Meeting report (part 4a): about the shifting classification of idiopathic inflammatory myopathies

What I also heard during my 2-day visit to the Karolinska Institute at Stockholm, Sweden, was a nice overview on the current status of both classification as well as (emerging) treatment options of idiopathic inflammatory myopathies. As a clinician, three take-home messages were what I took home from this oral presentation by professor Ingrid Lundberg MD PhD (photo), who can be regarded as one of the top-experts worldwide in this field of rheumatology.
The first two of three take-home messages are nothing new at all when I search the literature, but I must admit my knowledge of inflammatory myopathies was not as up-to-date as I thought, because they were both quite new for me. They were: (1) the so familiar classification into polymyositis, dermatomyositis and inclusion body myositis is becoming rather obsolete and may be rapidly replaced by a calssification that is much more defined by which (combination of) myositis specific autoantibodies (MSAs), which I will discuss in this blog post.
Furthermore (2) assessment of disease activity in inflammatory myopathies can be easily performed by any rheumatologist or paramedic and delivers information as valuable as the DAS-score in rheumatoid artritis. It should be a standard measurement upon routine follow-up of all inflammatory myopathy patients. I will discuss this in a short second blog posting (part 4b). The third take-home message was the only aspect that was really cutting edge, and new for everyone, and this one was about current and emerging treatment options for inflammatory myopathies. Shortly after my visit to Stockholm, an interesting paper was published in Rheumatology by a Dutch collegue of mine, and an editorial in the same issue was adressed to the findings but also specifically to study design, which nicely refers to measurement of disease activity (to be discussed in part 4b as just mentioned). I will discuss current treatment options for inflammatory myopathies in the third and final part of my blog postings on inflammatory myopathies, which will also conclude my remarks made in Sweden last November.

So for now, let’s review the classical versus upcoming way of classifying or stratifying the idiopathic inflammatory myopathies.

I will be short here with a rationale and an overview of the most important MSAs currently known and their clinically related phenotypes. And I can be short because an excellent review in this exact topic was published in 2009 in Rheumatology by the group of Neil J. McHugh, Department of Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath UK.
I would suggest once you have finished reading this blogpost (if you have some time) that you just go ahead by reading that review. The nice thing about it is that the full text (HTML or PDF if you like) is available online (open access). I copied some phrases from that review, they are between ” and ” symbols below.

Why change the way we classify inflammatory myopathies?
Because, like in sereveral other rheumatic conditions the current clinical and pathological classifications result in very heterogenous patient (and study!) populations both in adult and juvenile cases. And, now that a wide range of MSAs have been identified as well as shown to be indicative of the clinical phenotypes they are associated to, by stratifying inflammtory myopathy patients by the presence of which particular (combination of) MSAs far less heterogenous patient populations can be distinguished. This helps both clinical decision making in daily clinical practice as well as conducting clinical trials with specific treatment targets for specific myopathies.

Which myositis-specific autoantibodies are we talking about then?
To date a wide range of MSAs have been identified, most of them can be grouped to some extent. Professor Lundberg had a nice PowerPoint slide that visualised the MSAs spectrum and associated clinical phenotypes (given the BATH logo, she might have borrowed it from the Bath group just mentioned). However, I do not have that slide, so I will try to list some currently defined groups of MSAs below:

A) The anti-synthetases (the most well known and also most frequenty detected group in myositis targeting cytoplasmic aminoacyl-tRNA synthetase (ARS) enzymes). These include autoantibodies targeting Jo-1 (frequency 20%), PL-7, PL-12, EJ, OJ, KS, Ha and Zo. (frequency of patients with each non-Jo-1 anti-ARS is between 1 and 5%, taken together one of the non-Jo-1 anti-ARS is also found in 20%). So in 40% of all inflammatory myopathy patients one of these autoantibodies can be found, and taken the yield of non-anti-Jo1 autoantibodies into account, it is well worth testing these seven non-Jo-1 anti-ARS on a more routine basis as well! However unlike in adults, the frequency of anti-ARS autoantibodies in juvenile myositis is much lower.
Clinical phenotype: “The anti-ARS autoantibodies define the anti-synthetase syndrome (ASS) recognized as a spectrum of myositis, interstitial pneumonia, non-erosive arthritis (sometimes with a characteristic so called floppy-thumb sign, MZ), fever, Raynaud’s phenomenon and mechanic’s hands. In addition, patients can also have DM skin lesions including Gottron’s papules and heliotrope rash”

B) The anti-SRP autoantibodies: autoantibodies to the signal recognition particle (SRP). “Anti-SRP autoantibodies are found in ∼5% of patients with IIM. Patients with anti-SRP can present with acute onset severe myopathy with significant muscle enzyme elevation and systemic features including dysphagia that can be refractory to standard treatments.”

C) Anti-Mi-2 autoantibodies: classically detected in dermatomyositis (in up to 20% of patients). “This autoantibody specificity is described in patients with hallmark cutaneous DM lesions including Gottron’s papules, heliotrope rash, cuticular overgrowth and rashes on the neck and upper back or shoulders (V sign and shawl sign). Moreover, patients may have milder muscle involvement with a lower risk of interstitial pneumonia and respond well to therapy”. So this is -within the classical classified defmatomyositis group of patients- an autoantibody that predisposes to a relatively good prognosis and mild course of disease. This as opposed to the relatively new MSAs called Anti-p155/140 autoantibodies which predispose patients with a clinical dermatomyositis phenotype much more to developing any form of cancer and thus a poor prognosis.

D) Novel myositis-specific autoantibodies: these include the just mentioned anti-p155/140 autoantibodies, anti-p140 (which are likely to be the same as anti-NXP-2 and possibly associated to malignancies), anti-p100/p200 autoantibdoies asscoiated with recently identified statin induced myopathy which is necrotising and refractory to treatment thus far. Furthermroe in the review I refer to also mentioned are anti-CADM-140 associated with “rapidly progressive interstitial pneumonia” and often presence of cutaneous futures of dermatomyositis but with a mild subcliical myopathy of no clinical significanve and finally the so called anti-SAE: small-ubiquitin-like modifier activating enzyme autoantibodies also directing towards the adult dermatomyositis phenotype (“in 8.4% of DM cases and not in PM or myositis overlap cases”).
NOTE: “The description of the anti-p155/140 and anti-p140, two novel serological subsets in JDM, is a major finding because they occur collectively in > 40% of children and appear to identify those with more severe disease.”

What about inflammatory myopathies and cancer risk?
Most of us know that in particular dermatomyositis patients are at increased risk for developing malignancies in the course of their disease, and they are actively screened for malignancy upon diagnosis. Given the identification of novel MSAs as described above ELISAs testing for a set of MSAs which result in a good or on the other hand rather ominous prognosis regarding the development of malignancy in myositis patients are expected to be implemented in daily clinical practice in the near future.

So to end this blog post, also in the field of inflammatory myopathies some nice translational research from the biochemical laboratories to the rheumatology outpatient clinics is taking place. And it will surely have consequences in daily clinical practice for what we rheumatologists do and what we will not do as (additional) diagnostic testing and choice of treatment regimens concerns.