MDA-5 dermatomyositis complicated by interstitial lung disease and cutaneous ulcers: successful treatment with corticosteroids, mycophenolate mofetil and intravenous immunoglobulin
- 1 University of Southern California Keck School of Medicine, Los Angeles, California, USA
- 2 Division of Rheumatology, University of Southern California, Los Angeles, California, USA
- Correspondence to Dr Leanna Wise; leanna.wise@med.usc.edu
Abstract
Antimelanoma differentiation-associated gene 5 (MDA-5) dermatomyositis is a subtype of dermatomyositis that is associated with rapidly progressive interstitial lung disease (RP-ILD), as well as with a variety of cutaneous manifestations. Patients with MDA-5 dermatomyositis tend to have a poor prognosis that is often attributed to the high rates of concurrent RP-ILD. Given the severity of disease, early diagnosis and aggressive management is pivotal. We present a case of a 40-year-old woman diagnosed with MDA-5 dermatomyositis who presented with weakness, painful cutaneous ulcerations and interstitial lung disease. She was treated with monthly intravenous Ig (IVIg), weight-based prednisone and mycophenolate mofetil (MMF). After approximately 2 years of treatment, her interstitial lung disease remains stable and she has had significant improvement in weakness and cutaneous ulcerations. Our case provides evidence for early and aggressive treatment of MDA-5 dermatomyositis with a combination of weight-based prednisone, MMF and IVIg.
Background
The melanoma differentiation-associated gene 5 (MDA-5) antibody was first described by Sato et al in a small Japanese cohort.1 Presence of the MDA-5 antibody is highly specific to dermatomyositis and is not found in other connective tissue disorders including other types of myositis.2 3 In addition, the antibody appears to be mutually exclusive with other myositis-specific antibodies, suggesting that there is a unique immune response associated with the MDA-5 antibody leading to the specific clinical phenotype of the disease.2 4 Multiple cohort studies have demonstrated that the presence of the MDA-5 antibody is predictive of a poor prognosis compared with other subtypes of dermatomyositis, which has largely been attributed to the association with rapidly progressive interstitial lung disease (RP-ILD), although other factors may also be at play.3 5 6
We present a case of a 40-year-old woman with MDA-5 dermatomyositis complicated by interstitial lung disease treated with weight-based prednisone, mycophenolate mofetil (MMF) and monthly intravenous Ig (IVIg) infusions.
Case presentation
A 40-year-old previously healthy Hispanic woman was referred to our rheumatology clinic with 6 months of diffuse myalgias, inflammatory arthritis, Raynaud’s syndrome and weakness. On initial evaluation, the patient had diffuse weakness requiring her to use a wheelchair. She also had diffuse erythema of her face and body, alopecia, shallow ulcers on elbows, swelling of her digits and pitting of distal pulp on some digits. Review of systems was notable for a history of prior oral ulcerations, odynophagia, fever, dry cough and dyspnoea. Her review of symptoms was otherwise negative; pertinent negatives included no chest pain, orthopnoea, haemoptysis or dysphagia. She reported receiving intermittent doses of glucocorticoids from a clinic in Central America with some relief in her symptoms. She denied any family history of autoimmune disease, and denied exposure to solvents or pesticides, recreational drug use, tobacco use and alcohol use.
Investigations
Physical examination at her initial visit was significant for a chronically ill-appearing thin woman in a wheelchair. Examination of her upper extremities was notable for 4/5 strength on manual muscle testing of bilateral shoulder flexion and extension, bilateral shoulder adduction and abduction, bilateral elbow flexion and extension, bilateral hip flexion and extension, bilateral knee flexion and extension, and neck flexion and extension. Range of motion and strength testing of her wrists and digits was limited due to pain per patient. She had synovitis in bilateral metacarpophalangeal (MCPs) and knees. Cutaneous findings included tender digital nodules, hyperpigmentation over malar area from forehead to cheeks sparing eyelids, discrete erythematous and violaceous patches over her MCP joints, finger pads, bilateral elbows and bilateral knees, along with ulcerations with purulent drainage from her bilateral elbows (figures 1 and 2) and right third MCP. She also had erythema between all volar interphalangeal joints, hyperpigmentation on her chest and back, and diffuse alopecia.
Ulceration on patient’s left elbow at time of presentation.
Ulceration on patient’s right elbow at time of presentation.
Labs drawn soon after her initial visit revealed the following: white cell count of 5.8×109/L, haemoglobin of 136 g/L, haematocrit of 40.5%, platelets of 266 000 ×109/L, sodium of 134 mmol/L, potassium of 4.4 mmol/L, chloride of 98 mmol/L, bicarbonate of 21 mmol/L, blood urea nitrogen of 10 mg/dL, serum creatinine of 0.46 mg/dL, aspartate aminotransferase of 95U/L, alanine aminotransferase (ALT) of 165 U/L, alkaline phosphatase of 63 U/L, total bilirubin of 0.4 mg/dL, total protein of 7.2 g/dL and albumin of 3.5 g/dL. Patient’s creatine kinase level was 27 U/L and aldolase was elevated at 13.3 U/L. Her ferritin level peaked at 357 ng/mL. Her erythrocyte sedimentation rate was elevated at 70 mm/hour and her C reactive protein (CRP) was elevated at 25 mg/L. Workup for syphilis, HIV, viral hepatitis, chlamydia and gonorrhoea were all negative.
A myositis antibody panel showed MDA-5 antibody positivity by line immunoassay. Other myositis-specific antibodies including PL-7, EJ, OJ, SRP, Ku, PM/Scl 100, U2 sn ribonucleoprotein (RNP), Fibrillarin, Mi-2, P155/140, TIF-gamma, SAE1 and NXP-2 were all negative. Other pertinent negative serologies included a negative ANA, rheumatoid factor, Scl-70 antibody, Ro (SS-A) and La (SS-B) antibodies, cyclic citrullinated peptide antibody, Smith antibody and RNP antibody.
MRI of her shoulder girdle musculature demonstrated short tau inversion recovery hyperintensity and enhancement involving bilateral shoulder girdle musculature including the rotator cuffs, imaged portions of the pectoralis major, deltoids and posterior chest wall musculature, fascial enhancement and mild subcutaneous oedema. There was no notable atrophy or fat infiltration on T1-weighted images suggestive of steroid myopathy. A high-resolution CT (HRCT) of her chest was ordered given the concern for interstitial lung disease in the setting of dermatomyositis and complaints of mild dyspnoea. The HRCT showed bilateral patchy nodular and reticulonodular opacities with associated volume loss and peribronchovascular thickening; this was read as a non-specific interstitial pneumonia (NSIP) pattern (figure 3). A transthoracic echocardiogram showed an ejection fraction of 62% with normal systolic and diastolic function, normal wall motion and no signs of valvular disease or pulmonary hypertension. She was unable to perform pulmonary function tests (PFT) at that time due to persistent fatigue and poor effort. An electromyogram and nerve conduction study (EMG/NCS) was not performed due to the patient failing to show up to her outpatient appointment for this test. Given the patient’s clinical presentation and serologies, a muscle biopsy was not pursued.
Images of patient’s high-resolution CT of her thorax.
Differential diagnosis
Given the patient’s weakness, inflammatory arthritis and cutaneous manifestations, as well as her imaging findings, a diagnosis of dermatomyositis was highest in the differential diagnosis at her initial presentation. This included the possibility of not only an MDA-5 variant but also classic anti-synthetase syndrome, especially given her complaints of dyspnoea. However, also in the differential included an overlap connective tissue disease with systemic lupus erythematosus or systemic sclerosis; mixed connective tissue disease was also in the differential. An unusual paraneoplastic phenomenon could also be considered, although this was lower on the differential. Finally, given the intermittent steroid use, a steroid myopathy could be considered. When her MDA-5 positivity was confirmed on the myositis extended antibody panel, this confirmed her diagnosis of MDA-5 dermatomyositis.
Treatment
She was started on weight-based (approximately 1 mg/kg) prednisone 40 mg daily and MMF 500 mg oral two times per day, which was eventually increased to 1500 mg oral two times per day. She initially had improvement in her weakness, but worsening skin ulcerations, with concerns for osteomyelitis versus cellulitis. She was admitted to the hospital twice over a 2-month period and treated by orthopaedic surgery and dermatology with debridement, antibiotics and topical silver sulfadiazine. During this period, she was started on weight-based IVIg (2 g/kg in divided doses over 3 days, repeated every 4 weeks) in addition to continuation of prednisone and MMF. MMF was chosen as her initial first-line steroid-sparing agent due to her coexisting lung disease. A low threshold for switching to cyclophosphamide was considered should the patient have recalcitrant disease to mycophenolate. However, given the toxicities associated with cyclophosphamide therapy, the patient and her treating team did not want to use this as first line. Rituximab was also considered; however, given its long half-life and the patient’s infected ulcerations, this also did not appear to be the best first-line agent.
Outcome and follow-up
Over the next few months, she continued on oral prednisone as well as MMF and IVIg at the aforementioned doses. She followed closely with our rheumatology clinic as well as with our dermatology and pulmonary clinics; our colleagues in both of these clinics have agreed with the continued use of MMF and IVIg. As aforementioned, an EMG/NCS was not performed due to the fact that the patient failed to show up for her original appointment; by the time it was rescheduled, the patient was responding very well to therapy and it was deemed that it was unlikely to change management. Given improvement in weakness and dyspnoea on this treatment regimen, she was started on a prednisone taper. She was tapered from 40 mg daily to 3 mg daily over the course of a year without significant worsening of disease and was able to ambulate independently. The patient and her primary rheumatologist also noted dramatic improvement in ulcerations after the patient started applying topical honey to the lesions. She had mild pain at the site of old lesions that responded well to non-steroidal anti-inflammatories.
Over the next several months until time of writing, she remained clinically stable with no new disease activity. She specifically has not had new weakness, arthritis or pulmonary complaints. She reports improved exertion and can walk longer distances without shortness of breath. She reports decreased fatigability and weakness with improved energy as well as fully healed elbow ulcerations (figures 4 and 5). Her elevated aldolase, liver enzymes, ferritin and CRP all normalised within 4 months of the aforementioned treatment. Given her improvement of symptoms, IVIg was decreased from 30 g for 3 days every 4 weeks to 30 g for 2 days every 4 weeks, and a future taper is planned as well. She continues on MMF 1500 mg two times per day and prednisone 3 mg daily.
Healed ulceration on patient’s left elbow at time of writing.
Healed ulceration on patient’s right elbow at time of writing.
Repeat HRCTs at one and 2 years after her initial HRCT showed stable NSIP pulmonary disease with no new findings. Although the patient was initially unable to complete PFTs, within the last 2 years she was able successfully perform spirometry (table 1). Results of her PFTs showed a restrictive ventilatory defect with decrease in total lung capacity and diffusion capacity consistent with restrictive interstitial lung disease. Her spirometry measurements have remained stable for the past year and a half as of time of writing (table 1). A repeat transthoracic echocardiogram was performed approximately 2 years after treatment and showed normal cardiac function and no evidence of pulmonary hypertension.
Patient’s pulmonary function tests
| Spirometry | August 2018 | May 2019 | August 2019 |
| FVC (% predicted) | 50 | 48 | 51 |
| FEV1 (% predicted) | 58 | 52 | 54 |
| FEV1/FVC (% predicted) | 90 | 83 | 83 |
| DLCO (% predicted) | 45 | 44 | 57 |
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FVC, forced vital capacity; FEV1, forced expiratory volume in the first second;
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DLCO, diffusing capacity for lung of carbon monoxide;
Discussion
MDA-5 dermatomyositis is a rare subtype of dermatomyositis that is often associated with rapidly progressive lung disease and a variety of cutaneous manifestations. Given the rare nature of the disease and the relatively new discovery of the MDA-5 antibody, the optimal treatment regimen has yet to be fully clarified. Case reports and small case series suggest early and aggressive immunosuppression given the high risk of mortality with interstitial lung disease.7–9
A range of striking mucocutaneous manifestations may be seen in MDA-5 dermatomyositis, ranging from classic dermatomyositis lesions such as Gottron’s papules and heliotrope rash to more unusual manifestations such as panniculitis, palmar papules, digital pulp/periungual ulcerations, and both oral and cutaneous ulcerations.7 10–15 Cutaneous ulcerations are often painful, and can lead to other complications including osteomyelitis. When cutaneous ulcers are found in anti-MDA-5 antibody positive patients, they may be a significant predictor of interstitial lung disease.12
Patients with MDA-5 antibody positivity may have a variety of muscle manifestations, ranging from the classical proximal muscle myopathy to hypomyopathic or amyopathic disease, although degree of muscle involvement appears to vary depending on ethnic group.16 17 Our patient had significant muscle weakness in upper and lower extremities. Of note, although the patient had clinical and radiographic signs of muscle involvement, her CK and aldolase never reached significantly high levels, with peaks at 67 U/L and 13.9 U/L, respectively.
One of the major sources of morbidity and mortality in MDA-5 dermatomyositis is RP-ILD, which is often refractory to therapy.5 6 18 RP-ILD is a subtype of ILD defined by a quick onset of disease with a rapid and progressive decline in lung function, usually over the span of a few weeks to a few months. Not all MDA-5 dermatomyositis patients have RP-ILD; indeed, some may have ‘only’ ILD that follows a more insidious or smouldering course. Data thus far demonstrate that up to 42%–100% of MDA-5 positive patients have some evidence of interstitial lung disease, which is significantly higher than other subtypes of dermatomyositis.7 18 19
Interstitial lung disease remains the most significant cause of mortality, with some patients demonstrating a very rapid disease course with death less than a month after symptom onset.15 Given the severity of the disease, many clinicians recommend early and aggressive treatment to increase the chances of survival.3 7 8 A variety of immunosuppressive regimens have been tried as treatment for MDA-5 with ILD, including but not limited to high doses of glucocorticoids, cyclophosphamide, rituximab, MMF and calcineurin inhibitors, all with varying degrees of success.8 9 20–27 MMF, in particular, has demonstrated its utility in the treatment of interstitial lung disease, including in MDA-5-associated ILD.2 28–31 In addition, IVIg has demonstrated success in treating refractory cutaneous manifestations in dermatomyositis.32
Our case report supports the concept of treating MDA-5 dermatomyositis with early multimodality immunomodulation. With the use of monthly IVIg, along with daily MMF and oral prednisone, our patient showed significant improvement in systemic symptoms including decreased weakness and increased energy. Despite the classically poor pulmonary prognosis associated with MDA-5 positivity, our patient’s interstitial lung disease remained stable with improved dyspnoea and unchanged findings on repeat HRCTs. Further, she also had improvement in cutaneous manifestations of her disease. Despite her extensive and painful cutaneous ulcerations on presentation, she now only has mild pain at the sites of old ulcerations, and no new lesions after treatment with the aforementioned therapy (including topical honey applied by patient).
However, it should also be noted that at the time of the patient’s presentation to our clinic, she had been experiencing symptoms for almost 6 months. She had been receiving intermittent corticosteroids from an outside clinic which may have kept her disease at bay; regardless it appears that she was spared from having concurrent RP-ILD. It may be that her variant of MDA-5 dermatomyositis was not as severe as other cases that have been described in the medical literature, and thus, she responded better to therapy despite it not being started immediately after her very first symptoms arose.
Ultimately, more data are needed about the pathophysiology, treatment and prognosis of MDA-5 dermatomyositis. Clearly these patients warrant aggressive treatment, and similar to our patient, likely would benefit from multimodality therapy earlier rather than later in the disease course. Our patient is fortunate in that her pulmonary disease stabilised and her skin lesions and inflammatory arthritis also responded well to immunosuppression. She continues to follow in our rheumatology clinic on a regular basis.
Patient’s perspective
[Translated from Spanish using certified medical interpreting services]
When I was diagnosed it was difficult because before that I had never been sick or had that much pain. I quickly went from being completely healthy to being unable to do normal activities, and that was hard for me, especially because I didn’t get better right away and couldn’t live a normal life. Now, I know am doing so much better than I was a few years ago. I’m thankful to be strong again. But, I’m also often worried about my lungs because I know that they are not back to normal, and some days I worry about them more than others.
Learning points
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The melanoma differentiation-associated gene 5 (MDA-5) dermatomyositis is a rare connective tissue disease that is associated with high morbidity and mortality due to interstitial lung disease.
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MDA-5 dermatomyositis may have a range of clinical manifestations, including rapidly progressive interstitial lung disease, cutaneous ulcerations, and lack of overt myopathy.
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Early multimodality treatment for MDA-5 dermatomyositis is imperative, as is close clinical monitoring.
Footnotes
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Contributors LW was directly involved in the care of the patient and analysis of the data and contributed to the conception, planning and design of the report. KS and LW contributed to the drafting and revision of the report, and both KS and LW approved the final version of the manuscript to be submitted.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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