Classification of systemic sclerosis. Visions and reality*
F. A. Wollheim
Department of Rheumatology, Lund University hospital, S-21774 Lund, Sweden.
Correspondence to: F. A. Wollheim. E-mail: frank.wollheim{at}reum.lu.se
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Abstract
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Systemic sclerosis, scleroderma (SSc) is a disabling condition that shortens life expectancy. Disease heterogeneity and difficulties separating SSc from SSc-like conditions make classification an important issue. Limited cutaneous and diffuse cutaneous SSc, with different severity and survival, have been recognized for several years as distinct subsets. Some authors have suggested an intermediate cutaneous form with intermediate survival. This issue remains unsettled, however. The technique of capillaroscopy is helpful as an adjunct diagnostic tool to separate idiopathic Raynaud's phenomenon from SSc. Digitized video-capillaroscopy is developing as a powerful new method to assess individual capillaries over time. Using the simpler techniques of video-capillaroscopy, different patterns have been described and named early, active, late and slow. The value of nailfold video-capillaroscopy to distinguish different subsets or provide prognostic information for use in daily practice remains to be assessed. The features of CREST (calcinosis, Raynaud's, oesophagus dysmotility, sclerodactyly, telangiectasias) are not confined to single subsets of SSc. There is no convincing evidence of any advantage for distinguishing the limited, intermediate and diffuse forms of SSc rather than only the limited and diffuse forms.
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Introduction
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In the pathophysiology of systemic sclerosis, scleroderma (SSc), three abnormalities have been distinguished: a fibroblast dysfunction leading to increased deposition of extracellular matrix; a vascular abnormality resulting in tissue hypoxia; and an immune response manifested as altered T- and B-lymphocyte function and production of autoantibodies. The initiation of the disease and connection between the three disturbances is unclear. Experimental studies using transgenic animals implicate certain cytokinereceptor pathways and regulatory elements for profibrotic signals which may be relevant to human disease [1]. Genome-wide scanning has identified susceptibility factors on three different chromosomes outside the HLA region: fibrillin on chromosome 15, SPARC (secreted protein acidic and rich in cysteine) on chromosome 5 and topoisomerase I on chromosome 20. Microsatellite markers have confirmed polymorphism at these sites in Choctaw Indians [2]. Possible viral triggering factors have been reported recently [3]. Such new knowledge raises hopes that a classification based on genetic, aetiological or pathophysiological characteristics may become feasible. National and regional networks are formed in Europe under the auspices of EULAR (European League Against Rheumatism) and other organizations. Patient registries intended to enable basic studies as well as therapeutic trials, for which there is an increasing demand, are in progress. Distinct and simple classification standards are essential components of such registries. The late Carwile LeRoy (Fig. 1) published a paper in 1988 proposing the subdivision into limited and diffuse cutaneous scleroderma (lcSSc and dcSSc respectively). This was based on a number of clinical characteristics rather than on distinct criteria. This simple system has been widely accepted [4]. However, a number of SSc patients do not fit into the simple scheme. This paper discusses some recent suggestions for improving the classification of SSc.

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FIG. 1. Carwile LeRoy during a visit in Lund, Sweden, in August 1993. This figure may be viewed in colour as supplementary data at Rheumatology Online.
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General aims of disease classification
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The obvious first aim is to distinguish disease from non-disease. Such subsets could possibly reflect differences in pathogenesis. The 1980 ACR criteria for SSc [5] were based on consensus among leaders in clinical research and listed one major and three minor criteria. It should be emphasized that the entry criteria encouraged inclusion of classic newly diagnosed patients and that it did not address CREST-type patients. The diagnosis was established if a patient fulfilled either the one major criterion (sclerosis of the skin proximal to the metacarpophalangeal joints) or two of the three minor criteria (digital pitting scars, sclerodactyly and bilateral basal pulmonary fibrosis). Application of these criteria resulted in specificity of 98% and specificity of 97%. The vast majority of patients fulfilled the major criterion, which gave it a sensitivity of 91% for SSc. It should be stressed, however, that the criteria were intended for classification and not for diagnosis. They identify typical cases of established disease in a mixed North American population. The ACR criteria make no attempt to deal with disease heterogeneity. With a disease as heterogeneous as SSc, it is, however, desirable to search for more uniform subsets of patients, which may differ in pathology, prognosis and the need for management.
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CREST and limited SSc
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The CREST syndrome described by Winterbauer in 1964 [6], had actually been observed in its relation to scleroderma 5 yr earlier by a Danish investigator, Langaard, who did not publish his observation in English [7]. In 1962, Tuffanelli and Winkelmann proposed three forms of scleroderma based on skin involvement and severity: acrosclerosis, diffuse scleroderma, and acute diffuse scleroderma [8]. The CREST patients could have three, four or all five of the syndrome features, and the components were probably never meant to serve as criteria for a special subset of SSc patients. As mentioned below, features of CREST occur with time irrespective of other disease characteristics. Therefore, the use of CREST to define a subset of SSc patients is not helpful and may in fact be confusing.
In 1978 Barnett, based on his experience, suggested three subsets: type I, with skin changes involving only the fingers; type II, with sclerosis limited to the forearms; and type III, with diffuse skin involvement; and the author related them to differences in survival [9]. Type I was mostly identical with CREST. The CREST syndrome had thus been used to characterize a more restricted form of scleroderma, although many such patients eventually develop severe pulmonary hypertension and other internal organ complications. The association of pulmonary, cardiac and renal involvement with shorter survival is well documented by several authorities [10]. But it was thanks to Carwile LeRoy that an international consensus emerged with respect to the characterization of the diffuse and limited cutaneous forms of scleroderma [4]. The main features of the classification are depicted in Table 1. They have stood the test of time and are simple enough for use in everyday practice. Vascular changes seem to be relatively more prominent in lcSSc [11]. The question whether the diffuse and limited forms are different diseases or represent different phenotypes of the same disease is not settled, but transition from one to the other is seldom seen, which could favour the former interpretation. Importantly, the two classical SSc-selective autoantibodies segregate clearly between the subsets, lcSSc being associated with anticentromere and dcSSc with antitopoisomerase antibodies. This indicates that the subdivision may identify pathogenetically distinct subsets.
The lcSSc/dcSSc classification has been widely accepted and used in numerous clinical studies and therapeutic trials. It was, however, shown early on that features of CREST were common in both forms and that the extent of skin involvement, as measured by longitudinal skin scoring according to Rodnan, regressed in dcSSc with time, although internal organ involvement progressed [12, 13]. Life expectancy has also been confirmed to be shorter in the diffuse form in several studies, in particular in women [13, 14]. It is of interest, but not generally recognized, that the diffuse form is relatively more common in African Americans and among black patients in Africa [15]. The importance of ethnicity is also demonstrated in the Choctaw Indian form of scleroderma, which is of the diffuse form [16].
Realizing the shortcomings of the 1988 subsets in being too exclusive, and taking advantage of the increased experience with nailfold capillaroscopy and autoantibody determination, LeRoy and Medsger in 2001 proposed criteria for an additional early or limited form of scleroderma, lSSc, to supplement the previously recognized lcSSc and dcSSc forms (Table 1) [17]. Patients with lSSc must have Raynaud's plus scleroderma-type nailfold capillary changes and/or scleroderma-type autoantibodies. Patients with lSSc may or may not later develop lcSSc or dcSSc. It is important to include such patients in prospective population-based studies since they may be informative regarding development of complete SSc. Likewise, one may need to avoid aggressive therapy or iatrogenic aggravation of anxiety among this group of individuals, since many will probably not progress much with time. The proposal for lSSc has, however, not gained wide attention, perhaps because lSSc and lcSSc are easily confused. In order to stimulate attention to this group of patients, an alternative designation would be unclassifiable or pre-SSc.
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Is there a place for three subsets of SSc on the basis of cutaneous involvement?
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Following the footsteps of Giordano et al. [18] and Barnett [9], two groups have recently reported outcome studies using a classification of diffuse (truncal), intermediate (extremities but not the trunk), limited (fingers only) or no skin involvement. One was an Italian three-centre retrospective study involving 1012 patients [19]. The patients included represented the period from 1955 to 1999, and the conclusion was that survival was better in the intermediate than in the diffuse group, and better in the limited than in the intermediate group. The other was a French-Canadian prospective study of 309 patients recruited between 1984 and 1999, and found similar differences in mortality [20]. Based on their observations, both studies therefore suggest that the lcSSc/dcSSc classification should be replaced with three subsets: limited, intermediate and diffuse. However, the disease duration differed between the groups and it cannot be deduced that three distinct subsets could be identified at an early stage of disease. My conclusion would be that the intermediate groups in these studies constitute a mixture of lcSSc and dcSSc patients, which would explain the intermediate outcome features.
A 5-yr study in Britain that looked at prognostic features at inclusion identified advanced age, diffuse cutaneous disease (dcSSc), higher skin score, elevated ESR and signs of organ involvement as prognostic factors in univariate analysis. However, logistic regression analysis identified proteinuria, elevated ESR and reduced carbon monoxide diffusion capacity as the dominating prognostic factors [21]. A large Danish mortality study compared the two- and three-subset models and found no difference between the digital and extremity arms of the three-subset model [22]. Taking all the evidence together, there is at present no convincing reason to replace the two lcSSc and dcSSc subsets with the BarnettGiordano type-3 subset classification.
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Capillaroscopy and classification of scleroderma
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Capillaroscopy has a long history. Since early in the last century it has been possible to obtain good pictures using the oil-immersion method with a conventional microscope [23]. Hildegard Maricq has worked extensively to refine the assessment of the skin capillaries using modern microscopic and photographic equipment. She distinguished enlargement of capillary loops, loss of capillaries, disruption of the capillary bed appearance, distortion and budding of capillaries, and finally haemorrhages. This allowed her to grade the changes from I, which is normal, to V, the most pathological [24]. Combining classes II to V, an independent Hungarian study found that 70% of SSc patients were positive compared with only 10 and 7%, respectively, among control patients with Raynaud's phenomenon or undifferentiated connective tissue disease [25]. A simpler standardized counting of nailfold capillary density is perhaps as useful for diagnosis [26]. Extensive experience with this method from Lund confirms its diagnostic value but does not show any difference between lcSSc and dcSSc (A. Åkesson, personal communication).
The sensitive technique of video-capillaroscopy allows measurement of capillary width, and can help to differentiate between limited and diffuse scleroderma [27]. Ongoing work in Manchester, UK, uses powerful computer capacity to examine extended nailfold regions. This technique will enable the rescanning of individual capillaries over time (A. Herrick, personal communication). This will allow not only quantitative assessment but also the detection of progression or regression of changes in microcirculation. Clearly, this opens new and exciting perspectives for the monitoring of SSc patients over time.
In a recent study from Dr Cutolo's group in Italy, nailfold video-capillaroscopy was applied to 241 patients fulfilling the ACR criteria for scleroderma, using a blinded assessor who examined all 10 fingers. Distinction is made between a normal pattern and three categories of pathological patterns characterized by differences with regard to presence of enlarged capillaries, deformed capillaries, loss of capillaries and the presence of bleeding. These patterns were named early, active and late based also on clinical features [28]. The presence of the respective patterns did correlate with disease duration but overlapped between lcSSc and dcSSc. ANA positivity was similar and high in all patterns, but antitopoisomerase I antibodies were more prevalent among patients with the late pattern. It was not clear how much variation could be observed between individual fingers. It remains to be seen how reproducible and useful this method will be in clinical practice. One confusing finding in the Italian study was that patients with lcSSc had a shorter disease duration than those with dcSSc; one would have expected the opposite. In summary, sophisticated capillaroscopic techniques will help to explore pathogenic events. It is, however, uncertain whether they will be of much use in routine clinical practice or remain research tools.
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The MaricqValter subsets of 2004
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Experience with capillaroscopy in Charleston, South Carolina, USA, extends over three decades [29] and in a recent paper Hildegard Maricq has given her experience of 165 patients with scleroderma spectrum diseases, included in the period from 1976 to 1992 [30]. The nailfold capillary patterns were divided into active or slow; presence of bleedings; and telangiectasias.
Dr Maricq presents a comprehensive, mutually exclusive classification of scleroderma-related diseases. This classification has the disadvantage of seeming too complicated for easy use, and without substantial independent confirmatory work, it is unlikely to gain acceptance (Table 2). In essence, it was developed from the LeroyMedsger classifications of 1988 and 2001 [4, 17], with the addition of the undifferentiated connective tissue disease (UCTD) subset. CREST features were present in 30% in group I patients and 50% in group II patients in Table 2. This study again confirms that CREST features are not confined to lcSSc patients. Furthermore, it indicates that nailfold capillary patterns do change with time, and may one day become a valuable aid in the staging of SSc. There is still no evidence indicating the reversibility of nailfold abnormalities. The paper provides no data regarding the impact on survival or response to therapy in the subsets. It is unlikely that this complex classification will gain acceptance in its present form.
UCTD is a term used to characterize patients in which no definite connective tissue disease can be identified but who have features suggesting such a diagnosis. A large Hungarian population of UCTD patients followed for a minimum of 5 yr is instructive. Out of a total of 665 patients, 230 developed definite connective tissue diseases. Only 19 of these developed SSc. Thus, although UCTD is not uncommon, it contributes only modestly to bona fide SSc [31].
Autoimmunity in scleroderma subsets
Antinuclear antibodies are found in more than 90% of SSc patients. They are of interest as providing clues to pathogenesis, but may also help to characterize subsets. Anticentromere antibodies and Scl-70, later identified as antitopoisomerase I, were already associated with scleroderma 25 yr ago [32]. Their association with different scleroderma phenotypes was instrumental in the definition of lcSSc and dcSSc [17]. In recent years, additional autoantibodies related to different clinical features have been identified. Thus, for example, anti-RNA polymerase III antibodies in lcSSc correlated with severe skin involvement and renal crisis [33]. U3-RNP antibodies, including fibrillarin and other specificities, have been found in both lcSSc and dcSSc patients and correlated to pulmonary hypertension cardiac involvement and myositis [34]. Further clinical characteristics have been associated with a subset of lcSSc patients developing anti-Th/To antibodies [35]. Anti-topoisomerase II
has been found in 35 of 46 patients with localized scleroderma in one study [36]. Further research along these lines will result in better knowledge of pathogenic events and perhaps lead to more refined subset definitions in the future.
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Conclusions
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This review indicates that promising developments may result in the definition of new subsets of scleroderma patients. Capillary microscopy using a videoscopic technique is a research tool that will allow detailed prospective observation of individual capillaries and expand knowledge of the nature, extent, progression and perhaps reversibility of vascular abnormalities. Improved techniques for capillary microscopy may allow differentiation between different forms of SSc, but this requires further studies. The distinction of three rather than two subsets of skin involvement has been suggested [4, 17], but convincing evidence for an advantage over the widely accepted lcSSc/dcSSc classification has not come forward. A quarter of a century after the birth of the Rodnan skin score, standardized palpation is still the preferred method of assessing skin involvement, although ultrasonographic scoring is appealing as a more objective method [37]. Genomic screening is identifying candidate genes, such as fibrillin and SPARC [38], and may in the future identify still unrecognized phenotypes of SSc. Autoantibody features will also be refined for subset definition. Ethnic differences, such as the greater relative occurrence of dcSSc in African and American Indian populations, may be explained by genetic differences. Environmental triggers, such as silica and infectious agents, have been suspected to contribute to the development or modification of SSc. High prevalence of CMV antibodies has been found by several independent workers and in vitro studies indicate an effect on endothelial cell function [3945]. These studies have not, however, resulted in the recognition of any subsets. A fundamental goal must be to establish subsets which represent distinct pathogenic differences. In this sense, neither antifibrillin, silica nor indeed fetal maternal microchimerism have been helpful, which raises questions regarding their pathogenic role.
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Notes
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*Dedicated to the memory of E. Carwile LeRoy, 19332002. 
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Submitted 1 February 2005;
revised version accepted 1 April 2005.