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- PATIENTS AND METHODS
PM/DM-related ILD was initially described by Mills and Mathews in 1956 (27), and occurs in 5–64% of PM/DM patients (3, 6–12, 14, 24, 25, 28–31). Our retrospective study included 156 consecutive PM/DM patients without any prior selection based on clinical presentation, including pulmonary manifestations, which tends to be representative of the entire PM/DM population. Therefore, a selection bias based on the severity of the disease with overt or subclinical signs could be excluded. In the present series, we have also shown the high frequency (23.1%) of ILD in PM/DM patients.
ILD time of onset was variable in our patients, as previously mentioned (3, 7–10, 12, 14, 28–30, 32). In essence, with respect to the onset of symptoms of PM/DM and ILD, the majority of our patients experienced simultaneous occurrence of both conditions (41.7%), although ILD preceded (19.4%) or developed after (38.9%) PM/DM in other patients. Time of onset of ILD could not be considered as a predictive parameter of lung outcome.
In this instance, ILD often dominated the clinical course of PM/DM (75% of cases), masking the underlying muscle and skin manifestations (33). The clinical presenting characteristics of ILD in PM/DM patients were similar to those observed in idiopathic forms of ILD (10). Therefore, only a few patients had acute lung disease similar to the Hamman-Rich syndrome (16.7%), whereas other patients developed either a progressive or an asymptomatic pattern. Interestingly, we have further observed that patients with Hamman-Rich–like syndrome had significantly less favorable outcome of ILD than those with the progressive or asymptomatic forms (66.7% versus 14.3% versus 22.2%).
Different methods have been used for both initial assessment and followup of PM/DM patients with ILD. Our study confirms that both PFT and HRCT of the lungs are the methods of choice for diagnosis of ILD in PM/DM (9, 12, 14, 34, 35). PFT revealed restrictive changes with decreased DLCO in all patients. In particular, we have also noted that initial low values of DLCO (<45%), without underlying pulmonary arterial hypertension (at echocardiography), were associated with poor prognosis of ILD; among our 7 PM/DM patients with an initial DLCO of <45%, only 1 patient experienced ILD resolution.
HRCT scanning of the lungs was also a sensitive test, by accurately demonstrating evidence of ILD changes in all patients. These changes were localized predominantly in the pulmonary lower lobes, as reported by previous investigators (10, 12, 14, 18–20). In our PM/DM patients with ILD, linear opacities, irregularity of the interfaces, and ground-glass opacities were the more common HRCT abnormalities (50%–83%), whereas honeycombing (5%) and bronchiectases/bronchiolectases (16%) tended to be more rare. Another main finding in our series was that HRCT of the lungs provides data concerning ILD stage, because only patients with linear opacities, irregularity of the interfaces, or ground-glass opacities had clearing of lung radiographic abnormalities. These changes were related to both active and reversible stages of ILD, i.e., histologic NSIP and BOOP (10, 12, 14, 18–20). Our data confirm those of Mino et al (20) who noted in a series of 16 PM/DM patients that linear opacities, irregularity of the interfaces, and parenchymal opacities improved in 90% of cases at 23 months followup.
Only a few reports have included data about the BAL cell profiles in PM/DM patients with ILD (3, 5, 6, 11, 34, 36). As a guide to the severity and progress of alveolitis associated ILD, the significance of BAL differential cell count remains controversial in PM/DM (3, 6, 11, 36). In our experience, patients with ILD had poor outcome when the initial BAL showed neutrophil alveolitis. We have indeed observed that all patients with ILD deterioration exhibited neutrophil alveolitis. In turn, our findings suggest that BAL cell profiles may be a helpful prognostic indicator in PM/DM patients with ILD.
In addition, others have reported that histologic lung data are better indicators of survival than clinical or radiographic patterns in PM/DM patients with ILD (3, 8–12, 14, 24, 25, 32, 33, 35). Patients with BOOP (66%) appeared to have a more favorable course than those with UIP (40%) or diffuse alveolar damage (0%–25%) (9, 10, 12–14, 24, 25, 29, 30, 35). In our series, of the 11 PM/DM patients with ILD who underwent lung biopsies, 4 had NSIP, 5 had UIP, and 2 had BOOP; we have also observed a poorer course in patients with UIP compared with those with NSIP or BOOP.
To date, only few investigators have assessed long-term outcome of ILD in PM/DM patients, although ILD is still considered to have a high morbidity due to decreased functional pulmonary status (3, 5–14, 25, 28, 29, 34, 35, 37–40). In a recently reported series, survival of PM/DM patients with ILD was reported at 85.8%, 74.4%, and 60.4% at 1, 3 and 5 years, respectively (10). We have also observed roughly similar survival rates in ILD patients, i.e., 94.4%, 90.4%, and 86.5% at 1, 3 and 5 years, respectively. Moreover, our findings underscore that ILD is a negative risk factor for survival in PM/DM patients, after excluding paraneoplastic PM/DM. In this instance, we have also shown that ILD related to PM/DM is associated with a decrease of patients' functional status. Therefore, we have found that only 19.4% of PM/DM patients with ILD had resolution of pulmonary disorders; in contrast, 36.1% of PM/DM patients with ILD exhibited a marked reduction of activities due to ILD course, and 5 ILD patients further developed respiratory failure resulting in O2 dependency.
Finally, our retrospective study is, to our knowledge, the first to have investigated ILD outcome in PM/DM patients with anti–Jo-1 antibody. Our results demonstrate that ILD patients with anti–Jo-1 antibody less frequently developed an asymptomatic form of ILD compared with those without. Another relevant result was that no patient with anti–Jo-1 antibody developed ILD with histologic lung damage consistent with BOOP. Interestingly, we have also observed that patients with anti–Jo-1 antibody had similar ILD outcome, compared with those without, with respect to resolution, improvement, or deterioration of ILD and mortality rate related to ILD complications (18.2% versus 12%). Our findings suggest that patients with and without anti–Jo-1 antibody may require similar management and followup of ILD.
The specific therapy of ILD has not yet been clearly established in PM/DM patients. Corticosteroid therapy is considered the first-line therapy for PM/DM patients with ILD (3, 6–14, 24, 25, 28–30, 35, 39–41). Therapeutic response to steroids in patients with ILD depends on pulmonary histologic findings rather than clinical patterns (8–10, 12, 14, 24, 25, 28, 30, 34, 40, 41); in turn, BOOP and NSIP are considered to produce the highest steroid response forms (8–10, 12, 14, 24, 25, 28, 30, 34, 40, 41, 42). Our series has also shown an improved response to steroid therapy in patients with NSIP and BOOP compared with those with UIP, suggesting that early control of alveolitis may be required before it causes irreversible damage to the alveolar-capillary membrane.
Favorable outcome with immunosuppressive therapy in patients who failed to respond to steroids alone has been reported previously (3, 5, 8, 9, 10, 12, 14, 28, 34, 35, 39, 43–45), and cyclophosphamide may improve the 5-year survival rate in these patients (34). In this instance, cyclophosphamide was used in 10 of 36 PM/DM patients with ILD; half of the patients who received cyclophosphamide have either resolved (n = 3) or improved (n = 2) pulmonary status. Moreover, we have noted that cyclophosphamide was used at an earlier lung histologic stage in patients with improved pulmonary status. In our population, 8 patients with ILD were given azathioprine, resulting in improvement of lung impairment in 75% of cases. Our findings are in agreement with previously reported data (3, 10, 11, 46).
Cyclosporine may be an alternative therapy in patients with ILD resistant to high-dose steroids, alone or in combination with cytotoxic drugs, resulting in prolonged survival of patients (3, 9–12, 14, 28, 34, 35, 40, 47, 48). In our series, only 2 PM/DM patients with steroid-refractory ILD received cyclosporine, leading to improvement of lung parameters in 1.
From a practical point of view, the knowledge of predictive indicators associated with ILD in PM/DM patients appears crucial to improve management at an early stage of the disease. Previous authors have described numerous variables of ILD in PM/DM (3, 11). In the present series, neither age, sex, PM/DM, nor digestive features could be considered predictive factors in ILD, as described by other investigators (5, 7, 8, 13). Of the systemic manifestations of PM/DM, only arthralgia/arthritis were found to be associated with ILD, confirming that these may be predictive factors of ILD (5, 11, 13). Moreover, we failed to observe a relationship between malignancy and ILD; in turn, our findings do not corroborate the hypothesis of paraneoplastic forms of ILD in PM/DM (37).
In our experience, the prevalence of raised ESR and CRP levels was higher in PM/DM patients with ILD. Inflammatory anemia was also more commonly found in this subgroup of patients. The design of our study does not permit us to explain the reasons for these findings, although both inflammatory anemia and increased ESR and CRP could have been acute-phase reactants related to ILD. We have further noted that characteristic nailfold capillaroscopic microangiopathy is more frequent in patients with ILD; our findings suggest that the presence of capillaroscopic microangiopathy should encourage the investigation of ILD in PM/DM patients. If the relationship is confirmed, determination of microangiopathy may become an integral part of PM/DM evaluation for early detection of patients at risk for ILD.
In conclusion, our series highlights the high frequency of ILD in PM/DM patients, resulting in increased morbidity and mortality rates. Our findings also indicate that ILD should be routinely searched in all PM/DM patients, with or without anti–Jo-1 antibody, because frequency of ILD was as high as 73% in patients with anti–Jo-1 antibody and because 69% of patients with ILD were seronegative for anti–Jo-1 antibody. Our study further indicates that ILD assessment, including PFT and HRCT of the lungs, should be performed during both initial evaluation and followup of PM/DM patients. Finally, the following parameters could be considered as predictive of ILD poor outcome: Hamman-Rich–like pattern, initial DLCO of <45%, neutrophil alveolitis, and histologic UIP; the presence of these factors may suggest more aggressive therapy of PM/DM patients with ILD.