Journal of Autoimmunity xxx (2014) 1e4

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Diagnostic criteria of systemic sclerosis Marie Hudson a, b, c, *, Marvin J. Fritzler d a

Department of Medicine, McGill University, Jewish General Hospital, 3755 Côte Ste-Catherine, Montréal, H3T 1E3 Quebec, Canada Division of Rheumatology, Jewish General Hospital, 3755 Côte Ste-Catherine, Montréal, H3T 1E3 Quebec, Canada c Lady Davis Institute, Jewish General Hospital, 3755 Côte Ste-Catherine, Montréal, Quebec H3T 1E3, Canada d Faculty of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, T2N 4N1 Alberta, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 October 2013 Accepted 13 November 2013

Systemic sclerosis (SSc) is a multisystem disease characterized by vascular abnormalities, immune system activation manifested by SSc-specific autoantibodies and disturbances in fibroblast function. The clinical manifestations are highly heterogeneous and commonly include skin thickening, Raynaud’s phenomenon, digital ulcers, gastroesophageal reflux disease, interstitial lung disease and cardiac diastolic dysfunction. The diagnosis of SSc in a patient with typical end-organ disease is relatively straightforward, but is unsatisfactory because it implies that the diagnosis is delayed until irreversible tissue damage is present. Diagnostic criteria are generally designed to facilitate the clinical process and to allow early institution of therapy to relieve symptoms and possibly prevent irreversible damage. Several attempts at defining diagnostic criteria for SSc have been made in the past. Raynaud’s phenomenon, SScspecific autoantibodies and nailfold capillary abnormalities are among the most promising items likely to be retained in a final set of diagnostic criteria. The EULAR Scleroderma Trial and Research group (EUSTAR) is currently in the process of prospectively validating a set of diagnostic criteria for the very early diagnosis of SSc and results are expected in 2015. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Systemic sclerosis Diagnostic criteria

1. Introduction Systemic sclerosis (SSc) is a multisystem disease characterized by Raynaud’s phenomenon and other vascular abnormalities; immune system activation manifested by SSc-specific autoantibodies, in particular anti-centromere proteins (CENP), anti-topoisomerase I (topo I, also called Scl-70) and anti-RNA polymerase III (RNAP); and, disturbances in fibroblast function culminating in the telltale skin thickening and fibrosis of visceral organs. It is an uncommon disease, with an estimated prevalence ranging from 7 to 489/million and incidence from 0.6 to 122/million/year [1]. Nevertheless, it is a high social impact disease affecting predominantly women with age at onset around 45 years, associated with significant disability [2], high costs [3] and increased mortality [4], primarily from interstitial lung disease and pulmonary arterial hypertension [5]. Among the most common and earliest manifestations of SSc are Raynaud’s phenomenon, nailfold capillary abnormalities and the presence of autoantibodies. In a landmark, twenty-year prospective study of 586 consecutive patients with Raynaud’s phenomenon * Corresponding author. Jewish General Hospital, Room A-725, 3755 Côte SainteCatherine Road, Montreal, Quebec H3T 1E2, Canada. Tel.: þ1 514 340 8222x3476; fax: þ1 514 340 7906. E-mail address: [email protected] (M. Hudson).

referred for nailfold capillary microscopy, the presence of microvascular abnormalities detected on capillaroscopy and an SScspecific autoantibody (anti-CENP-B, anti-topo I, anti-Th/To, or anti-RNAP III) were independent predictors for the development of definite SSc, whereas their absence practically ruled out this outcome [6]. Indeed, subjects with both abnormalities at baseline were 60 times more likely to develop SSc compared to patients without these predictors, and 80% of the patients with both abnormalities developed SSc within 20 years of follow up. Nevertheless, 20% of the patients who fulfilled those criteria did not develop definite SSc. SSc is a very heterogeneous disease but two common subsets based on the extent of skin involvement are typically recognized, namely limited cutaneous SSc (lcSSc) with skin involvement distal to the elbows and knees and diffuse cutaneous SSc (dcSSc) with skin involvement of the proximal limbs and/or trunk [7]. Vascular disease is widespread and clinically apparent from digital pits and ulcers. Visceral involvement is manifold and commonly includes gastroesophageal reflux disease, interstitial lung disease and cardiac diastolic dysfunction. The diagnosis of SSc in a patient with Raynaud’s phenomenon and typical end-organ disease is relatively straight-forward, but is unsatisfactory because it implies that the diagnosis is delayed until irreversible tissue damage is present. Indeed, in the Canadian Scleroderma Research Group cohort, mean

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time to diagnosis from onset of Raynaud’s was 5.0  6.3 years and from the first non-Raynaud’s disease manifestation 2.6  4.5 years [8]. On the other hand, in a study of 115 patients referred for evaluation of Raynaud’s phenomenon, 19 were found to have SSc autoantibodies and/or typical capillaroscopic abnormalities but no other signs or symptoms suggestive of end-organ disease, including puffy fingers, arthritis, digital ulcers/scars, telangiectasia, dysphagia/heartburn and dyspnea [9]. Of those, 8 (42%) had cardiac, lung and/or esophageal abnormalities consistent with SSc when investigated by cardiac echocardiography, lung function tests and esophageal manometry. This supports the fact that the diagnosis of SSc is possible even before there is overt tissue damage. 2. Evolving criteria Preliminary criteria for the classification of SSc were published in 1980 [10] and included the presence of skin sclerosis proximal to the metacarpophalangeal (MCP) or metatarsophalangeal (MTP) joints as a major criteria, or the presence of two of three minor criteria, namely sclerodactyly, digital pitting scars and bibasilar pulmonary fibrosis [10]. However, these criteria were intentionally designed to be specific with two attendant shortcomings: first, tissue damage had to be present to classify a patient with SSc and second, this resulted in a commensurate loss in sensitivity of the criteria. Indeed, several reports have shown that these criteria lacked sensitivity especially for patients with lcSSc [11e13]. In those reports, nailfold capillary abnormalities and the presence of SScspecific autoantibodies were common features that appeared to improve the sensitivity of the 1980 classification criteria [11,14]. In 2012, an ACR-EULAR committee was established to develop new classification criteria for SSc [15]. These new criteria also include a major criterion (skin thickening of the fingers of both hands extending proximal to the MCP joints) and seven minor criteria (Raynaud’s phenomenon, skin thickening of the fingers (including puffy fingers or sclerodactyly), fingertip lesions, telangiectasia, abnormal nailfold capillaries, pulmonary arterial hypertension and/or interstitial lung disease, and SSc-related antibodies [any of anti-CENP, anti-topo I and anti-RNAP III]). Sensitivity and specificity were reported to be 0.91 and 0.92 (compared to 0.75 and 0.72 for the 1980 classification criteria). However, strict adherence to these criteria is still somewhat problematic because patients with Raynaud’s, an SSc-specific autoantibody, and abnormal capillaroscopy would not have enough features to be classified as SSc. Nevertheless, the additional presence of a fourth feature, for example puffy fingers or telangiectasia, could result in such a classification. It is generally accepted that classification criteria are important mostly for research purposes, primarily because they establish a standard for definite disease in order to permit proper comparison of observational cohort studies and selection of subjects into therapeutic trials. On the other hand, clinicians are more interested in the early and accurate diagnosis of individual patients and diagnostic criteria are generally designed to facilitate the clinical process [16], to have greater sensitivity, rather than specificity, and to allow early institution of therapy to relieve symptoms and possibly prevent irreversible damage. There are many challenges to developing diagnostic criteria for SSc. First, SSc is rare and it has been estimated that the average primary care provider may see only one or two cases in a lifetime [17]. Second, SSc is a highly heterogeneous disease in which organ involvement varies considerably from patient to patient. Third, many features of SSc such as arthritis, myositis and sicca, are not unique to this disease but are present in other systemic autoimmune rheumatic diseases. Differentiating “isolated” SSc from overlap disease is often difficult, and may explain why a wide range

of overlap disease (10e27%) has been reported in SSc [18]. Thus, identifying the proper cohort in which to develop diagnostic criteria is highly challenging. In addition, some clinical and serological features that are often present early in the disease course and that could be very helpful for diagnosis may not be widely or easily accessible (e.g. nailfold videocapillaroscopy, anti-RNAP III and anti-Th/To antibodies) [19]. Not surprisingly, there are no diagnostic criteria for SSc developed and validated using rigorous methodology [16]. Nevertheless, several attempts at defining diagnostic criteria for SSc have been made. In 2001, Leroy and Medsger were the first to propose criteria for the early diagnosis of SSc that reflected the vascular and serological advances of the time [14]. They proposed that, in the absence of skin involvement, a diagnosis of SSc was possible in the presence of Raynaud’s phenomenon, nailfold capillary abnormalities and SSc-specific autoantibodies (Table 1). In 2004, Nadashkevich et al. developed classification criteria that aimed at increasing the sensitivity of the 1980 ACR classification criteria, in part by including patients with early disease [20]. A set of criteria called ABCDCREST was proposed: 1) Antibodies to CENP, anti-topo I or fibrillarin; 2) Bibasilar pulmonary fibrosis; 3) Contractures of the digital joints or prayer sign; 4) Dermal thickening proximal to the wrists; 5) Calcinosis cutis; 6) Raynaud’s phenomenon (at least two phase color change); 7) Esophageal distal hypomotility or reflux esophagitis; 8) Sclerodactyly or nonpitting digital edema of the fingers; and 9) Telangiectasia. A classification of definite SSc would require 3 or more criteria. Hence, the presence of Raynaud’s, autoantibodies and puffy fingers would presumably be sufficient to fulfill these criteria. The sensitivity and specificity of the criteria were reported to be 99% and 100%, respectively. As such, the authors argued that classification criteria with sensitivity and specificity approaching 100% could serve as diagnostic criteria. In 2009, the EULAR Scleroderma Trial and Research group (EUSTAR) proposed a conceptual framework and preliminary criteria for the very early diagnosis of SSc based on expert opinion (Table 2) [21]. These criteria included Raynaud’s phenomenon, autoantibodies (anti-nuclear, anti-CENP, anti-topo I) and diagnostic nailfold videocapillaroscopy as major criteria, and calcinosis, puffy fingers, digital ulcers, dysfunction of the oesophageal sphincter, telangiectasia and ground glass on high-resolution computed tomography scan of the chest as additional criteria. Three major or 2 major plus one additional criterion would be required to satisfy a diagnosis of very early SSc. EUSTAR subsequently published the results of a Delphi exercise conducted to identify a core set of items considered important for the very early diagnosis of SSc [22]. The final list generated by that exercise (Table 3) included criteria considered as having a high clinical relevance for the very early diagnosis of SSc (Raynaud’s

Table 1 Leroy and Medsger’s constellation of criteria for diagnosis of SSc. Limited SSc (lcSSc)

Limited cutaneous SSc (lcSSc) Diffuse cutaneous SSc (dcSSc)

Raynaud’s phenomenon (objective documentation) plus any one: SSc-type nailfold capillary pattern or SSc selective autoantibodiesa or Raynaud’s phenomenon (subjective only) plus both: SSc-type nailfold capillary pattern and SSc selective autoantibodies Criteria for lcSSc plus cutaneous changes distal to elbows, knees and clavicles Criteria for lcSSc plus proximal cutaneous changes (i.e. arms and legs proximal to elbows and knees, chest, abdomen and/or back)

a anti-CENP, anti-topo I, anti-fibrillarin (U3-RNP), anti-PM-Scl, anti-fibrillin or anti-RNAP I or III in a titer 1:100.

Please cite this article in press as: Hudson M, Fritzler MJ, Diagnostic criteria of systemic sclerosis, Journal of Autoimmunity (2014), http:// dx.doi.org/10.1016/j.jaut.2013.11.004

M. Hudson, M.J. Fritzler / Journal of Autoimmunity xxx (2014) 1e4 Table 2 EUSTAR Preliminary criteria for the very early diagnosis of systemic sclerosis [21] .a Major criteria

Additional criteria

Raynaud’s phenomenon Antibodies (anti-nuclear, anti-CENP, anti-topo I) Diagnostic nailfold videocapillaroscopy Calcinosis Puffy fingers Digital ulcers Dysfunction of the oesophageal sphincter Telangiectasia Ground glass at chest high-resolution computed tomography

a Diagnosis will be achieved when at least 3 major criteria or 2 major plus one additional criteria are satisfied.

Table 3 EUSTAR Final list of criteria for the very early diagnosis of systemic sclerosis (VEDOSS) [22]. Criteria considered as having a high clinical relevance for the very early diagnosis of SSc

Criteria considered as leading to an early referral

Raynaud’s phenomenon Puffy swollen digits turning into sclerodactyly Abnormal capillaroscopy with scleroderma pattern Positive anti-CENP Positive anti-topo I Raynaud’s phenomenon Puffy fingers Positive anti-nuclear antibodies

phenomenon, puffy swollen digits turning into sclerodactyly, abnormal capillaroscopy with scleroderma pattern, positive antiCENP and positive anti-topo I antibodies) and criteria considered as leading to an early referral (Raynaud’s phenomenon, puffy fingers, positive antinuclear antibodies). Prospective validation of these diagnostic criteria is ongoing with the VEDOSS project and results are expected in 2015 (www.eustar.org). These efforts represent major advances towards developing diagnostic criteria for SSc. Raynaud’s phenomenon, SSc-specific autoantibodies and nailfold capillary abnormalities appear to be the items most likely to be retained in a final set of diagnostic criteria. However, the problem of lack of expertise in nailfold capillaroscopy in the primary and secondary care settings and inaccessibility to comprehensive serology for SSc remains unresolved. With these concerns in mind, we sought to define diagnostic criteria for SSc using clinical information that would be easily accessible to busy clinicians unfamiliar with the details of SSc [23]. Based on data from subjects in the Canadian Scleroderma Research Group database, we found that telangiectasia and anti-CENP or anti-topo I antibodies in the presence of Raynaud’s phenomenon and proximal skin thickening increased the sensitivity of a diagnosis of SSc from 57% to 97%. Thus, easily discernible clinical features (Raynaud’s phenomenon, telangiectasia) and easily available serology from most clinical laboratories also appear to be of considerable diagnostic value, even in the absence of nailfold capillary abnormalities or more detailed serology. 3. Conclusion Research into the cellular and molecular basis of SSc has provided new insights into the pathophysiology of the disease and potential targets of intervention. Efforts directed to translating these discoveries into effective therapies for SSc is proceeding at an unprecedented pace and emerging therapies based on immunomodulation, anti-fibrotics and vasoprotection hold the promise of preventing end organ damage and improving long term outcomes in SSc patients who can be benefactors of an early and accurate

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diagnosis. In this context, the current delay in diagnosis in SSc is now being re-considered as a “window of opportunity” [21] during which disease-modifying treatment could be initiated and would be of greatest benefit. This “window of opportunity” therefore provides strong rationale for the early diagnosis of SSc. The ongoing EUSTAR VEDOSS project is thus timely and represents the best ongoing work to develop and validate diagnostic criteria for SSc. Going forward, the use of autoantibodies and nailfold capillaroscopy as key features of diagnostic (and/or classification criteria) are not without challenges because different immunoassays, diagnostic platforms and imaging techniques present significant challenges to a unified schema. Clearly, the standardization of autoantibody testing and nailfold capillaroscopy and/or, at a minimum, a thorough understanding of the strengths and limitations of the various assays and techniques, is a pressing imperative. Funding Dr. Hudson is funded by the Fonds de la recherche en Santé du Québec and Dr. Fritzler holds the Arthritis Society Research Chair at the University of Calgary. References [1] Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008;37:223e35. [2] Steen VD, Medsger Jr TA. The value of the health assessment questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum 1997;40:1984e91. [3] Bernatsky S, Hudson M, Panopalis P, Clarke AE, Pope J, Leclercq S, et al. The cost of systemic sclerosis. Arthritis Rheum 2009;61:119e23. [4] Ioannidis JPA, Vlachoyiannopoulos PG, Haidich AB, Medsger Jr TA, Lucas M, Michet CJ, et al. Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med 2005;118:2e10. [5] Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 19722002. Ann Rheum Dis 2007;66:940e4. [6] Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twentyyear prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008;58:3902e12. [7] LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202e5. [8] Hudson M, Thombs B, Baron M. Time to diagnosis in systemic sclerosis: is sex a factor? Arthritis Rheum 2009;61:274e8. [9] Valentini G, Cuomo G, Abignano G, Petrillo A, Vettori S, Capasso A, et al. Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features. Rheumatol 2011;50:317e3232. [10] Masi AT, Rodnan GP, Medsger Jr T, Altman RD, D’Angelo WA, Fries JF, et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581e90. [11] Lonzetti LS, Joyal F, Raynauld JP, Roussin A, Goulet JR, Rich E, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001;44:735e6. [12] Hudson M, Taillefer S, Steele R, Dunne J, Johnson SR, Jones N, et al. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007;25:754e7. [13] Ziswiler H, Urech R, Balmer J, Ostensen M, Mierau R, Villiger P. Clinical diagnosis compared to classification criteria in in a cohort of 54 patients with systemic sclerosis and associated disorders. Swiss Med Wkly 2007;137:586e 90. [14] LeRoy EC, Medsger Jr TA. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573e6. [15] van den Hoogen F, Khanna D, Fransen J, Johnson S, Baron M, Tyndall A, et al. Classification criteria for systemic sclerosis: an ACR-EULAR Collaborative Initiative. Arthritis Rheum 2013;65(11):2737e47. [16] Dougados M, Gossec L. Classification criteria for rheumatic diseases: why and how? Arthritis Rheum 2007;57:1112e5. [17] Molitor JA. Toward the early diagnosis of systemic sclerosis: warning signs the practitioner needs to recognize. Minn Med 2009;92:42e4. [18] Hudson M, Walker JG, Fritzler M, Taillefer S, Baron M. Hypocomplementemia in systemic sclerosis e clinical and serological correlations. J Rheumatol 2007;34:2218e23.

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[19] Muro Y, Sugiura K, Akiyama M. What autoantibody tests should become widely available to help scleroderma diagnosis and management? Arthritis Res Ther 2013;15:116. [20] Nadashkevich O, Davis P, Fritzler MJ. A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit 2004;10:615e21. [21] Matucci-Cerinic M, Allanore Y, Czirjak L, Tyndall A, Muller-Ladner U, Denton C, et al. The challenge of early systemic sclerosis for the EULAR Scleroderma Trial and Research group (EUSTAR) community. It is time to cut

the Gordian knot and develop a prevention or rescue strategy. Ann Rheum Dis 2009;68:1377e80. [22] Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis 2011;70:476e81. [23] Hudson M, Fritzler MJ, Baron M. Systemic sclerosis: establishing diagnostic criteria. Med Baltim 2010;89:159e65.

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