Challenges in Treating Dermatomyositis-Related Rhabdomyolysis: A Case Report of Steroid-Induced Myopathy

Introduction

Dermatomyositis (DM) is an idiopathic autoimmune connective tissue disorder that causes muscle inflammation along with specific skin manifestations. Although the pathogenesis is not clear, external triggers (such as virus or bacteria) are suspected to play an important role in inducing the inflammation [1]. The diagnosis is based on characteristic criteria, which include symmetric proximal muscle weakness marked by the rise of muscle enzymes and the presence of specific skin symptoms. Cutaneous symptoms, which can precede the myositis or even occur independently, include various rashes, photosensitivity, and pruritus. The muscle biopsy, the EMG findings, and the myositis-specific autoantibodies (MSA) panels can support the process of diagnosis [1,2].

Rhabdomyolysis, although mainly associated with immobilization, injury, or the use of medications, can also be a manifestation of DM [3]. The breakdown of skeletal muscle fibers leads to the release of intracellular content into the plasma, often generating life-threatening complications. In case of DM-induced rhabdomyolysis, the standard therapy of forced diuresis and fluid therapy will not be effective. Therefore, in the aforementioned instances the first-line treatment is based on systemic glucocorticoids [1,4].

This report describes a rare case of rhabdomyolysis secondary to anti-Mi2-positive DM, highlighting the challenges in distinguishing myositis exacerbation from steroid-induced myopathy.

Case Report

A 50-year-old woman with arterial hypertension, with a previous medical history of appendectomy, was admitted to the Department of Gastroenterology at Provincial Hospital in Opole, Poland, due to elevated liver enzymes. She presented with acute muscle pain, progressive bilateral muscle weakness, and difficulty in walking, rising from a seated position, and lifting objects, for around 4 weeks. Two weeks prior to the first symptoms of myalgia, she had a sore throat, nasal discharge, feeling feverish. As an upper respiratory tract infection was diagnosed, she was treated with standard doses of acetaminophen and ibuprofen along with a 10-day course of amoxicillin. As there was a slight improvement, she decided to take part in a 20-km walking pilgrimage, which she could not finish due to fatigue. She experienced progressive myalgia that worsened with activity, which was accompanied by a mildly pruritic rash on the face, neck, anterior chest, and upper limbs (Figure 1). A day prior to hospital admission, she noticed dark reddish urine.

Physical examination revealed a symmetrical weakness of upper and lower limbs and neck muscles. She was moving with much difficulty, especially when changing position and lifting both arms. A skin rash presenting as maculopapular erythema on the upper chest and face was present. Further examination revealed initially overlooked cutaneous changes, including mild edema of the eyelids and periorbital area, an erythematous-papular rash with small petechiae and erosions on the upper limbs, and symmetric erythema at the dorsal aspect of the MCP joints (Figure 1).

Laboratory results at admission showed hypertransaminasemia (ALT 201 U/L; AST 552 U/L), elevated serum creatine phosphokinase (CPK) activity (4782 U/L), increased LDH activity (857 U/L), elevated levels of troponin T (93 ng/L), CK-MB (67 ng/ml), and elevated D-dimer levels. There was no sign of renal insufficiency, with normokalemia and creatinine level within the reference range. The inflammatory markers (CRP, PCT) and the tumor markers (AFP, CEA, CA19.9, CA125, CA15.3) were within normal ranges. Urinalysis revealed proteinuria (496 mg/L), and hematuria (2124 erythrocytes/μL). The suspicion of myoglobinuria was further supported in the days following the admission by a qualitative dipstick test result, which was positive for “myoglobin or hemoglobin” in a urine sample containing protein but no red blood cells.

As initial management, to preserve renal function, intravenous fluids and sodium bicarbonate were administered promptly. Due to increased peripheral edema, an osmotic diuretic (mannitol at a dose of 1–2 g/kg, depending on fluid balance, diuresis, and plasma osmolality) was used. Intravenous human albumin (1 g/kg for 2 days) was introduced to treat hypoalbuminemia.

As her symptoms did not improve and there was a significant rise in the activity of CPK (with its peak activity of 9704 U/L), idiopathic inflammatory myopathy was suspected. Initially, she received intravenous methylprednisolone at a dose of 1000 mg per day for 3 consecutive days, followed by oral prednisone (80 mg daily), with a noticeable reduction of myalgia in the first days of the treatment. As the CPK level decreased significantly, she developed dysphagia, coughing, dysphonia, and difficulty breathing, which she had not noticed previously. After a temporary improvement in motor functions, she also reported re-emergence of difficulties with sitting and moving the lower limbs. Prednisone was discontinued due to suspicion of acute steroid-induced myopathy (SIM). On the day following discontinuation of prednisone, she experienced partial reduction in the severity of new symptoms. She was again able to sit up on her own and had increased strength of the muscles in the lower limbs and notable mitigation of breathing problems. However, after 2 days with no further improvement observed, she had worsening muscle pain and the CPK level increased significantly once more. Therefore, we restarted the steroid treatment together with an intravenous immunoglobulin therapy (IVIG) at the total dose of 2 g/kg body weight divided into 5 days. Due to dysphagia and high risk of malnutrition, we started enteral nutrition through a nasogastric tube and supplementary parenteral nutrition was provided. The local ICU was preemptively notified to take over the patient’s care in the event of further deterioration of respiratory functions, but fortunately, after changes in the applied therapy, this was not necessary. Figure 2 illustrates the change in the plasma levels of the most important biomarkers over the course of the initial treatment.

Additional diagnostic procedures were performed during the patient’s stay at our department: the antinuclear antibody (ANA) screen test was positive, with a granular speckled pattern. No significant pathology was detected with chest X-ray, abdominal ultrasound, esophagogastroduodenoscopy, or abdominal and pelvic CT.

After the initial management, the patient was referred to the Department of Internal Medicine and Rheumatology in Katowice, Poland for further treatment and diagnosis. Subsequent serological studies confirmed the presence of Mi-2 and Ku antibodies at the threshold level. Neither antiphospholipid antibodies nor SLE-specific antibodies were detected, and the levels of C3 and C4 complement components were within the reference range. Electromyography (EMG) showed myogenic-dominant damages in the right upper-limb muscles. HRCT revealed bilateral hydrothorax and compressive atelectasis, especially in the left lower lobe. Cyclophosphamide was administered as an intravenous infusion, with good tolerance. Based on the clinical picture and further test results, the primary diagnosis of DM was confirmed.

The differential diagnosis included immune-mediated necrotizing myopathies (IMNM) and an overlap syndrome between DM and systemic lupus erythematosus (SLE). Although a muscle biopsy, which would be conclusive in this case, was not conducted, the characteristic clinical features, particularly the occurrence of specific skin changes, made the diagnosis of IMNM unlikely, as this condition does not usually involve the skin and is rarely accompanied by anti-Mi2 antibodies, which are highly specific for DM [1,2]. For an overlap syndrome to be confirmed, the diagnostic criteria for both SLE and DM must be satisfied. While the preliminary requirement of ANA presence was fulfilled, none of the immunological criteria were met. Moreover, the clinical manifestations associated with SLE are more likely explained by alternative causes, including pleural effusion secondary to fluid overload and proteinuria secondary to rhabdomyolysis.

As a result of the treatment, a considerable improvement was observed with reduction of myalgia and increased muscle strength. Thus, the patient was discharged from the hospital. As DM is associated with a higher oncological risk than in the normal population, she was advised to receive regular monitoring and follow-up.

Discussion

In theory, almost all factors that physically damage the cell membrane or lead to an imbalance between energy supply and consumption can lead to rhabdomyolysis [3,5]. In present case, several factors that could have independently initiated rhabdomyolysis were present (infection, medications, intense physical exertion); therefore, diagnosis of DM was not initially obvious to us, even though some elements of the clinical picture could indicate a connective tissue disorder. After several days of ineffective fluid therapy due clinical deterioration, it was concluded that the factor damaging muscle cells had not been eliminated and we needed to extend the differential diagnosis to initiate adequate cause-targeted treatment.

On the 5th day after the first dose of methylprednisolone, during the subsequent prednisone therapy, after a transient clinical improvement, the patient’s general condition deteriorated rapidly, and new symptoms appeared. She had difficulty sitting up on her own, developed dysphagia and dysarthria, and reported breathing problems and an ineffective cough. She underwent neurological consultation, during which the consulting neurologist found features of bulbar syndrome. Due to the temporal correlation, acute SIM was suspected, and immediate discontinuation of prednisone was recommended.

SIM occurs in 2 forms – chronic and acute. Chronic SIM most often develops after about a month of glucocorticosteroid use and is a consequence of sarcopenia and increased catabolism of muscle proteins. Although steroids remain the most common cause of drug-dependent myopathy, acute SIM is a rarely reported complication of steroid treatment [6]. Especially when high doses of fluorinated steroids are administered intravenously, acute SIM may occur within a few days or even a few hours after steroid intake [7–9]. Although not fully understood, it is suspected that non-transcriptional effects of steroids on the ability of skeletal muscle to produce energy, in particular increased ROS production and impaired mitochondrial function, play a key role in its mechanism [7,10].

Acute SIM can have a severe, life-threatening course or be relatively mild. Typical symptoms include weakness of the proximal muscles of the limbs, whereas the distal limb muscles, muscles innervated by the bulbar nerves, and respiratory muscles are less often involved [7–9]. All of the above can also be affected in DM [1]. Since SIM can overlap with the picture of rhabdomyolysis in DM, the clinical distinction between these 2 entities is particularly problematic. Moreover, in our opinion, some cases of severe and supposedly refractory DM are actually an overlap of acute SIM with inflammatory myopathy.

No single diagnostic test is pathognomonic for SIM; therefore, the diagnosis must be supported by clinical findings, typical history, pattern of muscle involvement, results of additional tests, and improvement after steroid discontinuation [7,9]. Although not completely specific, electroneuromyography (ENMG) of laryngeal muscles can be helpful in distinguishing dysphagia secondary to DM from SIM. ENMG usually does not reveal any changes in isolated SIM, or shows a picture of myopathy without spontaneous muscle activity. On the contrary, abnormal spontaneous muscle activity is very typical for active myositis [11]. However, if SIM appears secondarily to steroid therapy of myositis and involves a muscle previously affected by inflammation, the interpretation of this test is difficult. Unfortunately, due to the limited availability of ENMG of laryngeal muscles and the need for decisive action in the face of the rapidly deteriorating condition of the patient, we could not use this tool in the differential diagnosis.

Skin biopsy along with the biopsy of the affected muscle remain an important diagnostic procedure in identifying patients with myositis. In contrast to inflammatory myopathies, in SIM there is usually no inflammatory infiltrate, and a typical finding is, among others, type IIb muscle fiber atrophy [12]. However, since in the discussed case the SIM was superimposed on the inflammatory changes in DM, muscle biopsy would most likely not contribute significantly to distinguishing between the 2 disease entities.

In case of suspected SIM, steroid therapy should be ceased, but if it is indispensable, it is suggested to select a non-fluorinated agent at the lowest effective dose [11,12].

Considering that the high doses of methylprednisolone were the most probable cause of assumed acute SIM, and discontinuation of prednisone was associated with the recurrence of myalgia and increase in CK activity, in addition to starting IVIG therapy, we introduced parenteral hydrocortisone without noticing any further clinical deterioration.

Conclusions

Rhabdomyolysis without a clear initiating factor, especially in the absence of a response to initial fluid therapy, requires a broad differential diagnosis, including IMNM and, if skin symptoms are present, DM. Although in such cases high doses of steroids are the treatment of choice, they can trigger the onset of SIM, the symptoms of which overlap with the changes observed in DM, thereby complicating the selection of appropriate clinical management strategy. Differentiating between the exacerbation of myositis symptoms and SIM is problematic and not always possible. In case of suspected SIM, steroid should be used at the lowest effective dose or replaced by a non-steroidal agent.