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Clinical signs associated with an increased risk of interstitial lung disease: a retrospective study of 101 patients with dermatomyositis

Year: 2016

Type: article

Abstract: Dear Editor, Pulmonary complications are common in dermatomyositis (DM) and contribute to significant morbidity and mortality.1,2,3 Patients with DM and antisynthethase,4 anti‐PM/Scl5 or anti‐MDA56 antibodies have specific signs (mechanic's hands in antisynthetase phenotype; skin and oral ulcers, arthritis and arthralgia, and alopecia in anti‐MDA5 phenotype; and sclerodermatous changes in anti‐PM/Scl phenotype) and an increased risk of interstitial lung disease (ILD). Screening patients with DM for these myositis‐specific antibodies (MSAs) can help to predict ILD and allow targeted intervention. However, antibody testing at this juncture is neither routinely available nor standardized, although this is likely to change in the near future. Identifying cutaneous features associated with ILD will be an ideal and cost‐effective way to target its screening. The aim of our study is to determine which of the above clinical signs are associated with an increased risk of ILD in our cohort of patients with adult‐onset DM. The second aim is to look for any significant association between the presence of MSAs at enrolment, clinical signs and ILD in our patient cohort. The University of Pennsylvania DM database prospectively enrols patients with DM who agree to participate at the department of dermatology. These patients are examined and their clinical data recorded by the principal author (V.P.W.) and her research team at baseline and during study visits. We performed a retrospective analysis of patients enrolled in this database from May 2008 to September 2013. We included patients with adult‐onset DM defined by a cutaneous histology consistent with DM and typical clinical features. We excluded patients with juvenile DM or overlap connective tissue disease, or those with missing data. Assignment to classic or clinically amyopathic DM was based on established criteria.7,8,9,10 We recorded the presence of six signs (Gottron papules, mechanic's hands, arthralgia or arthritis, skin ulceration over existing inflamed papules and plaques, oral ulceration and diffuse alopecia), demographic data, disease information, Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) score and the results of pulmonary investigations. Our patients underwent pulmonary function tests (PFTs) and high‐resolution chest computed tomography (HRCT) per published protocol.1 Serum samples were collected at enrolment if the patients consented to a blood draw. The presence of MSAs (anti‐MDA5, anti‐TIF1‐γ, antisynthetases, anti‐NXP‐2, anti‐SAE, anti‐SRP and anti‐Mi‐2) were identified with immunoprecipitation assays using extracts of the leukaemia cell line K562.4 11 The patients were divided into two outcome groups for analysis. The first group had ILD (diagnosed on HRCT and/or lung biopsy) or an isolated reduced lung diffusion capacity for carbon monoxide (DLCO, < 80% predicted) on PFTs in the absence of significant findings on HRCT (indicating possible subclinical ILD).1 The other group had either normal screening PFTs or non‐ILD pulmonary pathology. The study was approved by the University of Pennsylvania institutional review board and was performed in accordance with the Declaration of Helsinki. Prism 5.0 software (GraphPad Software, La Jolla, CA, U.S.A.) was used for data analysis. We had two null hypotheses: there was no difference in the demographic variables between the two comparison groups, and there was no association between the clinical signs described above and ILD. Fisher's exact test was used to compare the proportions of patients with different clinical variables and ILD status, and to calculate the odds of having ILD or an isolated reduced DLCO in relation to each clinical sign. The comparison of median variables in Table 1 was performed with the Mann–Whitney test. The level of statistical significance was set at 0·05. Demographic data of patients with isolated low lung diffusion capacity for carbon monoxide (DLCO) and interstitial lung disease (ILD) compared with those with pulmonary function testing and high‐resolution chest computed tomography not diagnostic of ILD Values are n (%) or median (range). DM, dermatomyositis; CDASI, Cutaneous Dermatomyositis Disease Area and Severity Index. Demographic data of patients with isolated low lung diffusion capacity for carbon monoxide (DLCO) and interstitial lung disease (ILD) compared with those with pulmonary function testing and high‐resolution chest computed tomography not diagnostic of ILD Values are n (%) or median (range). DM, dermatomyositis; CDASI, Cutaneous Dermatomyositis Disease Area and Severity Index. In total, 101 patients from our database of 126 patients were included in the analysis. Fifty‐three patients (52%) had classic DM while 48 patients (48%) had clinically amyopathic DM. Thirty‐eight patients (38%) had an isolated low DLCO (19 patients), or ILD on HRCT and/or lung biopsy (19 patients). Sixty‐three patients (62%) had either normal screening PFTs (42 patients) or other pulmonary pathologies (21 patients). There was no statistically significant difference detected for the different demographic data between those with isolated low DLCO or ILD vs. the non‐ILD group, except for race. There was a higher proportion of white patients in the non‐ILD group than in the ILD and isolated low DLCO group (98% vs. 87%, P = 0·03) (Table 1). Twenty‐eight of 38 (74%) patients with all subtypes of DM and an isolated low DLCO or ILD had mechanic's hands, compared with 29 of 63 (46%) patients in the non‐ILD group (Table 2). The presence of mechanic's hands conferred a statistically significant odds ratio of 3·28 [95% confidence interval (CI) 1·37–7·88] of having an isolated low DLCO or ILD (P = 0·01) compared with those without mechanic's hands. Conversely, the presence of Gottron papules conferred a protective effect, with a statistically significant odds ratio of 0·36 (95% CI 0·14–0·94) of having an isolated low DLCO or ILD (P = 0·05) compared with those without Gottron papules. All the other clinical signs were not statistically associated with having an isolated low DLCO or ILD (Table 2). Comparison of the association between the different clinical signs of dermatomyositis (DM) and interstitial lung disease (ILD) status in patients with DM (n = 101) DLCO, lung diffusion capacity for carbon monoxide. aValues are n (%). Comparison of the association between the different clinical signs of dermatomyositis (DM) and interstitial lung disease (ILD) status in patients with DM (n = 101) DLCO, lung diffusion capacity for carbon monoxide. aValues are n (%). When we recomputed the statistics looking at 19 patients with established ILD vs. 82 patients in the non‐ILD group (normal screening PFT, other lung pathology, isolated low DLCO), the odds ratio for having ILD in those with mechanic's hands was 2·54 (95% CI 0·84–7·70, P = 0·13), and with Gottron papules 0·42 (95% CI 0·14–1·22, P = 0·13). Serum samples from 43 patients who consented to the blood draw were analysed. We found no detectable MSAs in 21 patients, anti‐TIF1‐γ antibody in 17 patients, anti‐MDA5 antibody in three patients, anti‐Jo‐1 antibody in one patient and anti‐OJ antibody in one patient. All of the subjects with anti‐MDA5, anti‐Jo‐1 and anti‐OJ antibodies had frank ILD. Three of 17 subjects (18%) with anti‐TIF1‐γ antibodies had ever had a malignancy. Both patients with antisynthetase (anti‐Jo‐1 and anti‐OJ) antibodies had arthritis and arthralgias. These associations were as expected for the respective MSA‐associated phenotypes, although the prevalence of malignancy in patients with anti‐TIF1‐γ antibodies seemed lower than expected. Twenty six of the 43 subjects had mechanic's hands at enrolment. Of these, all of the patients with detectable anti‐MDA5 antibodies had mechanic's hands, while 12 of 17 (71%) and 11 of 21 (52%) subjects with anti‐TIF1‐γ antibodies or no detectable antibodies had mechanic's hands, respectively. The two patients with anti‐Jo‐1 and anti‐OJ antibodies did not have mechanic's hands. In the large study of 166 Japanese patients with antisynthetase antibodies,4 mechanic's hands were present in a varying proportion of patients in the antibody subgroups, and were seen in up to 56% of their cohort with anti‐Jo‐1 antibodies. In our cohort of patients, mechanic's hands were also seen in patients with anti‐TIF1‐γ and anti‐MDA5 antibodies, as well as in those with no detectable antibodies. This suggests that mechanic's hands are a risk factor for ILD, regardless of the type of MSAs present. Thirteen of the 43 patients had both mechanic's hands and lung involvement (isolated low DLCO or ILD). There were no statistically significant associations between the presence of anti‐TIF1‐γ antibodies and cancer, mechanic's hands or the presence of isolated low DLCO/frank ILD (data not shown) in the 43 patients, although this was not generalizable to the entire cohort due to the low numbers analysed. There are several limitations to our study. We have a greater proportion of white patients in the non‐ILD group than in the isolated low DLCO/ILD group, which may influence the results. Our results are not representative of nonwhite patients. There is a potential for selection bias as we included only patients who agreed to be in the database, instead of all patients with DM seen in the clinic, although < 10% of patients refused to participate. Allocation bias may be introduced by placing the patients with isolated low DLCO (indicating possible subclinical ILD) into the ILD group for further analysis. When only frank ILD was compared with the rest of the study population, the association found between Gottron papules or mechanic's hands and frank ILD became statistically insignificant, probably from lack of statistical power. We attempted to reduce the potential for information bias by using a validated scoring system (CDASI) and having two assessors (V.P.W. and another study author) during each study visit. In conclusion, defining DM subsets using MSAs is appealing but is limited by the variable association between serotype and phenotype, differing sensitivity and specificity, limited access, and cost of the assays. We look forward to scientific advances that will address the above limitations. Until then, we recommend screening patients with DM for ILD, especially if mechanic's hands are present. We would like to thank Dr Kathleen Propert and Ms Carmen Kam for their assistance with the statistical analysis. Funding sources: this work was supported by the Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development) to V.P.W., NIH 1R21AR066286 and NIH K24‐AR 02207. Conflicts of interest: none declared.

Source: British Journal of Dermatology

DOI: 10.1111/bjd.14801