Amyopathic dermatomyositis combined with peripheral neuropathy

Background

The idiopathic inflammatory myopathies (IIMs) are a spectrum of systemic immune-mediated disorders that can cause damage to several organs other than skeletal muscles, such as the skin.1 As a subcategory of the IIMs, amyopathic dermatomyositis is characterised by the existence of cutaneous lesions of classic dermatomyositis, including Gottron’s sign, heliotrope rash and poikiloderma, along with the absence of myopathy. It is a rare disease, with an estimated incidence of two cases per million persons, and it represents 2%–21% of all cases of dermatomyositis.2 Amyopathic dermatomyositis can systemically involve organs other than the skin, and 13%–65% of patients with the disease develop interstitial lung disease, which is sometimes severe and rapidly progressive. Rapidly progressive interstitial lung disease in patients with amyopathic dermatomyositis is known to be associated with serum antibodies against melanoma differentiation-associated protein 5 (MDA5).2 The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria are the only validated classification criteria for IIMs including amyopathic dermatomyositis.3

There have been several reports of dermatomyositis occurring in conjunction with polyneuropathy, and such combined syndromes are referred to as ‘neuromyositis’.4–7 However, in many cases, the patients did not experience neuropathic symptoms while alive, and the diagnosis was therefore made at autopsy, which precluded the prospective collection of clinical data concerning such syndromes. The existing reports have also described heterogeneous findings. The relationship between peripheral neuropathy and inflammatory muscular diseases is therefore poorly understood.

Herein, we report a rare case of amyopathic dermatomyositis associated with peripheral neuropathy.

Case presentation

A 49-year-old woman presented to the University of Tsukuba Hospital (Tsukuba, Japan) with muscle weakness and sensory disturbances in her legs. Her symptoms had first manifested as frequent stumbling. She later felt weakness in her left leg muscles and a tingling sensation on the lateral side of her left lower leg, but she did not seek medical attention because she could still walk. However, her symptoms did not spontaneously dissipate, and she began to experience a burning pain in the soles of her feet.

She consulted an orthopaedist, and a physical examination revealed weakness in the left tibialis anterior muscle. However, MRI of the lumbar spine revealed no signs of lumbar spondylotic radiculopathy. The patient subsequently developed a tingling sensation in her left ring and little fingers. She next saw a neurologist, but nerve conduction studies and needle electromyography revealed no abnormalities. The abnormal sensations in her left extremities gradually extended to her buttocks, and her ambulatory difficulties worsened.

Three months later, she felt a tingling sensation on the lateral side of her right leg, and she began wobbling when she attempted to wash her face. She consulted another neurologist, and laboratory blood tests returned positive results for anticyclic citrullinated peptide (CCP) antibodies and antiganglioside-monosialic acid 1 (GM1) IgM antibodies. Peripheral neuropathy associated with collagen disease was suspected, and she was admitted to our hospital approximately 2 years after the initial onset of symptoms.

Her medical history was unremarkable apart from temporary renal dysfunction of unknown aetiology at 10 years of age, and she had no family history of neuromuscular diseases. She had not exhibited signs of viral infection before her symptoms appeared. She had smoked 10 cigarettes per day since she was ~20–24 years old, and she was a social drinker. She had never held a job that involved handling lead or organic solvents.

A physical examination revealed a blood pressure of 99/67 mm Hg, a regular pulse rate of 76 beats/min, a body temperature of 36.8°C, a percutaneous oxygen saturation level of 97%, a height of 166.8 cm and a weight of 53.0 kg. Her heart and respiratory sounds were normal. She had no finger deformities and no swelling or tenderness of her limb joints, but she did exhibit edematous erythema over both upper eyelids and light erythema over her neck and anterior chest (figure 1A,B).

During a neurological examination, the patient was alert and conscious. She had no cranial nerve abnormalities. No muscle atrophy was found, but mild muscle weakness (grade 4 in manual muscular testing) was noted in her left iliopsoas, quadriceps, hamstrings, gastrocnemius and flexor hallucis longus muscles. Deep tendon reflexes were absent in all limbs, and no pathological reflexes were observed. In the distal portions of her legs, she exhibited insensitivity to pain, impaired pallesthesia and paresthesia. She also had dysesthesia in her left ring and little fingers and both feet. No cerebellar ataxia was noted. She was not experiencing orthostatic hypotension, urinary difficulties, diarrhoea or constipation. An ophthalmic examination revealed no vitreous opacity or uveitis.

Investigations

Complete blood count testing revealed a white cell count of 3.4×10⁹/L (reference range, 3.5–9.0×10⁹/L), a red cell count of 4.47×10¹²/L (reference range, 3.5–5.0×10¹² /L), a haemoglobin concentration of 133 g/L (reference range, 115–150 g/L), a haematocrit level of 39.5% (reference range, 35%–45%), a platelet count of 227 000/ µL (reference range, 150 000–350 000/µL) and an erythrocyte sedimentation rate of 12 mm/hour (reference range, <13 mm/hour). Further testing revealed a blood urea nitrogen concentration of 12.1 mg/dL (reference range, 8.0–20.0 mg/dL), a creatinine concentration of 0.56 mg/dL (reference range, 0.4–0.8 mg/dL), a total protein concentration of 7.1 g/dL (reference range, 6.5–8.5 g/dL) and an albumin concentration of 4.0 g/dL (reference range, 4.1–5.0 g/dL). She had normal levels of serum muscle enzymes, including creatine kinase (83 IU/L), aspartate aminotransferase (29 IU/L), alanine aminotransferase (27 IU/L) and lactase dehydrogenase (201 IU/L). Her serum had a 1.17 ng/dL free thyroxine concentration (reference range, 1.00–1.70 ng/dL) and a 1.140-μIU/mL thyroid-stimulating hormone concentration (reference range, 0.500–5.00 μIU/mL).

A random blood sample had an 86 mg/dL glucose concentration and a 6.1% haemoglobin A1c level. Our patient had an elevated serum level of vascular endothelial growth factor (VEGF; 490 pg/mL; reference value, 262 pg/mL8). Her serum levels of IgG, IgA and IgM were all within reference ranges, as were her levels of angiotensin-converting enzyme, antinuclear antibodies, anti-Sjögren’s syndrome antigen A/B antibodies, myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA) and proteinase 3 (PR3)-ANCA. She did not have detectable levels of serum myeloma protein or urinary Bence Jones protein, and she tested negative for hepatitis C-related antibodies. A cerebrospinal fluid analysis revealed normocytosis and a normal protein concentration (33 mg/dL).

ECG revealed a normal sinus rhythm, and a chest X-ray at admission showed nothing abnormal. Head MRI revealed no abnormalities, but cervicothoracic spine MRI revealed bulging of the C3/4, C4/5 and C5/6 discs and mild spinal cord stenosis. No abnormal signals were observed in the spinal cord or nerve roots. MRI of the lower legs revealed no abnormal signals in her skeletal muscles. Gallium-67 scintigraphy revealed no abnormal gallium-67 accumulation.

Nerve conduction studies revealed that her F wave appearance rates were considerably reduced in the left median nerve and bilateral ulnar nerves despite her being awake during the examination. Additionally, decreased sensory nerve action potential amplitudes were observed in the bilateral ulnar and sural nerves, and a slightly decreased conduction velocity was noted in the right sural nerve (table 1). Neither conduction blockage nor temporal dispersion were observed. Needle electromyography revealed motor unit potentials with high amplitudes and long durations in the left first dorsal interosseous, vastus lateralis and tibialis anterior muscles.

The erythema that was noted at admission gradually spread to her shoulders, fingers, elbows and knees over 2 weeks (figure 1C,D). She developed a continuous slight fever on postadmission day 8, and she began experiencing a dry cough on day 15. Chest CT showed multiple interstitial shadows (figure 1E,F). A skin biopsy sample from an upper eyelid revealed inflammatory cell infiltration that mainly consisted of lymphocytes in the dermis (figure 2). Tests for serum antibodies against MDA5 yielded positive results.

Differential diagnosis

Based on the diffuse proximal muscle weakness in the patient’s lower limbs, the presence of sensory disturbances and anti-GM1 antibodies and the absence of deep tendon reflexes, we concluded that the peripheral nerves were the main loci of the lesion. The absence of abnormalities in early-stage nerve conduction study and needle electromyography assessments was probably due to the disorder mainly affecting the small fibres. The potential diagnoses included vasculitic neuropathy, sarcoidosis and chronic inflammatory demyelinating polyneuropathy and the asymmetric distribution of neuropathy and the nerve conduction study findings indicative of axonal damage were consistent with the known features of vasculitic neuropathy. The patient’s serum MPO-ANCA and PR3-ANCA levels were low, but this left open the possibility of ANCA-negative vasculitis. As for the possibility of sarcoidosis, the patient’s skin lesion presentation and serology findings were not supportive of that diagnosis. The patient’s nerve conduction study findings were inconsistent with those typically observed in demyelinating neuropathy, but her low F wave appearance rates were suggestive of the proximal peripheral neuropathy typically seen in patients with chronic inflammatory demyelinating polyneuropathy. A sural nerve biopsy was considered necessary to make a diagnosis of chronic inflammatory demyelinating polyneuropathy, but such a biopsy could not be performed because, based on the EULAR/ACR classification criteria, our patient was unexpectedly further diagnosed with amyopathic dermatomyositis associated with interstitial lung disease,3 which resulted in treatment for the lung disease being prioritised.

Treatment

Our patient was treated with prednisolone (50 mg/day), tacrolimus (4 mg/day) and four rounds of treatment with intravenous cyclophosphamide. She also underwent intravenous immunoglobulin therapy as a treatment for neuropathy (figure 3).

Outcome and follow-up

Following treatment, our patient’s fever abated, her skin rashes gradually disappeared and her serum anti-MDA5 antibody titre declined to within reference limits. Intravenous immunoglobulin therapy relieved her muscle weakness but only partially ameliorated her dysesthesia symptoms, although blood tests yielded negative results for anti-GM1 IgM antibodies. Nerve conduction studies performed 3 years after the onset of disease revealed an improved F wave appearance rate in the left median nerve (31%).