Clin Rheumatol DOI 10.1007/s10067-015-2928-8

CASE BASED REVIEW

Diagnosis and treatment of clinically amyopathic dermatomyositis (CADM): a case series and literature review Bornstein Gil 1 & Lidar Merav 2 & Langevitz Pnina 2 & Grossman Chagai 2

Received: 23 February 2015 / Accepted: 22 March 2015 # International League of Associations for Rheumatology (ILAR) 2015

Abstract The objective of this study was to report the clinical course of a cohort of patients with clinically amyopathic dermatomyositis (CADM) in correlation to the presence or absence of anti-melanoma differentiation-associated gene 5 (MDA-5) antibody. Five patients with CADM presented to our rheumatology unit between September 1, 2011 and March 31, 2014. We hereby present their clinical course, laboratory findings, imaging modalities, functional tests, and treatments regimens. Our cohort included five patients, with a mean age of 41.8±17.7. Three patients, all anti-MDA-5 antibody positive, developed rapidly progressive interstitial lung disease (ILD) within 4.3±4.5 months of presentation. Two of these patients succumbed to their disease within 30 months of diagnosis despite intensive immunosuppressive therapy. The third anti-MDA-5-positive patient with ILD is still stable, 20 months from disease onset, on massive combination therapy. One patient developed CADM associated with the anti-p155/140 antibody, a year after completing chemotherapy for non-seminomatous germ cell tumor. He presented with a benign clinical course with no evidence of ILD and no recurrence of malignancy after 20 months of follow-up. The fifth patient in our cohort, who is anti-MDA-5 negative and

* Bornstein Gil [email protected] 1

The Talpiot Medical Leadership Program and Department of Internal Medicine D, The Chaim ShebaMedical Center, Tel-Hashomer, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

2

Rheumatology Unit, The Chaim Sheba Medical Center, Tel-Hashomer, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

has no evidence of malignancy, also enjoys a benign clinical course. The presence of anti-MDA-5 antibodies in CADM patients is associated with rapidly progressive ILD and a poor prognosis. The serologic profile of patients with CADM should be routinely evaluated and integrated with clinical data in the management of these patients. Keywords Amyopathic dermatomyositis . Anti-melanoma differentiation-associated gene 5 antibody . Autoantibodies . Interstitial lung disease

Introduction Clinically amyopathic dermatomyositis (CADM), also known as dermatomyositis (DM) sine myositis, is characterized by typical dermatological findings of DM with either no muscular involvement at all or only minimal muscle weakness. It is estimated that approximately 20 % of DM patients have CADM [1]. Several studies have shown that patients with CADM have an increased risk of developing interstitial lung disease (ILD). CADM-associated ILD tends to follow a more severe clinical course compared to that of ILD in classic DM [2–5], despite no difference in the histologic pattern which is of non-specific interstitial pneumonia (NSIP) in both cases. Nearly a decade ago, Sato et al. first described autoantibodies to a 140-kD polypeptide in a cohort of Japanese patients with CADM [6]. This antibody was later shown to be directed against an RNA helicase encoded by melanoma differentiation-associated gene 5 (MDA-5) [7]. Recognition that the helicase is a critical molecule in innate immune defense against viruses led to the hypothesis that viral infection may play an important role in the initiation of CADM and rapidly progressive ILD. Clinically, the presence of anti-

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MDA-5 autoantibodies was shown to be associated with a worse prognosis mainly due to increased rates and severity of ILD [2–5, 8, 9] as well as skin ulcerations [5, 10]. It is well established that classic DM is associated with malignancy. According to several series, 20–25 % of patients have underlying malignancy or are at risk for developing one, with older patients carrying the highest risk. The prevalence of malignancy among CADM patients is similar or even lower than its prevalence in classic DM patients [1, 11, 12]. It should be also noted that CADM patients may develop classic DM in the course of their disease [12]. The present review summarized our experience with Israeli-Jewish patients with CADM in correlation with the presence of anti-MDA-5 antibodies.

Patients and methods A cohort of five patients (mean age 41.8±17.7, 3 males, 2 females) were retrospectively diagnosed with CADM among 16 consecutive patients with DM received at our institution from September 2011 to March 2014. Detailed information regarding clinical presentation, laboratory findings, imaging and functional tests (such as electromyography and pulmonary function tests) as well as cutaneous histopathology results were obtained. All patients were screened for the presence of the following autoantibodies: ANA, anti-synthetase profile (anti-JO, anti-PL7, and anti-PL12), anti-SRP, anti-Mi2, anti-Ku, anti-SCL70, anti-PM-SCL70, anti-p155/140, and anti-MDA-5. Disease course and outcome following treatment was recorded.

Results Demographic data, clinical and laboratory finding, as well as the medical therapy of all five patients are presented in Table 1. Patient 1 A 27-year-old healthy male presented to our clinic with typical cutaneous findings including gottron papules, heliotrope rash, severe photosensitivity rash over his scalp, chest and neck, and Raynaud syndrome involving his hands and feet. Periarticular tenderness was especially notable over his feet and ankles, but there was no synovial involvement. There was no muscle weakness or respiratory complains upon presentation. Skin biopsy was consistent with DM findings. He was initially treated with high-dose prednisone, methotrexate (MTX), and hydroxychloroquine (HCQ) with only mild improvement in his skin findings and symptoms. Initial pulmonary function tests (PFT) were normal. Four months after initial presentation, he developed shortness of breath and high-resolution computerized tomography (HRCT)

demonstrated pulmonary interstitial changes. PFT showed moderate restrictive pattern with borderline diffusion capacity. Echocardiography demonstrated normal pulmonary pressure. MTX treatment was discontinued due to the lung involvement, and cyclophosphamide pulses were initiated in addition to treatment with intravenous (IV) prostaglandins due to digital ulcers complicating the patient’s Raynaud syndrome. Treatment with azathioprine was discontinued because of gastrointestinal intolerability and drug fever. The patient’s ILD did not improve, and he also developed infected elbow bursitis and pneumonia after the fifth pulse. After cessation of cyclophosphamide, the patient received six courses of intravenous immunoglobulin (IVIG) and mycophenolate mofetil (MMF) was initiated. The patient died 30 months after initial presentation due to severe pneumonia complicating his lung disease. In the course of the patient’s disease, there were no remarkable laboratory findings except mildly elevated erythrocyte sedimentation rate (ESR) at the onset of the disease. No muscle involvement was recorded clinically or sub-clinically. Anti MDA-5 was positive with no other positive autoimmune serology. Patient 2 A 24-year-old healthy male presented to our clinic due to typical cutaneous findings including gottron papules, heliotrope rash, and diffuse erythematous rash over his chest, back, and upper limbs with severe pruritus. There were no respiratory complains and no muscle weakness. Skin biopsy was consistent with DM findings. All laboratory results including muscle enzymes and inflammatory markers were normal. Anti-MDA-5 was positive with no other positive autoimmune serology. Evaluation for underlying malignancy was negative. Baseline PFT and echocardiography were normal. High-dose prednisone and MTX were initiated along with topical creams, and anti-histamines and significant improvement in the cutaneous findings were observed. Treatment with HCQ was discontinued due to gastrointestinal intolerability. Nine months after initial presentation and while being on treatment with MTX and low dose of prednisone, the patient complained of shortness of breath on mild exertion, pleuritic chest pain, and weight loss. PFT showed moderate restrictive pattern with severe decline of diffusion capacity. HRCT showed interstitial changes. Echocardiography demonstrated decline in the left ventricle ejection fraction to 30 %, and cardiac magnetic resonance imaging (MRI) showed a weak enhancement. MTX treatment was discontinued. An open lung biopsy demonstrated NSIP pattern consistent with DM. The patient was treated with methylprednisolone pulse as well as with six courses of IVIG. Cyclosporine was added as maintenance therapy. Proximal muscle weakness in the lower limbs developed shortly after initiation of pulse steroids therapy, and EMG demonstrated a symmetric myopathic pattern, yet no elevation of muscle enzymes was recorded. Serial PFT and echocardiography done 3 and 6 months later demonstrated a

Caucasian Never smoked None

– Gottron papules, heliotrope rash, chest, back and upper limbs erythema, Raynaud 9 HCQ, OS, MTX, MP, IVIG, CYS 20 Anti-MDA-5 –

Caucasian Never smoked None

–

Gottron papules, heliotrope rash, V-neck and back of neck erythema, Raynaud with digital ulcers 4

HCQ, OS, MTX, AZA, CYC, IVIG, MMF 30 Anti-MDA-5

+/−

Malignancy

Skin findings

MP, CYC, RTX, plasma exchange 3 Anti-MDA-5 ANA +/+

0

Erythematous plaques over the MCPs, Raynaud

–

Caucasian 30 pack years Hyperlipidemia

Female 55

3

20 Anti-p155/140 ANA –

HCQ, OS, MTX

No ILD

Non-seminomatous mixed germ cell tumor Erythematous plaques over the hands and elbows, heliotrope rash

Caucasian Never smoked Morbid obesity

Male 38

4

+/−

12 ANA

HCQ, MTX

No ILD

Chest, back, and upper limbs erythema

Caucasian Never smoked Hypertension Hyperlipidemia Psoriasis –

Female 65

5

ILD interstitial lung disease, ESR erythrocyte sedimentation rate, CRP C-reactive protein, HCQ hydroxychloroquine, OS oral steroids, MTX methotrexate, AZA azathioprine, CYC cyclophosphamide, IVIG intravenous immunoglobulin, MMF mycophenolate mofetil, MP methylprednisolone pulse, CYS cyclosporine, RTX rituximab, MDA-5 melanoma differentiation-associated gene 5, ANA antinuclear antibodies, w metacarpophalangeal joint

Follow-up (months) Antibody status (positive serology) Elevated ESR/CRP at presentation

ILD onset (months after initial presentation) Medical therapy

Male 24

Male 27

Gender Age at disease onset (years) Race Smoking history Medical background

2

1

Summary of main clinical and demographic characteristics of patients

Patient

Table 1

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significant improvement. During a follow-up of 20 months, the patient developed Raynaud syndrome in his hands but was otherwise in a good condition. Patient 3 A 55-year-old female with a history of heavy smoking and untreated hyperlipidemia presented to our clinic with rapidly progressive shortness of breath and a mild rash that initiated approximately 4 months before presentation. The rash predominated on the dorsal aspect of the hands and neither gottron papules or heliotrope rash were noted. Raynaud syndrome was also recorded. The patient reported a 13-kg weight loss during a few months. There were no complains of muscle weakness and no elevation of muscle enzymes. Inflammatory markers were elevated. Skin biopsy was consistent with DM findings. HRCT demonstrated diffuse interstitial changes with wide areas of ground glass appearance. PFT showed a restrictive pattern with low diffusion capacity. EMG and echocardiography were normal. The patient had anti-MDA-5 antibody and anti-nuclear antibody with a speckled pattern. Due to her rapidly progressive respiratory decline, the patient was hospitalized and treatment with methylprednisolone pulse was initiated, yet shortly afterwards, the patient deteriorated and had to be mechanically ventilated. Additional treatment with cyclophosphamide, rituximab, and plasma exchange did not improve her respiratory failure, and the patient died 3 months after initial presentation and approximately 7 months after symptoms first developed. Patient 4 A 38-year-old morbid obese male with a history of schizoaffective disorder and non-seminomatous mixed germ cell tumor in remission 1 year after treatment presented with typical cutaneous findings including heliotrope rash, erythematous plaques over the extensor aspects of the hands and elbows, and a photosensitivity rash over the face and scalp. Skin biopsy was consistent with DM. Upon his presentation, there were symptoms and signs of muscle weakness, yet EMG demonstrated only a pattern of sensorimotor neuropathy that may have been related to the chemotherapy courses he received. There was no elevation of muscle enzymes. No respiratory complains were reported, and baseline PFT showed mild restrictive pattern with normal diffusion capacity. Inflammatory markers were within the normal limits. The patient had anti-p155/140 antibody and anti-nuclear antibody with a speckled pattern. High dose prednisone was combined with HCQ as an initial therapy, and while tapering down the prednisone dosage, MTX was initiated as maintenance therapy. Marked improvement in the cutaneous findings was observed with only mild photosensitivity rash remaining after 20 months of follow-up. Muscle weakness also resolved completely.

Patient 5 A 65-year-old female with a history of psoriasis, essential hypertension, and hyperlipidemia presented with typical cutaneous findings including erythematous rash over the upper back, neck, and chest as well as mild erythema over the upper limbs. Neither gottron papules nor heliotrope rash was noted. There was also a photosensitivity rash over her scalp. Psoriatic plaques were notable over the knees and the umbilicus. Skin biopsy taken from the back and from the knees was consistent with DM findings and with psoriasis, respectively. There were no respiratory complains and no muscle weakness. Sedimentation rate was elevated with no elevation of C-reactive protein (CRP) value. Muscle enzymes were not elevated. The patient had anti-nuclear antibody with no other autoimmune antibodies. A thorough work-up excluded underlying malignancy. Baseline PFT and EMG were normal. HCQ was initiated a few months before initial presentation to our clinic but was not tolerated. Initiation of MTX led to marked improvement of the cutaneous findings of DM with no improvement in the psoriatic plaques. During a follow-up of 12 months, the patient remained in remission.

Discussion CADM is a well-recognized clinical entity despite its relative rareness. Over the years, its association with ILD has been reported even more frequently than in the more common PM/DM subtypes. The link between anti-MDA-5 antibodies and CADM was first described less than a decade ago in Japanese patients. The present case series, which describes the clinical course of CADM patients in a rheumatology unit of a tertiary hospital in Israel, proves that this novel antibody is the major determinant of the clinical course and prognosis in this ethnic extraction as well. It is well established now that CADM carries an increased risk for developing ILD [2–5], yet in most cases, the cutaneous presentation precedes the internal organ involvement. In our series, only one patient presented with simultaneous skin and lung manifestation and this patient rapidly progressed to respiratory failure despite an intensive treatment. Patients without lung involvement had a benign course and showed a remarkable improvement in the cutaneous signs and symptoms after initiation of steroid treatment and steroid sparing agents such as HCQ and MTX. One of the most important issues regarding CADM as well as classic DM is an early diagnosis of ILD. Lung involvement carries a worse prognosis and therefore early and aggressive therapy is required. The presence of anti-MDA-5 is associated with the development

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of ILD [2, 4, 9]. In our series, all three patients who had anti-MDA-5 antibody developed severe ILD with a very poor outcome (two of the three died within 3 and 30 months of diagnosis). Screening for the anti-MDA-5 antibody is not yet routinely conducted in most of the referral clinical centers. In addition to their role in establishing the diagnosis of CADM, anti MDA-5 antibodies are useful in predicting and monitoring response to treatment. Low mean titers of anti MDA-5 prior to treatment initiation correlate with better treatment response and survival [13]. Early detection of specific autoimmune serology might prompt a decision to initiate more aggressive therapy as well as closer follow-up and vigilance for the development of ILD. Treatment options are not well established, and it is important to emphasize that there are currently no evidenced-based treatment algorithms. Most of our experiences regarding the treatment of connective tissue disease (CTD)-associated ILD are extrapolated from protocols that were suggested for systemic sclerosis [14–16]. However, some important differences exist between these diseases, mainly the use of oral high-dose steroids or methylprednisolone pulse as an induction therapy for idiopathic inflammatory myositis (IIM)-related ILD. The use of cyclophosphamide is considered to be a cornerstone in the treatment of severe lung involvement, yet it is important to keep in mind that it bares significant side effects, mainly infertility and infectious complications. Two patients in our series were treated with cyclophosphamide. One of them developed infections that prevented us from completing the course of therapy, while the other patient presented with an extremely severe and rapidly progressive ILD and died after only one pulse of cyclophosphamide. Mycophenolate mofetil emerges as a therapeutic option for IIM-associated ILD as well as other CTD-associated ILD [17–19], and its use should be considered in this context. The use of methotrexate has long been demonstrated to be safe and efficient as a steroid sparing agent and as maintenance therapy for the dermatologic manifestations of classic DM and of CADM but is problematic in the context of ILD due to its potential lung toxicity and is therefore usually not prescribed in these cases. In our series, MTX significantly improved the cutaneous findings of three fourths of patients yet had to be discontinued in two patients that developed ILD. Steroid myopathy is an important phenomenon that must be considered in the context of CADM patients since the use of high-dose steroids is a routine first-line treatment and might be confused with the emergence of classic DM symptoms. Muscle enzyme monitoring is crucial for this subset of patients in order to differentiate between disease progression and therapeutic side effects that might necessitate a prompt decline in steroid dosage combined with a switch to other agents. Two fifths of patients in our series presented in some stage of their clinical course with some degree of muscle

weakness, but there was no elevation of muscle enzymes, which strongly indicated the development of steroid myopathy which resolved as steroids were tapered down. Only one fifth of patients in our series had a malignancy, and although no conclusion can be drawn from these small series, it coincides with established data regarding the prevalence of malignancy among CADM patients which is equivalent to its prevalence among classic DM patients and even lower in some of the series [1, 11, 12]. An interesting finding was the existence of anti-p155/140 antibody in the abovementioned patient. This antibody has previously been shown to be associated with malignancy in DM patients [20, 21]. As with the case of anti-MDA-5, the detection of antip155/140 is not yet routinely conducted in most centers, and its presence should probably prompt a thorough screen for malignancy with a higher degree of suspicion beyond the routine initial and basic screen. Our small case series seems to shed more light on the distinct sub-group of patients with CADM. We presented the diagnostic and treatment challenges in these patients. The striking correlation between the presence of anti-MDA-5 antibody and the development of ILD in this series emphasizes the need to take into consideration the serological profile of patients with CADM in our clinical decisions. This may have several practical implications. First, in patients with CADM which have anti-MDA-5 antibody, we should be more vigilant for the development of ILD and frequent surveillance may be warranted, including serial PFT and imaging. Second, in CADM patients with anti-MDA-5, we may consider intensifying drug treatment, although it is not established whether early and intensive treatment alters prognosis in these patients. Third, as mentioned above, in CADM patients with anti-p155/ 140, we should be more vigilant for presence or future development of malignancy. Moreover, it may be suitable to conduct additional tests in seek of malignancy beyond the ageappropriate screening tests, e.g., total body computed tomography. Given the above, we think that the primary evaluation of patients with CADM should include assessment of specific auto-antibodies. The serological profile should be integrated with the clinical data when considering the proper management of these patients. Larger studies are needed in order to establish firm treatment protocols according to clinical and serological data in patients with CADM. The presence of anti MDA-5 antibodies emerges yet again as the central factor which determines not only the clinical phenotype of CADM or DM sine myositis but also its association with rapidly progressive ILD which warrants prompt recognition and institution of immunosuppressive therapy. Acknowledgments The study was supported by the Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, Israel. Disclosures None.

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