Anti-Melanoma Differentiation-Associated Gene 5 Dermatomyositis Without Cutaneous Findings or Rapidly Progressive Lung Disease: A Case Report

BACKGROUND

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) dermatomyositis is a rare subset of immune-mediated dermatomyositis in which an autoantibody against the MDA5 protein is present.¹ Initial reports of anti-MDA5 dermatomyositis arose in Asia, describing patients presenting with a clinically amyopathic form of dermatomyositis.^2,3 In amyopathic dermatomyositis, patients present with cutaneous findings of dermatomyositis, without the evidence of the muscle weakness seen in classic dermatomyositis.^2–8 As originally described, in addition to the lack of muscle involvement, anti-MDA5-positive dermatomyositis has also been distinguished by the presence of unique cutaneous and pulmonary manifestations.² More recently, particularly in North America, there has been increased recognition of an expanding spectrum of phenotypic and prognostic features associated with anti-MDA5 dermatomyositis.^2,9 We present the case of a 73-year-old male with an atypical clinical presentation of anti-MDA5 dermatomyositis to illustrate a wider spectrum of findings and complications associated with the disease.

CASE PRESENTATION

A 73-year-old male with a history of non-diabetic polyneuropathy, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) on 2 L of exertional home oxygen presented to the emergency department with a 2-week history of increasing proximal muscle weakness and recurrent falls. Falls were not associated with loss of consciousness, prodromal symptoms, or incontinence. At baseline, the patient ambulated with the help of a walker, though was no longer able to do so. He denied lower extremity paresthesia, skin rashes, myalgias, arthralgias, fevers, weight loss, or other acute complaints. While the patient did report a history of chronic dyspnea on exertion, he reported his degree of baseline dyspnea remained unchanged. His exposure history was notable for a 55-pack-year smoking history, possible agent orange exposure while serving in the military, and work in a steel mill.

On evaluation, the patient was noted to be afebrile and hemodynamically stable. He was found to be newly hypoxemic at rest, saturating 89–92% on room air, whereas at baseline his resting oxygen saturations ranged from 94 to 97%. A lung exam revealed bilateral crackles on auscultation. Jugular venous pressure was normal and the patient had no lower extremity edema. Strength testing revealed bilateral deficits in hip flexion, graded as a 4 out of 5, and decreased muscle mass was observed in the thighs bilaterally. Skin evaluation was unremarkable.

Initial laboratory testing was notable for a mild anemia with a hemoglobin (Hgb) of 12.0 g/dL (baseline Hgb 13.4–14.2 g/dL). Additional testing revealed a significantly elevated erythrocyte sedimentation rate (126 mm/h) and C-reactive protein (CRP) (28.6 U/L). Ferritin was elevated at 1270 ng/mL, with remaining iron studies showing a low total iron binding capacity (204 mcg/dL), low iron level (30 mcg/dL), and a transferrin saturation of 15%. Creatinine kinase (CK) was mildly increased at 498 U/L. Anti-nuclear antibody screen, rheumatoid factor, anti-cyclic citrullinated peptide antibody, myeloperoxidase antibody, proteinase 3 antibody, and complement levels were within normal limits.

Workup for the patient’s new resting hypoxemia included computed tomography (CT) of the chest, which showed new multifocal ground-glass opacities (GGOs) superimposed on emphysematous changes and findings suggestive of underlying interstitial lung disease (ILD). Though the patient had no documented history of ILD, review of a CT scan from 6 years prior did show changes consistent with early ILD. Furthermore, while the patient carried a diagnosis of COPD, his last pulmonary function tests (PFTs) from 10 years prior demonstrated no significant obstruction. However, PFTs did reveal an isolated low diffusing capacity for carbon monoxide, consistent with a baseline impairment in gas exchange. An echocardiogram and lung ventilation perfusion (V/Q) scan were unremarkable. Infectious evaluation revealed a positive urine streptococcal antigen test, prompting treatment with antibiotics for superimposed community-acquired pneumonia. Bronchoscopy was unrevealing. The patient’s oxygen requirements returned to baseline following completion of his antibiotic course.

To further evaluate the patient’s muscle weakness, spinal magnetic resonance imaging (MRI) and serum protein electrophoresis were obtained and unremarkable. Electromyography showed a previously documented length-dependent axonal neuropathy without evidence of myopathy. Serum aldolase returned elevated at 13.7 U/L. An MRI of the bilateral thighs revealed symmetric, mild anterior compartment thigh myositis bilaterally, along with generalized muscle atrophy (see Fig. 1). Given the patient’s ongoing weakness, lab abnormalities, and imaging findings, a dermatomyositis and polymyositis antibody panel was sent for further evaluation.

Figure 1.

Short T1 inversion recovery (STIR) MRI imaging showing mild generalized increased T2 signal in the anterior thigh compartment muscles bilaterally, compatible with myositis. A Coronal. B Axial.

The patient’s hospital course was complicated by 8 days of constipation associated with abdominal distention and pain. Abdominal X-ray showed marked cecal dilation (see Fig. 2). CT imaging of the abdomen and pelvis revealed pneumatosis with marked dilation of the cecum and colon without an obstructing mass or transition point, suggestive of acute colonic pseudo-obstruction (ACPO). The patient’s ACPO was refractory to treatment, which included an aggressive bowel regimen, electrolyte optimization, nasogastric tube placement, and two endoscopic sigmoid decompressions. Resolution was finally achieved after administration of two doses of intravenous (IV) neostigmine. Thereafter, he was started and maintained on oral pyridostigmine and did not have further recurrence.

Figure 2.

Abdominal AP X-ray showing cecal dilation to nearly 13 cm without evidence of a transition point, concerning for acute colonic pseudo-obstruction.

Twenty days following admission, the patient’s dermatomyositis and polymyositis antibody panel returned positive for anti-MDA5. Given the patient’s clinical constellation of muscle weakness, ILD, MRI findings, and return of a highly specific myositis-specific antibody (MSA), a clinical diagnosis of anti-MDA5 dermatomyositis was made and empiric treatment begun. A muscle biopsy was considered though ultimately deferred as the results were felt unlikely to change management. The patient was started on IV methylprednisolone 100 mg and intravenous immunoglobulin (IVIG) for 3 days, then transitioned to prednisone 40 mg daily. Eight days later, the patient was able to walk for the first time since admission and 3 weeks following treatment initiation, he was able to be discharged home on a prednisone taper. At 2-month rheumatology follow-up, mycophenolate mofetil was added as a steroid-sparing agent. A repeat CT scan performed 3 months after discharge demonstrated stable ILD. At 10-month follow-up, the patient’s chronic dyspnea on exertion remained unchanged, his 6-min walk test showed a stable, 2 L/min exertional oxygen requirement, and he remained at his functional baseline, ambulating with use of a walker.

DISCUSSION

Our patient’s case highlights an unusual presentation of anti-MDA5-positive dermatomyositis, providing an example of the broad spectrum of phenotypes that may be seen with this disease. Myositis-specific antibodies (MSAs), including the anti-MDA5 antibody, are antibodies unique to various forms of idiopathic inflammatory myositis and tend to correlate with particular phenotypic and prognostic features of disease.¹ Though they have variable sensitivity, anti-MDA5 antibodies have been found to be 96–100% specific in diagnosing the presence of anti-MDA5 dermatomyositis and are not typically found in polymyositis or other connective tissue diseases.^3,4,10 Although early reports suggested this diagnosis was more prevalent in Asian patient populations and among women, anti-MDA5 positivity is associated with 7–13% of all dermatomyositis diagnoses in North America.⁸ Additionally, in recent years, particularly in patient populations outside of Asia, there has been increasing recognition of heterogeneity in the anti-MDA5 phenotype and prognosis.^2,9,11

Clinically, anti-MDA5 dermatomyositis has classically been associated with specific skin and pulmonary phenotypic features. Cutaneous anti-MDA5 dermatomyositis findings have included those expected in classic dermatomyositis, such as a heliotrope rash and Gottron papules, as well as distinctive findings of palmar papules and ulcerations.^6,11 Rapidly progressing interstitial lung disease (RP-ILD) has been reported in upwards of 40% of patients, and is the most common cause of early mortality among patients with anti-MDA5 dermatomyositis.² For those patients who remain clinically stable for greater than 6 months following diagnosis, risk for progression appears to wane, though relapses can occur.^2,12

Our patient did not have the skin findings or RP-ILD characteristically associated with anti-MDA5 dermatomyositis. Rare case reports have described anti-MDA5 positivity in cases of dermatomyositis sine dermatitis, a form of dermatomyositis in which patients present primarily with muscle weakness and no cutaneous findings.¹³ Furthermore, while in Asian patient populations ILD is seen in 82–100% of patients with anti-MDA5 dermatomyositis, in non-Asian patient populations, variations in the incidence and severity of ILD have been increasingly observed.^2,9 Despite our patient having evidence of ILD on imaging, his presentation was not consistent with RP-ILD and given his history, it remained unclear whether his baseline ILD related to anti-MDA5 dermatomyositis versus prior occupational exposures.

Additionally, as first described, anti-MDA5 positivity has traditionally been seen in the context of clinically amyopathic dermatomyositis.⁶ However, in the USA, anti-MDA5 positivity has been observed with similar frequency in both clinically amyopathic and classic dermatomyositis.⁸ When anti-MDA5 dermatomyositis does present with muscle weakness, it tends to be proximal and mild, often with a normal muscle biopsy and only minimally elevated serum CK levels.² While our patient had a mildly elevated CK and his muscle weakness was proximal, his degree of weakness and associated muscle atrophy was significant, even after accounting for his relatively poor baseline functional status.

Notably, our patient’s hospital course was complicated by ACPO, a condition recognized by marked colonic dilation and bowel dysmotility, in the absence of an underlying physical obstruction.¹⁴ ACPO has been reported as a complication of other autoimmune processes, thought to be due to systemic vasculopathy within the intestinal mucosal tract that can progress to tissue ischemia.^15,16 Between 2002 and 2011, 5.4% of total systemic sclerosis cases in the United States had associated pseudo-obstruction complications. The condition has also been described in patients with polymyositis.^17,18 To date, only one case of chronic intestinal pseudo-obstruction has been reported in dermatomyositis in a patient with a positive anti-glycyl-transfer ribonucleic acid synthetase (anti-EJ) antibody; we are not aware of any reported cases of this complication occurring among patients with anti-MDA5 dermatomyositis.¹⁸ In the case of systemic sclerosis, anti-myenteric antibodies are thought to cause neuropathic and myopathic damage, raising the possibility that anti-MDA5 antibodies could play a similar role in the ACPO disease process.¹⁵

Historically, prognosis has differed significantly for anti-MDA5 dermatomyositis when compared to classic dermatomyositis. Specifically, in early cohort studies, 6-month mortality among treated anti-MDA5 patients with RP-ILD was as high as 66%, whereas the cumulative 5-year survival rate for all forms of dermatomyositis is greater than 60%.^19–22 The presence of RP-ILD is an independent risk factor for mortality among anti-MDA5 patients, even in those who receive aggressive combination immunosuppressive treatment.²³ Factors at time of diagnosis predictive of a poor prognosis and increased mortality include age over 60, male gender, fever on presentation, elevated CRP > 1 mg/dL, and oxygen saturation < 95%.²⁴ Newer data also suggests that elevated ferritin levels and a positive carcinoembryonic antigen (CEA) at any given point in the disease course may be independent predictors of mortality in this patient population.²⁵ Our patient is a 73-year-old male who presented with a CRP > 1 mg/dL, resting oxygen saturation < 95%, and ferritin level of 1270/L, predictive of a poor prognosis. A CEA was not obtained. Despite these predictors, our patient had dramatic improvement in his muscle weakness and at 10-month follow-up his respiratory and functional status remained unchanged. While anti-MDA5 dermatomyositis associated with RP-ILD typically carries a high mortality rate, anti-MDA5 dermatomyositis associated predominately with muscle weakness may represent a milder phenotypic variant with a more favorable prognosis, as appeared to be the case for our patient.^2,9

CONCLUSION

This case of an atypical presentation of anti-MDA5 dermatomyositis highlights the broad phenotypic spectrum, clinical trajectory, and prognosis that can be seen with the disease. Clinicians may want to consider the diagnosis of anti-MDA5 dermatomyositis in patients with unexplained proximal muscle weakness, even without the classic cutaneous findings or rapidly progressive pulmonary symptoms. Given its association with other forms of autoimmune disease, our patient’s course complication of ACPO suggests this diagnosis may also warrant consideration in anti-MDA5 dermatomyositis patients with refractory colonic ileus. While it remains unclear whether anti-MDA5 dermatomyositis presenting predominantly with muscle weakness carries a more favorable prognosis, as was seen in our patient, recent literature does suggest this may be the case.^2,9 Prompt recognition and treatment of anti-MDA5 dermatomyositis in this setting may have also positively impacted the patient’s disease course. At 10-month follow-up, our patient’s respiratory status remained unchanged and he had sustained improvement in his lower extremity weakness. Though his clinical trajectory thus far has been encouraging, he continues to require close interdisciplinary follow-up to monitor for symptom progression and sustained response to therapy.

Declarations:

Conflict of Interest:

The authors declare that they do not have a conflict of interest.