Pneumomediastinum: A severe complication of dermatomyositis

Dermatomyositis is an autoimmune disease that is considered a subset of idiopathic inflammatory myopathy. It is characterized by a skin rash with progressive muscle weakness. Pneumomediastinum is a rapidly progressive complication of dermatomyositis, which is hypothesized to be a result of ruptured subpleural cysts, pulmonary vasculopathy, and steroid-mediated weakening of alveolar walls. This complication is associated with a high mortality rate of 30%. Hence, it should be rapidly investigated and treated when there is a high clinical suspicion. In this article, we report a rare case of patient with dermatomyositis (DM) who developed pneumomediastinum and discussed a literature review of this occurrence.


Dermatomyositis
(DM) is an autoimmune inflammatory myopathy, characterized by muscle weakness in combination with a pruritic or burning rash predominantly present in sun-exposed areas of the body [1]. This report evaluates the presentation of pneumomediastinum (PnM) in a patient with DM. An extensive review of the literature reveals that this finding is not as uncommon as previously thought.

CASE REPORT
A 48-year-old Filipino female was diagnosed with DM, after presenting with Gottron papules, a heliotrope rash, and muscle weakness. Laboratory studies and muscle biopsy were used to confirm her diagnosis. She was treated in the Philippines and was discharged on a drug regime which included prednisolone, hydroxychloroquine (HCQ) 200 mg daily, and mycophenolate mofetil (MMF) 500 mg daily.
On her return to Australia, her general practitioner (GP) referred her to the outpatient department due to a poor clinical response to treatment after eight months. On outpatient review, she was found to have ongoing cutaneous manifestations and shortness of breath (SOB) ( Figure 1A-C). She also had per rectum bleeding, a weight loss of 12 kg in the past one year, severe proximal muscle weakness limiting her mobility, and ongoing arthralgia primarily affecting her wrists, interphalangeal joints, and left knee. On physical examination, she had a blood pressure of 118/78 mmHg, a heart rate of 110 bpm, a respiratory rate of 16 bpm, oxygen saturation of 96% on room air, and was afebrile with a temperature of 37.1°C. She was cachectic with a typical heliotrope rash over her eyelids, Gottron papules localized to her hands and feet, and swollen metacarpophalangeal and carpometacarpal joints. Respiratory examination revealed bibasal, end inspiratory crepitations and coarse crackles. She had proximal weakness with muscle power graded 4/5 in the upper and lower extremities bilaterally.
Imaging of the chest, abdomen, and pelvis revealed extensive PnM and multiple bilateral peripheral patches of consolidation (Figure 2A-C). In her previous chest radiograph five years prior, she was noted to have bilateral apical fibrosis so extensive progression was evident. Following CT, a PET-CT scan was arranged to exclude malignancy and it revealed mild fluorodeoxyglucose (FDG) uptake (SUV max : 4) within the multifocal, predominantly peripheral, and subpleural pulmonary consolidation. Other findings on imaging included subcutaneous emphysema (SE), peribronchial thickening, and ground glass opacities with mild avidity. There was no dominant nodule or mass visible. There was also mildly increased multifocal FDG uptake throughout the proximal upper and lower limbs and larger muscle groups of the shoulder and pelvic girdles. There was no associated abdominal or pelvic mass or lymphadenopathy. Finally, the colonoscopy and gastroscopy were performed and did not reveal any concerning pathologies.
The patient was commenced on Prednisolone 50 mg once daily. A bronchoscopy was then performed, revealing a posterior tracheal wall disruption ( Figure 2D) with bronchoalveolar lavage (BAL) showing bronchial epithelial cells, fungal elements, and alveolar macrophages. She was then prescribed Methylprednisolone IV 500 mg daily and antibiotics consisting of ceftriaxone and clarithromycin. Following clinical improvement on day four of admission, she was discharged from the hospital on Prednisolone 50 mg daily and MMF 1g BD, with outpatient follow-up arranged. Few days later, the patient was seen by her GP and was given antibiotics, which was not effective. She represented to the hospital one month later following a twoweek history of increasing swelling in her neck and face associated with difficulty swallowing solids; she denied shortness of breath. The patient was arranged for an inter-hospital transfer to a tertiary center for persisting PnM confirmed on repeat chest X-ray ( Figure 2E). A repeat bronchoscopy did show same anatomical defect in the tracheobronchial tree. A barium contrast swallow study revealed no concerning features and importantly, no sign of esophageal tear. As the patient showed clinical improvement, she was discharged home. At a one-month review, her chest radiograph (CXR) showed ongoing blunting of the left costophrenic angle, similar to her previous study, and a more prominent extensive SE overlying the neck and chest when compared to previous CXR, suggesting further deterioration. She was admitted to the hospital for observation and was managed conservatively with a constant input from cardio-thoracic team. One stable, she was discharged for outpatient follow-up.  Repeat CXR one month later: There is surgical emphysema over the chest wall extending to the neck with pneumomediastinum and no pneumothorax. There are some increased peribronchial lung markings peripherally in the right mid and at both lung bases particularly the left.

DISCUSSION
Dermatomyositis is an autoimmune condition that involves rash and muscle weakness with an estimated annual incidence of 1.9-7.7 cases per million people and a prevalence of 20 cases per million people with a predilection toward females (2:1) [2]. A five-point criterion was first conceptualized in 1975 by Bohan and Peter, who combined clinical findings, investigation results, and pathological features in order to diagnose this. The requirements include the presence of typical DM rashes, symmetrical proximal muscle weakness, elevated serum levels of muscle-associated enzymes, muscle biopsy showing evidence of myositis and myopathic changes on electromyography. Definite DM was defined as the presence of a rash with three other features; probable DM was defined as the presence of a rash with two other features; and possible DM was defined as the presence of rash with one other feature (Table 1) [3].
Dermatomyositis is sometimes associated with respiratory disease, such as bronchiolitis obliterans, organizing pneumonia, interstitial pneumonitis, and diffuse alveolar damage, in up to 50% of patients [4]. The authors would like to further add that spontaneous PnM is a rare but distinctive complication of DM. The first reported case of PnM in a patient with DM was in 1986 [5]. To date, there are 63 reported cases of PnM in the context of DM, presenting at a mean age of 40.7 years old, with an age range between 10 and 74 years ( Table 2) [1,[4][5][6][7][8][9][10][11][12][13]. Dermatomyositis can happen in any age groups, however, previous case reports suggest that are more common in the adult population with only 3 children. In these 63 cases, 36 were male and 27 were female. Pneumomediastinum in DM has been associated with a poor prognosis, especially when the patient has a normal CK level. Previous research reveals that the mortality rate of PnM in DM patients may reach as high as 50%, a rate which is directly related to the severity of the patient's interstitial lung disease (ILD) [6,7]. In our literature review of 63 patients, 20 patients (31.7%) had died, with the deaths mostly related to rapidly progressive ILD.
There are three hypotheses surrounding the pathogenesis of PnM in DM. The first of these is the rupture of subpleural cysts secondary to raised intraalveolar pressure in ILD patients with previously damaged alveoli. Secondly, pulmonary vasculopathy causing disruption of the mucosal barrier and rupture of airway lesions has been proposed. Finally, the use of glucocorticoids in the treatment of ILD resulting in alveolar wall weakening and thus increasing the risk of rupture has also been suggested [4,8,9]. Known risk factors for the development of PnM in DM include the presence of ILD, cutaneous vasculopathy, hoarseness of the voice, laryngeal lesions, previous steroid use, younger age, and normal CK levels [8,10].
Previously reported clinical features of DM-specific patients developing PnM include SOB, DM-specific dermatological features, no or little evidence of muscular involvement, the presence of cutaneous vasculopathy, normal or slightly elevated levels of CK, ILD and a history of systemic glucocorticoid use [13]. The differential diagnoses for dyspnoea in patients with DM should include: pulmonary infections, aspiration pneumonia from esophageal dysfunction, concomitant ILD or drugmediated ILD, pneumothorax, and hypoventilation from weakened respiratory muscle activity [8].
There are four categories of investigations that can be performed to assess this. These include laboratory studies, imaging, electromyography, and histology. In laboratory testing, the two foci are the assessment of muscle-associated enzyme levels, which include CK, aldolase, lactate dehydrogenase (LDH) and AST, as well as an autoimmune screen [3]. Of the muscle enzyme levels, the most sensitive and specific is CK [3,14]. Autoimmune assessment of DM is complex and fraught with low sensitivities [15]. Such tests should be subclassified into DM-specific autoantibodies and DM-associated           autoantibodies. There are six subtypes of DM-specific autoantibodies, namely, anti-aminoacyl transfer RNA synthetase (ARS) (including Anti-Jo-1) anti-DNA helicase (anti-Mi2); anti-melanoma differentiation-associated gene 5 (MDA5); anti-transcription intermediary factor (TIF-1γ); anti-nuclear matrix protein-2 (NXP-2); and anti-small ubiquitin-like modifier activating enzyme (SAE) [15]. DM-associated antibodies include anti-Ku, which is involved in DNA repair, antinuclear antibody (ANA), and anti-SSA/Ro, which are antibodies for ribonucleoprotein complexes with small cytoplasmic RNAs (hY-RNA) [15,16].
In terms of imaging modalities, chest radiograph (CXR) has a low sensitivity for early detection but is useful as a baseline assessment of the lungs and to assess for significant ILD. When diagnosed, serial CXR should be conducted to not only assess the progression of the disease, but also to determine the presence of complications, such as spontaneous pneumothorax (PTX), PnM, SE, and infection [17]. High-resolution CT (HRCT) of the chest can provide a better assessment of ILD, including findings of irregular linear opacities, consolidation, ground glass opacities, pleural effusion, and honeycombing, as well as providing information about the location and extent of PTX, PnM, and SE, when CXR is inconclusive [18]. The utility of bronchoscopy includes assessment of the site and size of laryngeal lesions, bronchial wall necrosis and the ability to perform a histological assessment when lung biopsy is performed [6,10,19]. Histological findings may include nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, and usual interstitial pneumonia [1]. Bronchoalveolar lavage plays a supportive role, as it may provide some information regarding disease progression, however, there is no characteristic BAL cell profile for parenchymal involvement in DM [20].
The management of DM with ILD is complex and involves a multi-disciplinary approach. With regard to dermatological presentation, non-pharmacological management includes avoidance of sunlight and using protective clothing. For extensive erythematous lesions and muscle weakness, steroids are titrated to CK levels. The addition of immunosuppressive agents and antipruritic agents are given as per treating rheumatologist or dermatologist recommendations, with due consideration of patient's tolerability and medication side effects [21]. The most effective treatment for ILD has yet to be decided. Currently, patients are treated with corticosteroids as first-line management. However, since high dose steroids alone are associated with poorer prognosis, patients are often given one or more immunosuppressive agents including azathioprine (AZA), cyclophosphamide (CYC), cyclosporine (CS), mycophenolate mofetil (MMF), and/or intravenous immunoglobulins (IVIG) [13,21].

CONCLUSION
In conclusion, PnM is a rapid progressive complication of DM with concomitant ILD. A respiratory physician should regularly follow up patients with PnM to ensure that the condition can be monitored and respiratory function optimized. *********

Author Contributions
Shawn Zhenhui Lee -Conception of the work, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Mohammed Tousif Syed -Design of the work, Interpretation of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Pranav Kumar -Acquisition of data, Interpretation of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Guarantor of Submission
The corresponding author is the guarantor of submission.