Interstitial lung disease in classic and clinically amyopathic dermatomyositis: a retrospective study with screening recommendations

Abstract

Objectives

(1) Determine the prevalence of interstitial lung disease and isolated low diffusing capacity for carbon monoxide (DLCO) in a large cohort of dermatomyositis outpatients. (2) Compare the pulmonary abnormalities of classic dermatomyositis (CDM) and clinically amyopathic dermatomyositis (CADM) patients.

Design

Retrospective cohort study.

Setting

University hospital outpatient dermatology referral center.

Patients

Records of 91 outpatients with adult-onset dermatomyositis seen between May 26, 2006 and May 25, 2009 were reviewed.

Main Outcome Measures

Presence of interstitial lung disease on thin slice chest computed tomography (CT) scans and DLCO.

Results

Of the 71 dermatomyositis patients who had CT or DLCO data, 23% (16/71, 95% confidence interval [CI] = 13–33%) had interstitial lung disease as defined by CT results. All interstitial lung disease patients had a reduced DLCO, and the interstitial lung disease prevalence was not different between CADM (29% [10/35]) and CDM (17% [6/36]) patients (p=0.27). Twenty-five percent (18/71, 95% CI = 15–36%) of patients (20% [7/35], CADM; 31% [11/36], CDM; p=0.41), had an isolated low DLCO in the absence of CT findings showing interstitial lung disease.

Conclusions

Established interstitial lung disease and isolated reductions in DLCO, which may signify early interstitial lung disease or pulmonary hypertension, are very common in both classic and clinically amyopathic dermatomyositis dermatology outpatients. As the DLCO is an inexpensive test that is sensitive for pulmonary disease, it may be appropriate to screen all dermatomyositis patients with serial DLCO measurements and base further testing on DLCO results.

Interstitial lung disease (ILD) is commonly associated with both classic dermatomyositis (cutaneous manifestations and symptomatic muscle disease) and clinically amyopathic dermatomyositis (cutaneous manifestations without symptomatic muscle disease) in adults.¹ Although ILD associated with either type of dermatomyositis can be asymptomatic or slowly progressive, the lung disease can also be debilitating or even rapidly fatal.^2–9 Interstitial lung disease associated with connective tissue disease may be responsive to immunosuppressive therapies such as corticosteroids, cyclophosphamide, azathioprine, and mycophenolate mofetil,^10–14 and it is vital that physicians discover the disease early to allow for treatment before irreversible fibrosis occurs.

Although many physicians are aware of the association between dermatomyositis and ILD, screening practices are highly variable. Pulmonary function tests (PFTs) are frequently the first line screening modality, but physicians may be uncertain about how to interpret results, when to repeat PFTs, when to obtain a chest computed tomography (CT), and when to refer patients to pulmonary specialists for further care.

Developing screening guidelines based on the available literature is problematic for several reasons. Most of the existing studies fail to address the dermatomyositis population with negative radiologic imaging but pulmonary function testing abnormalities that may be indicative of early ILD or pulmonary hypertension, such as a low diffusing capacity for carbon monoxide (DLCO) with or without restrictive impairment (low total lung capacity). Prior studies also frequently lack longitudinal documentation of the outcome of patients with normal or borderline low DLCO on initial testing. In addition, clinically amyopathic dermatomyositis patients have been excluded from numerous studies^{3, 7, 12, 15–17} because many investigators utilize a definition of dermatomyositis developed by Bohan and Peter,^{18, 19} which requires the presence of muscle disease.

The primary purpose of this retrospective study was to examine the prevalence and course of ILD and isolated low DLCO in a large cohort of dermatomyositis outpatients and to propose preliminary pulmonary screening and initial management guidelines for these patients. A secondary goal was to compare the pulmonary abnormalities of classic dermatomyositis and clinically amyopathic dermatomyositis patients, as previous reports have suggested that ILD may be more common and more severe in the clinically amyopathic dermatomyositis subset.^{9, 20}

PATIENTS AND METHODS

We performed a retrospective chart review at our outpatient dermatology clinic, a tertiary referral center at the Hospital of the University of Pennsylvania. All patients in this study were seen in the referral practice of the primary investigator (VPW). This practice has extensive experience with the cutaneous manifestations of dermatomyositis, which is important because dermatomyositis (especially clinically amyopathic dermatomyositis) is a clinical diagnosis that can be difficult to make, especially in patients with subtle or atypical cutaneous findings. Our institutional review board approved the study protocol and waived the requirement for consent of subjects.

Patients seen in our clinic between the dates of May 26, 2006 and May 25, 2009 with a primary diagnosis of dermatomyositis were identified by the International Classification of Diseases 9th Revision (ICD-9) code 710.3, and their clinic charts were retrospectively reviewed. When relevant new data became available during the course of data collection, these prospective data were also included in the review. Patients meeting any of the following criteria were excluded: juvenile dermatomyositis (defined as symptom onset before 18 years of age), the diagnosis of dermatomyositis was clinically uncertain as indicated in clinic notes from the patient’s latest date of follow-up by dermatology, the patient had chronic lung disease that would complicate the diagnosis of ILD, or the patient was miscoded as dermatomyositis.

Dermatomyositis classifications

Patients were categorized either as classic dermatomyositis (CDM) or clinically amyopathic dermatomyositis (CADM). CADM patients were subclassified as hypomyopathic dermatomyositis (HDM), amyopathic dermatomyositis (ADM), premyopathic dermatomyositis (PRMDM), treated amyopathic dermatomyositis (TADM), or treated hypomyopathic dermatomyositis (THDM). See Table 1 for full definitions of the dermatomyositis categories.

TABLE 1.

Definitions of dermatomyositis (DM) categories

Dermatomyositis category	Criteria
Classic dermatomyositis (CDM)	Hallmark cutaneous manifestations of DM Clinically significant muscle weakness Objective evidence of myositis (elevated serum muscle enzymes or abnormal electromyography or magnetic resonance imaging of muscles)
Clinically amyopathic dermatomyositis (CADM)	A category to capture patients whose skin disease is the only clinically significant manifestation of their disease. This includes ADM, HDM, TADM, THDM, and PRMDM patients.
Amyopathic dermatomyositis (ADM)	Hallmark cutaneous manifestations of DM lasting at least six months No objective evidence of myositis Not treated with systemic immunosuppressants for greater than two consecutive months during the first six months after rash onset
Hypomyopathic dermatomyositis (HDM)	Hallmark cutaneous manifestations of DM lasting at least six months No clinically significant muscle weakness Objective evidence of myositis (elevated serum muscle enzymes or abnormal electromyography or magnetic resonance imaging of muscles)
Treated amyopathic dermatomyositis (TADM)	Treated with systemic immunosuppressants for greater than two consecutive months during the first six months after rash onset Otherwise meets ADM criteria
Treated hypomyopathic dermatomyositis (THDM)	Treated with systemic immunosuppressants for greater than two consecutive months during the first six months after rash onset Otherwise meets HDM criteria
Premyopathic dermatomyositis (PRMDM)	Preliminary category for patients with the hallmark cutaneous manifestations of DM lasting less than six months who do not meet criteria for CDM

With the exception of TADM and THDM, these categories were derived from the previous literature.⁴ The new TADM and THDM classifications were created to encompass patients who were treated with systemic immunosuppressants for more than two consecutive months in the first six months after disease onset and never developed muscle symptoms. Patients presenting with lung disease (or recalcitrant skin disease) early in their disease course often receive long-term systemic immunosuppressants, and automatically classifying these patients as CDM may prevent accurate characterization of the dermatomyositis population without muscle symptoms.

Pulmonary function testing

Results of all available pulmonary function tests (PFTs) with diffusing capacity for carbon monoxide (DLCO) were recorded. DLCO values were not corrected for hemoglobin. Restrictive impairment was defined as total lung capacity (TLC) less than 80% predicted. If TLC was not available, forced vital capacity (FVC) less than 80% predicted and forced expiratory volume in one second divided by FVC greater than 80% was classified as restrictive impairment (only one patient was classified as having restrictive impairment using this criterion). When comparing serial DLCO and TLC values, improvement was defined as a 15% increase in DLCO and 10% increase in TLC as suggested in the American Thoracic Society’s international consensus statement on idiopathic pulmonary fibrosis.²¹

Chest computed tomography

Radiologist or pulmonologist reports of all thin slice (less than or equal to 3mm slices or specified as high resolution or pulmonary embolism protocol) computed tomography (CT) scans of the chest were recorded. Chest CT scans obtained for malignancy evaluation which used slices greater than 3mm were not considered sufficient to rule out the presence of early ILD and were not included in the data analysis.

Interstitial lung disease categories

We combined the data obtained from DLCO testing and thin section chest CTs to place patients into one of the following categories: (1) ILD, defined by compatible chest CT findings (regardless of DLCO); (2) lung diffusion abnormality of uncertain significance, defined by lowest DLCO below 80% predicted in the absence of chest CT findings compatible with ILD (including patients who never got a CT), and (3) no evidence of ILD, including patients with at least one normal lung test (DLCO, CT, or both) and no abnormal tests. Patients were subclassified based on the presence or absence of restrictive impairment on PFTs.

Statistical analysis

Statistics were calculated using SAS version 9.1 (SAS Institute, Cary, NC). p<0.05 was considered significant, and Fisher’s exact tests were 2-tailed. To compare the patient characteristics of the CADM and CDM groups, Fisher’s exact test was used for categorical variables, and t-tests were used for continuous variables. Ninety-five percent confidence intervals (CIs) were calculated for the prevalence of each lung disease category, and Fisher’s exact test was used to compare the prevalence of the lung disease categories in the CADM and CDM groups. Fisher’s exact test was also used to compare: (1) the prevalence of ILD in each initial DLCO group, (2) the percent of patients with male gender and overlap connective tissue disease in the ILD category versus the other lung disease categories, and (3) the percent of patients with individual skin findings in each lung disease category. Analysis of variance (General Linear Models) was used to compare the mean number of skin findings per patient in each lung disease category.

RESULTS

Patient population

From the 123 patients identified by the ICD-9 code 710.3, 32 were excluded for the following reasons: juvenile dermatomyositis (eight), uncertain diagnosis of dermatomyositis (eight), medical records could not be located (seven), miscoded (six), sarcoidosis (two), and pulmonary Langerhans cell histiocytosis (one). The remaining 91 patients were included in this study.

Seven patients (three CADM, four CDM) had overlap with other connective tissue diseases, including diffuse systemic sclerosis, limited systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. Antinuclear antibodies (considered positive if titer >1:160 or report specified positive but gave no titer) were common, occurring in 51% (21/41) of patients, with no difference between CADM and CDM (p=0.12). Anti-histidyl–transfer RNA synthetase (Jo-1) antibodies were negative in all 50 patients (26 CADM, 24 CDM) who were tested.

Table 2 details the other clinical and laboratory characteristics of the patient population. Aside from data pertaining to the assessment and treatment of muscle disease, the only significant difference between the CADM and CDM patients was a higher rate of malignancy in the CDM group (p=0.02). CDM patients had a 6% (3/47) prevalence of non-melanoma skin cancer and a 13% (6/47) prevalence of other malignancies, whereas only 2% (1/44) of CADM patients had a non-melanoma skin cancer, and no CADM patients had other malignancies.

TABLE 2.

Patient characteristics

		CDM (n=47)	CADM (n=44)	ADM (n=21)	HDM (n=9)	PRM- DM (n=1)	TADM (n=10)	THDM (n=3)	P-Value (CADM vs CDM)
Female	No. (%)	44 (94)	39 (89)	18 (86)	9 (100)	1 (100)	8 (80)	3 (100)	0.48
Male		3 (6)	5 (11)	3 (14)	0 (0)	0 (0)	2 (20)	0 (0)
White	No. (%)	42 (89)	41 (93)	20 (95)	9 (100)	1 (100)	8 (80)	3 (100)	0.44
Black		5 (11)	2 (5)	1 (5)	0 (0)	0 (0)	1 (10)	0 (0)
Other		0 (0)	1 (2)	0 (0)	0 (0)	0 (0)	1 (10)	0 (0)
Height (in), mean (SD)		65 (3)	65 (4)	65 (3)	65 (3)	NA	66 (3)	65 (4)	0.86
Weight (lbs), mean (SD)		171 (47)	163 (45)	153 (34)	133 (27)	NA	195 (58)	196 (32)	0.45
Age at DM diagnosis (years), mean (SD)		48 (12)	51 (14)	48 (14)	59 (15)	45	48 (11)	57 (4)	0.26
Smoking status	No. (%)
Current		4 (9)	6 (14)	1 (5)	2 (22)	1 (100)	2 (20)	0 (0)	0.72
Past		11 (23)	11 (25)	4 (19)	1 (11)	0 (0)	5 (50)	1 (33)
Past/Never1		20 (43)	14 (32)	9 (43)	4 (44)	0 (0)	1 (10)	0 (0)
Never		12 (26)	13 (30)	7 (33)	2 (22)	0 (0)	2 (20)	2 (67)
Malignancy2	No. (%)
Yes3		6 (13)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0.02
Non-melanoma skin cancer		3 (6)	1 (2)	1 (5)	0 (0)	0 (0)	0 (0)	0 (0)
No		38 (81)	43 (98)	20 (95)	9 (100)	1 (100)	10 (100)	3 (100)
Medications used	No. (%)
1. Corticosteroids		47 (100)	30 (68)	11 (52)	6 (67)	0 (0)	10 (100)	3 (100)	<0.001
2. Antimalarials		41 (87)	40 (91)	20 (95)	9 (100)	1 (100)	7 (70)	3 (100)	0.74
3. Non-steroidal immune modulators4		41(87)	32 (73)	12 (57)	8 (89)	0 (0)	9 (90)	3 (100)	0.11
Highest serum CK5 (U/l), mean (SD)		2745 (5034)	612 (679)	NA	380 (321)	NA	NA	2000 (NA)	0.02
MRI	No./Total
C/w DM (%)		6/14 (43)	2/8 (25)	0/3 (0)	1/1 (100)	0/0 (0)	0/3 (0)	1/1 (100)	0.65
Not c/w DM		8/14 (57)	6/8 (75)	3/3 (100)	0/1 (0)	0/0 (0)	3/3 (100)	0/1 (0)
EMG	No./Total (%)
C/w DM		24/28 (86)	3/17 (18)	0/8 (0)	3/6 (50)	0/0 (0)	0/2 (0)	0/1 (0)	<0.001
Non-specific abnormality		1/28 (4)	3/17 (18)	0/8 (0)	2/6 (33)	0/0 (0)	0/2 (0)	1/1 (100)
Not c/w DM		3/28 (11)	11/17 (65)	8/8 (100)	1/6 (17)	0/0 (0)	2/2 (100)	0/1 (0)
Muscle biopsy abnormal	No./Total (%)	11/16 (69)	1/2 (50)	0/0 (0)	1/1 (100)	0/0 (0)	0/0 (0)	0/1 (0)	>0.99
Skin biopsy findings	No./Total (%)
1. Interface dermatitis		25/30 (83)	24/28 (86)	10/11 (91)	6/7 (86)	NA	6/7 (86)	2/3 (67)	>0.99
2. Increased mucin		14/30 (47)	10/28 (36)	5/11 (45)	3/7 (43)	NA	1/7 (14)	1/3 (33)	0.44
3. Superficial perivascular infiltrate		22/30 (73)	13/28 (47)	5/11 (45)	4/7 (57)	NA	3/7 (43)	1/3 (33)	0.06

CK=creatine kinase, MRI=magnetic resonance imaging, EMG=electromyography. See Table 1 for definitions of CDM, CADM, ADM, HDM, PRMDM, TADM, and THDM.

¹Chart did not specify whether patient was a past smoker or never smoked.

²During the year before to five years after dermatomyositis symptom onset or during a dermatomyositis relapse.

³Not including non-melanoma skin cancer. Cancer types: 4 breast, 1 colon, 1 non-Hodgkin lymphoma.

⁴Methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, tacrolimus, cyclosporine, rituximab, infliximab, etanercept, adalimumab, thalidomide, intravenous immune globulin, interferons.

⁵Includes only patients with CK above the upper limit of normal per laboratory report.

Interstitial lung disease and pulmonary diffusion abnormalities

Out of the 91 patients reviewed, 71 had DLCO results, thin section chest CT results, or both. These patients were divided into lung disease categories as shown in Figure 1.

Figure 1. Lung disease categories.

JDM=juvenile dermatomyositis, ILD=interstitial lung disease, DLCO=diffusing capacity for carbon monoxide, CT=computed tomography (thin section).

Sixteen of these 71 patients (23%, 95% CI = 13–33%) were considered to have ILD based on thin section CT results (14 were definitely compatible with ILD, and two were possibly compatible with ILD per radiologist or pulmonologist read). The prevalence of ILD was higher in CADM (29% [10/35], 95% CI = 13–44%) than CDM (17% [6/36], 95% CI = 4–30%), but the difference did not reach statistical significance (p=0.27). All of the patients with CT scans compatible with ILD had a reduced lowest DLCO (mean 47% predicted, standard deviation [SD] 12, range 24–66%), and 69% (11/16) had restrictive impairment on PFTs at the time of their lowest DLCO value.

Patients with at least one normal lung test (DLCO, thin section CT, or both) and no abnormal tests were considered to have no evidence of ILD. Fifty-two percent of patients ([37/71], 95% CI = 40–64%) fell into this category, with no difference between the CADM (51% [18/35], 95% CI = 34–69%) and CDM (53% [19/36], 95% CI = 36–70%) groups (p>0.99). Only one patient in this category had restrictive impairment on PFTs, and the restriction in this patient was likely extrinsic given the patient’s morbid obesity (BMI of 53.2). This patient was also a CDM patient, and because maximal inspiratory and expiratory pressures were not performed, respiratory muscle weakness could not be ruled out as a contributing factor to the restrictive impairment seen on PFTs.

Twenty-five percent (18/71, 95% CI = 15–36%) of patients fit into a middle category of patients with lung diffusion abnormality of uncertain clinical significance. There was no difference between the percentage of CADM (20% [7/35], 95% CI = 6–34%) and CDM (31% [11/36], 95% CI = 15–46%) patients falling into this category (p=0.41). These patients had reduced DLCO (mean 66% predicted, SD 11, range 40–79%) in the absence of any findings of ILD on CT, which may represent an early stage of ILD or pulmonary hypertension. Only 11% (2/18) of these patients had restrictive impairment on PFTs at the time of their lowest DLCO. See Table 3 for detailed categorizations of ILD and pulmonary function abnormalities in CADM and CDM patients.

TABLE 3.

Lung disease categories, limited to 71 patients who had DLCO, thin section CT, or both

	Interstitial lung disease			Lung diffusion abnormality of uncertain significance				No evidence of lung disease
	CT: ILD	CT: ILD	CT: possible ILD	CT: no ILD	CT: none	CT: no ILD	CT: none	CT: no ILD	CT: none	CT: no ILD
	PFTs: low DLCO and restriction	PFTs: low DLCO, no restriction	PFTs: low DLCO, no restriction	PFTs: low DLCO and restriction	PFTs: low DLCO and restriction	PFTs: low DLCO, no restriction	PFTs: low DLCO, no restriction	PFTs: normal DLCO, no restriction	PFTs: normal DLCO, no restriction except as noted	PFTs: no DLCO done
Total	11/71 (15)	3/71 (4)	2/71 (3)	1/71 (1)	1/71 (1)	12/71 (17)	4/71 (6)	8/71 (11)	25/71 (35)	4/71 (6)
CDM	4/36 (11)	1/36 (3)	1/36 (3)	1/36 (3)	1/36 (3)	8/36 (22)	1/36 (3)	3/36 (8)	14/361 (39)	2/36 (6)
CADM	7/35 (20)	2/35 (6)	1/35 (3)	0/35 (0)	0/35 (0)	4/35 (11)	3/35 (9)	5/35 (14)	11/35 (31)	2/35 (6)
ADM	1/17 (6)	1/17 (6)	1/17 (6)	0/17 (0)	0/17 (0)	1/17 (6)	1/17 (6)	4/17 (24)	8/17 (47)	0/17 (0)
HDM	1/6 (17)	0/6 (0)	0/6 (0)	0/6 (0)	0/6 (0)	1/6 (17)	0/6 (0)	1/6 (17)	2/6 (33)	1/6 (17)
TADM	4/9 (44)	1/9 (11)	0/9 (0)	0/9 (0)	0/9 (0)	2/92 (22)	0/9 (0)	0/9 (0)	1/9 (11)	1/9 (11)
THDM	1/3 (33)	0/3 (0)	0/3 (0)	0/3 (0)	0/3 (0)	0/3 (0)	2/3 (67)	0/3 (0)	0/3 (0)	0/3 (0)

All values expressed as No./Total (%). There was no significant difference in lung disease category (interstitial lung disease, lung diffusion abnormality of uncertain significance, no evidence of lung disease) between CADM and CDM patients (p=0.38).

CT=computed tomography, ILD=interstitial lung disease, PFTs=pulmonary function tests, DLCO=diffusing capacity for carbon monoxide. See Table 1 for definitions of CDM, CADM, ADM, HDM, TADM, and THDM.

¹One of these patients had restrictive impairment (total lung capacity 75%), but this was considered to be more consistent with extrinsic restriction (see text).

²One of these patients had no lung volumes, forced vital capacity (FVC) of 79%, and forced expiratory volume in one second divided by FVC of 78%, so mild restrictive impairment could not be ruled out.

Skin findings and lung function abnormalities

To assess for an association between the severity of skin disease and the presence of ILD, we compared the mean number of unique skin findings (heliotrope rash, Gottron’s papules/sign, V-sign, shawl sign, periorbital edema, calcinosis cutis, periungual erythema/telangiectasia, cuticular changes, mechanic hands, facial erythema, livedo reticularis, and scalp disease) of the patients in each lung disease category. This analysis was limited to the 37 patients who had both DLCO and thin section CT performed. Although the mean number of skin findings was lower in patients with lung disease (mean 3.8 [SD 2.2, range 1–8], ILD group; mean 4.9 [SD 1.6, range 2–7], lung diffusion abnormality of uncertain significance group; mean 5.3 [SD 1.7, range 3–8], no evidence of lung disease group), this finding was not statistically significant (p=0.13). The V-sign (erythema in a V-neck distribution) was less common in patients with ILD than those without ILD (p=0.047), but no other individual skin finding had a statistically significant association with lung disease category.

Outcome based on initial DLCO

When patients were grouped into categories based on their initial DLCO values (categories shown in Figure 2), the prevalence of ILD was higher in patients with lower initial DLCO values (p<0.001). However, ILD did occur in 5% (2/38) of patients with an initial DLCO in the normal range (both of whom developed a low DLCO within 1.5 years of ILD diagnosis on CT) and in 42% (5/12) of patients with a mild initial reduction in DLCO. Table 4 shows the prevalence of ILD, the timing of ILD diagnosis on CT relative to the initial DLCO measurement, and the percent of patients who had a thin section CT performed in each initial DLCO category.

Figure 2. Initial diffusing capacity for carbon monoxide (DLCO) categories and serial DLCO measurements.

All values expressed as: No. patients (%). Serial DLCO defined as >1 DLCO measurement.

TABLE 4.

Prevalence of ILD based on initial DLCO, limited to patients with a DLCO measured at least once

DLCO category at initial measurement	Had a thin section CT performed	ILD Prevalence (as defined by thin section CT)1	Time after initial DLCO that ILD diagnosis was made by CT (range in months)
	No./Total (%)	No./Total (%)
Normal (>79% predicted)	12/38 (32)	2/38 (5)	−7 and 0
Borderline low (76–79% predicted)	4/5 (80)	0/5 (0)	NA
Mild reduction (61–75% predicted)	10/12 (83)	5/12 (42)	−1 to 56
Moderate reduction (40–60% predicted)	8/9 (89)	6/9 (67)	−2 to 7
Severe reduction (<40% predicted)	3/3 (100)	3/3 (100)	0 to 1

CT=computed tomography, ILD=interstitial lung disease, DLCO=diffusing capacity for carbon monoxide.

¹Numerator includes all patients who had a CT definitely or possibly consistent with ILD per radiologist or pulmonologist report at any point during follow-up.

Figure 2 shows the results of serial DLCO testing. Some patients with initial DLCO values in the normal, borderline low, and mild reduction categories dropped into the moderate or severe reduction categories on repeat testing. Among those with an initial DLCO in the normal range who subsequently dropped below normal, the mean time from the initial DLCO to dropping below 80% predicted was 482 days (range 155–974 days).

Characteristics of patients with ILD confirmed by CT scan

Sixteen patients had thin slice CT chest findings that were consistent with ILD (14 were definitely consistent with ILD, and two were possibly consistent with ILD per radiologist or pulmonologist interpretation). In comparison to the other lung disease groups, the ILD group had more males (3/16 [19%], ILD group; 3/55 [5%], not ILD group; p=0.12) and more patients who had overlap with other connective tissue diseases (3/16 [19%], ILD group; 3/55 [5%], not ILD group; p=0.12), but neither of these differences were statistically significant. See Table 5 for detailed characteristics of the patients with ILD on CT scan.

TABLE 5.

Patients with interstitial lung disease on chest CT scan¹

Age (years) at ILD diagnosis by CT	Sex	DM type	ILD before (B), concurrent with (C), or after (A) rash onset2	Lung biopsy results	Medications (immunosuppres sants and anti- fibrotic agents used since ILD diagnosis)	PFT results (%predicted) at ILD diagnosis by CT	PFT results (%predicted) at time of lowest DLCO	PFT results (% predicted) at latest testing	Months of ILD follow- up3	Other connective tissue disease overlap
61	F	CADM	C	none	GC, MM	DLCO:75 TLC: 89	DLCO:46 TLC: 70	DLCO:65 TLC: 103	40
68	F	CADM	C	BOOP	GC, AZA, CYC	DLCO:39 TLC: 49	DLCO:24 TLC: 50	DLCO:33 TLC: 60	49
62	F	CDM	A	none	GC, MTX	DLCO:60 TLC: 75	DLCO:60 TLC: 75	DLCO:65 TLC: 83	9
53	F	CADM	C	none	unknown	DLCO:57 TLC: 94	DLCO:39 TLC: 88	DLCO:44 TLC: 79	40
64	F	CADM	A	NSIP	GC	DLCO:37 TLC: 108	DLCO:37 TLC: 108	DLCO:79 TLC: 104	9
48	F	CADM	B	NSIP	GC, AZA, adalimumab, etanercept, bosentan	DLCO:NA TLC: 59	DLCO:35 TLC: 33	DLCO:35 TLC: 33	49	RA
33	M	CDM	C	none	GC, AZA	DLCO:55 TLC: 92	DLCO:48 TLC: 78	DLCO:58 TLC: NA	32	dSSc
53	F	CDM	C	NSIP	GC, AZA, interferon-γ	DLCO:41 TLC: NA	DLCO:41 TLC: NA	DLCO:NA TLC: 73	83
42	F	CADM	C	none	GC, MM, MTX, rituximab	DLCO:45 TLC: 65	DLCO:45 TLC: 65	DLCO:62 TLC: 83	2	SLE
63	M	CDM	C	none	GC, MM	DLCO:37 TLC: 77	DLCO:37 TLC: 77	DLCO:76 TLC: 83	6
49	M	CADM	C	none	GC, AZA, CYC, MTX, adalimumab	DLCO:98 TLC:103	DLCO:47 TLC: 63	DLCO:68 TLC: 76	28
36	F	CDM	A	none	GC, AZA, MM	DLCO:85 TLC: 88	DLCO:65 TLC: 83	DLCO:72 TLC: 88	21
36	F	CADM	C	none	GC, MM, MTX	DLCO:44 TLC: 73	DLCO:44 TLC: 73	DLCO:44 TLC: 73	0
61	F	CADM	C	none	GC, MM	DLCO:66 TLC: 56	DLCO:66 TLC: 56	DLCO:79 TLC: 83	10
55	F	CADM	A	none	MM	DLCO:65 TLC: 102	DLCO:65 TLC: 102	DLCO:123 TLC: 97	11
62	F	CDM	A	none	MM	DLCO:61 TLC: 99	DLCO:60 TLC: 90	DLCO:60 TLC: 90	5

CT=computed tomography, ILD=interstitial lung disease, PFT=pulmonary function test, DLCO=diffusing capacity for carbon monoxide, TLC=total lung capacity, GC=high dose glucocorticoids, AZA=azathioprine, MTX=methotrexate, MM=mycophenolate mofetil, CYC= cyclophosphamide, RA=rheumatoid arthritis, dSSc=diffuse systemic sclerosis, SLE=systemic lupus erythematosus, BOOP=bronchiolitis obliterans with organizing pneumonia, NSIP=nonspecific interstitial pneumonia. See Table 1 for definitions of DM, CADM, and CDM.

¹CT scans of last two patients were possibly consistent with ILD (radiologist/pulmonologist read).

²“Concurrent with” defined as ILD on CT scan within one year before to one year after rash onset.

³Calculated from month of ILD diagnosis on CT to month of last PFT results.

Outcome of patients with ILD confirmed by CT scan

The mean duration of ILD follow-up, defined as the date of ILD diagnosis on CT scan to the last PFT follow-up, was 25 months (range 0–83 months). For varying durations during this time, the 13 patients with definite ILD on CT scan for whom treatment data were available were all treated with high dose glucocorticoids, and 12/13 (92%) were also treated with other immunosuppressants. The two patients with possible ILD on CT were treated only with mycophenolate mofetil. All immunosuppressants and anti-fibrotics used after ILD diagnosis are listed in Table 5, with the caveat that some were administered for treatment of connective tissue disease manifestations in other organs than the lung.

Of the patients with at least 6 months of ILD follow-up, 73% (8/11) experienced improvement (15% or greater increase from baseline) from the lowest DLCO (percent predicted) as assessed at the last date of PFT follow-up (mean increase 55%, range 21–111%). Two patients were excluded from this DLCO comparison, one because DLCO was measured only once during serial PFTs, and one because DLCO was not measured at the final PFT follow-up. The TLC values from the corresponding dates were also compared for patients with at least 6 months of ILD follow-up. 50% (5/10) of the patients had an improvement in TLC (defined as 10% or greater increase from baseline: mean increase 31%, range 11–47%), while 10% (1/10) had a deterioration in TLC (13% decrease from baseline), and 40% (4/10) had a stable TLC percent predicted (less than 10% change from baseline). Three patients were excluded from TLC analysis due to missing values. Only one patient (6%) out of 16 had complete normalization of TLC and DLCO (both >79%) at the date of latest follow-up. Table 5 lists the DLCO and TLC percent predicted of each patient at the time of ILD diagnosis by CT, the date of the lowest DLCO, and the final date of PFT follow-up.

Among the patients who had repeat thin section CT scans of the chest, four showed complete resolution of interstitial lung disease, two were improved but still showed interstitial changes, three showed stable ILD, and one showed worsening of ILD. Five patients had no repeat scans available, and one repeat scan showed ILD but was not compared with prior imaging.

DISCUSSION

This retrospective review of a large cohort of dermatomyositis patients seen in the outpatient dermatology setting demonstrates several important findings. First, the prevalence of ILD in both CADM and CDM outpatients is high. In this study, 23% (95% CI = 13–33%) of dermatomyositis patients with at least one thin slice chest CT or DLCO measurement had ILD as defined by CT imaging. This ILD prevalence estimate is at the lower end of the wide prevalence range (approximately 20–70%) that has been reported in recent studies of dermatomyositis and polymyositis patients done predominately by rheumatology departments.^{3, 7, 9, 12, 20} Although CADM patients appeared to have a higher prevalence of ILD than CDM patients, this difference was not statistically significant. We also found no significant differences in the number of skin manifestations seen in patients with and without lung abnormalities, but a prospective study using a reliable and validated measure of skin disease, such as the Cutaneous Dermatomyositis Disease Area and Severity Index,²² could more accurately discern any correlations between the severity of skin disease and the presence of lung disease.

Another interesting finding in this study was that our CADM patients had a very low prevalence of malignancy. Although a recent literature review found a 14% malignancy prevalence in CADM patients,⁴ only one (2%) of the 44 CADM patients in this study had a malignancy, and the malignancy was a non-melanoma skin cancer. Further studies areneeded to determine the necessity of malignancy screening in CADM patients.

We also demonstrate that a substantial percentage of the dermatomyositis population have lung diffusion abnormalities of uncertain significance, characterized by a low DLCO in the absence of CT findings consistent with ILD. In this study, 25% (95% CI = 15–36%) of patients fell into this category, with no prevalence differences between CADM and CDM patients. Patients in this isolated low DLCO group had a higher mean lowest DLCO (mean 66% predicted, SD 11, range 40–79%) than the patients with ILD seen on CT (mean 47% predicted, SD 12, range 24–66%). Among patients with an isolated low DLCO, restrictive impairment on PFTs was uncommon (11%), whereas in the group of patients with confirmed ILD on CT, the majority (69%) had restrictive impairment on PFTs. Notably, five of the patients in the isolated low DLCO category did not have a thin section CT to rule out ILD, possibly because their DLCO values were not severely reduced (range 60–79% predicted).

The cause and significance of a reduced DLCO in the absence of CT findings consistent with ILD is uncertain. Etiologies of a substantial isolated reduction in DLCO include early ILD and pulmonary hypertension. Whereas pulmonary hypertension has a strong association with systemic sclerosis,²³ there is not a well-recognized association with dermatomyositis.²⁴ However, measurement of pulmonary artery systolic pressure is needed to more definitively rule out pulmonary hypertension as an etiology for the isolated DLCO reductions observed in this study. Anemia and active cigarette smoking can also decrease DLCO, although the reduction is typically very small. While dermatomyositis has no known association with anemia, and only 9% of patients in this study were current smokers, these variables may have contributed to DLCO reductions seen in individual patients. Although most studies of dermatomyositis patients do not address the population with an isolated DLCO reduction, the authors of a recent prospective study of nine classic dermatomyositis and 14 polymyositis patients report that 33% of patients had an isolated reduction in DLCO.³ The authors note that an isolated reduction of DLCO did not predict progression to restrictive lung disease but acknowledge that a larger study with longer follow-up is needed to assess the clinical significance of this finding. Such a study would ideally include CADM patients.

Although this study is limited both by the retrospective design and the small sample size, the findings of a high prevalence of both definite ILD and an isolated low DLCO are concerning. These findings may justify screening all dermatomyositis patients with PFTs. Although patients should be routinely questioned about dyspnea, it is important to also systematically screen all patients with PFTs because using symptoms to diagnose ILD is notoriously unreliable in connective tissue disease patients.²³ Dyspnea in connective tissue disease patients without ILD may be secondary to muscle disease, join pain, and general deconditioning, and some connective tissue disease patients with ILD do not have respiratory symptoms. In one prospective study of classic dermatomyositis and polymyositis patients, there was no significant difference in the prevalence of respiratory symptoms (cough, dyspnea) between patients with ILD and patients without ILD.³

If a patient has a moderately or severely reduced DLCO (<61% predicted) upon initial testing, we recommend obtaining a high resolution CT of the chest and referring the patient to pulmonary specialists for further management. Based on our data, it seems reasonable that those with a mild reduction of DLCO (61–75% predicted) should also have a high resolution CT to assess for ILD, but if this is negative, following these patients closely with serial PFTs and monitoring for clinical symptoms of ILD (cough, dyspnea) would be appropriate. Echocardiography should also be obtained to rule out pulmonary hypertension as a cause for the low DLCO, and a complete blood count should be checked to evaluate for anemia. In addition, it may be beneficial to obtain serial DLCO measurements for all dermatomyositis patients because this study demonstrates that DLCO values may drop over time, even in patients with normal or borderline low DLCO at initial measurement. However, many patients in this study did not have multiple measurements of DLCO, and a prospective study is needed to better establish the need for serial PFT measurements in patients with a normal DLCO at baseline. Figure 3 summarizes our preliminary suggestions for initial screening and management of ILD and low DLCO in the dermatomyositis population.

Figure 3. Initial screening and management of interstitial lung disease in dermatomyositis patients.

HRCT=high resolution computed tomography (of the chest), ILD=interstitial lung disease, R/O=rule out, PFTs=pulmonary function tests, CBC=complete blood count, FEV1=forced expiratory volume in one second, FVC=forced vital capacity.

*If spirometry shows obstructive disease (FEV1/FVC<70%) and the patient has a smoking history, note that reduced DLCO may be due to emphysema. However, this will not change management as HRCT is needed to rule out concomitant ILD.

Treatment of patients with established ILD will be predominantly managed by pulmonary specialists. However, the question of whether to treat patients with isolated reductions in DLCO is controversial and may be decided by dermatologists or rheumatologists. In our experience, some patients with isolated low DLCO values who are given immunosuppressants such as mycophenolate mofetil or azathioprine for their skin and/or muscle disease experience improvement upon repeat testing of DLCO. Given the uncertain clinical significance and natural history of an isolated reduction in DLCO, it is difficult to make recommendations regarding treatment. If a low DLCO is indicative of early ILD and can be reversed before significant fibrosis occurs by immunosuppressants with relatively few side effects, intervention at an early stage could be crucial.

This retrospective study was limited by missing data. Because many patients did not have serial DLCO measurements, it is difficult to make definitive evidence-based recommendations for serial DLCO screening. In addition, few patients with low DLCO values had echocardiography with estimation of pulmonary artery systolic pressure to evaluate for pulmonary hypertension, and 5 of the 42 patients with low DLCO values did not have thin section CTs to assess for ILD. Furthermore, we had to rely on reports of chest CTs as the images were not available, and PFTs lacked standardization because they were performed in a variety of laboratories. We also had to use DLCO values that were not corrected for hemoglobin because few PFT laboratories performed this correction. In addition, although to our knowledge this is one of the largest studies of CADM patients in the literature, our sample size was limited by the rarity of this disease, and our statistical power may have been inadequate to show differences between the lung disease seen in CADM and CDM patients. Larger studies would also help discern whether patients with male gender and overlap connective tissue diseases are at a higher risk for ILD. Although these groups appeared to have a high prevalence of ILD in this study, this observation was not statistically significant.

Prospective studies of dermatomyositis patients are needed to more accurately characterize the prevalence and course of ILD, the natural history of an isolated reduction in DLCO, and the effect of immunosuppressants on this history. An ideal observational study would include serial pulmonary function testing and high resolution CT of the chest, systematic assessment of skin disease activity, and documentation of pulmonary artery systolic pressure and hemoglobin. Randomized controlled interventional studies assessing the effect of immunosuppressants on isolated DLCO reductions will be complicated to perform because the same medications are used to manage skin, muscle, and lung disease in these patients, but such trials are needed to determine optimal management.

Of note, we used a slightly different definition of CADM in this study from that employed previously, as we included patients in the new categories of TADM and THDM (as defined in Table 1). The designation CADM (ADM plus HDM) has been used in prior studies to encompass patients whose predominant clinical problem is skin disease. When the categories of ADM and HDM were originally developed, patients receiving systemic immunosuppressives for greater than two consecutive months during the first six months after dermatomyositis onset were excluded due to the possibility that this early immunosuppression prevented the development of laboratory and/or clinical evidence of muscle disease. This exclusion criterion was important in establishing the existence of ADM as a distinct clinical entity from CDM,²⁵ but it is problematic in clinical research because it biases studies that attempt to characterize the CADM population. Patients who have severe, refractory skin disease or significant extracutaneous dermatomyositis manifestations such as ILD often receive extended courses of immunosuppressives, and it is important to include these patients in studies of CADM rather than classifying them into the CDM category or excluding them from research entirely. In this study, the majority of CADM-ILD patients (not surprisingly) were TADM or THDM, and excluding these patients from the CADM category would have suggested an erroneously low prevalence of ILD in this population. Now that the existence of CADM is widely accepted, we propose that patients should no longer be excluded from the categories of ADM and HDM on the basis of immunosuppressive treatment, as this will facilitate the characterization of the CADM population and ultimately improve patient care.