Rheumatology Advance Access originally published online on April 27, 2008
Rheumatology 2008 47(7):1101-1102; doi:10.1093/rheumatology/ken135
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Autoimmunity manifesting as dermatomyositis associated with oligoastrocytoma and dendritic cell immunotherapy
Centre for Rheumatology, University College Hospitals NHS Foundation Trust, London, UK
Correspondence to: E. C. Derrett-Smith, UCL-Centre for Rheumatology, Hampstead Campus Royal Free and University College London Medical School, London NW3 2PF, UK. E-mail: e.derrett-smith{at}medsch.ucl.ac.uk
SIR, A case of severe dermatomyositis occurring after completion of dendritic cell (DC) immunotherapy as a treatment for grade II oligoastrocytoma is described. This is the first report to our knowledge of dermatomyositis associated with either a primary brain tumour or DC immunotherapy.
A 39-yr-old man presented with a 4-week history of muscle pain and weakness, fatigue, fever and a rash. He had been fit and well, and was a keen athlete until a year prior to this presentation when he had been diagnosed with a grade II oligoastrocytoma. This had been debulked 6 months earlier, with 85% clearance and minimal neurological deficit. No further conventional therapy had been indicated post-operatively and follow-up MRI scans of the tumour over the following months had not shown any change in tumour volume or structure.
He contacted a centre in Germany specializing in DC immunotherapy. This process uses monocyte-derived DCs, unique in their capacity to initiate a primary T-cell response. The cells are matured with a combination of cytokines and then loaded with tumour cell product (lysate, peptides, RNA or DNA) with the intention of inducing a tumour-directed cytotoxic T-cell response. Results in a wide spectrum of malignant disease are variable, though promising [1].
The group involved in this patients’ care matured the DCs as described above, without the tumour-loading stage, but additionally used Newcastle disease virus, one of the class of oncolytic viruses thought to promote tumour death [2]. The virus was infused into the patient and added to the DCs to enhance the immune-mediated anti-tumour effect, with additional IFN infusion. The exact protocol for cell and cytokine administration given to this patient is unknown.
The patient presented 2 weeks following the completion of therapy with a rash classical of dermatomyositis and profound peri-orbital oedema. He had mild proximal muscle weakness. The only other clinical finding was of non-specific mucositis and oral candidiasis.
Basic laboratory investigations revealed a low-grade inflammatory response with CRP 11, ESR 30, creatine kinase (CK) 4280 IU/l and normal parameters otherwise. Chest radiography was unremarkable and MRI of the brain revealed no change in tumour compared with the study 3 months beforehand (and prior to DC therapy). ANA, ENA and ANCA were negative and complement studies were within normal range. The EMG revealed a proximal myopathy, MRI of the thighs revealed an inflammatory process most prominent in the adductors and skin and muscle biopsies confirmed the diagnosis of dermatomyositis (Fig. 1). A PET scan, performed to exclude a second malignancy, revealed abnormal uptake in the proximal muscles only. He was treated with intravenous and then oral steroid therapy and received a single dose of 7.5 mg MTX.
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The patient then developed cellulitis at the site of his muscle biopsy (left quadriceps) and synovitis of his right elbow. Cultures were taken from both sites and the blood. He was treated with intravenous flucloxacillin and benzylpenicillin and cultures later revealed a sensitive Staphylococcus aureus from the elbow aspirate and negative cultures elsewhere.
Over 2 days, the cellulitis had spread rapidly and there were concerns regarding an underlying collection. The site was opened surgically and revealed extensive and deep myonecrosis and necrotizing fasciitis. The patient did not mount a clinical systemic inflammatory response at any time, and developed only a late rise in CRP to 125. He was treated with intravenous immunoglobulin (a total of 2 g/kg in three divided daily doses) and then transferred for specialist plastic surgical care. Multiple further resections of necrotic tissue were required prior to a major skin graft and, following two further monthly intravenous immunoglobulin infusions, the patient made a notable recovery and, in spite of losing a significant amount of muscle bulk, was able to run again. His CK returned to normal range and the rash resolved completely.
This case highlights a number of interesting points. The underlying mechanism of his dermatomyositis could be paraneoplastic, an unrelated autoimmune pathology or driven by the DC immunotherapy.
Dermatomyositis presenting as a paraneoplastic phenomenon from many types of tumour is well described. Primary brain tumours can be responsible for paraneoplastic phenomena but neither our personal experience nor a search of the literature revealed a known association between myositis and this type of tumour. The spectrum of paraneoplastic phenomena is wide, and the pathophysiology in most cases is not fully understood. In general terms, the heightened immune response to a tumour coupled to the aberrant release of autoantigens normally confined to a specific tissue is thought to be responsible in most neurological, rheumatological and ophthalmological cases. Case–control studies have attempted to identify serological markers of cancer-associated myositis but full serological profiles are yet to emerge [3].
Myositis-associated autoantibodies are present in up to 40% of cases of myositis. They are thought to play a role in the pathogenesis of the condition, as different autoantibodies define distinct clinical subsets. A novel autoantibody, anti-155/140 antibody, has recently been reported, which is present when other autoantibodies are not [4, 5]. A study to define the diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis in particular, has recently been published which, amongst other findings, associated anti-155/140 with both dermatomyositis and cancer-associated myositis [6]. The negative ANA and negative anti-155/140 antibody (N. McHugh, personal communication) make a ‘classic’ autoimmune cause unlikely in this case.
The contribution of DC immunotherapy to the disease in this case is, again, uncertain though the temporal relationship between the end of the DC therapy and the development of the dermatomyositis strongly suggests that these events were linked. The treatment is promising, particularly for malignancy, with clinical responses sometimes coinciding with a specific cytotoxic T-cell response to antigens present in the DC vaccine. However, the variables in vaccination procedure make the planning of large-scale clinical trials between centres difficult. These variables include the mode of DC preparation, the subtype, maturation and activation status of the cells, dosing and timing intervals, route of administration and mode of antigen loading. The co-administration of cytokines and other immune system enhancers (such as Newcastle disease virus) will promote autoimmunity, and though this is listed as a side-effect of the procedure, there are no specific reports of an association with dermatomyositis. Anecdotally, we felt that the patient did not mount the expected immune response to his life-threatening infection, and felt that his immunotherapy may have contributed to this through attenuation of his immune response.
Disclosure statement: The authors have declared no conflicts of interest.
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- Targoff IN, Mamyrova G, Trieu EP, et al. A novel autoantibody to a 155-kD protein is associated with dermatomyositis. Arthritis Rheum (2006) 54:3682–9.[CrossRef][Web of Science][Medline]
- Kaji K, Fumajito M, Hasegawa M, et al. Identification of a novel autoantibody reactive with 155 and 140 kDa nuclear proteins in patients with dermatomyositis: an association with malignancy. Rheumatology (2007) 46:25–8.
[Abstract/Free Full Text] - Chinoy H, Fertig N, Oddis CV, Ollier WER, Cooper RG. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis. Ann Rheum Dis (2007) 66:1345–9.
[Abstract/Free Full Text]
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