Mysteries of Myositis

 Elucidating the mechanisms of the aetiopathology of the rare idiopathic inflammatory myositis types may help to develop novel drugs for the condition.

KEY POINTS

• Rare disorders are usually genetic.
• Studying the genotypes and phenotypes of rare myositis subtypes may help in the development of new treatments.
• HLA haplotypes and linkage disequilibrium is a reliable way to classify myositis subtypes.

The inflammatory myopathies that cause myositis are rare muscle disorders. Symptoms of myositis include muscle weakness and inflammation and, although rare, it can be fatal and cause heart failure.

Treatment options

There are treatments available, including immunosuppression, intravenous immunoglobulin and steroids, but the options available are inadequate and despite drugs patients can develop debilitating irreversible muscle weakness and interstitial lung disease (ILD).

Research Ambitions

Research is being performed to find the cause of the aetiology and pathogenesis of the spectrum of myositis disease. The long-term aim is to elucidate pathological mechanisms and then to make targeted therapies for the future.

Rareness of the Disorder

Myositis is a rare disease with an estimated only 2-8 cases per million per year, which translates roughly into one case presenting to a rheumatologist every four years.

Myositis Subtypes

Dermatomyositis (DM) and polymyositis (PM) are the most frequent subtypes of myositis and where Dr Cooper initially focused efforts. It is hoped that research into these types would also provide information on inclusion body myositis (IBM), which usually presents in neurology, and juvenile dermatomyositis (JDM).

In the muscle, there are observable pathological differences between PM and DM. In DM there is often a heliotrope rash around the eyes, and there is the increased risk of malignancy. There are also serological differences and the presence of the more common autoantibodies in DM are anti-Mi2s and in PM are anti-SRPs.

Genetic Evidence

There is increasing evidence for genetic factor involvement in myositis pathogenesis.

There are about 35 case reports where there are multiple cases in families, so there seems to be familial aggregation. Also in the disease there are environmental trigger factors as, for example, DM seems to be light sensitive.

Candidate gene studies in the HLA class II region have shown an association with DM and PM of DRB1*03 and DQA1*05 polymorphisms respectively.

It has suggested by Dr Fred Miller that instead of classifying myositis into PM and DM perhaps it should be defined by autoantibody type into anti-synthetase, anti-Mi2 and anti-SRP subtypes. Anti-synthetase disease involves interstitial lung disease, arthritis, mechanics hands and fever. Anti-SRP disease involves acute severe muscle weakness, cardiac involvement and myalgias. Anti-Mi2 disease involves the y-sign rash, shovel sign rash and cuticle overgrowth.

Genetic associations in the HLA class II has provided some evidence for this approach to myositis classification. For example, HLA-DRB1*03 is more associated with PM than DM, but is even more closely associated with the presence of anti-synthetase autoantibodies.

Similarly, HLA-DRB1*07 is more associated with DM than PM and seems to be a protective factor, but there is a greater association with anti-Mi2 autoantibodies.

Linkage Disequilibrium

The HLA class II genes are in strong linkage disequilibrium and are inherited in haplotypes. A haplotype causing a disease manifestation is maintained throughout a population.

Thus the haplotype HLDRB1*03/ DQA1*05/DQB1*02 (3:5:2) has been found to predispose to both PM and DM. There is a strong association between antisynthase antibody positivity and the 3:5:2 haplotype with ILD. This association held even I the anti-synthetase anti-Jo-1 antibody is negative.

DRB1*07, DQA1*02 and DQB1*02 (7:2:2) is very highly associated with the anti-Mi-2 antibody, DM, and the absence of ILD.  It seems to be a protective haplotype for PM.

There is a genetic association of DM with cancer, which remains to be fully elucidated. If there is cancer detected plus DM is present and on treating the cancer the DM improves, then it is defined as cancer associated myositis.

Patients who are antibody-negative with routinely tested myositis antibodies are seven times more likely to get cancer in the next three years.

If they have DM and they are anti-155/140 antibody positive, then they are 20 times more likely to get cancer in the next three years. So it is important to target these patients for further investigations.

The DP locus, with 23 alleles, of the class II region has also investigated research group. This locus is situated on the other side of a recombination hotspot between it and the DQ/DR region and is known to play a role in renal transplantation. There seemed to be an independent association between DPB1*01 and all of the subtypes of myositis tested.

This DP association showed that class II alleles outside the DR/DQ region had an effect on antibody production, but also on clinical phenotype.

Disease in Children

JDM is the juvenile manifestation of DM. In genetic studies the 3:5:2 haplotype has been found at increased frequency. In JDM, the genotype to serotype correlations are the same but the serotype to phenotype is different.

Serologically there is increased presence of autoantibodies to 155/140kd in both, but anti-Jo1 autoantibodies are rare in JDM so they get less ILD. It seems that in adults the increase in anti-155/140 autoantibodies is associated with cancer associated myositis, but in children it is associated with more aggressive skin disease, which is less of a problem in adults. In JDM it is the skin and the calcinosis which is the major problem as the myositis gets better but they are sometimes left with fractures as a result of calcinosis.

If there is an antibody for worse skin ulceration and calcinosis, then it might be worth treating those children aggressively from the start. That is why identifying these antibodies is going to become so important.

Genome wide association studies are the next step in myositis and preliminary results pending publication have identified SNPs that are associated with the individual myositis subtypes.

Better Diagnosis

Immunology and genetic analysis has opened the potential for a new classification of myositis has identified a whole spectrum of disease with overlap between the various subtypes and perhaps between myositis and connective tissue disorders, such as RA.

There is a complex correlation between antibody status and HLA DRB1 and DQB1.The HLA haplotype better defines serological subtypes that traditionally clinically defined PM and DM. The differences in serotype profile between PM and DM are explained by the differences in HLA haplotypes.

 Conor Caffrey is a writer on medicine and science.