Short Report
Journal of
CLINICAL NEUROMUSCULAR DISEASE
157
Volume 15, Number 4 June 2014
Clinically Amyopathic Dermatomyositis: Analysis of a Monocentric Cohort Rossella Neri, MD, Simone Barsotti, MD, Valentina Iacopetti, MD, Alessandra Tripoli, MD, Anna d’Ascanio, MD, Antonio Gaetano Tavoni, MD, Marta Mosca, MD, PhD, and Stefano Bombardieri, MD, PhD
Abstract Objective: Clinically amyopathic dermatomyositis (CADM) is characterized by the presence of specific cutaneous manifestations of dermatomyositis (DM) without clinical signs of muscular involvement. The aim of this study was to examine the prevalence, clinical characteristics, and outcome of patients with CADM followed at our Rheumatology Unit. Methods: Clinical charts of patients diagnosed as DM were retrospectively examined. Epidemiological, clinical, laboratory, instrumental, and histological features of the patients at the time of diagnosis were collected. CADM was diagnosed in the presence of DM-like rash without muscular involvement. Results: A total of 103 DM patients were identified, of these, 8 were diagnosed with CADM. Six of patients with CADM had subclinical muscle involvement, and were therefore classifiable as hypomyopathic DM.
DM in which muscle involvement is absent, and hypomyopathic DM in which muscle involvement is only detectable with specific instrumental investigation. Amyopathic DM and hypomyopathic DM are also grouped as clinically amyopathic dermatomyositis (CADM), on the basis of the absence of an overt clinical muscle involvement.1,2 Contrasting data are available on CAM prevalence, where some authors report a prevalence ranging between 2% and 8% of DM and others report a prevalence as high as 20%. The aim of this study was to examine the prevalence, clinical characteristics, and outcome of patients with CADM who were followed at the Rheumatology Unit of the University of Pisa.
Patients and Methods
INTRODUCTION
Data of patients diagnosed with DM according to the criteria proposed by Bohan and Peter3 and followed between 1974 and 2012 were input to a database and were retrospectively examined. Patients were diagnosed with CADM according to the following criteria: 1. Presence of DM-specific pathognomonic manifestations—Gottron sign and Gottron papules, heliotrope erythema. 2. Absence of clinically overt muscle involvement for at least 6 months.
Dermatomyositis (DM) is a disease characterized by the association of typical cutaneous manifestations (heliotrope rash, Gottron sign, and Gottron papules) and muscle inflammation. Different DM subgroups have been identified: namely, classical DM, amyopathic
Patients were excluded from the analysis based on the following criteria: 1. Disease onset before 18 years. 2. High-dose immunosuppressive therapy in the 6 months preceding the onset of cutaneous manifestations.
Conclusions: In our case series, CADM represents 7.7% of the total DM. However, if investigated with instrumental methods, most patients with CADM result to have subclinical muscular involvement. Key Words: dermatomyositis, amyopathic dermatomyositis, prevalence, monocentric cohort, clinical features
( J Clin Neuromusc Dis 2014;15:157–160)
From the Rheumatology Unit, University of Pisa, Pisa, Italy. The authors report no conflicts of interest. Reprints: Rossella Neri, MD, Rheumatology Unit, University of Pisa, Italy, Via Roma, 67 56126 Pisa, Italy (e-mail: [email protected]. unipi.it). Copyright © 2014 by Lippincott Williams & Wilkins
158
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Volume 15, Number 4 June 2014
Neri et al
3. Treatment with drugs that could induce DM-like cutaneous manifestations. The following epidemiological clinical and laboratory data were collected from clinical charts: sex, age at disease onset, disease duration, presence of muscular symptoms such as reduced muscle strength (since 2008, all patients routinely underwent a quantitative evaluation of muscular strength performed with manual muscle test 84; before, muscle strength was deduced by the symptoms reported by the patients and by physician judgment reported in clinical charts) and myalgia, presence of DM-specific cutaneous manifestations, constitutional symptoms, Raynaud phenomenon, dyspnea, dysphonia, dysphagia, arthritis, digital ulcers, creatine kinase (CK) and lactade dehydrogenase (LDH) values, the presence of antinuclear antibodies (with indirect immunofluorescence test on Hep-2 cells), and antiextractable nuclear antibodies (with counterimmunoelectrophoresis). Sera were tested for anti-Jo1 antibodies, and for autoantibodies directed to SM, RNP, SSA, Ku, PCNA, SL, PM/SCL; no data are available on MDA-5 antibodies, which are not available in our laboratory. Finally, the results of electromyogram (EMG), performed on proximal and distal arm and leg muscles and muscle biopsy were also recorded. EMG was considered to be indicative of muscle involvement in the presence of an increase of spontaneous activity (fibrillations, positive waves, and complex repetitive discharges), excessive percentage (.20%) of polyphasic motor unit potentials5 and shortduration motor unit potentials. The presence of perifascicular atrophy and/or perivascular infiltrates on muscle biopsy was considered to be suggestive of inflammatory muscle involvement.6 Each patient underwent a paraneoplastic screening during the first clinical assessment. The first level examination included chest X-ray, abdomen and pelvis echographic examination, and fecal occult blood test; in female patients, a mammography was also performed. Second-level examination was reserved only for selected patients. © 2014 Lippincott Williams & Wilkins
RESULTS One hundred three patients with DMspecific cutaneous lesions were identified; based on the previously mentioned criteria, 95 patients (65 females and 30 males) were classified as classical DM and 8 patients (6 females and 2 males) as CADM (7.7%). Interestingly, patients with CADM were younger than those with DM (46.2 vs. 54.5 years), although the finding was not statistically significant. In Table 1, we report the major clinical data at the onset of the disease. By definition, patients with CADM did not have clinical evidence of muscle involvement; interestingly, muscle assessment either with EMG or biopsy showed the presence of subclinical muscular involvement in 6 of 8 patients classified as CADM. One patient with CADM also had pulmonary fibrosis (Table 1). Antinuclear antibodies were positive in 2 patients with CADM (25%) and no extractable nuclear antibodies positivity was found. All patients with CADM were treated with low daily dose of corticosteroids (methylprednisolone 4 mg/d), 6 with hydroxychloroquine, 3 with methotrexate, and 1 with cyclosporin. One patient with CADM died of myocardial infarction within 1 week from diagnosis, this event was not considered to be related with the disease; the remaining 7 patients were followed for a mean period of 76.6 months. During the follow-up, 2 patients with CADM developed clinically evident muscle involvement, 10 months and 6 years after cutaneous disease onset and were classified as classical DM.
DISCUSSION In this study, CADM was observed in 7.7% of patients who were referred to a Rheumatology Unit for the presence of DM-specific skin lesions. In our cohort, CADM prevalence seems to be lower than that reported in the literature.7–9 Discrepancies may be related with ethnic differences, assessments of different patients, the inclusion criteria, and the
Clinically Amyopathic Dermatomyositis
Journal of
CLINICAL NEUROMUSCULAR DISEASE Volume 15, Number 4 June 2014
TABLE 1. Epidemiological and Clinical Characteristics of Patients With CADM Patient Interstitial number Sex Age Fibrosis 1 2 3
4
5 6 7 8
F F F
M
M F F F
62 51 47
46
20 49 57 62
Yes No No
No
No No No No
EMG
Biopsy
Myopathic
NA
Therapy
Low-dose steroids, Myopathic Myositis Low-dose steroids, Normal NA Low-dose steroids, Cya Normal NA Low-dose steroids, MTX Normal Myositis Low-dose steroids, Myopathic NA Low-dose steroids, Myopathic NA Low-dose steroids, Myopathic NA Low-dose steroids,
Diagnosis at Onset
Diagnosis at the Last Follow-up
HDM
HDM
HDM
DM
ADM
ADM
ADM
ADM
HDM
HDM
HDM
DM
HDM
HDM
HDM
HDM
HCQ HCQ HCQ,
HCQ
HCQ MTX HCQ MTX
ADM, amyopathic dermatomyositis; Cya, cyclosporin; F, female; HCQ, hydroxychloroquine; HDM, hypomyopathic dermatomyositis; M, male; MTX, methotrexate; NA, not assessed.
retrospective nature of our study. In this respect, in fact, patients were thoroughly examined for the presence of muscle involvement even in the absence of overt clinical manifestation. In addition, differences could also be related to the different referral; in fact, the majority of data in the literature derive from dermatologic centers, on the contrary, this cohort is represented by patients followed at a Rheumatological Unit. Interestingly, in most patients, a more detailed muscle assessment showed the presence of subclinical signs of myopathy, and 2 patients have developed an overt muscle involvement during the follow-up. Even if muscular and systemic involvement was absent, all patients were treated with lowdose corticosteroids and DMARDs: 4 patients with hydroxychloroquine alone, 2 with methotrexate alone, and 2 with a combination therapy (methotrexate + hydroxychloroquine and cyclosporine + hydroxychloroquine). During the follow-up, patients with CADM had a good prognosis, only 2 patients developed a mild muscular involvement 1 year after
diagnosis and no patients showed systemic involvement. Particularly, as opposed to the data reported in the literature, no patients with CADM developed a pulmonary involvement.10 In view of the small number of patients, it is not possible to correlate treatment with the development of an overt DM. Although the number of patients enrolled is low to allow definite conclusions, nonetheless, to the best of our knowledge, this cohort represents one of the largest monocentric case series described in the literature.9 The observation that most patients presenting with CADM have subclinical muscle involvement suggests the need to perform an accurate screening for muscle involvement in all patients with DM-like cutaneous lesions. This should include determination of muscular necrosis enzymes (CK, LDH, and aldolase), leg and arm EMG, and, in selected cases, muscular biopsy. Importantly, although most patients presenting with CADM have subclinical muscle involvement, few develop a clinically relevant DM over time. Future multicenter www.jcnmd.com
159
160
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Volume 15, Number 4 June 2014
Neri et al
studies should aim at understanding whether this evolution is related to therapy or represents the natural history of this subgroup of patients as well as defining prognostic factors for DM development and the optimal therapeutic approaches. REFERENCES 1. Sontheimer RD. Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis siné myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness? J Am Acad Dermatol. 2002; 46:626–636.
5. Uncini A, Lange DJ, Lovelace RE, et al. Long-duration polyphasic motor unit potentials in myopathies: a quantitative study with pathological correlation. Muscle Nerve. 1990;13:263–267. 6. Pestronk A, Schmidt RE, Choksi R. Vascular pathology in dermatomyositis and anatomic relations to myopathology. Muscle Nerve. 2010;42:53–61. 7. Bendwald MJ, Wetter DA, Li X, et al. Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota. Arch Dermatol. 2010;146:26–30. 8. Yamasaki Y, Yamada H, Ohkubo M, et al. Longterm survival and associated risk factors in patients with adult-onset idiopathic inflammatory myopathies and amyopathic dermatomyositis: experience in a single institute in Japan. J Rheumatol. 2011;38:1636–1643.
3. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344–347.
9. Gerami P, Schope JM, McDonald L, et al. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol. 2006;54:597–613.
4. Rider LG, Koziol D, Giannini EH, et al. Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken). 2010;62:465–472.
10. Ye S, Chen X, Lu X, et al. Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study. Clin Rheumatol. 2007;26:1647–1654.
2. Sontheimer RD. Clinically amyopathic dermatomyositis: what can we now tell our patients? Arch Dermatol. 2010;146:76–80.
© 2014 Lippincott Williams & Wilkins
Journal of
CLINICAL NEUROMUSCULAR DISEASE
157
Volume 15, Number 4 June 2014
Clinically Amyopathic Dermatomyositis: Analysis of a Monocentric Cohort Rossella Neri, MD, Simone Barsotti, MD, Valentina Iacopetti, MD, Alessandra Tripoli, MD, Anna d’Ascanio, MD, Antonio Gaetano Tavoni, MD, Marta Mosca, MD, PhD, and Stefano Bombardieri, MD, PhD
Abstract Objective: Clinically amyopathic dermatomyositis (CADM) is characterized by the presence of specific cutaneous manifestations of dermatomyositis (DM) without clinical signs of muscular involvement. The aim of this study was to examine the prevalence, clinical characteristics, and outcome of patients with CADM followed at our Rheumatology Unit. Methods: Clinical charts of patients diagnosed as DM were retrospectively examined. Epidemiological, clinical, laboratory, instrumental, and histological features of the patients at the time of diagnosis were collected. CADM was diagnosed in the presence of DM-like rash without muscular involvement. Results: A total of 103 DM patients were identified, of these, 8 were diagnosed with CADM. Six of patients with CADM had subclinical muscle involvement, and were therefore classifiable as hypomyopathic DM.
DM in which muscle involvement is absent, and hypomyopathic DM in which muscle involvement is only detectable with specific instrumental investigation. Amyopathic DM and hypomyopathic DM are also grouped as clinically amyopathic dermatomyositis (CADM), on the basis of the absence of an overt clinical muscle involvement.1,2 Contrasting data are available on CAM prevalence, where some authors report a prevalence ranging between 2% and 8% of DM and others report a prevalence as high as 20%. The aim of this study was to examine the prevalence, clinical characteristics, and outcome of patients with CADM who were followed at the Rheumatology Unit of the University of Pisa.
Patients and Methods
INTRODUCTION
Data of patients diagnosed with DM according to the criteria proposed by Bohan and Peter3 and followed between 1974 and 2012 were input to a database and were retrospectively examined. Patients were diagnosed with CADM according to the following criteria: 1. Presence of DM-specific pathognomonic manifestations—Gottron sign and Gottron papules, heliotrope erythema. 2. Absence of clinically overt muscle involvement for at least 6 months.
Dermatomyositis (DM) is a disease characterized by the association of typical cutaneous manifestations (heliotrope rash, Gottron sign, and Gottron papules) and muscle inflammation. Different DM subgroups have been identified: namely, classical DM, amyopathic
Patients were excluded from the analysis based on the following criteria: 1. Disease onset before 18 years. 2. High-dose immunosuppressive therapy in the 6 months preceding the onset of cutaneous manifestations.
Conclusions: In our case series, CADM represents 7.7% of the total DM. However, if investigated with instrumental methods, most patients with CADM result to have subclinical muscular involvement. Key Words: dermatomyositis, amyopathic dermatomyositis, prevalence, monocentric cohort, clinical features
( J Clin Neuromusc Dis 2014;15:157–160)
From the Rheumatology Unit, University of Pisa, Pisa, Italy. The authors report no conflicts of interest. Reprints: Rossella Neri, MD, Rheumatology Unit, University of Pisa, Italy, Via Roma, 67 56126 Pisa, Italy (e-mail: [email protected]. unipi.it). Copyright © 2014 by Lippincott Williams & Wilkins
158
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Volume 15, Number 4 June 2014
Neri et al
3. Treatment with drugs that could induce DM-like cutaneous manifestations. The following epidemiological clinical and laboratory data were collected from clinical charts: sex, age at disease onset, disease duration, presence of muscular symptoms such as reduced muscle strength (since 2008, all patients routinely underwent a quantitative evaluation of muscular strength performed with manual muscle test 84; before, muscle strength was deduced by the symptoms reported by the patients and by physician judgment reported in clinical charts) and myalgia, presence of DM-specific cutaneous manifestations, constitutional symptoms, Raynaud phenomenon, dyspnea, dysphonia, dysphagia, arthritis, digital ulcers, creatine kinase (CK) and lactade dehydrogenase (LDH) values, the presence of antinuclear antibodies (with indirect immunofluorescence test on Hep-2 cells), and antiextractable nuclear antibodies (with counterimmunoelectrophoresis). Sera were tested for anti-Jo1 antibodies, and for autoantibodies directed to SM, RNP, SSA, Ku, PCNA, SL, PM/SCL; no data are available on MDA-5 antibodies, which are not available in our laboratory. Finally, the results of electromyogram (EMG), performed on proximal and distal arm and leg muscles and muscle biopsy were also recorded. EMG was considered to be indicative of muscle involvement in the presence of an increase of spontaneous activity (fibrillations, positive waves, and complex repetitive discharges), excessive percentage (.20%) of polyphasic motor unit potentials5 and shortduration motor unit potentials. The presence of perifascicular atrophy and/or perivascular infiltrates on muscle biopsy was considered to be suggestive of inflammatory muscle involvement.6 Each patient underwent a paraneoplastic screening during the first clinical assessment. The first level examination included chest X-ray, abdomen and pelvis echographic examination, and fecal occult blood test; in female patients, a mammography was also performed. Second-level examination was reserved only for selected patients. © 2014 Lippincott Williams & Wilkins
RESULTS One hundred three patients with DMspecific cutaneous lesions were identified; based on the previously mentioned criteria, 95 patients (65 females and 30 males) were classified as classical DM and 8 patients (6 females and 2 males) as CADM (7.7%). Interestingly, patients with CADM were younger than those with DM (46.2 vs. 54.5 years), although the finding was not statistically significant. In Table 1, we report the major clinical data at the onset of the disease. By definition, patients with CADM did not have clinical evidence of muscle involvement; interestingly, muscle assessment either with EMG or biopsy showed the presence of subclinical muscular involvement in 6 of 8 patients classified as CADM. One patient with CADM also had pulmonary fibrosis (Table 1). Antinuclear antibodies were positive in 2 patients with CADM (25%) and no extractable nuclear antibodies positivity was found. All patients with CADM were treated with low daily dose of corticosteroids (methylprednisolone 4 mg/d), 6 with hydroxychloroquine, 3 with methotrexate, and 1 with cyclosporin. One patient with CADM died of myocardial infarction within 1 week from diagnosis, this event was not considered to be related with the disease; the remaining 7 patients were followed for a mean period of 76.6 months. During the follow-up, 2 patients with CADM developed clinically evident muscle involvement, 10 months and 6 years after cutaneous disease onset and were classified as classical DM.
DISCUSSION In this study, CADM was observed in 7.7% of patients who were referred to a Rheumatology Unit for the presence of DM-specific skin lesions. In our cohort, CADM prevalence seems to be lower than that reported in the literature.7–9 Discrepancies may be related with ethnic differences, assessments of different patients, the inclusion criteria, and the
Clinically Amyopathic Dermatomyositis
Journal of
CLINICAL NEUROMUSCULAR DISEASE Volume 15, Number 4 June 2014
TABLE 1. Epidemiological and Clinical Characteristics of Patients With CADM Patient Interstitial number Sex Age Fibrosis 1 2 3
4
5 6 7 8
F F F
M
M F F F
62 51 47
46
20 49 57 62
Yes No No
No
No No No No
EMG
Biopsy
Myopathic
NA
Therapy
Low-dose steroids, Myopathic Myositis Low-dose steroids, Normal NA Low-dose steroids, Cya Normal NA Low-dose steroids, MTX Normal Myositis Low-dose steroids, Myopathic NA Low-dose steroids, Myopathic NA Low-dose steroids, Myopathic NA Low-dose steroids,
Diagnosis at Onset
Diagnosis at the Last Follow-up
HDM
HDM
HDM
DM
ADM
ADM
ADM
ADM
HDM
HDM
HDM
DM
HDM
HDM
HDM
HDM
HCQ HCQ HCQ,
HCQ
HCQ MTX HCQ MTX
ADM, amyopathic dermatomyositis; Cya, cyclosporin; F, female; HCQ, hydroxychloroquine; HDM, hypomyopathic dermatomyositis; M, male; MTX, methotrexate; NA, not assessed.
retrospective nature of our study. In this respect, in fact, patients were thoroughly examined for the presence of muscle involvement even in the absence of overt clinical manifestation. In addition, differences could also be related to the different referral; in fact, the majority of data in the literature derive from dermatologic centers, on the contrary, this cohort is represented by patients followed at a Rheumatological Unit. Interestingly, in most patients, a more detailed muscle assessment showed the presence of subclinical signs of myopathy, and 2 patients have developed an overt muscle involvement during the follow-up. Even if muscular and systemic involvement was absent, all patients were treated with lowdose corticosteroids and DMARDs: 4 patients with hydroxychloroquine alone, 2 with methotrexate alone, and 2 with a combination therapy (methotrexate + hydroxychloroquine and cyclosporine + hydroxychloroquine). During the follow-up, patients with CADM had a good prognosis, only 2 patients developed a mild muscular involvement 1 year after
diagnosis and no patients showed systemic involvement. Particularly, as opposed to the data reported in the literature, no patients with CADM developed a pulmonary involvement.10 In view of the small number of patients, it is not possible to correlate treatment with the development of an overt DM. Although the number of patients enrolled is low to allow definite conclusions, nonetheless, to the best of our knowledge, this cohort represents one of the largest monocentric case series described in the literature.9 The observation that most patients presenting with CADM have subclinical muscle involvement suggests the need to perform an accurate screening for muscle involvement in all patients with DM-like cutaneous lesions. This should include determination of muscular necrosis enzymes (CK, LDH, and aldolase), leg and arm EMG, and, in selected cases, muscular biopsy. Importantly, although most patients presenting with CADM have subclinical muscle involvement, few develop a clinically relevant DM over time. Future multicenter www.jcnmd.com
159
160
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Volume 15, Number 4 June 2014
Neri et al
studies should aim at understanding whether this evolution is related to therapy or represents the natural history of this subgroup of patients as well as defining prognostic factors for DM development and the optimal therapeutic approaches. REFERENCES 1. Sontheimer RD. Would a new name hasten the acceptance of amyopathic dermatomyositis (dermatomyositis siné myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness? J Am Acad Dermatol. 2002; 46:626–636.
5. Uncini A, Lange DJ, Lovelace RE, et al. Long-duration polyphasic motor unit potentials in myopathies: a quantitative study with pathological correlation. Muscle Nerve. 1990;13:263–267. 6. Pestronk A, Schmidt RE, Choksi R. Vascular pathology in dermatomyositis and anatomic relations to myopathology. Muscle Nerve. 2010;42:53–61. 7. Bendwald MJ, Wetter DA, Li X, et al. Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota. Arch Dermatol. 2010;146:26–30. 8. Yamasaki Y, Yamada H, Ohkubo M, et al. Longterm survival and associated risk factors in patients with adult-onset idiopathic inflammatory myopathies and amyopathic dermatomyositis: experience in a single institute in Japan. J Rheumatol. 2011;38:1636–1643.
3. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344–347.
9. Gerami P, Schope JM, McDonald L, et al. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol. 2006;54:597–613.
4. Rider LG, Koziol D, Giannini EH, et al. Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken). 2010;62:465–472.
10. Ye S, Chen X, Lu X, et al. Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study. Clin Rheumatol. 2007;26:1647–1654.
2. Sontheimer RD. Clinically amyopathic dermatomyositis: what can we now tell our patients? Arch Dermatol. 2010;146:76–80.
© 2014 Lippincott Williams & Wilkins
