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Interstitial lung disease (ILD), which often develops in systemic sclerosis (SSc), is associated with a better prognosis than idiopathic usual interstitial pneumonia (UIP) because only a limited number of patients with SSc progress to end stage fibrosis.1,2 Mechanisms driving the fibrotic evolution of ILD are still poorly understood, but, recently, on the basis of animal models, a pathogenetic role has been ascribed to an imbalance in the local Th1/Th2 response, with an expansion of the Th2 profile.3
METHODS AND RESULTS
We studied the cytokine profile of bronchoalveolar lavage fluid (BALF) of 28 patients with SSc-ILD (6 men, 22 women; mean (SD) age 50.3 (8.9) years). All patients with SSc satisfied the preliminary American College of Rheumatology (ACR) criteria for classification of the disease,4 and respiratory disease was defined on the basis of functional tests and high resolution computed tomography findings as at least grade 1 severity, according to the disease severity scale for SSc.5 Seven (25%) patients with SSc had limited and 21 (75%) diffuse disease. All were positive for antinuclear antibodies; 18 for anti-topoisomerase I, and one for anti-RNA polymerase I and III. Results were compared with those obtained in 13 patients with UIP (10 men, three women; mean (SD) age 56 (16.8) years; all newly diagnosed, previously untreated patients); and nine normal controls (seven men, two women, mean (SD) age 42.7 (12.1) years).
The following cytokines were assessed on concentrated (by ultrafiltration) BALF: two proinflammatory chemokines interleukin (IL)8 and monocyte chemotactic protein-1 (MCP-1), two Th1 related factors IL12 and IL18, and one anti-inflammatory Th2 related cytokine IL10. Data, expressed as medians (25th–75th centile) were analysed with the Mann-Whitney U test (Kolmogornov-Smirnov test, p⩽0.05).
Table 1 shows that BALF levels of IL8 were increased in patients with SSc-ILD and UIP in comparison with controls (p = 0.05 and p = 0.004). In addition, a trend towards an increase of IL8 levels in UIP compared with SSc-ILD was found (p = 0.07). Levels of MCP-1 were markedly and significantly raised only in patients with UIP in comparison with both SSc-ILD and controls (fig 1). For the Th1 related cytokines, IL18 values did not differ significantly among the groups (table 1), but higher levels were detected in control BALFs. These findings suggest a relatively high constitutional release of IL18 in physiological conditions. On the contrary, IL12 was almost undetectable in BALF from controls, but it was markedly increased in patients with SSc-ILD (p = 0.0008) (fig 1). Moreover, IL10 levels were higher in SSc-ILD than in controls (p = 0.02; table 1). Finally, no differences in the BALF cytokine levels were seen among patients with SSc-ILD according to their clinical or serological subset (p>0.05).
Data presented here suggest the presence of a different BALF cytokine profile in SSc-ILD than in UIP. In particular, we found that patients with SSc-ILD had increased levels of IL12, a cytokine shown to attenuate bleomycin induced lung fibrosis in rats.6,7 This might suggest a protective activity of IL12 with respect to the fibrotic evolution in SSc-ILD. In addition, we found that MCP-1 was significantly raised in UIP BALF but only slightly increased in SSc-ILD. Moreover, MCP-1 BALF levels correlated significantly (p = 0.004) with BALF eosinophil counts that are known to be a prognostic factor in SSc-ILD. In fact, MCP-1 has been shown to provoke chronic fibrogenic lung inflammation in animal models of lung fibrosis induced by bleomycin, radiation, or FITC.8–10 Finally, levels of the anti-inflammatory IL10 were higher in SSc-ILD than in controls.
In conclusion, the BALF cytokine profile in SSc-ILD seems to express a more favourable balance between fibrotic (MCP-1) and anti-fibrotic or anti-inflammatory factors (IL12 and IL10) than that in UIP, and this may account for the better prognosis of interstitial damage associated with SSc. Further longitudinal studies are necessary to confirm whether a different cytokine phenotype might be considered predictive of clinical outcome.
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