Wednesday, 21 December 2016

Dermatomyositis

Case

A 72 year-old female presented in June 2015 with rash on her hands, face and around her nostrils. She was referred to dermatologist, skin biopsy was performed and showed lichen planus, which was subsequently treated with topical steroids and emollients.

5 months later rash recurred, spreading to the arms and torso. She developed progressive myalgia affecting the neck and proximal limb muscles in combination with progressive swallowing difficulty. Mobility deteriorated such that she started to fall in the community and was unable to perform activities of daily living independently.

After dermatological review polymyalgia rheumatic was suspected for which she was started on 20 mg prednisolone. Despite this, two months later she was unable to stand or sit without assistance. Further deterioration in swallow resulted in presentation to Whipps Cross Hospital and subsequent transfer to Royal London Hospital.

Interview revealed no significant past medical history except for idiopathic thrombocytopaenia and longstanding osteoarthritis. She was on no regular medication and had no history of alcohol use or smoking.


On examination she was short of breath (FVC<0.9) and failed both bedside and formal swallow assessments. There was a heliotrope rash and Gottron’s papules as well as erythematous rash on left elbow, torso and behind both ears. There were dry mucous membranes (eyes and mouth). Weakness was pronounced in the proximal muscle groups with distal sparing. She was areflexic, sensation was intact.

Investigations
Blood results showed normal ESR and CRP with increased CK of 900, ANA 1/160 and ENA negative.
MRI head and whole spine showed increased signal within the neck and paraspinal muscles.
Nerve conduction studies showed incidental mild left carpal tunnel syndrome, whilst needle EMG sampling revealed no spontaneous activity in any of the muscles sampled. However, voluntary activated motor units were markedly polypahsic and short in duration with evidence of early recruitment. 
Muscle MRI showed increased signal in relation to the musculature of the pelvic girdle  and within the thigh musculature bilaterally, which would support the diagnosis of myositis.
Muscle biopsy showed widespread upregulation of MHC Class I, fibre necrosis with prominent macrophagic (and milder lymphocytic) infiltration as well as fibre regeneration.

Diagnosis
Inflammatory myopathy with dermatological involvement (Dermatomyositis)

Next steps
The priority was to excluding underlying malignancy.
CXR, CT CAP and Mammogram were performed.
CT CAP showed early bronchiectatic changes in the left lung base but no malignancy. Mammogram showed a dense, nodular background pattern with scattered benign calcifications.

PET revealed mildly increased uptake in the muscles and basal pleural thickening.

An extended ENA panel including HMGCR antibodies were negative. Anti-TIF1 gamma antibody was positive.


Treatment:
The focus of acute treatment was to control the inflammatory drive leading to muscle damage. As such we administered 3 days of IV methylprednisolone followed by 60 mg prednisolone. One week later she was given four days of IV immunoglobulins. She also received IV cyclophosphamide.

For maintenance therapy, methotrexate was given with folic acid, PPI cover and bone protection.

Owing to the swallowing difficulties a radiological guided gastrostomy tube was inserted for nutritional support.

She was discharged to an inpatient rehabilitation unit and finally to home.

Outcome:
Since August 2016 there are no further dermatological manifestations and she remains rash free.  There has been ongoing improvement in her muscle strength such that she is able to rise from a chair without the use of her arms and is independently mobile. Swallow has improved such that she is meeting her nutritional needs orally and no longer requires supplementation via gastrostomy tube.

Unfortunately just 3 months after last clinic review she developed severe and rapidly progressive abdominal swelling and large bilateral PEs. She has now been diagnosed with ovarian teratoma, not previously evident on malignancy screen


Learning Points:

1)    Dermatomyositis is a multisystem disorder.
2)    Early recognition of myositis and treatment can lead to excellent outcomes
3)    TIF1 Gamma antibody is strongly associated with malignancy. The dermatological and muscle disease can pre-date malignancy by 2 years or more.


Discussion
Malignancy
Dermatomyositis and Polymositis are strongly associated with malignant disease, particularly ovarian, cervix, lung, pancreatic, stomach, colorectal and non-Hodgkin lymphoma. In both, incidence of malignant disease is highest at time of myositis diagnosis and for one year afterwards but may arise before, or even > 5 years after diagnosis.[1]

Predictors for low risk (ie good prognostic signs) include, interstitial lung disease, Anti-Mi2 or Antisynthethase. Anti-TIF1-gamma antibody (like in the case of the patient described), Nuclear matrix protein (NMX), older age and dysphagia are associated with increased risk of malignancy and are thus poor prognostic signs.

TIF1-gamma
Recently, it has been revealed that an anti–transcriptional intermediary factor 1 g antibody (TIF1-g-Ab) is frequently detected in the sera of patients with cancer associated myositis (CAM).
Because TIF1-g regulates the tumor growth factor b pathway, it is reported to be related to tumor growth in some malignancies, and may therefore be involved in the key biological mechanisms linking cancers and myositis.

Treatment

Despite the lack of placebo-controlled trials, glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy and myositis-associated interstitial lung disease.  First-line conventional immunosuppressive drugs include either methotrexate or azathioprine, and when they fail, more aggressive therapy includes mycophenolate mofetil, tacrolimus or cyclosporine, intravenous immunoglobulin, rituximab, or cyclophosphamide.[2]
IVIg demonstrated efficacy in DM in a double-blind, controlled trial in 15 patients with refractory DM. In another prospective open-label trial with 35 patients with PM, treatment with IVIg was associated with a significant clinical improvement in 70% of the patients, with stable efficacy reported in half of the patients, 3 years after stopping IVIg. [3]

IM is a multisystem disorder and concern should be given to extramuscular aspects of the disease, particularly the potential for respiratory and cardiac involvement.
Also of relevance is the occurrence of other complicating issues: pain, fatigue, dysphagia and depression.

Written by Dominika Raciborska & Rachelle Shafei

[1] Chinoy et al. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis. Ann Rheum Dis 2007; 66 (10):1345

[2] Siamak Moghadam-Kia, Rohit Aggarwal, and Chester V Oddis. Treatment of inflammatory myopathy: emerging therapies and therapeutic targets. Expert Rev Clin Immunol. 2015; 11(11): 1265–1275.

[3] Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. 1993;329(27):1993–2000