MDA5-positive dermatomyositis: an uncommon entity in Europe with variable clinical presentations

DM is a rare autoimmune disease characterized by skin involvement, striate muscle
inflammation which may include the upper oesophagus and possible damage of internal
organs frequently marked by the presence of autoantibodies 23]. Several autoantibodies have been described in inflammatory myopathies and distinguished
into myosytis-associated (MAA) and myositis-specific antibodies (MSA) 1] with recent novelties in this field. In particular, cortactin has been recognized
as a new target antigen in polymyositis and immune-mediated necrotizing myopathies
24] along with anti-nuclear matrix protein 2/MJ (NXP2), associated with calcinosis 25] and, possibly, ILD 26]. The p155 recognized by anti-TIF-1? and the small ubiquitin like modifier activating
enzyme heterodimer eliciting anti-SAE have been related to malignancy in adults and
severe course of DM, respectively 1], 25], 27]. Finally, anti-MDA5 (also known as anti-CADM140) were claimed to mark a DM variant
with low grade/absent muscle inflammation (amyiopathic dermatomyositis) but severe
skin manifestations, hyperferritinemic status, frequent and rapidly progressive interstitial
lung disease (ILD) and poor prognosis 28]–31].

The term of clinically amyiopathic dermatomyositis (CADM) was coined by Pearson 32] almost 50 years ago describing those 2–20 % DM patients with skin findings but without
muscle weakness. In the early nineties classification criteria of CADM were proposed
but never validated 33] and association with cancer and ILD was found. In a retrospective study from United
States CADM appeared to mostly be a favourable disease 34] but soon after a study reviewing 301 patients underlined an unusual frequence of
lung involvement (13 %). Interestingly enough, 111 patients in this cohort came from
Eastern Asia 35].

In addition to heliotrope rash, Gottron and shawl sign, skin (and mucosa) involvement
actually covers a wide spectrum of manifestations, including papules (frequently tender
on palm), plaques, nodules and ulcerations. Painful ulcers usually localize on extensor
surface of joints (fingers, elbow, knees), lateral nailfolds or digital pulp 36]. They can be also present in classic DM (usually below 20 %) but more frequently
associate with malignancy, resistance to immunosuppressive therapy or, in Asian populations,
lung disease 30]. A recent retrospective study partially confirms these findings as ulcers did not
significantly associate with myopathy or other classical clinical features of DM (dysphagia,
Raynaud’s or joint pain) but more commonly affected Asian patients. On the other hand,
ulcers of finger pulp and nailfolds were more frequent in patients with anti-MDA5
autoantibodies and/or anti-Ro52 kDa 36], 37].

Hyperferritinemia can be a primary condition (hemochromatosis, ferritin gene mutations),
expression of primary or acquired hemophagocytic lymphohistiocytosis (HLH) or associated
with inflammatory, infectious or malignant disorders. In autoimmunity, hemophagocytic-like
syndromes or macrophage activation syndromes (MAS) can occur in lupus erythematosus,
systemic onset of juvenile arthritis, catastrophic anti-phospholipid syndrome and
adult onset Still’s disease 38]. MAS have been rarely described in the setting of DM, both classic and amyopathic
one and are characterized by a septic-like spectrum with high fever, hepato-splenomegaly,
lymphoadenopathies, cytopenias and increased levels of transaminases 39], 40]. In the Japanese series of CADM patients with circulating anti-MDA5 antibodies, hyperferritinemia
was associated with severe ILD and fatal outcome with an estimated cut-off as predictor
of death 1500 ng/ml 31], 41].

The interplay between CADM and interstitial lung disease is more intriguing. In the
early 2000, several case reports from Japan, China and Korea suggested that CADM was
someway related to severe ILD, rapid onset of respiratory failure and death within
few months from the diagnosis (2–6 mo). Depending from the studies, 30–60 % of CADM
Asian patients had ILD and the 6-month survival rate was about 40 % despite adequate
treatment with high dose steroids and immunosuppressants 29], 42]. As a fact, in 2005 Sato et al. 30] had already described Japanese patients with CADM and severe ILD as showing circulating
anti-CADM140 antibodies and 4 years later the same group identified MDA5 as the target
antigen 43]. However, ethnicity seems to play a fundamental role as suggested by the relationship
between MDA5 positivity and ILD 29], 44]. Actually, aggressive course of DM in the lung has not been confirmed by American
authors 37].

The demonstration of anti-MDA5 may still represent a challenge as the first commercially
available immunoblot assay was only recently introduced into the market in the context
of other myositis-specific target antigens. Immunoprecipitation using
³⁵
S and extractive MDA5 originally used by Japanese authors 30] has been replaced by ELISA assays set up by the use of recombinant molecules from
a home-made cDNA library 20] or a commercial source 45] for coating. The same commercial recombinant MDA5 has been also applied in a self-made
immunoblot 45]. As a fact, no extensive study comparing the efficiency of the different methods
to detect anti-MDA5 has been produced so far. Anyhow, in the last 2 years, DM cases
with circulating anti-MDA5 antibodies have been also described in populations of non-Asian
descent. Three studies regarding epidemiology and clinical features of anti-MDA5+
DM in European Caucasian patients have been published so far. In the unique retrospective
Italian study of Ceribelli et al. 46], anti-MDA5 antibodies were found in 5 of 34 consecutive patients with DM (15 %).
This seems to be slightly above the percentages found in American studies (6 and 7 %,
respectively) 36], 37]. In a Hungarian cohort of 337 patients with idiopathic inflammatory myopathies including
DM, anti-MDA5 antibodies were never found 25]. On the other hand, and confirming the Italian data, in a large number of DM patients
from the Mediterranean area 45], the presence of anti-MDA5 was found in 12 %, half of them with amyopathic disease.
In this study, more than 50 % of the patients suffered from rapidly progressive ILD
and showed significant shorter survival rate in addition to higher frequency of panniculitis.
Interestingly enough and similarly to our patient #1, the Spanish Authors found that
most of the MDA5+ patients with DM and severe ILD also showed circulating anti-Ro52
autoantibodies in an association which has been only recently recognized. Viceversa,
probably due to the very low number of MDA5+ patients in the Italian study, no statistical
differences in the severity of skin involvement or mortality was found in MDA5+ in
comparison with non-MDA5 DM patients and the frequency of ILD itself was statistically
borderline (p 0.048). It was indeed confirmed that MDA5+ patients were more frequently
amyopathic (p  0.001) but, again, no differences could be demonstrated in digit pulp
necrosis, Raynaud’s phenomenon or joint pain between the two groups.