. Oral iloprost in Raynaud’s phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dosecomparison study. Br J Rheumatol 1998;37:952-60.
A
nticentromere antibodies (ACA) directed against a 19-kd nuclear protein (CR-19) are present in 35% to 96% of cases of limited systemic sclerosis (lSSc), in fewer than 10% of cases of diffuse systemic sclerosis (dSSc) and infrequently in systemic lupus erythematosus, primary Sjögren’s syndrome, primary biliary cirrhosis, rheumatoid arthritis, immune thrombocytopenic purpura, Graves’ disease, immune hemolytic anemia, vitiligo, and Raynaud’s syndrome.1 The clinical significance of ACA is widely discussed. It has been suggested that the association of ACA and Raynaud’s phenomenon (RP) could be the earliest sign of SSc preceding other manifestations by several years. In a study of 77 patients with RP, the presence of ACA was associated with a 163-fold increased risk of a connective tissue disease.2 The patients with ACA but without a definitive diagnosis of connective tissue disease presented a risk to develop a limited scleroderma, which has been evaluated with a sensitivity of 60% and a specificity of
Abbreviations used: ACA: CT: dSSc: lSSc: RP: SSc:
anticentromere antibodies computed tomography diffuse systemic sclerosis limited systemic sclerosis Raynaud’s phenomenon systemic sclerosis
98%.3 In patients with SSc, ACA seem to be associated with an increased risk of major peripheral vascular occlusive disease and could be a predictor of digital ischemic loss.4 We describe 4 patients with ACA and RP, without any skin thickening or internal organ sclerosis, who experienced severe digital necrosis. To our knowledge, only two reports have described similar cases so far, and this subject has not been highlighted in the dermatologic literature.
CASE REPORTS From the Department of Dermatology, J-W Goethe University Hospital, Frankfurt,a and the Clinic of Dermatology, University Hospital DHURDV, Geneva.b Accepted for publication March 28, 2000. Reprint requests: E. M. Sachsenberg-Studer, MD, Department of Dermatology, J-W Goethe University Hospital,Theodor-Stern-Kai 7, 60590 Frankfurt a.M., Germany. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/107499 doi:10.1067/mjd.2000.107499
Case 1 A 43-year-old woman, an occasional smoker without diabetes or hypertension, had suffered from RP and fluctuating digital edema for 2 years. She consulted us for painful finger necrosis of 1 week’s duration. We observed digital edema and important necrosis of the third left and second right fingertips without any sclerodactyly, telangiectases, or cutaneous calcinosis. A capillaroscopy revealed giant cap631
632 Sachsenberg-Studer et al
J AM ACAD DERMATOL OCTOBER 2000
Fig 1. Histologic examination of amputated digit. Photomicrograph shows luminal arterial narrowing from thrombosis and thickening of the media without any cutaneous sclerosis.
Fig 2. Severe necrosis of third and fourth left, and second and third right fingers.
illaries of the right finger 2-5 but no pathology of the left fingers. Investigations showed ACA at the dilution of 1:20,000, but no antibodies directed against Scl-70, Ro, La, Sm, RNP, or antiphospholipids. Investigations for pulmonary, esophageal, and renal involvement including pulmonary function tests, chest x-ray, high-resolution computed tomographic (CT) scan of the lungs, esophageal radionuclide transit, and creatinine clearance remained negative. We started a treatment with intravenous iloprost, 2 ng/kg per minute, over 7 days. Two weeks later the necrotic lesions had disappeared and the RP became less important. After a follow-up of 2 years no sclerodactyly or internal organ sclerosis has been observed.
globulins, antiphospholipid antibodies, or antibodies against Scl-70, Ro, La, Sm, or RNP. We started a treatment with intravenous alprostadil 40 µg/day for 18 days and observed a progressive improvement of digital perfusion and digital necrosis.
Case 2 A 73-year-old woman was hospitalized with necrotic lesions of the second right and the second and third left fingers that had appeared 6 weeks earlier and progressively worsened. She was a nonsmoker and without diabetes, but she had hypertension treated by enalapril and clonidine. She had suffered with RP for the past 12 years. We observed no cutaneous sclerosis, telangiectases, or calcinosis cutis. Esophageal and pulmonary fibrosis was excluded by means of esophageal radionuclide transit, esophageal manometry, pulmonary function tests, chest x-ray examination, and high-resolution CT scan. Creatinine clearance was within the normal range. A capillaroscopy showed no dilated capillary loops, but several loop dropouts of the right finger 2 and left fingers 2 and 3 were noted. An arteriography revealed a reduced perfusion of all digital arteries, especially of right and left digits 2 and 5. ACAs were detected at a titer of 1:20,000. There were no cryo-
Case 3 In February 1994, an 84-year-old woman, a nonsmoker and without diabetes but with a long-standing hypertension treated by enalapril, presented with dry necrosis of the second right and left fingers of 1 week’s duration. Clinical and serologic examination, pulmonary function tests, chest x-ray, CT scan, and barium meal showed no evidence of sclerodactyly, telangiectases, calcinosis cutis, or renal, pulmonary, or esophageal sclerosis. A cold test for RP was positive. A capillaroscopy showed a mild degree of loop dropout, but no dilated capillary loops. ACAs were detected at a titer of 1:10,000. No antibodies directed against Scl-70, Ro, La, Sm, RNP, antiphospholipids, or cryoglobulins were detected. A treatment with anticalcic drugs (nifedipine 20 mg twice a day) was initiated without improvement. In May 1994, transmetacarpal amputation of the second left finger was necessary. Histologic examination of the amputated digit showed luminal arterial narrowing caused by thrombosis and thickening of the media without any dermal sclerosis (Fig 1). A treatment with pentoxifylline (800 to 1200 mg/day) was started. One year later, necrosis of the third and fourth left fingers, second and third right fingers, and first left and second right toes was observed (Fig 2). The first left toe had to be amputated, and infusions of iloprost 2 ng/kg per minute over 7 days were started. Initially, this treatment limited the extension of digital necrosis. However, a few months later, new digi-
Sachsenberg-Studer et al 633
J AM ACAD DERMATOL VOLUME 43, NUMBER 4
Table I. Patients with RP and severe digital ischemic lesions without sclerodactyly associated with an increased level of ACA Patient No.
Sex
Age (y)
RP
1
F
43
+
2 3 4 5 6 7 8
F F F F F F M
73 84 86 60 74 79 67
+ + + + + + +
Interval between RP and digital necrosis
2 y (fingers) 1 y (toes) 12 y RP clinically silent RP clinically silent 0.3 y 54 y 30 y ?
Amputation
Sclerodactyly
Systemic involvement
1:20,000
-
-
-
1:20,000 1:10-20,000 1:10,000 + 1:640 + 1:1280
+ + -
-
-
ACA
ACA, Anticentromere antibodies; RP, Raynaud’s phenomenon. 1-4: our cases; 5-7: cases of Takahashi, Okada, and Kondo6; 8: case of Barr and Robinson.5
tal necrosis appeared and ACA was measured at a titer of 1:20,000. The left fingers 4 and 5 had to be amputated distally. Histologic investigation showed severe subocclusive endofibrosis of the digital arteries without any calcification or thrombosis. We introduced prednisone at 10 mg/day together with aspirin without any success. One month later, the patient died of severe bronchopneumonia. Case 4 An 86-year-old woman, nonsmoker without diabetes or hypertension, was hospitalized with severe necrotic lesions of the second and third right fingers and the right big toe of 2 months’ duration. There was no cutaneous sclerosis, digital telangiectases, or calcinosis. A cold test for RP was positive. Laboratory investigations showed ACA at a titer of 1:10,000. Extractable nuclear antigens, antiphospholipids, and cryoglobulins were not detected. Vascular investigations did not show any signs of macroangiopathy. Capillaroscopy was normal as were findings of chest x-ray, arterial gases, pulmonary function tests, barium meal, and creatinine clearance. We started a treatment with prednisone without any significant success. Under a therapy with iloprost infusions, 2 ng/kg per minute, over 7 days with subsequent anticalcic drugs, we observed a disappearance of the toe necrosis and subsequently a disappearance of the necrosis of the right index and middle fingers. After a follow-up of 1 year, no relapse has been observed.
DISCUSSION We report 4 cases demonstrating that severe digital necrosis may occur in ACA-positive patients without any skin or internal organ sclerosis. These 4 female patients with RP and severe digital ischemic lesions presented with a very high level of ACA with-
out diabetes or chronic arteriopathy (Table I). None of them showed any skin or visceral involvement that suggested the diagnosis of systemic scleroderma. Histopathologic examination did not reveal any dermal sclerosis or specific signs of arterial disease. In 2 cases, the interval between the appearance of RP and the onset of digital ischemia ranged between 1 and 12 years. In 2 cases RP was clinically silent and diagnosed by a cold test when the patients were admitted for vascular problems. The onset of skin thickening in SSc has been suggested to be associated with vascular damage.7 Sclerodactyly with ischemic digital lesions is seen predominantly in patients with the limited form of scleroderma. In this subset, ACAs are found in 35% to 96% of patients and seem to be a risk factor for losing 1 or more digits because of major peripheral vascular occlusive disease independent of age, race, smoking status, and duration of RP and SSc disease.4 The characteristics common to our 4 patients were that all had RP and ACA, but although severe vascular damage of the skin was present, skin or internal organ sclerosis, telangiectases, and calcinosis cutis were absent. In contrast to the patients with severe digital ischemic lesions reported by other authors,4,8 they did not seem to have lSSc respectively dSS as defined by the American Rheumatism Association in 1980.9 In this classification, fibrosis was the only definitive diagnostic criterion for SSc. However, recent studies showed that RP may predate systemic illness with sclerosis by up to 2 decades in patients testing positive for ACA.2 These antibodies in association with RP seem to be a predictor of SSc. Therefore, in that our patients had a relatively short follow-up, the possibility is not excluded that some cases might develop into SSc at a later stage.
634 Sachsenberg-Studer et al
For different authors, such as LeRoy et al,10 patients presenting with such features as RP with either abnormal capillaroscopy or ACA, but without cutaneous sclerosis, should be considered as having “scleroderma sine sclerosis” and therefore as lSSc. For them, these features are part of the pathobiologic continuum of SSc. The purpose of our report is not to enter into the semantic controversy of “scleroderma sine sclerosis,” but rather to focus on the fact that ACAs are a factor of risk for severe digital necrosis with loss of one or more digits even without sclerosis detectable, especially in elderly and female patients. To our knowledge, this fact has been pointed out only twice so far (Table I).5,6 In other reports skin thickening remained unclear.11 The mechanism of vascular damage in our patients remains to be elucidated. ACA could be related to the factors supposed to be responsible for arterial occlusion in patients with SSc, such as enhanced platelet activation,12-14 endothelial damage,15 increased levels of soluble mediators of vasoconstriction,12 or a hypercoagulation state.16,17 It is also possible that they are directly toxic to endothelial cells, as suggested by Takahashi, Okada, and Kondo.6 With regard to therapeutic, in particular prophylactic interventions, it seems important to think over the pathologic significance of ACA. Treatments like anticalcic drugs, phenoxybenzamine, pentoxifylline, and systemic steroids either alone or in combination did not have any significant effect on our patients. However, we observed a major improvement of digital ischemia after intravenous prostaglandin (iloprost in 3 cases and alprostadil in 1 case). This treatment has been described for RP or ischemic ulcers in SSc.18,19 In our patients it prevented the progression of necrosis in 3 patients without recurrence after 1 and 2 years of follow-up. Nevertheless, in the most severe case, it could not prevent the occurrence of new episodes of digital necrosis. Therefore it seems important to start prostaglandins early. In conclusion, our observations demonstrate that vasculopathy and skin thickening are not necessarily related and suggest that ACA are a risk factor for digital necrosis independent of the presence of cutaneous sclerosis. Therefore the triad RP, ACA, and necrosis of digits without sclerodactyly should be identified as an entity distinct from the various subsets of systemic scleroderma with established sclerosis. To coin a name for this entity, we propose the acronym “RACAND syndrome.” REFERENCES 1. Chan HL, Lee YS, Hong HS, Kuo TT. Anticentromere antibodies ACA: clinical distribution and disease specificity. Clin Exp Dermatol 1994;19:298-302.
J AM ACAD DERMATOL OCTOBER 2000
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