Dermatomyositis masquerading as a crucial differential not to overlook

Authors: Kevin Chan, Gemma Kwan, Hwei Choo Soh, Louise Evans

Abstract

Dermatomyositis is a rare autoimmune disease that typically affects the skin, muscle and respiratory system. Patients with dermatomyositis usually require prompt treatment with intense immunosuppression to reduce disease progression and multiorgan damage. A previously well male in his 40s initially presented to an emergency department with severe neck swelling. He was reviewed initially by ear, nose and throat surgeons for a probable deep neck space infection. Having been cleared of this as a cause, he was referred to clinical immunology for investigation and treatment of suspected idiopathic angioedema. A creatine kinase level was promptly requested due to the atypical nature of neck oedema that was inconsistent with angioedema, along with the presence of skin and nail changes. The patient was given a provisional diagnosis of dermatomyositis and subsequently was shown to have a positive small ubiquitin-like modifier-1 activating enzyme (SAE1) autoantibody and typical muscle biopsy. This case highlights non-histamine and non-bradykinin-mediated neck swelling as an unusual presentation of dermatomyositis that manifested with dysphagia and significant muscle involvement requiring prompt treatment.

Background

Dermatomyositis is an idiopathic inflammatory myopathy typically involving skin and muscles but can also affect the gastrointestinal tract, joints, lungs and heart. The estimated incidence is 10 cases per million population.^1^ It has a bimodal distribution, with a peak onset in children aged 5–14 years and in adults aged 45–64 years.^2^ Characteristic cutaneous features include Gottron’s papules, shawl sign, heliotrope eruption and periungual telangiectasias. Other findings include proximal weakness, interstitial lung disease and dysphagia.^2^ Pseudoangioedema is uncommon in dermatomyositis, with one study finding it was present in only 8 out of 121 patients diagnosed with dermatomyositis.^3^ It may masquerade as a primary otolaryngology disorder when affecting the neck or be mistaken as histaminergic or bradykinin-mediated angioedema.

Case presentation

A male in his 40s initially presented to an emergency department with a 3-week history of progressive neck swelling and proximal muscle weakness in his hip flexors accompanied by mild myalgia. He had no significant medical history and was a lifelong non-smoker. He had not been taking a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The initial impression was Ludwig’s angina and he underwent a CT scan of his neck, which displayed diffuse neck oedema involving the strap muscles and inflammation extending to the retropharyngeal space (figure 1). He was afebrile, saturating 99% on room air and not tachypnoeic. Proximal nailfold microhaemorrhages, along with avascular areas, were found on nailfold capillaroscopy. His white cell count was 9.1×10^9^/L and C-reactive protein (CRP) was 55.6 mg/L on presentation. Due to persistent swelling with no cause, he was transferred to a quaternary hospital with ear, nose and throat (ENT) surgery services for further evaluation. A flexible nasendoscopy performed by ENT showed no significant anatomical abnormalities in the soft palate, vallecula, larynx or post-cricoid space, but notably, there were increased secretions and coughing during the examination.

The case was discussed with the on-call immunologist for suspected angioedema, as no clear structural or infective cause was found. On review, he was noted to have generalised erythema of the face including over the nasolabial folds and an erythematous, swollen and non-tender neck. He denied being on any medication including angiotensin-converting enzyme inhibitors, dipeptidyl peptidase-4 inhibitors or non-steroidal anti-inflammatory drugs and had no personal or family history of angioedema. Overall, his clinical profile was atypical for acquired or hereditary angioedema. A thorough physical examination revealed subtle nailfold changes suggestive of periungual erythema, along with a rash on the right lateral thigh and reduced hip flexor power of 4/5. Gottron’s papules and a heliotrope eruption were absent. A creatine kinase level was requested and was found on the next day to be significantly elevated at 16 184 U/L. His renal function was normal and his urine myoglobin screen was negative. He was also found to have elevated transaminases with an alanine aminotransferase (ALT) of 143 U/L, aspartate aminotransferase (AST) of 396 U/L and an elevated lactate dehydrogenase (LDH) of 692 U/L.

Investigations

Given the initial concern for angioedema, several tests were performed to look for causes of spontaneous angioedema. His C3 and C4 complement levels were normal and the C1 esterase function and quantification were within the normal range.

The patient had a positive anti-nuclear antibody (ANA) with titre 1280 with a speckled pattern. He was anti-neutrophil cytoplasmic antibody (ANCA) negative. A myositis antibody panel consisting of 16 antigens linked to autoimmune inflammatory myopathy was performed via Euroimmun Euroline immunoassay. This was strongly positive for anti-small ubiquitin-like modifier activating enzyme subunit 1 (SAE1) antibodies, signal intensity 173 (normal range <35). It was negative for other myositis antibodies including anti-Mi-2 alpha (anti-Mi-2α), anti-Transcription Intermediary Factor-1 gamma (anti-TIF1-γ), anti–Histidyl-tRNA synthetase (anti-Jo-1) and anti–Isoleucyl-tRNA synthetase (anti-OJ) antibodies. His immunoglobulin G (IgG) level, including subclasses, was normal. In terms of his immunosuppression screen, he was hepatitis B surface antigen (HBsAg), hepatitis C core antibody (HBcAb), hepatitis B e antibody (HBeAb), hepatitis C virus (HCV) negative, HIV negative, varicella zoster virus (VZV) IgG negative and cytomegalovirus (CMV) IgG/immunoglobulin M (IgM) negative. He had an indeterminate QuantiFERON-TB Gold; however, acid-fast bacilli for Mycobacterium tuberculosis on three sputum samples were negative.

Pulmonary function tests revealed an extrathoracic restrictive pattern, with no significant bronchodilator response. CT of his chest showed multiple non-cavitating pulmonary nodules with a mid to lower zone distribution (largest measuring 15 mm in the right lower lobe), patchy areas of peribronchial consolidation likely from aspiration pneumonitis, but no radiological evidence of pulmonary fibrosis. CT of his abdomen showed no enlargement of abdomino-pelvic lymph nodes and no evidence of primary or metastatic malignancy in the abdomen or pelvis. A video fluoroscopic (barium) swallow study showed severe pharyngeal dysphagia. This led to severe pyriform fossae residue and post-swallow penetration of thin and mildly thick fluids to the vocal cords.

MRI of the thighs showed changes consistent with active myositis in the bilateral obturator internus and externus muscles and milder myositis involving the hip adductors, bilateral gracilis muscles and bilateral distal iliopsoas muscles (figure 2). Active muscle inflammation was further supported by fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan which showed diffuse and abnormal FDG accumulation within multiple muscle groups and most prominent in the head and neck, bilateral deltoids, forearms, chest wall, abdomen and pelvis (figure 3). There was no metabolically active disease elsewhere to suggest a malignancy. Tumour markers including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA-125) and prostate-specific antigen (PSA) were normal.

A muscle biopsy of the thigh showed foci of moderate numbers of necrotic, vacuolated degenerate, myophagocytosed and regenerative myofibres in a perifascicular distribution and scattered perimysial inflammation consisting of dispersed histiocytes (figure 4). Immunohistochemistry for membrane attack complex showed complement component 5b-9 (C5b-9) deposition in perifascicular endomysial capillaries, a feature typical of dermatomyositis. A diagnosis of moderate to severe SAE1 antibody positive dermatomyositis with inflammatory swelling, peribronchial consolidation secondary to micro-aspiration, dysphagia and myositis was made. Cutaneous manifestations included a positive Holster sign and periungual erythema.

Differential diagnosis

Given his subacute presentation with neck swelling and elevated CRP, there was initial concern for Ludwig angina or idiopathic angioedema. Muscle weakness, including dysphagia, was not a prominent feature of his early presentation. Differential diagnoses included other inflammatory myopathies (eg, immune-mediated necrotising myopathy, inclusion body myositis), infection-related causes (eg, cellulitis/erysipelas of the neck, deep neck space infections, bacterial sialadenitis), neuromuscular junction disorders such as myasthenia gravis, delayed drug hypersensitivity reaction (eg, drug rash with eosinophilia and systemic symptoms), acute contact dermatitis, orofacial granulomatosis, hypocomplementaemic urticarial vasculitis and superior vena cava syndrome.

Treatment

Due to significant airway muscle involvement, the patient underwent 3 days of intravenous methylprednisolone treatment, at a dose of 1000 mg daily. He was then stepped down to a prednisone tapering regimen starting at 60 mg daily, weaned by 5 mg every 2 to 3 weeks. Loading dose intravenous immunoglobulin (IVIG) (Gamunex 10%) of 2 g/kg (= a total of 165 g) was given over 5 days (= 35 g daily), followed by a further 5 cycles, 4 weeks apart at a total dose of 2 g/kg (=165 g) split over these doses. He was commenced on mycophenolate mofetil 1 g two times a day and given two rituximab doses at 1000 mg intravenous 2 weeks apart. Methotrexate was not used due to the association with interstitial lung disease and pulmonary fibrosis, noting that the patient had abnormal lung function tests, as well as in discussion with the patient, in consideration of its side effects. Azathioprine and tacrolimus were not used as mycophenolate was well-tolerated. For Pneumocystis jirovecii pneumonia prophylaxis, he was initially commenced on sulfamethoxazole-trimethoprim, though this was ceased due to the development of haemolytic anaemia (in the absence of glucose-6-phosphate dehydrogenase (G6PD) deficiency) and he subsequently tolerated nebulised pentamidine 300 mg every 4 weeks.

He was discharged after a 21-day inpatient stay. His oral medications were administered through nasogastric tube as he had persistent dysphagia at the time of discharge.

Outcome and follow-up

After 3 weeks of hospitalisation and treatment, the patient demonstrated moderate improvement in hip flexor weakness and marked improvement in cervical soft tissue swelling, although the latter had not fully resolved at the time of discharge. Dysphagia persisted, necessitating nasogastric tube feeding, which was required for a further 2 months.

Three weeks after discharge, proximal muscle strength had fully recovered and serum creatine kinase had normalised to 37 U/L. At immunology review 2 months post-discharge, cervical swelling continued to improve, with only residual violaceous facial erythema and periungual changes evident on examination. Swallowing function had improved sufficiently to allow removal of the nasogastric tube and progression to soft solids. The patient remained on mycophenolate mofetil, monthly intravenous immunoglobulin and a tapering course of prednisone.

By 3 months post-discharge, proximal muscle strength was stable, chest examination was unremarkable and cervical soft tissue swelling had completely resolved. Prednisone was successfully discontinued 7 months post-discharge, by which time dysphagia had fully resolved. Repeat pulmonary function tests showed mild improvement, with a residual restrictive pattern thought to reflect baseline physiology (figure 5a, b). A follow-up CT chest at 11 months demonstrated near-complete resolution of previously observed basal ground-glass opacities and airspace consolidation, initially attributed to aspiration. At 12 months following diagnosis, respiratory function remained stable with good exercise tolerance.

From a malignancy perspective, he denied constitutional symptoms on follow-up and will continue to be monitored on the basis of symptoms, clinical examination, regular blood tests and relevant imaging including serial CT chest imaging. He will undergo a gastroscopy and colonoscopy to exclude occult gastrointestinal/colorectal malignancy.

A plan was made to continue IVIG and to taper the mycophenolate dose in the upcoming 6 months depending on clinical progress. He will continue to be closely monitored to determine if there is a need for medication regimen change.

Discussion

We report a case of anti-SAE1 antibody–positive dermatomyositis presenting with prominent cervical soft tissue swelling, initially mistaken as idiopathic angioedema. Recognition of dermatomyositis as a potential differential diagnosis, combined with careful physical examination revealing subtle cutaneous signs, led to timely diagnosis and treatment.

Anti-SAE1 antibodies are targeted against the small-ubiquitin-like modifier (SUMO) activating enzyme, a protein structurally similar to ubiquitin, involved in post-translational modification of several target proteins by ‘sumoylation’.^4^ SAE1 antibody-positive dermatomyositis is typically characterised by cutaneous features such as heliotrope rash, Gottron’s papules, V-neck sign and shawl sign.^5^ In a large literature review encompassing 215 patients, dysphagia and interstitial lung disease were reported in 46% and 43% of cases of SAE1 dermatomyositis, respectively, while malignancy occurred in 18%.^5^

Subcutaneous tissue oedema, especially facial or neck swelling, is an uncommon feature in dermatomyositis. In a large cohort study of 121 patients with dermatomyositis, only 8 (6.61%) were affected by angioedema.^3^ A literature review of articles from 1985 to 2013 found only 19 cases of dermatomyositis manifesting with oedema.^6^ Antibodies such as anti-melanoma differentiation-associated gene (MDA)-5 antibody and anti-transcriptional intermediary factor 1γ (TIF1-γ) antibody were found to be more commonly associated with angioedema than other antibodies.^3^ Facial swelling was described in a number of cases, though neck swelling itself was less frequently described.^7^ Our literature review of 10 cases of SAE1-positive dermatomyositis found that only three cases described oedema, with one mentioning swelling around the throat region, demonstrating that involvement of the neck region is uncommon.79

This case raises awareness to emergency physicians, ENT surgeons, immunologists and rheumatologists that dermatomyositis may be a possible differential to neck swelling, especially localised ‘angioedema’ that is otherwise unexplained or idiopathic. Symptoms of dysphagia and other involvement may be subtle, thus examining for physical signs of dermatomyositis and requesting a creatine kinase level is critical. The subcutaneous oedema in our patient’s case arises from muscle inflammation in the setting of myositis, rather than histaminergic or bradykinin-mediated angioedema.

In accordance with the International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening by the International Myositis Assessment and Clinical Studies Group (IMACS), the patient had two high risk factors (dermatomyositis, dysphagia) and two intermediate risk factors (SAE1 antibody positive, male sex) and thus was considered high risk for malignancy.^10^ He underwent malignancy screening including CT scans, testing for tumour markers and a PET scan, with plans for upper and lower GI endoscopy. Comprehensive baseline and interval surveillance has remained reassuring to date.

There is limited evidence to guide optimal pharmacotherapy in anti-SAE1–positive dermatomyositis. In the largest published cohort to date, treatment approaches were heterogeneous, with most patients receiving glucocorticoids in combination with a range of steroid-sparing agents, most commonly methotrexate, but also mycophenolate mofetil, rituximab and azathioprine; intravenous immunoglobulin was used in selected cases.^11^ Our patient was treated with steroids, mycophenolate mofetil, intravenous immunoglobulin and rituximab and has achieved remission. Mycophenolate was selected based on patient preference for a daily oral regimen and consideration of its tolerability and established use in dermatomyositis. Fortunately, our patient has a good prognosis when compared with other patients with significant tissue oedema in the setting of dermatomyositis.^3^