Understanding Scleroderma Diagnosis Criteria: A Comprehensive Guide for Accurate Classification

Systemic sclerosis (SSc), also known as scleroderma, is a complex autoimmune disease characterized by vasculopathy, autoantibody production, and fibroblast dysfunction, leading to excessive extracellular matrix deposition. This results in a range of clinical manifestations, from skin thickening to internal organ involvement, with varying degrees of severity and prognosis. Accurate classification is crucial for research and clinical management of SSc.

The Evolution of Scleroderma Classification Criteria

For many years, the 1980 American Rheumatism Association (ARA) preliminary criteria were the standard for classifying systemic sclerosis. However, these criteria, developed based on patients with established SSc, lacked sensitivity, particularly in early-stage SSc and limited cutaneous SSc (lcSSc). This insensitivity meant that a significant portion of patients, especially those in the early stages of the disease or with milder forms, were not correctly classified, hindering their inclusion in clinical studies and potentially delaying appropriate management.

Recognizing the limitations of the 1980 criteria and advancements in understanding SSc, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) joined forces to develop new, improved classification criteria. The goal was to create a system that is more sensitive and specific, encompassing a broader spectrum of SSc, including early disease stages and diverse clinical presentations. These new criteria aim to incorporate vascular, immunological, and fibrotic manifestations of SSc, be practical for daily clinical use, and align with diagnostic approaches in clinical practice. The ultimate objective is to accurately identify individuals with SSc for inclusion in clinical studies, thereby advancing research and improving patient care.

Development and Validation of the ACR-EULAR SSc Classification Criteria

The development of the ACR-EULAR classification criteria was a rigorous process, combining expert consensus and data-driven analysis.

Item Generation and Reduction

The process began with identifying a comprehensive list of 168 candidate criteria through Delphi exercises, a structured communication technique involving a panel of experts. Through multiple rounds of Delphi exercises and face-to-face consensus meetings, this extensive list was reduced to 23 candidate items. These items were then evaluated for their ability to differentiate between SSc cases and scleroderma-like disorders using existing databases.

Item Reduction and Weighting: Multi-Criteria Decision Analysis

To further refine the criteria, a multi-criteria decision analysis approach was employed. A panel of eight SSc experts from Europe and North America participated in a face-to-face meeting. These experts, selected for their geographical representation, scientific and practical diagnostic knowledge, and availability, were tasked with reducing the 23 items and assigning preliminary weights.

The experts first defined the target population for the criteria and identified features sufficient for SSc classification. They then used a conjoint analysis technique, facilitated by 1000Minds decision-making software, to rank the remaining 23 items and derive weights for each. This involved pairwise comparisons of hypothetical cases, allowing experts to vote on which case was more likely to have SSc based on the presence or absence of specific criteria. Through iterative voting and discussion, the items were ranked and weighted, forming a draft classification system.

Threshold Identification and Iterative Refinement

To establish an initial threshold score for SSc classification, the committee presented 45 challenging SSc cases to 22 SSc experts for classification as definite SSc or not. The draft scoring system was applied to these cases, and the scores were compared to the expert classifications. This comparison helped determine an initial threshold score that best aligned with expert opinion.

Further refinement involved iterative changes to the draft system, including reducing the number of items, simplifying weights, and adjusting the threshold score. Data from a prospective collection of 605 patients (368 SSc and 237 controls with scleroderma-like disorders) across 23 centers in North America and Europe were used. A derivation sample of 200 patients (100 SSc, 100 controls) and a validation sample of the remaining patients were created. The scoring system was simplified by removing low-frequency or redundant items, combining similar items, and simplifying weights to single-digit integers. The threshold was adjusted accordingly, and the impact of these changes on sensitivity and specificity was continuously evaluated in the derivation cohort, using expert physician diagnosis as the reference standard. Additionally, the system was tested against 38 difficult-to-classify cases to further refine item weights and improve alignment with expert consensus.

Validation of the Final Criteria

The final ACR-EULAR SSc classification criteria underwent independent validation using the validation sample. The sensitivity and specificity of the new criteria were compared to the 1980 ARA criteria and the 2001 LeRoy and Medsger criteria. The new criteria were also tested in patients with a shorter disease duration (≤3 years) to assess their performance in early SSc. Furthermore, the system was validated against expert consensus on the 38 challenging cases.

The 2013 ACR-EULAR SSc Classification Criteria: A Point System Approach

The 2013 ACR-EULAR classification criteria represent a significant advancement in SSc classification. They employ a point-based system, assigning weights to various clinical and serological features of SSc.

Key Components of the New Criteria

The criteria include:

• One Sufficient Criterion: Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal (MCP) joints. The presence of this criterion alone is sufficient for SSc classification, assigning 9 points.

• Exclusionary Criteria: The criteria are not applicable to patients with:

  • Scleroderma-like disorders that better explain their manifestations (e.g., nephrogenic sclerosing fibrosis, eosinophilic fasciitis).
  • Skin thickening sparing the fingers.

• Additive Point System: If the sufficient criterion is not met, a point system is applied based on the presence of seven additive items:

  1. Skin thickening of the fingers:

     • Puffy fingers: 2 points
     • Sclerodactyly of the fingers (distal to MCP but proximal to PIPs): 4 points

  2. Finger tip lesions:

     • Digital tip ulcers: 2 points
     • Finger tip pitting scars: 3 points

  3. Telangiectasia: 2 points

  4. Abnormal nailfold capillaries: 2 points

  5. Pulmonary arterial hypertension (PAH) or Interstitial lung disease (ILD): 2 points

  6. Raynaud’s phenomenon: 3 points

  7. Scleroderma-related autoantibodies (anti-centromere, anti-topoisomerase I [anti-Scl70], or anti-RNA polymerase III): 3 points

Image Alt Text: Table 1. ACR-EULAR Criteria for the classification of Systemic Sclerosis. This table outlines the point-based system used to classify systemic sclerosis, including a sufficient criterion, exclusionary criteria, and weighted items such as skin thickening, finger tip lesions, telangiectasia, nailfold capillaries, pulmonary involvement, Raynaud’s phenomenon, and scleroderma-related antibodies.

Scoring and Interpretation:

• The maximum possible score is 19.
• A total score of 9 or more classifies a patient as having definite systemic sclerosis.
• When a patient has multiple manifestations within a category (e.g., both digital tip ulcers and pitting scars), only the item with the highest score is counted.

Definitions of Criteria Items

Clear definitions for each item in the criteria ensure consistent application. These definitions are outlined in Table 2.

Image Alt Text: Table 2. Definitions of the SSc classification criteria items. This table provides detailed definitions for each criterion item, including skin thickening, puffy fingers, finger tip ulcers or pitting scars, telangiectasia, abnormal nailfold capillary pattern, pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, and scleroderma-specific antibodies, ensuring consistent interpretation and application of the classification criteria.

Superior Performance of the ACR-EULAR Criteria

Validation studies demonstrated that the ACR-EULAR classification criteria significantly outperform the 1980 ARA criteria and the LeRoy/Medsger criteria in terms of both sensitivity and specificity.

Improved Sensitivity and Specificity

In the validation sample, the ACR-EULAR criteria achieved a sensitivity of 0.91 and a specificity of 0.92, compared to 0.75 and 0.72 for the 1980 ARA criteria, respectively. This significant improvement highlights the ability of the new criteria to correctly identify more SSc patients while minimizing false positives. The new criteria also showed superior performance in patients with early SSc (≤3 years disease duration).

Validation Against Expert Consensus

Further validation against expert consensus on a set of 38 challenging cases demonstrated excellent agreement with the ACR-EULAR classification system. All cases scoring 9 or above were considered SSc, aligning perfectly with expert opinions. The new criteria also classified all cases identified by the 1980 ARA criteria as SSc and captured additional cases missed by the older criteria.

Characteristics of Validation Samples

Tables 3 and 4 provide detailed characteristics of the derivation and validation samples, including demographics, disease duration, and the prevalence of various SSc manifestations. These tables offer valuable insights into the patient populations used to develop and validate the new criteria.

Image Alt Text: Table 3. Characteristics of derivation sample and validation sample. This table presents a detailed comparison of the derivation and validation samples used in the study, including demographics, time since onset of symptoms, and the prevalence of various scleroderma-like disorders and SSc manifestations, providing context for the criteria development and validation process.

Image Alt Text: Table 4. Sensitivity and specificity of SSc classification criteria including in early SSc. This table compares the sensitivity and specificity of the 1980 ARA criteria, 2001 LeRoy and Medsger criteria, and the 2013 ACR-EULAR SSc classification criteria in both the derivation and validation samples, as well as in a subgroup with early SSc, demonstrating the improved performance of the new ACR-EULAR criteria.

Expert Consensus vs. Classification Systems

Table 5 demonstrates the alignment between expert consensus and the ACR-EULAR classification system on selected case profiles. This table highlights the practical application of the criteria and their ability to reflect expert clinical judgment.

Image Alt Text: Table 5. Expert Consensus versus Classification Systems for Selected Case Profiles. This table presents a comparison of expert consensus and classification systems for selected case profiles, illustrating how the ACR-EULAR criteria align with expert clinical judgment in classifying challenging cases of systemic sclerosis.

Discussion: Implications for Research and Clinical Practice

The development of the ACR-EULAR SSc classification criteria addresses the critical need for improved sensitivity, particularly in early SSc and lcSSc. These new criteria incorporate key aspects of SSc pathogenesis, including fibrosis, autoantibodies, and vasculopathy, reflecting the current understanding of the disease.

Enhanced Sensitivity and Broader Spectrum of SSc

The increased sensitivity of the ACR-EULAR criteria means that a wider range of SSc patients, including those in early stages and with limited cutaneous involvement, can be accurately classified. This is crucial for enrolling more representative patient populations in clinical research, leading to more generalizable and impactful study results.

Incorporation of Advances in SSc Understanding

The new criteria thoughtfully integrate advancements in SSc diagnostics, notably the inclusion of SSc-specific autoantibodies and abnormal nailfold capillaries. The recognition of specific autoantibodies like anti-topoisomerase I, anti-centromere, and anti-RNA polymerase III, and the inclusion of nailfold capillaroscopy as a valuable diagnostic tool, reflect the progress in SSc diagnosis over the past decades. The criteria also acknowledge the evolving definitions of pulmonary arterial hypertension, emphasizing the importance of right heart catheterization for accurate PAH diagnosis.

Practicality and Clinical Relevance

While designed primarily for research classification, the ACR-EULAR criteria are based on assessments routinely performed in clinical practice. The point system, while more complex than the 1980 ARA criteria, is designed to be user-friendly, even in the absence of electronic tools. The criteria items are readily assessable, making them practical for rheumatologists and other clinicians involved in SSc care.

Limitations and Future Directions

Despite their significant improvements, the ACR-EULAR criteria are not without limitations. They may not capture all nuances of SSc diagnosis in individual patients, and clinical diagnosis may still incorporate factors not included in the classification criteria, such as tendon friction rubs or dysphagia. The criteria are intended for research classification and not as strict diagnostic criteria. Furthermore, validation in ethnicities beyond North America and Europe is needed to ensure global applicability. The criteria also allow for the possibility of classifying patients with overlapping rheumatic diseases as having SSc, which researchers may need to consider in study design.

Conclusion: A New Standard for SSc Classification

The ACR-EULAR classification criteria for systemic sclerosis represent a significant advancement over previous criteria. Their improved sensitivity and specificity, incorporation of current SSc knowledge, and validation against expert opinion establish them as a new standard for SSc classification in research settings. The use of these criteria is recommended for inclusion in epidemiological, clinical, and experimental studies of SSc, promising to enhance the accuracy and relevance of SSc research and ultimately improve patient outcomes. Further validation in diverse populations and ongoing refinement will continue to optimize the classification of this complex disease.

Acknowledgements

This research was supported by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Dr. Johnson is supported by a Canadian Institutes of Health Research Clinician Scientist Award and the Norton-Evans Fund for Scleroderma Research. Dr. Khanna was supported by the Scleroderma Foundation (New Investigator Award), and a National Institutes of Health Award (NIAMS K24 AR063120).

Footnotes

Key message: The ACR-EULAR criteria for the classification of systemic sclerosis performed better than 1980 Preliminary ARA Criteria for SSc and should allow for more patients to be classified correctly as SSc. The use of these criteria is recommended for including patients in epidemiological, clinical or experimental studies.

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