ARTICLE
Dermatomyositis
is a rare inflammatory myopathy characterized by proximal symmetric muscle
weakness with a characteristic cutaneous eruption which differentiates it
from polymyositis.
An increased association of dermatomyositis with malignancy has been
hypothesized since it was first reported in 1916 [1]. Since that first
description, several epidemiological reports [2] and some population-based
cohort studies [3, 4] supported this hypothesis. Despite some reports
with negative findings [5, 6], the association of dermatomyositis with
cancer is now generally accepted [7]. Rates of cancer vary, in different
studies, from less than 10% to over 50% [8].
It is generally recommended that otherwise asymptomatic dermatomyositis
patients should have an age-specific examination for occult malignancies,
either symptoms- and signs-directed or with extensive and in depth screenings
[9]. Given the frequency of the association of dermatomyositis with cancer,
for cost-effectiveness reasons it might be important to develop simple
and appropriate diagnostic tests in dermatomyositis patients. Different
signs and serologic evaluations have been suggested as predictive factors
for malignancy in dermatomyositis: age [10], autoantibody expression [11],
HLA association [12], erythrocyte sedimentation rate (ESR) [10], skin
lesions [13], neoplastic markers [14]. According to different studies
the presence of necrotic skin ulcerations and pruritus [13], elevated
ESR [10], periungual erythema or dysphagia [15] may predict the association
of dermatomyositis with a neoplasia. However, the studies are discordant,
and some failed to demonstrate the importance of one or more of these
factors as a predictive feature of malignancy in dermatomyositis.
We performed a retrospective case-control study on 59 patients with
dermatomyositis admitted to the Dermatology department of Chieti University
and at the IDI-IRCCS dermatological center in Rome between 1980 and 1996
to identify clinically relevant markers of malignancy in dermatomyositis.
Material and methods
Hospital admission registers of the Dermatology department of the University
of Chieti and of the Division of Immunodermatology of the I.D.I. institute
in Rome were reviewed for the period from January 1980 to December 1996,
and a total of 80 patients were found to have been admitted with a diagnosis
of dermatomyositis. On the basis of the Bohan and Peter diagnostic criteria
[16], two dermatologists re-evaluated the clinical diagnosis and 59 patients
who fulfilled the criteria for the diagnosis of definite, probable and
possible (clinically obvious) dermatomyositis were included in the study.
These patients' medical records from the first hospital admission were
reviewed for several parameters including: gender, age at the time of
the diagnosis, presence of some clinical characteristics (heliotrope rash,
muscular weakness, Gottron papules, skin necrosis, itch) and altered laboratory
tests such as ESR, serum muscle enzymes, neoplastic markers, autoantibodies.
Moreover, the diagnostic procedures (electromyography, cutaneous biopsy,
TC scan, muscle biopsy) also performed were reviewed.
At the moment of the first hospital admission none of the patients included
was undergoing any treatment for dermatomyositis; however 5 patients,
in whom cancer was present before the development of dermatomyositis,
were receiving specific treatment for the neoplasia.
For the purpose of our case-control analysis, we classified as "cases"
subjects with dermatomyositis who had or who developed a malignancy (DMC)
within two years from the primary diagnosis; while "controls" were all
other patients enrolled in the study who did not have nor develop cancer
(DM) during the follow-up period.
Statistical analysis
Descriptive statistics were performed to investigate differences between
the two study groups: the categorical variable (i.e., gender) was
analyzed using the Pearson khi2 test; the continuous variables
were tested using the Mann-Whitney non-parametric test.
For ESR we identified the cut-off point after calculation of a receiver
operating characteristic (ROC) curve. The ROC curve plots sensitivity
vs 1-specificity for all ESR values measured in subjects with dermatomyositis
included in the study. The ideal cut-off is indicated by the point in
the curve closest to the upper left corner. This point represents the
ESR value with the highest sensitivity and specificity. To evaluate the
independent association of the serum levels of serum muscle enzymes, ESR,
and all the other study variables with malignancy, we performed a multiple
logistic regression analysis. Finally, the relationship between the different
laboratory values was studied using a linear regression analysis. All
statistical analyses were carried out using the SPSS/PC+ statistical package
[17].
Results
A total of 59 subjects were included in the study. The diagnosis of
dermatomyositis was definite in 90% of cases and probable in 10%. Follow
up time was 3 years for most patients. We found 14 patients out of 59
(23.7%) in whom dermatomyositis was associated with a neoplasia. Tumour
types are summarized in Table
I. Ten patients died because of the cancer and 4 have experienced
an improvement of the dermatomyositis signs and symptoms after tumour
removal and are still followed in our institutions.
Females were 37 (62.7%), with similar proportions in the two study groups
(71.4% vs 60.0% in DMC and DM, respectively, chi square p = 0.44).
Mean age of patients in the DM group was 55.6 years, compared to 59.0
in the DMC group (Mann-Whitney test, p = 0.31). No statistically significant
differences were found between DMC and DM groups for clinical presentations
such as periungual erythema, cutaneous necrosis, pruritus, muscular weakness,
and specific dermatomyositis skin lesions. Neoplastic markers and autoantibodies
values were not available for all patients; however, no differences were
observed among the two populations.
The values for the variables under study (ESR, CK, LDH and aldolase)
were available for each patient included, the mean values are summarized
in Table II. In general,
values were higher in the DMC group, but the non-parametric Mann-Whitney
rank test revealed that the only statistically significant difference
was present for ESR (p < 0.001).
To identify the optimal cut-off point for ESR to distinguish between
DMC and DM patients, we calculated a ROC curve (Fig.
1). This analysis showed that a cut-off point of 35 mm/hr for ESR
had a sensitivity of 92.9% and a specificity of 93.3% in identifying DMC
patients in our sample. In fact, almost all the DMC patients (13/14, or
93%) had ESR values higher than the chosen threshold, while only 7% (3/45)
of DM patients reached this value. These figures correspond to a positive
predictive value of 81.2%, and to a negative predictive value of 97.7%
which are highly informative values.
To verify whether ESR was an independent marker of presence or development
of malignancy in subjects with dermatomyositis we performed a multiple
logistic regression analysis. After adjustment for age, sex and all the
other variables considered, the ESR values remained strongly associated
with the risk of malignancy. In particular, when ESR values were dichotomized
according to the chosen threshold, the adjusted odds ratio for values
>= 35 mm/hr vs values < 35 mm/hr was 197.5 (95% confidence
interval, 12.0 to 3,254.6), indicating that patients with above-threshold
values are at extremely high risk of having or developing cancer. Since
a predictive marker is useful in patients in whom dermatomyositis precedes
cancer development, we repeated the statistical analysis excluding from
the DMC group the patients (n = 5) in whom cancer was present before the
development of dermatomyositis. Even excluding those subjects, the ideal
ESR cut-off value at 35 mm/hr did not change. In this case sensitivity
was 88.9% and specificity was 91.1%, respectively, with a negative predictive
value of 97.6%. The adjusted odds ration calculated considering this different
group was 87.0 (95% confidence interval, 6.9-3,718.1) indicating that
the risk for developing cancer in dermatomyositis patients with ESR over
35 mm/hr was still extremely high even considering this more stringent
study group.
Furthermore, in our series we investigated the relationship between
the serum markers commonly used in dermatomyositis to assess clinical
activity and response to treatment. We observed that CK values, the most
specific marker, has a strong correlation with aldolase values. In linear
regression, the correlation between the values of these two markers was
0.799 (p = 0.01), indicating that aldolase values can be reliably predicted
by CK values, and thus making the determination of aldolase probably not
cost effective.
Discussion
Dermatomyositis is a rare inflammatory myopathy which has been associated
with an increased risk of cancer development. Although there has been,
since the earliest reports, controversy on the exact relationship between
cancer and dermatomyositis, it is now generally accepted that adult dermatomyositis
patients are frequently prone to cancer development. The cancer incidence
has ranged in the different studies from 10% to over 50% [8, 18]. Cancer
may develop in DM patients before, concurrently or after the onset of
the myositis. The excess risk of cancer is highest around the time of
diagnosis, and for patients with DM remains high for at least 2 years
[19, 20].
Various malignancies have been described in dermatomyositis, and it
has been suggested that they reflect those found in an age-matched population,
with a prevalence for ovarian and lung cancer.
Although some studies have shown that extensive laboratory testing and
radiological examination in asymptomatic patients with dermatomyositis
are not useful [21, 22] and that the diagnosis of malignancy can be made
based on the complete clinical examination and simple laboratory tests
[23], many other authors prefer a more aggressive approach [14, 24] and
request an in-depth evaluation of patients with exhaustive radiological,
endoscopic and ultrasound assessment [25, 26]. Since the development of
cancer is not always concomitant, these studies have to be repeated in
time.
For these reasons there has been always an effort to find a reliable
and cost effective prognostic or predictive factor that could suggest
the diagnosis of cancer in dermatomyositis.
Several prognostic or predictive markers have been proposed: age [10],
autoantibody expression [11], HLA association [12], ESR [10], cutaneous
rash and skin lesions [10, 13] and neoplastic markers [14]. However, most
of these studies focused on survival, and not on cancer presence or incidence.
Some studies have revealed that older age and increased incidence of pruritus,
cutaneous necrosis, periungueal erythemas or dysphagia are associated
with cancer in dermatomyositis patients [10, 13, 15, 27].
Other studies have failed to confirm the predictive power of some of
these findings such as pruritus or periungual erythema [10]; moreover
clinical reports have suggested that elevation of tumour markers is not
always useful in limiting extensive instrumental examinations [28].
In our study we found no statistical difference
in the presentation of the clinical parameters (pruritus, cutaneous necrosis,
periungual erythema) in the two study groups. We found that, as already
reported in the literature, the muscle enzyme evaluation is of limited
value to predict any cancer association since DMC patients present values
comparable to those of DM patients.
In a study by Basset-Seguin et al. [10] an ESR higher than 40
mm/hr has been found more frequently in dermatomyositis patients with
malignancy. The validity of this sign has been confirmed by our study,
and our data indicated that a lower threshold could be set for this value.
In fact, in our study group an ESR higher than 35 mm/hr was very strongly
associated with the presence or the development of a malignancy, this
association resulted valid even when the ESR value was adjusted for other
variables such as age and gender or when the study group considered did
not include dermatomyositis patients with a preceding cancer diagnosis.
Given the high positive and negative predictive values observed in our
study, ESR evaluation using this cut-off point could be very useful in
alerting dermatologists about the need for more in-depth diagnostic procedures
in dermatomyositis patients.
Article accepted on 13/11/01
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