Treatment of myopathy and cutaneous ulcers in anti-MDA5-positive dermatomyositis with triple therapy

Abstract

Antimelanoma differentiation-associated protein 5 positive dermatomyositis (MDA5 DM) is a rare subtype of idiopathic inflammatory myopathy. There are limited data available regarding the cutaneous manifestations of MDA5 DM in the African American population. We presented the case of a male patient in his early 20s who presented with debilitating cutaneous ulceration and myopathy. Workup revealed interstitial lung disease (ILD) and positive MDA5 serology consistent with MDA5 DM. He made a remarkable recovery in terms of myopathy and cutaneous ulcerations with a multipronged regimen of prednisone, intravenous immunoglobulin and mycophenolate mofetil. However, there was a progression of ILD on this regimen which warranted use of rituximab.

Background

Dermatomyositis (DM) is a type of immune-mediated myopathy (IIM) that typically presents with symmetrical muscle weakness and cutaneous findings like Gottron’s papules, heliotrope rash and erythema of neck and shoulders.¹ Various myositis-specific autoantibodies (MSA) have been identified which are associated with unique clinical presentations within the IIM spectrum.² Antimelanoma differentiation-associated protein 5 (MDA5) is a novel MSA associated with a rare subtype of DM characterised by cutaneous vasculopathy and rapidly progressive interstitial lung disease (RP ILD).^3–5 Other clinical features of MDA5 DM include fever and arthritis.² More importantly, it follows an aggressive course and is associated with poor prognosis with no clear guidelines on treatment of the cutaneous manifestations of the disease. There is a bimodal age distribution with a peak onset at 4–12 years in children and 40–60 years in adults and is well documented in white and Asian patients with a female predominance. While the clinical presentation is driven by ethnicity, such data from African American population are sparse.2 4 6 7 Here, we describe a male patient with MDA5 DM with atypical age of disease onset in the early 20s with extensive cutaneous ulcerations, progressive ILD and clinically significant myopathy. This case adds to the limited data available on cutaneous manifestations of MDA5 DM in the African American population and its successful treatment. Further, it adds to the recently identified subcluster of MDA5 with clinically significant myopathy.

Case presentation

A male patient, in his early 20s without comorbidities, presented to the emergency department for worsening lower extremity weakness over 3 months. His symptoms began with a poikilodermic rash over his right chest 2 years prior, which spread to involve his anterior and posterior trunk over the last 3 months. He also reported progressive shortness of breath, dysphonia and an unintentional 50-pound weight loss over 6 months. Prior to this admission, he received a 4-week trial of prednisone (60 mg × 2 weeks, 40 mg × 1 week, 60 mg × 1 week), topical tacrolimus and mupirocin without improvement of his rash.

The patient’s physical examination was notable for scabbing and hypopigmentation over the periorbital region bilaterally, hyperpigmented plaques over the cheeks, ulceration and erythema over intertriginous areas including neck, axillae, bilateral elbows (figure 1A, B) and third metacarpophalangeal joints bilaterally. He was also found to have a well-circumscribed necrotic scar on his lower back (figure 2), and poikilodermic rash over the chest (figure 3). Multiple painful macular lesions were evident over his palms (figure 4), as well as dilated nailfold capillary loops. His motor strength was 2/5 proximally and 3/5 distally in all 4 limbs with normal tone and reflexes. The joint examination was normal.

Figure 1.

Ulcerations over the (A) left elbow and (B) right elbow.

Figure 2.

Necrotic rash over the buttocks.

Figure 3.

Poikilodermic rash over the anterior chest and abdomen.

Figure 4.

Painful macular lesions over the hand.

Investigations

Investigations: admission laboratory values are available in table 1. Initial biochemistry and complete blood count panels were within normal limits except for mild normocytic normochromic anaemia and hypoalbuminaemia. Antineutrophil cytoplasmic antibody, HIV, hepatitis B and hepatitis C serologies were negative.

Table 1.

Laboratory values at admission

Test	Value	Normal range
Haemoglobin	11.5 g/dL	14–17.4 g/dL
Albumin	3.3 g/dL	3.5–5 g/dL
ESR (erythrocyte sedimentation rate)	65 mm/hour	0–15 mm/hour
CRP (C reactive protein)	3 mg/dL	<0.8 mg/dL
C3	128 mg/dL	80–300 mg/dL
C4	43 mg/dL	20–60 mg/dL
Creatine kinase (ck) at admission	87 IU/L	<200 IU/L
CK 6 weeks prior to admission	448 IU/L	<200 IU/L
Ferritin	3008 ng/mL	25–270 ng/mL
Aldolase	11.3 U/L	<8.1 U/L
ANA (antinuclear antibody)	1:160 speckled pattern
Myomarker panel anti-MDA5 anti-SS-A 52kD	51 U 118 U	<20 U <20 U

IU, international units; U, units.

Imaging: CT scan of the chest and abdomen showed few segmental pulmonary emboli within the left lower lobe and organising pneumonia in bilateral lower lobes (figure 5A) and diverticulitis of the ascending colon. An MRI of the lower extremity showed increased signal on T2 and STIR (short tau inversion recovery) imaging within the adductor muscles, consistent with myositis.

Figure 5.

(A) Consolidation in lower lobe on chest CT consistent with organising pneumonia at admission. (B) Progression of interstitial lung disease with worsening of patchy bilateral basilar predominant subpleural reticular and ground glass opacities at 8 months of follow-up.

Biopsy: a skin biopsy from the thigh revealed non-specific changes including hyperkeratosis and mild spongiosis. Right vastus lateralis biopsy revealed type 2 fibre atrophy without evidence of an inflammatory myopathy.

Treatment

The patient was anticoagulated with intravenous heparin for pulmonary embolism and treated with ceftriaxone and metronidazole for diverticulitis based on the CT imaging although he was asymptomatic. In view of progressive cutaneous manifestations, interstitial lung disease and myopathy, immunosuppressive therapy with intravenous methylprednisolone (48 mg daily) was initiated. He also received intravenous immunoglobulin ((IVIG) 140 g, 2 g/kg over 4 days) and was initiated on mycophenolate mofetil ((MMF) 500 mg daily orally for 9 months, increased to 1500 mg two times a day) and tacrolimus (1 mg two times a day orally) as steroid-sparing agents. His course was complicated by steroid-induced psychosis and febrile neutropenia (absolute neutrophil count ANC-0) and resultant septic shock. He was managed with broad-spectrum antibiotics and granulocyte colony-stimulating factor injections with improvement in both his clinical status and ANC. An extensive haematological workup, including flow cytometry testing, was negative; thus, the neutropenia was attributed to a medication adverse event and a bone marrow biopsy was not pursued. Tacrolimus was discontinued in view of neutropenia after a brief course of 5 days.

Outcome and follow-up

His muscle power improved significantly with IVIG, MMF and prednisone over a course of 3 months and he was discharged. At 1-month follow-up, power improved to 4/5 in proximal muscles and 5/5 in the distal muscles of both upper and lower extremities. A repeat CT scan of the chest at 8-month follow-up showed progression of ILD with a non-specific interstitial pneumonia pattern (figure 5B). Pulmonary function test at admission and 8 months was with suboptima1l effort. Over the course of the year, his cutaneous ulcerations dramatically improved (figures 6–9) despite the ILD progression. Prednisone was tapered to 20 mg over the course of 3 months. He was tapered off steroids completely over the course of 1 year and maintained on monthly IVIG (2 g/kg over 4 days) and MMF (1500 mg two times a day). He was started on rituximab (1000 mg/day intravenous infusion 2 weeks apart every 6 months) due to the progression in ILD. He received 6 doses of rituximab (6000 mg over 15 months) till date with the CT chest following the fourth dose of rituximab demonstrating slight improvement in ILD. He is currently following with the advanced pulmonary failure and transplant clinic for close monitoring of ILD progression.

Figure 6.

Healed right elbow ulcer.

Figure 7.

Healed left elbow ulcer.

Figure 8.

Healed right hand ulcer with third proximal interphalangeal joint flexion contracture.

Figure 9.

Healed left hand ulcer.

Discussion

Here, we described the successful treatment of cutaneous ulcerations and myopathy in a young man with MDA5 DM. Patient’s age of onset, ethnicity and presence of myopathy add to the growing literature on the heterogenous presentation of MDA5 DM.

Our patient’s presentation is interesting given his disease onset occurred in his early 20s, which is an atypical age for both juvenile dermatomyositis (JDM) and adult MDA5 DM.2 4 6–9 There is a paucity of data comparing the clinical presentation between adult and juvenile form of MDA5 DM. Juvenile MDA5 DM were likely to have arthritis, fever, lymphadenopathy, cutaneous and oral ulcerations compared with those with MDA5-negative JDM.^{7 8 10} Clinically significant myopathy was rare in both adult and juvenile forms of MDA5 DM. Among adult patients, arthritis and cutaneous ulceration were less prevalent beyond 60 years old.¹¹ Our patient has overlapping features from both JDM and MDA5 DM.

Cutaneous vasculopathy is a hallmark of MDA5 DM. Cutaneous ulcers are significantly more prevalent in MDA5 DM compared with other subtypes of DM. Non-vasculopathic manifestations such as heliotrope rash, mechanic’s hand, Gottrons papules and palmar papules were commonly seen in association with both MDA5 JDM and adult DM compared with other subtypes of DM; however, this difference was not statistically significant.2 6 12–14 Majority of the studies evaluating skin lesions in DM, MDA5 DM and JDM versus adult have been predominantly studied in white patients. This is relevant given the clinical presentation of MDA5 DM varies widely depending on ethnicity. For example, cutaneous ulcerations are more prevalent in the white population compared with the Japanese population, while ILD is more prevalent among the latter.3 4 12 15 An observational study from the USA compared the frequency of cutaneous ulcers in MDA5-positive and MDA5-negative patients across various ethnicities, noting higher prevalence in the Asian and African Americans compared with Hispanic and white patients.¹⁶ However, black subjects formed less than 5% of the total cohort. As evident in our patient, the identification of skin lesions in non-white population can be challenging leading to late diagnosis. More studies are needed to help adequately categorise adult and paediatric cohorts as well as identify the skin manifestations in non-white patients to guide diagnosis and treatment options.^{16 17}

Historically, MDA5 DM has been defined by the absence of clinically significant myopathy.^2–5 Our patient’s presentation with myopathy adds to the growing literature of myositis in MDA5 DM. It is intriguing that although MRI identified evidence of myositis in the adductor muscles of thigh, biopsy results had evidence of muscle atrophy without any evidence of myositis. CK and aldolase were only mildly elevated. The discrepancy between the degree of clinical weakness, imaging and biopsy findings posed a diagnostic and therapeutic dilemma. Lack of evidence of myositis on the biopsy could be attributed to the 4-week course of steroid he received prior to presentation and lack of ongoing inflammation in the lateral compartment of thigh at the time of the biopsy.

A recently published French study identified three subclusters within the MDA5 DM–RP ILD, vasculopathic and rheumatoid cluster, based on the clinical presentation and prognosis.¹⁴ This is the first study to identify the subgroups within MDA5 DM. This is the only large-scale study that has a significant representation of the black population, comprising approximately half of the studied population. The vasculopathic cluster was characterised by cutaneous ulcers, digital necrosis and proximal weakness. These patients had a low prevalence of RP ILD and low mortality. A male predominance was noted in contrast to other two clusters and MDA5 DM in general. Our patient fits well into this subset based on his cutaneous manifestations and myopathy; however, he is unique in his development of progressive ILD that remains a challenge in the treatment of his case.

Management of MDA 5 DM is challenging due to the refractory nature of disease, limited treatment options and associated adverse events. Randomised studies comparing treatment strategies are lacking. Immunosuppressive therapy with high-dose prednisone, calcineurin inhibitors and cyclophosphamide remain the first-line treatment in ILD.^18–20 Aggressive upfront use of triple therapy showed survival advantage in ILD compared with step-up immunosuppressive therapy, while addition of IVIG demonstrated a decrease in mortality by 30.3% in RP ILD.^19–21 Rituximab has shown promise as an effective second-line agent in those with ILD.²² In patients with MDA5 ILD treated with steroids and at least one other immunosuppressive agent, rituximab showed 71.43% response rate.²³

Vasculopathic and non-vasculopathic skin manifestations of MDA5 DM are refractory to treatment with immunosuppressives agents. Systemic steroids, rituximab, sildenafil, bosentan and botulinum toxin local injection have been tried with variable success.^{18 24} There are limited data on use of MMF and IVIG. A larger study that looked at cutaneous manifestations in various subtypes of DM noted MMF to be associated with remission of skin lesions while no such association was noted with IVIG.²⁵ Resolution of cutaneous ulcers were noted with the combination of MMF and prednisone in two case reports.^{26 27} However, progression of cutaneous ulcerations was noted on similar regimen in another patient warranting the addition of IVIG.²⁸

In our patient, both myopathy and cutaneous ulcers resolved with prednisone, IVIG and MMF. Based on our patient, we recommend triple therapy with prednisone, MMF and IVIG as an initial therapy in patients with myopathy and cutaneous vasculopathy. However, more studies are needed to develop optimal treatment regimen for various clusters within MDA 5 DM. In our patient, ILD progressed on this regimen, necessitating rituximab initiation. Rituximab was chosen as an alternative to cyclophosphamide in this young patient to preserve fertility. We were unable to continue calcineurin inhibitors due to cytopenias/septic shock which also limited aggressive immunosuppression upfront. It is hard to predict if upfront use of either rituximab or cyclophosphamide could have halted the progression of the ILD.

Given the unusual factors in this case, the diagnosis and management of our patient were challenging. Our case highlights the heterogeneity within DM presentations, particularly within MDA5 DM that requires further investigation. As these patients can present with cutaneous findings without systemic involvement, more awareness is required among physicians for early identification of MDA5 given the high rates of RP ILD and mortality. Although there are data from the white and Asian population, there is an unmet need for such data from non-white population. Further studies are required for the development of predictive models for cluster identification in MDA5 DM to guide early aggressive immunosuppressive therapy.

Learning points.

• Cutaneous vasculopathy can be the presenting clinical feature of melanoma differentiation-associated protein 5 (MDA5) dermatomyositis (DM). Cutaneous manifestations in MDA5 include cutaneous ulcers, heliotrope rash and poikilodermic rash.

• Triple therapy with prednisone, intravenous immunoglobulin and mycophenolate mofetil can lead to remission of myositis and cutaneous ulcers in MDA5 DM.

• There can be progression of interstitial lung disease despite control of other aspects of disease like myositis and cutaneous ulcers warranting addition of further immunosuppressive agents like rituximab.

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