Anti-SRP-positive necrotising myopathy concurrent with breast malignancy

Abstract

Anti-signal recognition particle (anti-SRP)-positive necrotising myopathy causes severe progressive proximal weakness with a propensity to involve pharyngeal, laryngeal and respiratory muscles. It is one of the aggressive inflammatory myopathies. First-line treatment is with high-dose steroids followed by other immunosuppressants, but this conventional therapy is often ineffective. Second-line treatment involves use of either rituximab or intravenous immunonoglobulin (IVIG). Anti-SRP-positive necrotising myopathy is frequently treated as refractory myositis due to its poor responsiveness to steroid monotherapy and conventional immunosuppressive therapies. Therefore, anti-SRP-positive necrotising myopathy differs from immune-mediated myopathy. Although anti-SRP autoantibody is found in only 4–6% of patients with idiopathic inflammatory myopathy, the actual proportion of patients with refractory anti-SRP-positive necrotising myopathy is unknown. We describe a patient with multiple comorbidities who had subacute-onset anti-SRP-positive immune-mediated necrotising myopathy (IMNM). After failing steroids, methotrexate and IVIG therapy, she made a considerable recovery with rituximab. She was later diagnosed to have breast malignancy. Malignancy-associated anti-SRP-positive IMNM is rarely reported.

Background

Immune-mediated necrotising myopathy (IMNM) is a type of inflammatory myopathy. It can be due to underlying connective tissue disorder, especially scleroderma or mixed connective tissue disorder, malignancy, or it can be idiopathic. Three definite forms of IMNM are identified, two of which are associated with specific autoantibodies, namely anti-3-hydroxy-3-methylglutaryl-coenzyme reductase (anti-HMGCR), anti-signal recognition particle (anti-SRP) and autoantibody-negative IMNM. It may be challenging to differentiate IMNM from other inflammatory myopathies based on clinical features alone.This may be important because clinical course and response to conventional treatment may be different. Prompt diagnosis and treatment of IMNM can lead to significant clinical improvement. Treatment with steroids, other immunosuppressants and intravenous immunoglobulin (IVIG) is often ineffective, especially in patients with anti-SRP IMNM. Cancer-associated anti-SRP autoantibody IMNM is reported occasionally, but individualisation of investigations and patient education like breast self-examination and awareness of postmenopausal bleeding play important roles in the early detection of cancer. We describe a patient with anti-SRP-positive necrotising myopathy with breast malignancy, which was successfully treated with rituximab and subsequently with chemotherapy for breast malignancy.

Case presentation

A female patient in her late 60s, a known case of type 2 diabetes mellitus, hypertension and hypothyroidism, presented with intermittent low-grade fever followed by gradually progressive weakness in all four limbs with myalgia but no fatigable weakness. The weakness started 1 month earlier and progressively worsened. The patient had difficulty combing her hair, getting up from the squatting position and climbing stairs. She had started taking the support of her relatives for walking. She had no blurring vision, diplopia, speech abnormalities, chewing difficulty, swallowing difficulty, difficulty in holding neck, slippage of slippers, difficulty in holding of comb and buttoning/unbuttoning her clothes, any twitching movements, bowel and bladder abnormalities, limb stiffness, any sensory abnormalities or skin rash. She had no autonomic symptoms. She had no family history of any neuromuscular disorder. She had no addiction and was on a mixed diet. She was diagnosed with hypertension and type 2 diabetes mellitus 10 years ago and has taken antihypertensive (telmisartan) and antidiabetic (metformin/glimepiride) since then. She had also been diagnosed with hypothyroidism and was on thyroid supplementation (thyroxine 50 µg/day).

On examination, all her four limbs’ bulk and tones were normal. No hypertrophy and fasciculations were noticed. There was proximal weakness in all four limbs (Medical Research Council grade 4/5). Deep tendon reflexes were preserved with no delayed relaxation of deep tendon reflexes (the Woltman sign was absent). No contractures were noticed. Gower’s sign was positive, with the presence of a waddling gait. Cranial nerve examinations were unremarkable, with normal neck flexion/extension power. The sensation was intact. Percussion stimulus on the muscle of the arm does not cause any palpable bulging or ridge around the site of percussion.

Investigations

The creatine kinase (CK) level was raised to >7800 U/L, which was more than 10 times the normal range of 30–145 U/L. The aspartate transaminase (AST) and alanine transaminase (ALT) were raised to 747 U/L (normal range: 10–55 U/L) and 639 U/L (10–50 U/L), respectively. Alkaline phosphatase (ALP) and bilirubin were normal. In complete blood count analysis, platelet counts were found to be 120 x 10⁹/L. The erythrocyte sedimentation rate value was 57 mm in first hour, serum lactate dehydrogenase was 1180 U/L (normal range: 140–280 U/L), serum thyroid-stimulating hormone was 19.3 mIU/L (normal range: 0.5–5 mIU/L) and haemoglobin A1c was 7.2%. Hepatitis B, hepatitis C and HIV serologies were found to be negative. Vitamin D level was 16 ng/mL (blood level <20 ng/mL considered to be deficient). Renal function test and serum electrolytes, which include serum sodium, potassium, calcium magnesium and phosphate, were all normal.

Electromyography (EMG) showed fibrillatory potentials and positive spike waves. Small polyphasic motor unit action potentials, early recruitment and complete reduction in the interference patterns were observed in deltoids, biceps brachii, vastus lateralis and tibialis anterior muscles, suggestive of a myopathic pattern.

Histopathological analysis of the vastus lateralis muscle biopsy sample showed maintained fascicular architecture with both atrophic fibres and few hypertrophic fibres. There was scattered myofibre necrosis with minimal mononuclear infiltrate. Periodic acid-Schiff was negative for inclusions and trichrome stain shows no fibrosis (figures 1 and 2).

Figure 1.

Pathological findings of the vastus lateralis biopsy (H&E ×400). Muscle fibres show multiple internal nuclei with relatively basophilic cytoplasm surrounding, suggestive of regenerating fibres (black arrow in main figure). Pale stained fibres with phagocytosis known as myophagocytosis (seen occasionally) with myonecrosis (yellow arrow in main figure); split myofibre shown in inset.

Figure 2.

Pathological findings of the vastus lateralis biopsy (H&E ×400) show pale cytoplasm with internal nuclei suggestive of degenerating myofibre (black arrow).

Serum antinuclear antibodies and extractable nuclear antigen panel was negative. Myositis profile including myositis-specific antibodies (MSA), namely Mi-2, TIF1γ (transcription intermediary factor 1-gamma), MDA5, NXP2, anti-HMGCR, anti-SRP, anti-aminoacyl-tRNA synthetase antibodies (PL-7, PL-12, EJ, OJ, Jo-1) and myositis-associated antibodies viz. PM-Scl75, PM-Scl100, Ro-52 and Ku, was performed. It showed strong positivity of anti-SRP and confirmed the provisional diagnosis of ‘IMNM’.

Differential diagnosis

The clinical findings of symmetrical proximal muscle weakness with preserved reflexes without any upper motor neuron lesion findings and the raised ALT, AST and CK were consistent with an acquired myopathy. The EMG findings also supported myopathy. EMG, though not useful in determining the actual cause of myopathy, is useful in localising the site of the lesion. The patient has proximal muscle weakness with a power of 4/5, along with raised CK.

A female patient with hypothyroidism exhibited symmetrical proximal muscle weakness. Before conducting any laboratory investigation, we considered metabolic myopathy due to hypothyroidism as one of our differential diagnoses. However, the patient did not display any clinical features commonly associated with poorly controlled hypothyroidism, such as cold intolerance, weight gain or hair loss. Moreover, on examination, there was no bradycardia, delayed relaxation of deep tendon reflexes and myxoedema upon percussion. A significantly raised CK (>7800 U/L) is not compatible with hypothyroid myopathy. Painful proximal muscle weakness and low vitamin D levels in a postmenopausal female patient led us to consider osteomalacic myopathy in our list of differential diagnoses. However, the patient’s serum calcium level and ALP level were normal. She had been started on high-dose vitamin D therapy and subsequent investigations ruled out osteomalacic myopathy. Dystrophic myopathy was less likely based on the age of presentation, lack of positive family history and absence of certain clinical findings like calf hypertrophy and contractures. After the history, clinical examination and hyperCKemia, we kept inflammatory myopathies as our major differential diagnosis. Lack of cutaneous lesions viz. heliotrope rash, Gottron sign, shawl sign or any other erythematous rashes and absence of laboratory features like MSA associated with dermatomyositis and histopathology of muscle biopsy helped us to rule out dermatomyositis. Based on disease progression, a markedly raised CK level and pattern of muscle involvement, inclusion of body myositis was ruled out. A markedly raised CK level with histopathological findings consistent with IMNM and positive autoantibody against SRP confirmed the diagnosis of ‘anti-SRP-induced IMNM’.

Treatment

A revised dose of thyroid supplementation (changed to 100 µg of thyroxine from 50 µg) and a high-dose vitamin D therapy were initiated. It is usually recommended starting the therapy with oral prednisolone and combining it with an immunosuppressive agent like azathioprine, methotrexate or mycophenolate mofetil.¹

We started the patient on oral prednisolone (1 mg/kg of body weight) and azathioprine 50 mg/day. Over the next 10–12 days, after the initiation of immunosuppressive treatment, she developed distal and neck muscle weakness, and proximal muscle weakness worsened. Hence, steroid pulse therapy with methylprednisolone 1000 mg/day for 3 days was initiated with periodical glycaemic monitoring. Then, the patient was kept on an oral immunosuppressive regimen, but a few days later, she developed dysarthria and dysphagia. So as per standard protocol, a total dose of 100 g IVIG, equivalent to 2 g/kg of body weight, was administered for over 5 days (the dose of IVIG for inflammatory myopathies is 2 g/kg).² A subcutaneous methotrexate regimen was initiated because of severe weakness and lung involvement in the form of interstitial lung disease (ILD) (figure 3) on radiological evaluation. Methotrexate has low risk of idiosyncratic hypersensitivity pneumonitis. Around 10 days after the administration of IVIG, the patient developed type 2 respiratory failure and she was kept on mechanical ventilation with minimal sedation but no muscle relaxant. Then, she received rituximab (1 g followed by a second infusion 2 weeks later; the dose of rituximab for inflammatory myopathies is 750 mg/m² body surface area up to 1 g).² Subsequently, she was on prednisolone and subcutaneous methotrexate. ‘Wean screen’ was performed daily, and she was tracheostomised. With daily monitoring of underlying conditions and haemodynamic parameters, a spontaneous breathing trial was given, and we were able to keep her off the ventilator 2 months after the first rituximab infusion.

Figure 3.

High-resolution CT of the chest shows ground-glass opacities with interlobular septal thickening and perilymphatic nodules in subpleural locations on both sides of inferior lobes.

Though the presence of anti-SRP, anti-MDA5 or anti-Mi-2 antibodies is non-significant for the risk of cancer,³ she underwent contrast-enhanced CT of the thorax and abdomen. Subsequently, we could stop methotrexate and taper the prednisolone dose to 20 mg daily. Around 1.5 months after the rituximab infusion, CK in the serum fell to 380 U/L. Tracheostomy was decannulated and her swallowing and neck muscle power improved (around 2.5 months after the rituximab infusion). Her weakness in the upper limbs improved, and subsequently, around 4 months after the first rituximab infusion, power in her lower limbs improved such that she could walk with support.

Outcome and follow-up

At the first follow-up (4 weeks after the discharge from the hospital on 15 mg prednisolone daily), she could walk with the help of a walker. There was no worsening of pharyngeal, respiratory or axial muscle power. CK did not show any further increase and glycaemic control was satisfactory. In her first follow-up visit, prednisolone was tapered down to 10 mg.

Eight weeks later, in her second follow-up visit, there was no worsening of power. She could walk with only a stick. The prednisolone was further reduced to 5 mg daily.

Four to 5 months after the discharge from the hospital, the patient noticed a lump in her left breast (progressively increasing in size over the next 2 weeks). Bilateral breast mammography with ultrasonography (USG) showed a large, non-circumscribed, irregularly shaped heterogeneous iso-hyperdense lesion in the upper outer quadrant with an indistinct margin with regionally distributed fine pleomorphic and amorphous microcalcifications with involvement of overlying skin and underlying chest wall. USG correlation revealed a large, partly circumscribed, irregularly shaped heterogeneous hypoechoic confluent mass lesion with interspersed echogenic areas involving almost whole of the left breast parenchyma showing mild peripheral vascularity. There were subcentimetric ipsilateral axillary nodes, one with raised cortical thickness and one with rounded morphology and loss of fatty hilum. These imaging features suggested inflammatory breast malignancy (Breast Imaging Reporting and Data System-4) with suspicious nodal deposits. Histopathology of the core biopsy of the left breast lump showed invasive ductal carcinoma of no special type. Immunohistochemistry (IHC) of the core-cut biopsy sample revealed HER2/neu-positive ductal carcinoma. The whole-body positron emission tomography-CT revealed a hypermetabolic left breast lesion, left axillary node and liver segment VIII lesions, likely malignant. Histopathology of the USG-guided liver biopsy report showed a metastatic lesion. On IHC, the lesion was HER2/neu positive. She had been started with a chemotherapy regimen containing gemcitabine, carboplatin and trastuzumab.

Discussion

Idiopathic inflammatory myopathies (IIMs) are acquired myopathies that are associated with muscle weakness, hyperCKemia and myopathic patterns in EMG. Histopathology with IHC findings varies among IIMs. IMNMs are aggressive and relative refractory myopathies among IIMs.² Anti-SRP and anti-HMGCR autoantibodies are MSA associated with IMNM, but their role in the pathogenesis of the disease is unknown.^4–6

Patients with anti-SRP IMNM present with severe proximal myopathy with rapid progression with markedly elevated CK.⁷ We usually get dysphagia in these patients.⁸ Distal and axial muscles are also involved in anti-SRP IMNM. Various extramuscular manifestations occur that comprise thrombocytopenia, ILD and cardiac involvement (conduction abnormalities and cardiac insufficiency).⁸ ILD is not typically associated with anti-SRP antibody myositis, unlike polymyositis and dermatomyositis. In this case, the patient had proximal and distal muscle involvement in both upper and lower limbs, and axial, respiratory and bulbar involvement. In the complete blood picture of the patient, she had thrombocytopenia.

An SRP is a ribonucleoprotein (RNP) that mediates protein translocation to the endoplasmic reticulum.^{9 10} Muscle co-culture with anti-SRP-positive serum has been shown to reduce myoblast activity.¹¹ In another study, anti-SRP antibody-induced myotubular atrophy increased proinflammatory cytokines and impaired myoblast fusion due to decreased interleukin-4/13.¹² Apart from the intracellular effect of anti-SRP antibodies, sarcolemmal SRP expression and subsequent complement activation are other proposed pathogenic mechanisms.¹³ The actual immune-mediated events that lead to muscle fibre damage remain unclear. This RNP is present in all protein-processing cells and due to its ubiquitous nature along with muscle involvement, lungs, heart and blood cells are involved. Between both anti-SRP and anti-HMGCR patients, anti-SRP myopathy is usually more severe with more severe muscle damage with a relatively refractory course.⁴ In accordance with Zhao et al,¹⁴ refractory anti-SRP-positive patients are individuals who, despite 12 months of rigorous steroid therapy, show little to no improvement. In addition to a myriad of clinical factors, such as male gender, the severity of myopathy at its inception and the presence of ILD, the influence of race is prominent in the determination of refractoriness.

The mean age of anti-SRP IMNM onset is 40–50 years, and it affects more females than males with a ratio of 1.6:3.6.^{11 15 16}

A markedly elevated CK level is prominent in anti-SRP IMNM. Serum CK levels positively correlate with myofibre necrosis.¹⁷ An extremely high CK level is usually seen in dermatomyositis (70–80% of cases), polymyositis, necrotising myopathy and anti-synthetase syndromes. In IMNM, elevated CK levels are almost always associated with disease activity. An asymptomatic patient with raised serum CK level is rarely observed in anti-SRP IMNM.¹⁸ Human leucocyte antigens DRB1*08:03, B*5001 and DQA1*11:01 are more commonly detected in anti-SRP autoantibodies associated with IMNM.^{19 20}

Malignancy associated with anti-SRP IMNM is rarely reported. Compared with anti-HMGCR IMNM, anti-SRP IMNM has a lower risk of malignancy.²¹ Various extramuscular presentations, especially ILD, cardiac abnormalities and malignancy, may be the key factors affecting the prognosis of anti-SRP IMNM.

Many systematic reviews and meta-analyses have been conducted to identify factors associated with cancer risk in inflammatory myopathies. Dermatomyositis, advanced age, male gender, dysphagia, skin ulceration and presence of anti-TIF1γ are associated with enhanced risk of cancer. The risk of cancer in patients with IMNM depends on autoantibody positivity: anti-HMGCR autoantibody-positive IMNM is associated with a high risk of cancer while anti-SRP autoantibody positivity is not. Markedly raised lactate dehydrogenase and CK levels are associated with reduced cancer risk.^{3 21} Malignancy-associated anti-SRP IMNM is rarely reported. No predominant type of malignancy has been observed in association with IMNM, so no specific cancer screening can be formulated. However, cancer screening should be done for those patients who have IMNM without MSA or anti-HMGCR autoantibodies, who are older than 50 years and who are diagnosed within 3 years (as the majority of cancers occurred within 3 years of myopathy diagnosis).^21–23 Autoantibody-negative IMNM has the highest risk of concomitant neoplastic disease, so a complete paraneoplastic panel and CT of the chest, abdomen and pelvis must be done.

Anti-SRP IMNM responds poorly to conventional therapy; hence, use of a combination of steroids, other immunosuppressive agents and courses of rituximab is beneficial. Once respiratory involvement occurs in IMNM, intensive care and aggressive therapy are required. It prevents permanent muscle damage and myofibre atrophy.²⁴ The B cell-depleting therapy helps in improving quality of life by significant and sustained improvement of muscle power and decreasing steroid-induced systemic adverse effects indirectly by allowing clinicians to reduce the steroid dose. Regarding the long-term safety of rituximab, a study by Van Vollenhoven et al in 2012 found no higher risk of cancer in rituximab-treated patients. When comparing age-matched and sex-matched incidence ratios for confirmed malignancies and breast cancer with data from the general US population (SEER Database) and published data on adults with rheumatoid arthritis, no increased risk was identified.²⁵

Anti-SRP IMNM has less strong association with malignancy compared with anti-HMGCR or seronegative IMNM. However, this case report reveals a unique instance of breast malignancy in a patient with anti-SRP-positive IMNM. This underscores the importance of vigilance for malignancy in patients with anti-SRP positivity. To ascertain the true prevalence of malignancies in patients with anti-SRP IMNM, a broader clinical cohort is needed. Also, anti-SRP-positive IMNM can cause severe disability, even life-threatening respiratory muscle paralysis leading to type 2 respiratory failure. Hence, it must be considered if a patient presents with subacute progressive symmetrical proximal weakness with markedly increased serum CK. In refractory anti-SRP IMNM, rituximab may be preferred to IVIG.

Learning points.

• Anti-signal recognition particle (anti-SRP) autoantibody-positive immune-mediated necrotising myopathy (IMNM) may rarely be associated with malignancy.

• Extramuscular features like interstitial lung disease, malignancy and cardiac involvement can impact the prognosis of the disease.

• Rituximab therapy may be useful in refractory and severe anti-SRP IMNM.

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