Significance of Anti-Neutrophil Cytoplasmic Antibodies in Systemic Sclerosis

Jayne Moxey; Molla Huq; Susanna Proudman; Joanne Sahhar; Gene-Siew Ngian; Jenny Walker; Gemma Strickland; Michelle Wilson; Laura Ross; Gabor Major; Janet Roddy; Wendy Stevens; Mandana Nikpour

Disclosures

Arthritis Res Ther. 2019;21(57) 

In This Article

Results

Study Population

A total of 1303 patients fulfilled the inclusion criteria for this study, and the characteristics of this cohort are summarised in Table 1. Of the 1303 patients included in the study, 1125 (86.3%) were females, 974 (74.8%) had limited disease and 329 (25.2%) had diffuse disease. The majority of patients were Caucasian (90.4%) followed by Asian (4.5%). The mean ± standard deviations (SD) of the age of SSc onset and the age at recruitment were 46.4 ± 14.3 and 57.7 ± 12.5 years, respectively. The median ± interquartile range (IQR) duration of follow-up was 3.46 ± 2.69 years. Almost half (49%) of the cohort had ever smoked.

The autoantibody profile of the cohort is summarised in Table 1. Overall, 93.8% were anti-nuclear antibody (ANA) positive, 47.0% were anti-centromere positive and 13.9% were anti-Scl-70 positive. Other autoantibodies with significant prevalence within the cohort were rheumatoid factor (RF) (25.9%), anti-cardiolipin (20.1%), RNA polymerase (8.9%) and anti-Ro (6.7%).

Disease features of the cohort are summarised in Table 1. ILD was present in 311 patients (23.9%), and 163 patients (12.5%) had PAH. Almost half (49.6%) of patients had digital ulcers, 39.7% had synovitis, 8.6% had GAVE and 2.7% had a renal crisis. Overlap features with another connective tissue disease were present in 5.8%, and comorbid rheumatoid arthritis was the most common overlap syndrome, present in 27 patients (2.1%).

Treatment characteristics of the cohort are summarised in Table 1. A significant proportion of the cohort had received calcium channel antagonists (65.0%) and prednisolone (44.5%). With respect to immunosuppressive therapies, 8.1% of patients received azathioprine, 7.9% had received mycophenolate and 9.1% had received cyclophosphamide. Only 26 patients (2.0%) had received biologics.

ANCA-positive vs ANCA-negative Groups

Of the cohort of 1303 patients, 116 patients (8.9%) were ANCA positive, and 1187 (91.1%) were ANCA negative. Univariable analyses comparing demographic characteristics between the ANCA-positive and ANCA-negative groups are summarised in Table 2.

Only 3 ANCA-positive patients had AAV (2.6% of the ANCA-positive cohort, 0.23% of the entire study cohort). One patient with AAV had biopsy-proven vasculitis with mononeuritis multiplex and anti-MPO antibodies. The second patient had p-ANCA-positive biopsy-proven crescentic glomerulonephritis, and the third patient had anti-MPO antibodies and biopsy-proven focal necrotising glomerulonephritis.

There was no statistically significant difference in gender, disease subtype, age of scleroderma onset, disease duration at recruitment, or duration of follow-up between ANCA-positive and ANCA-negative groups. There was a higher proportion of Asian patients in the ANCA-positive group (12.9% vs 3.7%, p = 0.001). ANCA-positive patients were less likely to have ever smoked (36.2% vs 50.3%, p = 0.004).

With respect to autoantibodies, ANCA-positive patients were more likely to be anti-Scl-70-positive (25.0% vs 12.8%, p < 0.001) and anti-Ro-positive (11.2% vs 6.2%, p = 0.040) than ANCA-negative patients. Anti-centromere antibodies were less common in the ANCA-positive group (29.3% vs 48.8%, p < 0.001).

Several clinical features were more common in the ANCA-positive group, including a significantly higher prevalence of ILD (44.8% vs 21.8%, p < 0.001), synovitis (54.3% vs 38.2%, p = 0.001), overlap features with another connective tissue disease (12.1% vs 5.2%, p = 0.003) and overlap features with Sjogren's syndrome (4.3% vs 1.6%, p = 0.038). ANCA-positive patients were more likely to have had a pulmonary embolism (8.6% vs 3.0%, p = 0.002) and malignancy (26.7% vs 18.6%, p = 0.035). ANCA-positive patients were more likely to be hospitalised (49.1% vs 36.5%, p = 0.007).

The ANCA-positive group was more likely to have received azathioprine (13.8% vs 7.5%, p = 0.017) and calcium channel antagonists (75.0% vs 64.0%, p = 0.018). There was a trend towards increased use of prednisolone and biologics in ANCA-positive patients, but this did not reach statistical significance.

Anti-MPO-positive vs Anti-MPO-negative Groups

A total of 13 patients were anti-MPO positive (11.2% of the ANCA-positive group). Univariable analyses comparing demographic characteristics between anti-MPO-positive and anti-MPO-negative patients are summarised in Table 3.

Demographic characteristics including gender, race, disease subtype and age of scleroderma onset were similar between anti-MPO-positive and anti-MPO-negative groups. For autoantibodies, anti-MPO-positive patients were more likely to be anti-Scl-70 positive (38.5% vs 13.6%, p = 0.006) and were less likely to be ANA positive (76.9% vs 93.9%, p = 0.036) than the anti-MPO-negative group. Anti-MPO-positive patients were more likely to have an overlap syndrome with rheumatoid arthritis (15.4% vs 1.9%, p = 0.028). There was a trend towards a higher prevalence of ILD in the anti-MPO-positive group, but this did not reach statistical significance (38.5% vs 23.7%, p = 0.213). There were no other statistically significant differences in disease features between anti-MPO-positive and negative groups. Anti-MPO-positive patients were more likely to receive cyclophosphamide (30.8% vs 8.8%, p = 0.023).

Anti-PR3-positive vs Anti-PR3-negative Groups

A total of 18 patients were anti-PR3 positive (13.8% of the ANCA-positive cohort). Univariable analyses comparing demographic characteristics between anti-PR3-positive and anti-PR3-negative patients are summarised in Table 3.

A higher proportion of male patients (33.3% vs 13.4%, p = 0.014) and Asian patients (22.2% vs 4.2%, p = 0.024) were found in the anti-PR3 positive compared to anti-PR3-negative groups. Other demographic characteristics including disease subtype, age of scleroderma onset, age at recruitment and duration of follow-up were similar between the two groups.

Anti-PR3-positive patients were more likely to be anti-Scl-70 positive than the anti-PR3-negative group (44.4% vs 13.4%, p < 0.001). A significantly higher prevalence of ILD (50.0% vs 23.4%, p = 0.009) and pulmonary embolism (16.7% vs 3.3%, p = 0.022) was found in the anti-PR3-positive group. There was a higher prevalence of overlap syndrome with rheumatoid arthritis (61.1% vs 39.3%, p = 0.061) and synovitis (11.1% vs 1.9%, p = 0.052) in the anti-PR3-positive group, but this did not reach statistical significance. A higher proportion of anti-PR3-positive patients had received mycophenolate compared to the anti-PR3-negative group (22.2% vs 7.6%, p = 0.046).

Multivariable Correlates of ANCA

Variables included in a multivariable model of associations of ANCA were based on those statistically significant in univariable analysis. We excluded "overlap syndrome with Sjogren's" due to multicollinearity with other variables. The final multivariable model included ILD (OR 2.85, 95% CI 1.92–4.23, p = <0.0001), PE (OR 2.82, 95% CI 1.34–5.95, p = 0.007), overlap syndrome (OR 2.25, 95% CI 1.19–4.25, p = 0.013) and synovitis (OR 1.73, 95% CI 1.16–2.56, p = 0.007) (Table 4).

Multivariable Analysis of the Relationship Between ANCA and Interstitial Lung Disease

In multivariable regression analysis, ANCA was independently associated with ILD (OR 2.63, 95% CI 1.72–4.0, p < 0.001) after taking into account anti-Scl-70 antibodies.

Multivariable Analysis of the Relationship Between ANCA and Pulmonary Embolism

In multivariable regression analysis, ANCA was independently associated with pulmonary embolism even after taking into account the presence of anti-phospholipid antibodies (OR 3.11, 95% CI 1.49–6.48, p = 0.003).

Survival Analysis

Kaplan-Meier analysis comparing survival in ANCA-positive and ANCA-negative patients (Figure 1) revealed ANCA-positive patients had significantly increased mortality (p = 0.006). ANCA remained associated with higher mortality after adjusting for age at SSc onset and sex in Cox regression analysis (HR 1.622, 95% CI 1.04–2.54, p = 0.034).

Figure 1.

Kaplan-Meier curve comparing survival in the ANCA-positive and ANCA-negative patients. SSc onset refers to the date of onset of first non-Raynaud's manifestation. Abbreviations: ANCA anti-neutrophil cytoplasmic antibodies, SSc systemic sclerosis

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