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Pulmonary impairment, not muscle injury, is associated with elevated ESR in the idiopathic inflammatory myopathies.

Sir, Despite the presence of systemic inflammation with muscular and extramuscular disease manifestations, the ESR is elevated in only about half the patients with DM and PM [1, 2]. Interstitial lung disease (ILD), an extramuscular manifestation of DM and PM, is common, with a reported prevalence of 40–65% [3, 4]. It is especially high among the idiopathic inflammatory myopathy (IIM) subgroup with antisynthetase autoantibodies, which can manifest with a severe form of ILD and increased mortality. Given that the lung is an extramuscular target of immune-mediated injury in IIM, we hypothesized that ESR elevation is associated with ILD. 
 
In the present report, 48 patients with IIM according to the Bohan and Peter criteria, without overlapping rheumatic diseases [5, 6], evaluated at the Johns Hopkins Myositis Center between March 2007 and April 2009, were analysed. The presence of ILD was confirmed by typical high-resolution CT evidence and pulmonary function testing [7]. Mann–Whitney and χ2 tests were used for comparison between groups of continuous and categorical variables, respectively. Spearman correlation was performed to examine the association between ESR and the duration of ILD, or creatine phosphokinase (CPK) and aldolase. 
 
Mean age of patients was 48.3 ± 1.6 years, with the majority being Caucasian (63%) and female (81%). Mean disease duration from diagnosis of IIM to evaluation at our centre was 19.9 ± 3.1 months. There were 21 (44%) patients with and 27 (56%) without ILD. Age, gender and race did not differ between these groups. Notably, 9 (43%) were newly diagnosed with ILD while 12 (57%) had established ILD at their first centre visit. The mean haematocrit level was 40.5 ± 0.6%. Antisynthetase antibodies were present in 14 (67%) of 21 ILD patients and uniformly absent in the non-ILD group. Anti-Jo-1 was most common, present in 9 (69%) of the 14 patients, followed by 3 with anti-PL-12 (23%) and 1 each with anti-PL-7 and anti-EJ. Malignancy was present in 5 (10%) of the 48 IIM patients and distributed as follows: 4/28 (14.3%) ILD-negative and 1/21 (4.3%) ILD-positive patients had a malignancy (P = 0.38). The prevalence of inflammatory arthritis and RP did not differ between the ILD and non-ILD groups, but mechanic’s hands were more common in the ILD group (33% vs 7%, P = 0.022). Mean levels of CPK (normal range 24–170 U/l) and aldolase (normal ≤8.1 U/l) did not differ between the non-ILD and the ILD group (1100 ± 2650 vs 1740 ± 3281 U/l, P = 0.83 and 17.5 ± 22.5 vs 26.6 ± 37.3 U/l, P = 0.68, respectively). 
 
In contrast, mean ESR was significantly higher in the ILD group (42 ± 38 vs 17 ± 16 mm/h, P = 0.027) (Fig. 1A); however, there was no correlation between ILD duration and ESR. The six outliers in the ILD group with the highest ESR were older (54.8 ± 8.0 vs 46.1 ± 9.4 years, P = 0.06), African American (83.3% vs 26.7%, P = 0.046), female (100% vs 66.7%, P = 0.26), with lower haematocrit (35.0 + 1.3 vs 41.6 + 2.87, P = 0.001) and lower forced vital capacity (FVC) (55.3 + 13.7 vs 70.9 + 14.7, P = 0.038). As antisynthetase antibodies can be associated with severe lung disease, the ILD group was further divided into the antisynthetase-negative (n = 7) and antisynthetase-positive ILD groups (n = 14). As expected, ESR was significantly higher in the antisynthetase-positive ILD group (50 ± 41 vs 17 ± 16 mm/h, P = 0.029), whereas there was no difference between the antisynthetase-negative ILD group and the non-ILD group (Fig.1B), suggesting that the ESR elevation in ILD is driven by the antisynthetase-positive group. Strikingly, ESR levels did not correlate with the extent of muscle injury as CPK or aldolase levels (Fig. 1C and D). 
 
 
 
Fig. 1 
 
Elevated ESR in ILD (A, B) and dissociation between ESR and CPK and aldolase (C, D). 
 
 
 
The daily prednisone dose did not differ between the non-ILD and antisynthetase-positive ILD group (23 ± 21 vs 16 ± 15 mg/day, P = 0.37). Further, 17 (63%) of the 27 non-ILD, 3 (43%) of 7 antisynthetase-negative ILD and 9 (64%) of 14 patients with antisynthetase-positive ILD were on other immunosuppressive medications. 
 
Consequently, we herein demonstrate that ESR elevation is associated with the concurrent presence of ILD and does not reflect the biochemical measurement of muscle inflammation in IIM. Patients with active DM and PM demonstrate the type I IFN signature in blood, which in turn suppresses production of acute phase reactants in the liver [8, 9]. However, the lung, as an extramuscular site of inflammation, may override this suppression via additional cytokine production. Indeed, after processing by immune cells, Jo-1 synthetase can become immunogenic in lungs, but not muscles, to mount an immune response [10]. 
 
In conclusion, we demonstrate that ESR elevation, an acute phase reactant, is significantly associated with the presence of ILD and does not correlate with conventional measures of muscle inflammation. Thus ESR should be strongly considered as a routine laboratory marker in clinical care of DM/PM. Its elevation should prompt physicians to carefully screen for lung disease. 
 
 
 
Rheumatology key message 
 
 
 
 
 
ESR elevation should prompt physicians to carefully screen for lung disease in patients with myositis. 
 
 
 
 
 
 
 
 
Funding: This work was supported by NIH grant K23-AR-053197 (to L.C.-S.) and the Huayi and Siuling Zhang Discovery Fund. 
 
Disclosure statement: The authors have declared no conflicts of interest.