Classification of systemic sclerosis

Classification of Systemic Sclerosis GABRIELE VALENTINI, MD

lassification (Latin classis, major division) is the systematic arrangement of similar conditions on the basis of certain features. It is concerned essentially with deIining reliable boundary criteria between two or more related diseases or between two or more subsets of the same disease. Criteria for classifying a disease must include manifestations that are characteristic of and frequent in the disease in question (sensitivity) but absent or infrequent among persons without the disease (specificity). The process of classification is devoted to defining the guidelines for categories of disorders. It is different from diagnosis, which fits the disease of a single patient into one category.*,z Systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by thickening and fibrosis of the skin (scleroderma), Raynaud’s phenomenon, and widespread damage of small arteries and microvessels, musculoskeletal manifestations, and distinctive forms of visceral involvement, notably of the gastrointestinal tract, lungs, heart, and kidneys.3-7 From a nosologic point of view, SSc has been long considered as a connective tissue disease (CTD) or systemic autoimmune rheumatic disease.8-10 In fact, SSc shares some clinical, pathologic, and serologic features with other diseases of the same family, such as systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), and it may overlap with them.“J2 Proposed criteria for the classification of SSc mainly discriminate it from other connective tissue diseases. On the other hand, SSc patients show a remarkable heterogeneity in the extent of skin sclerosis and visceral involvement, the pace of the disease, and consequently

C

From the Institute of Clinical Medicine, Rheumatology Unit, Second University of Naples, Italy. Address all correspondence to Gabriele Valentini, MD, Associate Professor of Clinical Physiopathology, Institute of Clinical Medicine, Rheumatology Unit, Second University of Naples, Italy.

0 1994 by Elsevier Science Inc.

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0738-081x/94/$7.00

the prognosis. 13-16 In this respect, a number of authors have long tried to classify clinical subgroups with different prognoses.

Criteria for the Classification of SSc SSc shows distinctive features in its later stages. The coexistence of skin sclerosis and quite typical visceral and vascular manifestations makes the diagnosis as well as the proper classification quite easy in these stages. The small percentage of patients affected with SSc sine scleroderma”J* may pose some diagnostic problems that are commonly overcome by the skilled clinician. In the early stages, however, SSc may be difficult to differentiate from other systemic autoimmune rheumatic diseases, Raynaud’s phenomenon, and various nonrheumatic disorders. It may present early as an undifferentiated connective tissue disease (CTD). In 1968, a subcommittee on Criteria for Scleroderma was appointed within the Committee on Diagnostic and Therapeutic Criteria of the American Rheumatism Association (ARA).19 At the December 1972 Interim Scientific Session of the ARA a multicenter prospective study devoted to providing criteria for the classification of early diagnosed SSc was officially announced. The results of this prospective study were published in 1980 (Table 1).20 These criteria have enjoyed wide acceptance. Nonetheless, some comments should be made to avoid their incorrect use. As Masi et al.2o clearly stated, these criteria are not intended to assist in the diagnosis of the individual patient. Diagnostic criteria should include the full spectrum of manifestations of a disease and the sufficient combinations of findings that must be present for the patient to be affected by that disease. As far as SSc is concerned, Raynaud’s phenomenon, which affects about 98% of the cases, and esophagogastrointestinal involvement would be considered. However, their low discriminating power

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VALENTINI

Table 1. Preliminary Criteria for the Classification Svstemic Sclerosiszo*

of Definite

Major Criterion Proximal sclerodema Minor Criteria Sclerodactyly Digital pitting scars or loss of substance on the distal finger pad Bibasilar pulmonary fibrosis l The maior criterion or anu combination of 2 or more minor criteria were found in 97% of definite SSc patients (s&sitiuihj and in’ 2% of comparison cases (98%‘specificity). Localized scleroderma and pseudosclerodenatous disorders represent criteria of exclusion.

makes them inefficient as criteria for classification. When ACR (formerly ARA) criteria for SSc are erroneously used for diagnostic purposes, they may be misleading. Proximal scleroderma (i.e., skin sclerosis involving sites proximal to metacarpophalangeal or metatarsophalangeal joints) is a manifestation shared by many conditions, some of which are related to SSc while others are only minimally related or unrelated to it (e.g., eosinophilic fasciitis, morphoea, linear scleroderma, amyloidosis, the recently described eosinophilia myalgia syndrome, etc). A complete analysis of this topic is beyond the scope of this article. The reader is referred to Jablonska3 and Rowe11 and Goodlield.’ Masi et a1.20considered all these pseudosclerodermatous conditions as criteria of exclusion. In each case the clinical investigator has the task of making the differential diagnosis, before checking whether classification criteria are satisfied by his or her patients. On the other hand, a number of patients diagnosed by authorities as affected by definite SSc do not satisfy the criteria. Eight of the 264 definite SSc cases studied by Masi et al.zo did not present either proximal scleroderma or any combination of two of the three minor criteria. MedsgeP reported that 67 out of 639 SSc patients first seen at the University of Pittsburgh during 1972 - 1983 did not satisfy the criteria. All of them were affected with the CREST variant of SSc. The exclusion of such cases (about 10% of the SSc patients seen at a referral center) from clinical investigations might introduce a selection bias. Another point to address concerns which diseases are discriminated by SSc by applying the criteria. The ACR subcommittee derived their conclusions from protocols of 797 cases, out of whom 264 suffered from detinite SSc, 35 from probable or early stage SSc, 85 from overlap syndromes, 172 from SLE, 120 from PM/DM and 121 from Raynaud’s phenomenon. In 97% of SSc patients (definite, probable, and overlap syndromes) and 96% of comparison cases, the diagnosis had been made within 2 years from entry to study. Proximal scleroderma was detected in 9 1% of definite SSc, 5 1% of probable or early

stage SSc, 58% of overlap syndromes, and 1 out of 172 SLE cases. This last patient was likely suffering from an overlap syndrome. l9 Any combination of two out of the three minor criteria was found in 17 out of the 25 definite and in 4 out of the 17probable SSc cases not satisfying the major criterion, in no SLE case, in 3 PM/DM cases, and in 6 Raynaud’s patients. The exact percentage of patients with overlap syndromes satisfying the minor criteria cannot be inferred. Nonetheless, sclerodactyly, digital pitting scars, and bibasilar pulmonary fibrosis were detected in 71%, 38%, and 26% of them, respectively. In the final step of elaboration of the criteria, the subcommittee, for simplicity, did not consider either probable SSc or overlap syndromes. Moreover, after criteria had been formulated, they were tested in an independent population of 1,300 patients stored in the ARAMIS data bank at Stanford University, giving 92% sensitivity and 96% specificity. Once more, overlap syndromes do not seem to have been considered at that stage of criteria development.19,20 Therefore, the very high specificity of the criteria must be intended against the following comparison disorders: SLE, PM/DM, Raynaud’s phenomenon and not UCTD or overlap syndromes. Overlap syndromes constitute a heterogenous group of conditions. They may include coexistence of at least two definite diseases (e.g., SSc and PM/DM), the presence of features of one condition in patients affected with another definite disease or a combination of non-distinctive features from several CTD.“,‘* The members of the subcommittee clearly stated that “they had resisted the temptation to rigidly define the overlap group . . . and, given the present state of knowledge, the proposed criteria can be expected to serve as guidelines to standardized classification without implying rigid diagnostic boundaries.” Nonetheless, it is presently unknown whether the possible inclusion of overlap syndromes cases in SSc series has any impact on the proper evaluation of the results of clinical investigations and the comparison among patients from different centers. The final comment emerges from the last 13 years’ advances in the study of autoimmune response in SSc. During this period, two antibody specificities, anticentromere antibodies (ACA) and anti-Scl-70, have been found to be almost specific for SSc and detectable in a signiticant percentage of patients with this disease. The prognostic significance of these antibodies in patients with Raynaud’s phenomenon has been investigated, their presence being quite sensitive in predicting clinical progression.22,23 Recently, a points system based on clinical, capillaroscopic, and serologic features has been developed for diagnosis of early SSc.*’ It is time to undertake a proper prospective study to investigate the role of such antibodies, for the purpose of disease classification, in

Clinics in Dermatology 1994;12:217-223

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Table 2. SScSubsetsAccording to LeRoy et a1.16 Diffuse CutaneousSSc l Onset of Raynaud’s phenomenon within 1 year of onset of skin changes l Truncal and acral skin involvement l Presence of tendon friction rubs l Early and signitlcant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement l Presence of anti-DNA topoisomerasi I (anti-Scl-70) antibodies l Absence of anticentromere antibodies l Nailfold capillary dilatation and destruction* Limited Cutaneous SSc Raynaud’s phenomenon for years at presentation l Skin sclerosis limited to hands, feet, face, and forearms, or absent l Significant late incidence of pulmonary hypertension, trigemlnal neuralgia, calcinosis, and telangiectasia l Dilated nailfold capillary loops, usually without capillary dropouts* l

Figure 1. Skin sclerosisextent in four SScsubsets.LcSSc patients may present minimal sclerotic lesion at eyelids, neck and armpits. From Giordano et al.15

OverlapSyndromes l

Either diffuse or limited SSc with typical features of one or more of the other connective tissue diseases l

Detected by widefield nailfold capillaroscopy.

discriminating early stage SSc from related disorders, including localized scleroderma and pseudosclerodermatous conditions.

SSc Subsets Clinical The modem era of SSc subsetting was opened by the papers of Winterbauer,z5 Carr et a1.,26Frayha et al.,*’ and Rodnan et al.,** which led to the definition of CREST Ealcinosis, Raynaud’s phenomenon, Esophageal dysfunction, Sclerodactyly, xelangiectasia) syndrome as a benign variant of SSc. The CREST concept enjoyed consensus for many years. Recently, it has been realized that the term CREST is confusing and inaccurate in defining a SSc subset, since sclerodactyly (i.e., a limited extent of skin sclerosis) is the main feature of the syndrome and the one correlated to a longer survival, other manifestations (C, E, T) being either absent in some cases (incomplete CREST syndrome) or present in many patients with a more diffuse extent of skin sclerosis.H-3* In the last few years, two classifications of SSc into subsets have been proposed. The first distinguishes a diffuse cutaneous (dcSSc), a limited cutaneous (IcSSc), and overlap syndromes subsets (Table 2). Proposed in 1988 by a number of authorities in scleroderma field,16 this system represents a revision of the subsetting first proposed by Rodnan et al. in 1979l’ and subsequently modified by the same team. 32The extent of skin sclerosis is the

main subsetting criterion. LcSSc includes patients with skin sclerosis confined to fingers (sclerodactyly), those with face and distal extremities involved (distal to the elbow), and the small group of SSc sine scleroden-na. The minimum features suggested to satisfy the classification of a patient as 1cSSc is the presence of Raynaud’s phenomenon with either ACA or abnormal capillaries. In patients with dcSSc, trunk skin is involved. In addition, many other aspects characterizing each subset are underlined, namely, the antibody specificities, the lag time between the onset of Raynaud’s phenomenon and that of skin sclerosis, the capillaroscopic alterations, and the main features of visceral and musculoskeletal involvement. In a large series of patients referred to a tertiary center from 1981 to 1990,6 47% of the cases were affected with dcSSc, 43% with lcSSc, and 10% with overlap syndromes. At present, this subsetting scheme enjoys the widest acceptance. The second classification was first proposed by Bamett in 197813 and subsequently by Giordano et a1.15and by a team of German authors.33 Bamett13 distinguished three SSc subsets according to the extent of skin changes detected within 2 years from presentation: type I sclerodactyly; type II skin changes beyond the fingers, but mainly in the extremities; type III with diffuse skin involvement. In 1986, Giordano et a1.15reached similar conclusions by subdividing SSc patients according to the maximal extent of skin sclerosis within 2 years from its onset and demonstrating differences in the antibody pattern and survival among the three subsets. These were respectively named lcSSc, intermediate cutaneous SSc (icSSc), and dcSSc. In addition, for clinical reasons, SSc sine scleroderma (ssSSc) was considered as a fourth subset (Figure 1). Our results were subsequently confirmed by Bamett et al.% in

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0 m +

Anticentromere Antinucleolar + Giordano

%

I

s U R V I V

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60 -

et al.

40

A L 20

70

-

60

-

50

-

40

-

30

-

20

-

+

cumulative

-O-

SSc intermediate

10 0 Digital (26 + 45 = 73)

Proximal Extremity (25+21=46)

Truncal (37+7=44)

Figure 2. Percent prevalence of ACA, anti-S&70 and antinucleolar antibodies in SScpatients subdivided according to early cutaneous involvement. From Masi.35 a large series of SSc patients in whom the subset had been defined within 1 year from presentation. Masi35 collected data from Bamett et al. and this author concerning both the antibody profile (Figure 2) and survival. He deduced that subgrouping SSc patients into three early cutaneous subsets seems advisable for prognostic purposes. This author, moreover, suggested a modified terminology (Table 3). Finally, he thought it justified to consider ssSSc as a fourth subset. This last opinion is now shared by other authorities.5*7 Recently, Ferri et a1.31subgrouped 15 1 SSc patients by either the two subsets (dcSSc and 1cSSc)or the three subsets (dcSSc, icSSc, and 1cSSc) classification as deiined at presentation. The latter was found to better discriminate SSc patients as far as antibody specificities (ACA and anti-SC1 70) and survival are concerned. Figure 3 from Ferri et al. paper shows the survival curves of the three subsets. In our present series, 36% of the patients have been diagnosed as dcSSc, 28% as icSSc, 27% as lcSSc, and 9% as SSSSC.~~ In other series of SSc patients subdivided according to the same subsetting scheme, a higher percentage of 1cSSc has been registered.3*,34 The main purpose of disease subsetting is to enable the physician to make a prognostic evaluation and to plan a suitable surveillance program and the investigator to Table 3. Subsettinx of SScby Early Cutaneous Involvement* Digital

Proximal Tnmcal l

Extremity

Finger or toes. Minimal nonextremity involvements allowed: eyelid, neck, and axillary changes Protial extremity or face, but not trunk Thorax or abdomen

The subset is defined within

1 year from presentation.

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’

’

’

’

’

1

2

3

4

5

6

7

6

9

10

years

of

follow-up

Figure 3. Survival curvesfor cutaneous subsetsof SScpatients: 68 with IcSSc,46 with icSSc,and 37 with dcSSc.From Ferri et a1.31

study homogeneous groups of subjects. The use of each of the two schemata allows us to reach these goals.37 The classification discussed here do not reflect the entire spectrum of SSc. Some patients have been reported to cross from one subset to another during the follow-up (so-called transitional forms).38 Another subgroup of dcSSc patients (17.6% of a series of 91 patients reported by Lally et a1.)3gshows a rapidly progressive course that is unpredictable at the time of presentation (acute dcSSc?). Moreover, SSc or scleroderma-related conditions arising after exposure to environmental agents40,41 are not considered. Since pathological alterations and clinical manifestations of such a complex disease as SSc are evolving continuous-gradient phenomena, any discrete SSc subsetting as well as the use of extent of skin sclerosis as the main differentiating aspect is arbitrary and restrictive. Nevertheless, the differences registered among subsets support the validity of the presently used SSc subgrouping. 16,35,42Moreover, the degree as well as the extent of skin sclerosis seems to have a prognostic value. In fact, Clements et a1.43have found an inverse relationship between survival and skin score at study entry. Such relationship was more signiticant than that detected by using the subsetting schemata related to the distribution of skin sclerosis (h3). Many factors appear to condition the evolution of SSC.‘~-‘~ An accurate study of each patient, particularly devoted to investigating the status of kidney, heart, and lung involvements, will help the physician to make a prognostic evaluation in individual cases.

Clinics in Dermatology 1994;12:217-223

Serologic In 1980, Tan et al.*’ reported a very high prevalence (96%) of antinuclear antibodies in the sera of SSc patients when using HEp-2 cells as substrate in the indirect immunofluorescence method. These authors found three types of such antibodies to be specific for SSc: ACA, antiScl-70 (after shown to be directed against an epitope of DNA topoisomerase 14B), and antinucleolar antibodies. Subsequently, a number of reports have been devoted to investigate the correlations between each of these antibodies and clinical and prognostic aspects of c&

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Table 4. Main Autoantibody SpecificitiesGiving a Nucleolar Pattern of Fluorescence

Antigen

Percent Frequency in SSc

Fibrillarian (U3-RNP)

8

RNA polymerase I

4

Th

4

PM-Scl

3

15,30-32,34,49-51

ACA are almost specific for SSc, being infrequently detected in patients with conditions other than scleroderma or Raynaud’s phenomenon.50~52~53 Their prevalence in IcSSc (32 - 71%) is remarkably higher than that found in dcSSc (0 - 8%), with frequencies from 0 to 24% reported in icSSc in those studies in which such patients are considered as a distinct subset. In SSc, ACA positivity has been found to be associated with less severe disease, longer duration, and a favorable prognosis.‘9,50 Among patients with lcSSc, those with ACA have been reported to show more frequently calcinosis and telangiectasia30*32*34 and less frequently lung fibrosis.30*32 These associations have not been confirmed.31 However, survival rates of 1cSScACA-positive patients do not differ from those of 1cSScACA - negative cases.30-32$4 Anti-Scl-70 are quite specific of SSc, having occasionally been detected in patients with Raynaud’s phenomenon or UCTD, and in controls.31,50 They have been found in 20 to 60% of SSc sera, their prevalence being higher in dcSSc (20 - 66%) and icSSc (38- 84%) than in 1cSSc (4 39%). Anti-S&70 positivity has been reported to be correlated with severe organ involvement and poorer prognosis* 30,50and to have, together with DR52a positivity, a predictive value for the development of lung fibrosis.55,56However, within dcSSc patients, anti-Scl-70 does not appear to be predictive of any other organ involvement, nor are they associated with a shorter survival.30,31 Antinuclear antibodies showing a nucleolar pattern of fluorescence are relatively specific for SSc, having been detected in higher percentages (7-46%) than in other connective tissue diseases.15,30~31~34~47~51 In the last few years, a number of antinucleolar antibodies have been characterized and found to be correlated with disease features51,57-60 (Table 4). The reported associations appear very interesting from both a pathogenetic and a clinical point of view. Nevertheless, each of these antibodies identifies just a small number of SSc patients. At present, no substantial evidence suggests the opportunity of including any antibody-defined subset in a subgrouping scheme. In the care of the individual patient,

OF SYSTEMIC

Clinical Associations Men with more lung and heart and less joint involvement. DcSSc with telangiectasia DcSSc with high frequency of internal and musculoskeletal involvements and shorter disease duration at presentation LcSSc with reduced survival. Pulmonary hypertension, small bowel involvement LcSSc in overlap with myositis. Higher frequency of renal involvement

however, the knowledge of these associations can be useful to the clinician in programming a suitable surveillance.

Conclusions SSc subsetting is still an evolving process. Classifications are already available to guide the physician in making a prognostic evaluation in the patient and to help the investigator in the analysis of clinical studies. In the future, advances in clinical, serologic, and genetic aspects of SSc might allow a subsetting more closely reflecting the heterogeneity of the disease and its varied prognosis. Acknowledgments The author thanks Prof. Alfonse T. Masi for his helpful suggestions.

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College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 1990;33:106567. 3. Jablonska S, editor. Scleroderma and pseudoscleroderma. Warsaw: Polish Medical Publishers, 1975. 4. Rowe11 NR, Goodfield MJD. The “connective tissue diseases”. In: RI-I Champion, JL Burton, FJG Ebling (eds):

Rook/Wilkinson/EbBng textbook of dermatology, fifth edition. London: Blackwell Scientific Publications, 1992, pp 2133-94.

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5. LeRoy EC. Systemic sclerosis (scleroderma). In: JB Wyngaarden, LH Smith Jr, JC Bennett (eds): Cecil textbook of medicine, 19th edition. Philadelphia: WB Saunders Company, 1992, pp 1530-35. 6. Medsger TA Jr. Systemic sclerosis (scleroderma), localized forms of scleroderma and calcinosis. In: DJ McCarty, WJ Koopman, editors, Arthritis and allied conditions, 12th edition. Philadelphia: Lea and Febiger, 1993, pp 1253-92. 7. Seibold JR. Scleroderma. In: WN Kelley, ED Harris, S Ruddy, CB Sledge, editors, Textbook of rheumatology, 4th edition. Philadelphia: WB Saunders Company, 1993, pp 1113-43. 8. Banks BM. Is there a common denominator in scleroderma, dermatomyositis, disseminated lupus erythematosus, the Libman-Sacks syndrome and polyarteritis nodosa? N Engl J Med 1941;225:433-34. 9. Klemperer P, Pollak AD, Baehr G. Diffuse collagen diseases: Acute disseminated lupus erythematosus and diffuse scleroderma. JAMA 1942;119:331-32. 10. Tuffanelli DL, Winkelmann RK. Scleroderma and its relationship to the “collagenoses”: dermatomyositis, lupus erythematosus, rheumatoid arthritis and Sjogren’s syndrome. Am J Med Sci 1962;243:133-146. 11. Maddison PJ. Mixed connective tissue disease, overlap syndromes and eosinophilic fasciitis. Ann Rheum Dis 1991; 50, suppl4:887-93. 12. Mukerji B, Hardin JG. Undifferentiated, overlapping, and mixed connective tissue diseases. Am J Med Sci 1993; 305:114- 19. 13. Bamett AJ. Scleroderma (progressive systemic sclerosis): Progress and course based on a personal series of 118 cases. Med J Aust 1978;2:129-34. 14. Rodnan GP, Jablonska S, Medsger TA Jr. Classification and nomenclature of progressive systemic sclerosis (scleroderma). Clin Rheum Dis 1979;5:5-13. 15. Giordano M, Valentini G, Migliaresi S et al. Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis. J Rheumatol 1986;13:911-16. 16. LeRoy EC, Black C, Fleischmajer R et al. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol 1988;15:202-05. 17. Rodnan GP, Fennell RI-I. Progressive systemic sclerosis sine scleroderma. JAMA 1962;180:665-70. 18. Giordano M, Valentini G, Vatti M et al. Systemic sclerosis sine scleroderma and correlated diagnostic problems. Conn Tiss Dis 1982;1:115-36. 19. Masi AT, Medsger TA Jr, Rodnan GP et al. Methods and preliminary results of the scleroderma criteria cooperative study of the American Rheumatism Association. Clin Rheum Dis 1979;5:27-48. 20. Masi AT, Rodnan GP, Medsger TA Jr et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-90.

Clinics in Dermatology 1994;12:217-223 2 1. Medsger TA Jr. Comment on Scleroderma Criteria Cooperative Study. In: CM Black, AR Myers, editors, Systemic sclerosis (scleroderma). New York: Gower Medical Publishing, 1985, pp 16-17. 22. Kallenberg CGM, Wouda AA, Hoet MH et al. 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;47:63441. 23. Weiner ES, Hildebrandt S, Seneca1 JL et al. Prognostic significance of anticentromere antibodies and antitopoisomerase I antibodies in Raynaud’s disease: a prospective study. Arthritis Rheum 1991;34:68-77. 24. Ihn H, Sato S, Tamaki T et al. Clinical evaluation of scleroderma spectrum disorders using a points system. Arch Dermatol Res 1992;284:391-95. 25. Winterbauer RH. Multiple telangectasia, Raynaud’s phenomenon, sclerodactyly and subcutaneous calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia. Bull Johns Hopkins Hosp 1964;114:361-83. 26. Carr RD, Heisel EB, Stevenson TD. CRST syndrome. A benign variant of scleroderma. Arch Dermatol 1965; 92:519-25. 27. Frayha RA, Scarola JA, Shulman LE. Calcinosis in scleroderma: reevaluation of the CRST-syndrome. Abstract. Arthritis Rheum 1973;16:542. 28. Rodnan GP, Medsger TA Jr, Buckingham RB. Progressive systemic sclerosis- CREST syndrome: Observations on natural history and late complications in 90 patients. Abstract. Arthritis Rheum 1975;18:423. 29. Giordano M. The CREST acronym and some related problems. Letter. Arthritis Rheum 1985;28:359. 30. Steen VD, Powell DL, Medsger TA Jr. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988;31:196-203. 31. Ferri C, Bernini L, Cecchetti R et al. Cutaneous and serologic subsets of systemic sclerosis. J Rheumatol 1991; 18:1826-32. 32. Steen VD, Ziegler EL, Rodnan GP et al. Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis. Arthritis Rheum 1984;27:125-31. 33. Arbeitsgruppe der ADF. Klinik der progressiven systemichen Sklerodermie (PSS): Multizentrische untersuchungen an 194 patienten. Der Hautartz 1986;37:320-24. 34. Bamett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (19531983): The value of a simple cutaneous classification in the early stages of the disease. J Rheumatol 1988;15:276-83. 35. Masi AT. Classification of systemic sclerosis (scleroderma): Relationship of cutaneous subgroups in early disease to outcome and serologic reactivity. Editorial. J Rheumatol 1988;15:894-98.

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36. Tirri G, Valentini G. Unpublished observations. 37. Vayssairat M, Baudot N, Abuaf N et al. Long-term followup study of 164 patients with definite systemic sclerosis: Classification considerations. Clin Rheumatol 1992;ll: 356-63. 38. Rodnan GP, Jablonska S. Classification of systemic and localized scleroderma. In: CM Black, AR Myers, editors, Systemic sclerosis (scleroderma). New York: Gower Medical Publishing, 1985, pp 3 - 6. 39. Lally EV, Jimenez SA, Kaplan SR. Progressive systemic sclerosis:Mode of presentation, rapidly progressive disease course and mortality based on an analysis of 91 patients, Sem Arthritis Rheum 1988;18:1-13. 40. Straniero NR, Furst DE. Environmentally-induced systemic sclerosis-like illness. Bailliere’s Clin Rheum 1989;3:63-79. 41. Perez MI, Kohn SR.Systemic sclerosis,JAm Acad Dermatol 1993;28:525-47. 42. Valentini G, Migliaresi S, Picillo U et al. Antibody pattern and other criteria for diagnosis and classification in PSS (Reply to a letter). J Rheumatol 1988;15:154. 43. Clements PJ, Lachenbruch PA, Ng SC et al. Skin score: A semiquantitative measure of cutaneous involvement that improves prediction of prognosis in systemic sclerosis. Arthritis Rheum 1991;33:1256-63. 44. Medsger TA Jr, Masi AT, Rodnan GP et al. Survival with systemic sclerosis (scleroderma): A life table analysis of clinical and demographic factors in 309 patients. Ann Intern Med 1971;75:369 -76. 45. Altman RD, Medsger TA Jr, Bloch DA et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991;34:403-13. 46. Bulpitt KJ, Clements PJ,Lachenbruch PA et al. Early undifferentiated connective tissue disease: III. Outcome and prognostic indicators in early scleroderma (systemic sclerosis). Ann Intern Med 1993;118:602-9. 47. Tan EM, Rodnan GP, Garcia I, et al. Diversity of antinuclear antibodies in progressive systemic sclerosis: Anticent-romere antibody and its relationship to CREST syndrome. Arthritis Rheum 1980; 23:617-25. 48, Shero JH, Bordwell B, Rothfield NF et al. High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science 1986;231:737-40. 49. McCarty GA, Rice JR, Bembe ML et al. Anticentromere an-

VALENTINI 223 CLASSIFICATION OF SYSTEMIC SCLEROSIS tibody. Clinical correlations and association with favorable prognosis in patients with scleroderma variants. Arthritis Rheum 1983;26:1-7. 50. Weiner ES,Eamshaw WC, Seneca1JL et al. Clinical associations of anticentromere antibodies and antibodies to topoisomerasi I: A study of 355 patients. Arthritis Rheum 1988;31:378-85. 51. Reinter G, Steen VD, Penning CA et al. Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma). Arthritis Rheum 1988;31:525-32. 52. Migliaresi S, Picillo U, Tirri G et al. Infrequency of anticentromere antibody in patients without systemic sclerosisand without Raynaud’s phenomenon. Letter. Arthritis Rheum 1987;30:358-59. 53. Vlachoyiannopoulos PG, Drosos AA, Wii A et al. Patients with anticentromere antibodies, clinical features, diagnoses and evolution. Br J Rheumatol 1993;32:297-301. 54. Giordano M, Tii G, Valentini G et al. Prognostic significance of anticentromere antibody in progressive systemic sclerosis.X European Congress of Rheumatology, Moscow, June 26-July 2, 1983. Abstract n. 382. 55. Briggs DC, Vaughan RW, Welsh KI et al. Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis. Lancet 1991;338:661-62. 56. Briggs D, Stephens C, Vaughan R et al. A molecular and serologic analysis of the major hi&compatibility complex and complement component C4 in systemic sclerosis. Arthritis Rheum 1993;36:943-54. 57. Reichlin M, Maddison PJ, Targoff I et al. Antibodies to a nuclear/nucleolar antigen in patients with polymyositis overlap syndromes. J Clin Immunol 1984;4:40-44. 58. Okano Y, Medsger TA Jr. Autoantibody to Th ribonucleoprotein (nucleolar 7-2-RNA protein particle) in patients with systemic sclerosis. Arthritis Rheum 1990;33: 1822-28. 59. Kurzhals G, Meurer M, Krieg T et al: Clinical association of autoantibodies to fibrillarin with diffuse scleroderma and disseminated telangiectasia. J Am Acad Dermatol 1990; 23:832-36. 60. Kuwana M, Kaburaki J, Mimori T et al. Autoantibody reactive with three classes of RNA polymerases in sera from patients with systemic sclerosis. J Clin Invest 1993; 91:1399-404.