2013 Classification Criteria for Systemic Sclerosis
A classification system for systemic sclerosis is needed to ensure that all patients categorised as having SSc for inclusion in studies do indeed have the disease, based on specific defined characteristics. The major reason to revise the 1980 ACR criteria was that those criteria lacked adequate sensitivity, especially in patients with early SSc or with limited cutaneous SSc. The proposed classification criteria are superior and exhibit greater sensitivity and specificity compared to the 1980 criteria and the classification criteria proposed by LeRoy and Medsger. All profiles of patients who were considered to have SSc by a majority of experts were indeed classified as SSc with the new classification system, and the new system is more inclusive and also performs well in patients with early disease (≤3 years since diagnosis).
The newly developed classification system includes disease manifestations of the three hallmarks of SSc: fibrosis of the skin and/or internal organs, production of certain autoantibodies, and vasculopathy. The four items comprising the 1980 ACR classification criteria (scleroderma proximal to the metacarpophalangeal joints, sclerodactyly, digital pitting scars (not pulp loss), and bilateral basilar pulmonary fibrosis) are also included, as are the items in the criteria proposed in 2001 by LeRoy and Medsger (Raynaud's phenomenon, autoantibodies, nailfold capillaroscopy abnormalities, skin fibrosis).
The new criteria include one criterion that alone is sufficient for classification as SSc: skin thickening of the fingers extending proximal to the metacarpophalangeal joints, which is similar to the 1980 criteria. If the single sufficient criterion is not fulfilled, the point system is applied and patients with a score of ≥9 are classified as having SSc. All items in the classification criteria represent measurements that are performed in routine clinical practice. The criteria are meant for inclusion of SSc patients in studies, not for SSc diagnosis. Although the list of items in the classification criteria mimics the list of items one usually uses for diagnosis, in practice the diagnosis of SSc may also be informed by items not included in the classification criteria, such as tendon friction rubs, calcinosis, and dysphagia. Consequently, patients classified as having SSc are a subset of patients being diagnosed as having SSc, with diagnosis being more sensitive. Ideally, there would be no difference between diagnosis and classification criteria.
As intended, the new classification system incorporates the considerable advances made in the diagnosis of SSc. It includes the concept of specific serum autoantibodies such as anti–topoisomerase I, anticentromere, and anti–RNA polymerase III. There is the possibility that testing for additional SSc autoantibodies, such as anti-Th/To, anti–U3 RNP, and others, may become more widely available. The criteria also acknowledge the value of magnified nailfold visualisation in the diagnosis of SSc. Although capillaroscopy can be performed with highly specialised equipment such as videocapillaroscopy cameras, simple in-office ophthalmoscopes or dermatoscopes suffice for distinguishing between normal and abnormal nailfold capillaries. Capillaroscopy is now widely used, and considering the value of magnified nailfold visualisation in the diagnosis and management of SSc, these new criteria may encourage acquisition of this skill by physicians caring for SSc patients. Likewise, criteria for pulmonary artery hypertension have changed over the years. The ACR/EULAR committee recognises this, and the diagnosis of pulmonary artery hypertension should be based on the most recent accepted criteria from right-sided heart catheterisation.
Several items that are useful for recognising SSc in clinical practice, such as calcinosis, flexion contractures of the fingers, tendon or bursal friction rubs, renal crisis, oesophageal dilatation, and dysphagia are not included in the criteria. These were considered but did not substantially improve sensitivity or specificity. For example, renal crisis is a strong indicator of SSc, but its low frequency of occurrence makes it less useful for the purpose of classification. The committee considered a non–point-based additive system, such as the ACR systemic lupus erythematosus criteria or the 1980 ACR SSc criteria. We concluded, however, that assigning weights yielded superior results for SSc classification. Indeed, the weights were simplified to single-digit numbers to make the system easy to use even in the absence of a computing device. Similar weighted systems have been used for other rheumatic diseases. The committee also decided not to include 'probable' or 'possible' SSc in the classification.
Examples of profiles not captured by the 1980 ACR criteria that fulfilled the new classification criteria are combinations of skin thickening of the whole finger, SSC-related autoantibodies, and pulmonary arterial hypertension and/or Raynaud's phenomenon. A patient with Raynaud's phenomenon, autoantibodies, and abnormal nailfold capillaries is not classified as having SSc, although such a patient may develop SSc over subsequent years.
Patients may have disease manifestations similar to those of SSc that are better explained by another well-defined disorder, such as nephrogenic sclerosing fibrosis, generalised morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, porphyria, lichen sclerosis, graft-versus-host disease, or diabetic cheiroarthropathy. We decided it was not necessary to develop criteria that differentiated SSc specifically from these conditions. Patients with some of these diseases were included in the validation cohort of patients with SSc-like disorders, and it is possible that specificity may have been slightly higher had they been excluded.
In developing the revised SSc classification criteria, we followed the recommendations and guidelines of the ACR and EULAR, which included (1) collaboration between clinical experts and clinical epidemiologists in criteria development, (2) evaluation of the psychometric properties of each candidate criterion, and (3) description of the test sample (origin of the patients and control subjects) Ideally, phases of criteria development should have a balance between expert opinion and data-driven methods; yet, there should be avoidance of circularity of reasoning (a bias that can occur when the same experts developing the criteria are the ones contributing cases and comparison patients). We included different experts at different steps in the development of the SSc criteria, to avoid circularity.
Testing and validating a classification system for SSc is difficult because there is no gold standard for defining a particular case as SSc; that is, there is no incontrovertible test or criterion. We relied on expert opinion for our gold standard, which is similar to the process used in the development of other criteria.
In the absence of a gold standard, we developed and tested the proposed classification system against two standards of expert opinion: (1) the opinion of the clinician who selected cases for the North American and European derivation and validation cohorts, and (2) the combined opinion of a group of clinical experts in SSc. Both standards have strengths and weaknesses. Each individual clinician who selected cases had access to information that could have included aspects not captured by the forms, which were restricted to 23 particular manifestations. Data were obtained from several sites in Europe and North America, so this should improve generalisability and reduce selection bias. However, it is possible that other expert clinicians may have had a different opinion about particular cases. The consensus opinion of a group of experts who had the opportunity to discuss controversial cases strengthens the combined expert opinion. However, the group may not have been aware of some relevant information not included in the available data. It is also difficult for a group of experts to consider hundreds of cases in depth; however, this was managed by having the group consider in depth only those cases, or combinations of items, that appeared to be controversial. In this way, the expert group was able to form a consensus over the whole range of cases in the database. A key strength of the present work is the use of both standards for testing and validation of the proposed system.
The approach we used has other strengths and limitations as well. The methodology was state of the art, with validation by data and by expert opinion at every step. Various methods used in the development process have already been described. The criteria have face validity, because the items are routinely assessed in daily clinical practice and also were included in other important SSc classification criteria sets. The criteria allow for new developments in for example, autoantibody testing availability and/or new identification of scleroderma-associated autoantibodies, or assessment of nailfold capillaries. Formal conjoint analysis to derive the weights associated with items improved the sensitivity and specificity of the items, as was found also in the development of the recent ACR/EULAR criteria for the classification of rheumatoid arthritis.
The criteria have not been validated in ethnic groups that are not common in North America and Europe. This will require further studies. Regarding clinical use, the number of items and weights may not be easy to remember, but wide availability and (electronic) applications can be developed. The SSc classification criteria steering committee and the expert consultants agreed that the criteria could allow for classification of patients with another rheumatic disease as also having SSc (eg, having both systemic lupus erythematosus and SSc, or rheumatoid arthritis and SSc, etc.). Although this is a possible limitation, it permits individual researchers to decide whether to include subjects who fulfill criteria for more than one rheumatic disease in any particular study.
Discussion
A classification system for systemic sclerosis is needed to ensure that all patients categorised as having SSc for inclusion in studies do indeed have the disease, based on specific defined characteristics. The major reason to revise the 1980 ACR criteria was that those criteria lacked adequate sensitivity, especially in patients with early SSc or with limited cutaneous SSc. The proposed classification criteria are superior and exhibit greater sensitivity and specificity compared to the 1980 criteria and the classification criteria proposed by LeRoy and Medsger. All profiles of patients who were considered to have SSc by a majority of experts were indeed classified as SSc with the new classification system, and the new system is more inclusive and also performs well in patients with early disease (≤3 years since diagnosis).
The newly developed classification system includes disease manifestations of the three hallmarks of SSc: fibrosis of the skin and/or internal organs, production of certain autoantibodies, and vasculopathy. The four items comprising the 1980 ACR classification criteria (scleroderma proximal to the metacarpophalangeal joints, sclerodactyly, digital pitting scars (not pulp loss), and bilateral basilar pulmonary fibrosis) are also included, as are the items in the criteria proposed in 2001 by LeRoy and Medsger (Raynaud's phenomenon, autoantibodies, nailfold capillaroscopy abnormalities, skin fibrosis).
The new criteria include one criterion that alone is sufficient for classification as SSc: skin thickening of the fingers extending proximal to the metacarpophalangeal joints, which is similar to the 1980 criteria. If the single sufficient criterion is not fulfilled, the point system is applied and patients with a score of ≥9 are classified as having SSc. All items in the classification criteria represent measurements that are performed in routine clinical practice. The criteria are meant for inclusion of SSc patients in studies, not for SSc diagnosis. Although the list of items in the classification criteria mimics the list of items one usually uses for diagnosis, in practice the diagnosis of SSc may also be informed by items not included in the classification criteria, such as tendon friction rubs, calcinosis, and dysphagia. Consequently, patients classified as having SSc are a subset of patients being diagnosed as having SSc, with diagnosis being more sensitive. Ideally, there would be no difference between diagnosis and classification criteria.
As intended, the new classification system incorporates the considerable advances made in the diagnosis of SSc. It includes the concept of specific serum autoantibodies such as anti–topoisomerase I, anticentromere, and anti–RNA polymerase III. There is the possibility that testing for additional SSc autoantibodies, such as anti-Th/To, anti–U3 RNP, and others, may become more widely available. The criteria also acknowledge the value of magnified nailfold visualisation in the diagnosis of SSc. Although capillaroscopy can be performed with highly specialised equipment such as videocapillaroscopy cameras, simple in-office ophthalmoscopes or dermatoscopes suffice for distinguishing between normal and abnormal nailfold capillaries. Capillaroscopy is now widely used, and considering the value of magnified nailfold visualisation in the diagnosis and management of SSc, these new criteria may encourage acquisition of this skill by physicians caring for SSc patients. Likewise, criteria for pulmonary artery hypertension have changed over the years. The ACR/EULAR committee recognises this, and the diagnosis of pulmonary artery hypertension should be based on the most recent accepted criteria from right-sided heart catheterisation.
Several items that are useful for recognising SSc in clinical practice, such as calcinosis, flexion contractures of the fingers, tendon or bursal friction rubs, renal crisis, oesophageal dilatation, and dysphagia are not included in the criteria. These were considered but did not substantially improve sensitivity or specificity. For example, renal crisis is a strong indicator of SSc, but its low frequency of occurrence makes it less useful for the purpose of classification. The committee considered a non–point-based additive system, such as the ACR systemic lupus erythematosus criteria or the 1980 ACR SSc criteria. We concluded, however, that assigning weights yielded superior results for SSc classification. Indeed, the weights were simplified to single-digit numbers to make the system easy to use even in the absence of a computing device. Similar weighted systems have been used for other rheumatic diseases. The committee also decided not to include 'probable' or 'possible' SSc in the classification.
Examples of profiles not captured by the 1980 ACR criteria that fulfilled the new classification criteria are combinations of skin thickening of the whole finger, SSC-related autoantibodies, and pulmonary arterial hypertension and/or Raynaud's phenomenon. A patient with Raynaud's phenomenon, autoantibodies, and abnormal nailfold capillaries is not classified as having SSc, although such a patient may develop SSc over subsequent years.
Patients may have disease manifestations similar to those of SSc that are better explained by another well-defined disorder, such as nephrogenic sclerosing fibrosis, generalised morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, porphyria, lichen sclerosis, graft-versus-host disease, or diabetic cheiroarthropathy. We decided it was not necessary to develop criteria that differentiated SSc specifically from these conditions. Patients with some of these diseases were included in the validation cohort of patients with SSc-like disorders, and it is possible that specificity may have been slightly higher had they been excluded.
In developing the revised SSc classification criteria, we followed the recommendations and guidelines of the ACR and EULAR, which included (1) collaboration between clinical experts and clinical epidemiologists in criteria development, (2) evaluation of the psychometric properties of each candidate criterion, and (3) description of the test sample (origin of the patients and control subjects) Ideally, phases of criteria development should have a balance between expert opinion and data-driven methods; yet, there should be avoidance of circularity of reasoning (a bias that can occur when the same experts developing the criteria are the ones contributing cases and comparison patients). We included different experts at different steps in the development of the SSc criteria, to avoid circularity.
Testing and validating a classification system for SSc is difficult because there is no gold standard for defining a particular case as SSc; that is, there is no incontrovertible test or criterion. We relied on expert opinion for our gold standard, which is similar to the process used in the development of other criteria.
In the absence of a gold standard, we developed and tested the proposed classification system against two standards of expert opinion: (1) the opinion of the clinician who selected cases for the North American and European derivation and validation cohorts, and (2) the combined opinion of a group of clinical experts in SSc. Both standards have strengths and weaknesses. Each individual clinician who selected cases had access to information that could have included aspects not captured by the forms, which were restricted to 23 particular manifestations. Data were obtained from several sites in Europe and North America, so this should improve generalisability and reduce selection bias. However, it is possible that other expert clinicians may have had a different opinion about particular cases. The consensus opinion of a group of experts who had the opportunity to discuss controversial cases strengthens the combined expert opinion. However, the group may not have been aware of some relevant information not included in the available data. It is also difficult for a group of experts to consider hundreds of cases in depth; however, this was managed by having the group consider in depth only those cases, or combinations of items, that appeared to be controversial. In this way, the expert group was able to form a consensus over the whole range of cases in the database. A key strength of the present work is the use of both standards for testing and validation of the proposed system.
The approach we used has other strengths and limitations as well. The methodology was state of the art, with validation by data and by expert opinion at every step. Various methods used in the development process have already been described. The criteria have face validity, because the items are routinely assessed in daily clinical practice and also were included in other important SSc classification criteria sets. The criteria allow for new developments in for example, autoantibody testing availability and/or new identification of scleroderma-associated autoantibodies, or assessment of nailfold capillaries. Formal conjoint analysis to derive the weights associated with items improved the sensitivity and specificity of the items, as was found also in the development of the recent ACR/EULAR criteria for the classification of rheumatoid arthritis.
The criteria have not been validated in ethnic groups that are not common in North America and Europe. This will require further studies. Regarding clinical use, the number of items and weights may not be easy to remember, but wide availability and (electronic) applications can be developed. The SSc classification criteria steering committee and the expert consultants agreed that the criteria could allow for classification of patients with another rheumatic disease as also having SSc (eg, having both systemic lupus erythematosus and SSc, or rheumatoid arthritis and SSc, etc.). Although this is a possible limitation, it permits individual researchers to decide whether to include subjects who fulfill criteria for more than one rheumatic disease in any particular study.