The degree of skin involvement identifies distinct lung disease outcomes and survival in systemic sclerosis

Abstract

Objective: To determine whether the pattern of skin involvement can predict clinical features, risk of restrictive lung disease (RLD) and survival in a large scleroderma (SSc) cohort.

Methods: Demographic and clinical data collected over 30 years from 2205 patients with SSc were retrospectively analysed after subdividing subjects into four subtypes based on pattern of skin fibrosis: type 0 (no skin involvement), type 1 (limited to metacarpophalangeal joints), type 2 (distal to elbows/knees) and type 3 (proximal to elbows/knees). Clinical features associated with skin subsets were identified by regression analyses. Kaplan-Meier and Cox proportional hazards models were used to compare time to RLD and survival across subtypes.

Results: The presence and severity of RLD were positively associated with skin subtype (p<0.001). RLD prevalence incrementally ranged from 51.9% in type 0 to 76.7% in type 3 (p<0.001). Type 2 SSc exhibited a distinct phenotype with intermediate risk for RLD relative to type 1 (higher, p<0.001) and type 3 (lower, p<0.001) and a unique autoantibody profile, with a prevalence of anticentromere antibodies lower than type 1 (28.9% vs 44.1%, p=0.001) and of anti-topoisomerase I antibodies similar to type 3 (32.8% vs 28.7%, p=0.38). These autoantibodies were also found to be significant negative (OR=0.33, p<0.001) and positive (OR=1.6, p=0.01) predictors of RLD risk, respectively. Mortality was also intermediate in type 2 patients relative to type 3 (p=0.0003) and type 1 (p=0.066).

Conclusions: These data suggest that the current classification subdividing SSc into limited and diffuse cutaneous subtypes misclassifies an intermediate group of patients exhibiting unique autoantibody profile, disease course and clinical outcomes.

Keywords: Autoantibodies; Pulmonary Fibrosis; Systemic Sclerosis.

Figure 1

A, Percentage of patients with Type-0 (n=81), Type-1 (n=1070), Type-2 (n=197), and Type-3 (n=857) scleroderma with evidence of RLD (FVC<80%) at their first pulmonary function test (*p<0.001, **p=0.03). B, Percentage of patients in each subtype analyzed by severity of restrictive lung disease: none (FVC>80% predicted), mild (FVC 70-80% predicted), moderate (FVC 50-69% predicted), or severe (FVC<50% predicted) (*p<0.001). RLD = restrictive lung disease; PFT = pulmonary function test; FVC = forced vital capacity (% of predicted)

Figure 2

Kaplan-Meier curves of the association between scleroderma subtype and the detection of restrictive lung disease (RLD). All available pulmonary function tests were analyzed from the time of scleroderma (SSc) onset (first non-Raynaud's symptom) and patients were considered to have RLD when their forced vital capacity dropped below 80% of predicted for an average person of the same height, weight, sex, age, and race. The logrank test for Type-2 patients vs. Type-1 and Type-3 patients indicated significant differences in both comparisons (*p≤0.0001).

Figure 3

Scleroderma (SSc) specific autoantibodies association with skin involvement subtypes and the risk of restrictive lung disease (RLD). A, Percentage of patients who are positive for anti-centromere (ACA, n=393) and anti-topoisomerase I (Scl-70, n=304) antibodies in each of the four skin subtypes. * ACA Type-1 vs. Type-2; ** anti-Scl-70 Type-1 vs. Type-2; † ACA Type-2 vs. Type-3; ‡ anti-Scl-70 Type-2 vs. Type-3. B-D, Kaplan-Meier curves showing the association between scleroderma subtypes and RLD among patients with the same autoantibody status: ACA positive (B), anti-Scl-70 positive (C) and patients negative for both ACA and anti-Scl-70 antibodies (D).

Figure 4

Mortality of scleroderma (SSc) patients based on skin involvement subtype (A) and antibody status (B). Kaplan-Meier survival curves were analyzed from the time of SSc onset (first non-Raynaud's symptom). (C) Risk of mortality analyzed by Cox proportional hazards models.