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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
  1. M Matucci-Cerinic1,
  2. Y Allanore2,
  3. L Czirják3,
  4. A Tyndall4,
  5. U Müller-Ladner5,
  6. C Denton6,
  7. G Valentini7,
  8. O Distler8,
  9. K Fligelstone9,
  10. A Tyrrel-Kennedy9,
  11. D Farge10,
  12. O Kowal-Bielecka11,
  13. F van den Hoogen12,
  14. M Cutolo13,
  15. P D Sampaio-Barros14,
  16. P Nash15,
  17. K Takehara16,
  18. D E Furst17
  1. 1
    Department of Biomedicine, Division of Rheumatology AOUC, University of Florence, Florence, Italy
  2. 2
    Paris Descartes University, Rheumatology A Department, Cochin Hospital, Paris, France
  3. 3
    Department of Immunology and Rheumatology, Medical School, University of Pécs, Pécs, Hungary
  4. 4
    Department of Rheumatology, University of Basel, Basel, Switzerland
  5. 5
    Justus-Liebig University Giessen, Department of Rheumatology and Clinical Immunology, Kerckhoff Clinic Bad Nauheim, Bad Nauheim, Germany
  6. 6
    Centre for Rheumatology, Royal Free Hospital, London, UK
  7. 7
    Department of Clinical and Experimental Internal Medicine, Rheumatology Unit, Second University of Naples, Naples, Italy
  8. 8
    Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  9. 9
    Federation of the European Scleroderma Associations (FESCA)
  10. 10
    Department of Internal Medicine and Vascular Diseases, Assistance Publique-Hôpitaux de Paris, Denis Diderot Paris 7 University, Paris, France
  11. 11
    Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  12. 12
    Rheumatology Centre Sint Maartenskliniek, Nijmegen, The Netherlands
  13. 13
    Research Laboratories and Clinical Academic Unit of Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy
  14. 14
    Department of Internal Medicine, Unit of Rheumatology, State University of Campinas, Campinas, Brazil
  15. 15
    Department of Medicine, University of Queensland, Brisbane, Australia
  16. 16
    Department of Dermatology Kanazawa University of Medical Science, Kanazawa, Japan
  17. 17
    Geffen School of Medicine, University of California, Los Angeles, USA
  1. Correspondence to Professor M Matucci-Cerinic, Department of Biomedicine, Division of Rheumatology AOUC, Villa Monna Tessa, Viale Pieraccini 18, I-50139 Florence, Italy; cerinic{at}unifi.it

Abstract

Early diagnosis of systemic sclerosis (SSc) may allow the start of treatment that could slow disease progression. For this reason early diagnosis of the disease is of pivotal importance. However, the lack of diagnostic criteria and valid predictors significantly limit patient evaluation and the use of potentially effective drugs in the earliest phase of SSc. Early SSc may be suspected on the basis of Raynaud's phenomenon, puffy fingers, autoantibodies and SSc capillaroscopic pattern. In practice, the aim is to have criteria for the diagnosis of very early SSc. The criteria that are proposed are obviously provisional and need to be validated: (a) initially through a Delphi technique; (b) thereafter perhaps using already available datasets; but (c) of critical importance, through prospective studies. Only after prospective studies can these potential criteria be considered validated. The consensus on criteria for the classification of very early SSc might be part of the evolving EULAR/ACR project of reclassification of SSc.

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Systemic sclerosis (SSc) is an orphan disease with the highest case-specific mortality of any of the connective tissue diseases (CTDs).1 It is characterised by early generalised microangiopathy and culminates in systemic fibrosis. The key steps in disease pathogenesis are endothelial injury, autoimmune response and matrix deposition by activated fibroblasts.2

SSc is often well established at diagnosis, when the disease has already evolved to an irreversible obliterative vasculopathy, with fibrosis and significant end-organ damage. The present classification criteria3,4 perform poorly when attempting to make an early diagnosis,5,6,7 limiting the possibility that early treatment might block disease evolution and avoid tissue damage. This inability, then, may lead to loss of function and impairment of quality of life.

SSc is an important disease with significant mortality, causing significant disability, at times quickly and dramatically, especially in patients with diffuse cutaneous SSc.8 At other times, when the disease follows a more indolent course (more often in limited cutaneous SSc), early diagnosis may allow treatment that could block, or at least slow, disease progression. However, this task is not easy when facing the patient in clinical practice. As reliable predictors of the future course of disease are still unknown, the patients must be followed up regularly even though the ideal frequency of such visits has not yet been established. In particular, the lack of diagnostic criteria and valid predictors of disease evolution significantly limit patient evaluation and the use of potentially effective drugs in the earliest phase of the disease. The position of the doctor is characterised by uncomfortable uncertainty in a phase where the patient may not even have any discernible skin involvement. In this phase, the main clinical features of “early SSc” may be Raynaud’s phenomenon (RP), positive autoantibodies (antinuclear with anticentromere, antitopoisomerase I or antinucleolar specificities) and SSc capillaroscopic pattern.9,10 Signs of the disease may be restricted to puffy fingers or a dysfunctional lower oesophageal sphincter.

At this point, doctors face two challenges: (a) confirmation that the patient has SSc—or at least a condition within the scleroderma spectrum: “prescleroderma”,11 undifferentiated connective tissue disease (UCTD),12 or mixed connective tissue disease (MCTD)13; (b) a decision as to how to treat this patient—aggressively or symptomatically. In reality, these decisions are compromised by lack of agreement and validation of criteria to define early disease, and lack of adequate clinical trials targeting patients when they still have early “presclerodermatous” disease.

Although these patients, with RP, autoantibodies and SSc capillaroscopic pattern could be easily followed up, we lack the ability to identify the predictors that may allow us to understand the disease prognosis. Knowing the prognosis would, in turn, allow doctors to predict the likelihood that SSc would damage the visceral organs, thus prompting early treatment, if necessary. Therefore, our research agenda should require that we cut the Gordian knot and fill the gap between what has been previously defined as “prescleroderma”—RP, nailfold capillary changes, autoantibodies (antinuclear, anticentromere, antitopoisomerase I, antinucleolar), and features of severe digital ischaemia11—and what is overt SSc.

“Prescleroderma–UCTD–MCTD” are all characterised by RP but this does not mean that they will evolve to the defined clinical picture of SSc. When facing these different conditions (fig 1) doctors become disorientated and struggle to decide what to do,14 potentially leading to a poor outcome for the patient. Patients with signs and symptoms suggestive of CTDs but not fulfilling the American College of Rheumatology (ACR) classification criteria for SSc are commonly seen in clinical practice.5 Certainly, RP is a common initial symptom in CTDs: we know that it can be primary, and innocent, but also know that it can be the sentinel sign of an underlying disease still in development, most commonly SSc.15 Moreover, RP may precede, sometimes by decades, the onset of cutaneous or visceral sclerosis (especially in limited SSc). For this reason, RP, despite its lack of specificity, has been proposed as one of the main clinical features in a previous attempt to define criteria for the diagnosis of early SSc.16

Figure 1

The three main diseases—undifferentiated connective tissue disease (UCTD), mixed connective tissue disease (MCTD) and prescleroderma—and the main early signs and symptoms—Raynaud phenomenon, antibodies positivity and capillaroscopic abnormalities—are presented in two overlapping “triangles” in a composite pyramid whose key to very early SSc still needs to be identified. Puffy fingers are presented in the centre of the black pyramid as a sign present in MCTD, UCTD and prescleroderma.

Recently, the Canadian registry of 359 patients showed that the diagnosis of SSc occurs a mean of 6.1 years after the onset of RP and 2.7 after the onset of extra-RP symptoms.17 Preliminary data from the EULAR Scleroderma Trial and Research group (EUSTAR) database6 indicate that the time between the onset of RP and the first non-RP symptom or sign in SSc is a mean of 4.8 years in limited cutaneous SSc in contrast to a mean of 1.9 years in diffuse cutaneous SSc. This time gap between symptoms and diagnosis, mainly based on dermal or internal organ fibrosis, could be regarded as a “window of opportunity” for SSc and therefore should be our future target.

We propose that “early SSc” could be defined as a state characterised by RP, puffy fingers, disease-specific autoantibodies and pathognomonic microvascular alteration detected by capillaroscopy requiring at least two, or better, all three items to be present. Indeed, these parameters may represent the three corners of another triangle, defining true “prescleroderma” phase before skin becomes really involved (fig 1). Capillaroscopy may identify early structural microvascular abnormalities that are useful for the preclinical diagnosis of secondary RP due to SSc as differentiated from primary RP.18 In recent studies after an extended screening programme during a mean (SD) follow-up period of 11.2 (3.9) years, the prevalence of transition from primary to secondary RP, identified by diagnosis of an associated disease, was 14.9% of cases.19 In contrast, another study, after a capillaroscopic analysis, found a similar prevalence for secondary RP (14.6%) but defined during a shorter follow-up of 29.4 (10) months.20 These criteria are intended for early diagnosis of patients with diffuse SSc who will develop even more severe organ involvement, and not for classification of the disease into subsets or for prediction of the disease evolution. For this subset of patients, another strategy will be necessary—for example, identification of clinical and biomarker predictors or detection of genetic risk factors or other risk factors present before any clinical sign occurs. RP may also be the first sign of UCTD,12 a term proposed by some to define the early phases of CTDs that, at their onset, are undefined and may or may not evolve into defined CTDs. Among a series of patients with UCTD, 25–33% progress into a specific CTD such as SSc, systemic lupus erythematosus or myositis, 33–50% remain as UCTD, while 12.5–25% seem to go into complete remission.21,22 The highest probability of evolution to a defined CTD seems to be during the first 2 years after onset.

When RP is associated with high-titre anti-ribonuclear protein (anti-RNP), there is a reasonably predictable evolution into MCTD. The question of whether MCTD is a distinct disease entity is still debated.23,24,25,26 At disease onset, patients usually manifest RP, polyarthritis and swollen hands and are often initially diagnosed as having another CTD rather than MCTD. Whatever the complexity of this clinical and immunological entity, the disease shares similarities with SSc as with other CTDs.26 The initial presence of antinuclear antibodies, thickening of fingers and higher age at onset are important predictors for a possible transition from RP to a CTD.19,27,28 The components of the warning triangle—that is, antinuclear antibodies, RP and SSc capillaroscopic pattern could thus be regarded as a potential “gateway” to CTDs.

The spectrum of clinical pictures of “early SSc” may be heterogeneous but in practice can be summarised in two levels: “early SSc” can be suspected on the basis of RP, puffy fingers, autoantibodies and SSc capillaroscopic pattern. From a clinical point of view, SSc can develop from “prescleroderma”, MCTD, or UCTD (fig 1) and progress to internal organ damage. In practice, we aim at having criteria for the diagnosis of very early SSc (box 1): (a) initially using a Delphi technique; (b) thereafter using already available datasets; but (c) of critical importance, through prospective studies; we are aware that these are provisional and need further validation. Only prospective studies can lead to validation of these provisional criteria. Indeed it is important to have “red flags” that can help us in the very early phase of the disease to track those patients at risk of progressing to overt disease (fig 2).

Figure 2

The two red flags necessary to formulate a suspect of systemic sclerosis (SSc) are presented with the further two consecutive levels of investigations necessary to achieve the very early diagnosis of SSc (VEDOSS). ACA, anticentromere antibodies; ANA, antinuclear antibodies; ENA, extractable nuclear antigen antibodies; HRCT, high-resolution computed tomography; TOPO-I, antitopoisomerase I antibodies.

Box 1 Preliminary criteria, still to be validated, for the very early diagnosis of systemic sclerosis (SSc)*

  • Major criteria

    • Raynaud’s phenomenon

    • antibodies (antinuclear, anticentromere, antitopoisomerase I)

    • diagnostic nailfold videocapillaroscopy

  • Additional criteria

    • calcinosis

    • puffy fingers

    • digital ulcers

    • dysfunction of the oesophageal sphincter

    • telangiectasia

    • ground glass at chest high-resolution computed tomography

*Provisional criteria for the diagnosis of very early systemic sclerosis proposed by EULAR Scleroderma Trial and Research group (EUSTAR) (to be validated through a Delphi Technique)

Diagnosis will be achieved when at least three major criteria are satisfied or two major plus one additional criteria are satisfied

The current division of SSc into subsets is useful in the clinic but cannot help to define or understand early SSc. Nevertheless, these subsets teach us that the target may be different among different subsets. In fact, the predominance of one or the other of different pathogenetic features of SSc (vascular, immune, fibrotic) will generate different disease phenotypes.

With this background we propose that a definition for “early SSc” or even “prescleroderma” is clearly needed. Based on such a definition, reasonably reliable predictors of evolution and even, perhaps, outcome may be possible, creating a “window of opportunity” for pre-emptive treatment. Given this definition, SSc could be treated before irreversible organ damage occurs. The SSc community might learn from the recent advances in rheumatoid arthritis, showing that aggressive treatment in patients with early, active rheumatoid arthritis offers a unique opportunity to control the disease and avoid joint damage and disability.29

At present, no drug or combination of drugs has been studied adequately in “very early” disease, which challenges the usefulness of early diagnosis. Nevertheless, the survival of patients with SSc has improved in the past 25 years following the introduction of calcium channel blockers, ACE inhibitors, cyclophosphamide, methotrexate and endothelin receptor antagonists/phosphodiesterase inhibitors/prostanoids. These drugs, recommended in SSc,30 as well as other treatments being used in therapeutic trials, make it necessary to attempt to define SSc at a stage when treatment may be more effective and may induce durable remission.

In conclusion, it is clear that our present definition of SSc is not adequate to deal with the needs of patients with “very early” or “prescleroderma” SSc. It is, perhaps, during the “very early” or “prescleroderma” phases of the disease that there is the greatest opportunity to change the course of SSc. It is thus important that the scleroderma community defines and validates a definition of “early disease”, or even a preclinical stage of disease and that it defines and demonstrates predictors of outcome, so that appropriately targeted treatment can begin to prevent or ameliorate organ damage—particularly as more effective treatments are developed. The identification of diagnostic criteria of very early diagnosis of SSc is a clear clinical priority that might help the doctor in practice, and provide further help in the reclassification process of SSc launched by the EULAR/ACR task force.

REFERENCES

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Footnotes

  • For numbered affiliations see end of article

  • Funding EUSTAR is funded by a grant from EULAR and by an unrestricted grant from Actelion, Encysive and Pfizer.

  • Competing interests None.

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