Background/Purpose

Anti-MDA5 auto-antibodies are thought to be specifically associated with dermatomyositis (DM). Nevertheless anti-MDA5 auto-antibody positive patients (MDA5⁺ DM) predominantly suffer from extra-muscular involvement with severe interstitial lung disease, and arthritis. Further, skin lesions may be atypical with skin ulcers and mechanics’ hands. Importantly, clinical signs of myopathy are rather mild or absent and morphology and immunology of skeletal muscle tissue has not been studied yet. Thus, the previously described characteristic ‘IFN signature’ in classical DM may not be found in MDA5⁺ DM patients. We aim to describe the histological pattern of the skeletal muscle and the intrinsic immune response  MDA5⁺ DM patients.

Methods

Muscle specimens were subjected to conventional staining and immunohistochemical analysis to describe muscle fibers, vessel morphology and inflammatory features. Morphometry of vessels was performed using imageJ software on digitally completely scanned slides and by electron microscopy. A panel of six interferon stimulated genes (ISGs) (OAS1, OAS3, ISG15, MX1, RIG1 and MDA5), involved in the IFN immune response were tested by quantitative PCR in muscle biopsie (results expressed as normalized fold change relative to a normal muscle). The median fold change of the six ISGs, was used to create an IFN score. Results are compared to anti-MDA5 auto-antibody negative DM patients (based on ENMC criteria). Serum level of IFN-α was tested using a bioassay.

Results

In MDA5⁺ DM patients (n=9) the mean MRC-score (five score) of the weakest muscular group was 4.5±0.5 and CK levels were 498±809 IU/l.  Muscle biopsies (n=10) were analyzed compared to MDA5^– DM patients (n=7).  Histological analysis showed that anti-MDA5⁺ patients did not present the classical feature of perifascicular fiber atrophy. Inflammation was focal in the perimysium and mainly perivascular but significantly less intense as it is shown by density scores of CD45⁺ leukocytes (35.8±28 vs. 5.9±7.6 cells/mm², p<0.05). MHC-class I staining was also less intense and more focal compared to MDA5^– DM patients who harboured a diffuse staining pattern with a perifascicular re-inforcement. MDA5⁺  DM patients did not show signs of capillary loss since the capillary density was 279.9±17.7/mm² vs. 340.9±16.5/mm² (p=0.05) in MDA5^– DM patients. In the same line the frequency of enlarged capillaries (diameter >10µm) was decreased 5.8±1.1% vs. 13.9±2.5%. Tubulo-reticular formations were observed in only 50% of MDA5⁺ patients, but in all cDM patients. In MDA5⁺ DM patients a strong up-regulation of ISGs expression was observed with RQ values ranging from 74.5±17.2 for RIG to 1107±406 for ISG15even though, the IFN score was less increased than in controls (139.5 vs 634; p=0.005). Finally IFN-α serum levels were increased in all active MDA5⁺DM patients (n=2). 

Conclusion

These results show that myositis in patients with anti-MDA5 Ab positivity shows a distinct morphological pattern compared to MDA5^– DM patients, but is associated with an IFN signature as well, underlining the importance of this pathway in the pathogenesis of both entities.

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-mda5-antibody-associated-myositis-compared-to-dm-patient-a-distinct-muscular-pattern-associated-with-a-shared-ifn-signature/