Introduction
The advent of molecular science has not only heralded the discovery of the pathogenic origins of disease but has also complemented knowledge on autoantibodies and their links with disease behavior in various immune-mediated disorders.
Most of the myositis subsets are currently better understood and recognized as clinico-serologic syndromes than the traditional clinical classifications used in the past. Together with newer myositis autoantibodies, the proportion of patients with idiopathic inflammatory myositis (IIM), especially among those with polymyositis (PM), dermatomyositis (DM) or necrotizing myopathy (NM) subsets, who have an identifiable and specific autoantibody is up to 70% if comprehensive testing is done.
Treatment of a disease entails timely diagnosis, identifying the risks of associated conditions, understanding prognosis, prediction of disease trajectory over time, and responsiveness to therapy. The extended spectrum of myositis autoantibodies caters to each of these aspects of patient care.
Role in diagnosis of myositis
Although most trained rheumatologists can diagnose dermatomyositis patients with high certainty due to their characteristic rashes and other clinical signs (see Figure 1), polymyositis and necrotizing myopathy are often misdiagnosed owing to a large number of mimics, including metabolic myopathies, muscle dystrophies, and inclusion body myositis. Despite characteristic rashes, some forms of dermatomyositis, especially clinically amyopathic forms, is often labeled as lupus, mainly due to identical skin biopsy, responsiveness to immunosuppressive agents, as well as the non-specific nature of antinuclear antibodies (ANA). Presence of myositis-specific autoantibodies provides high specificity and diagnostic confirmation to the treating physician.
Figure 1. Mechanic's hand in a ptient with anti-synthetase syndrome
Delay in the diagnosis of idiopathic inflammatory myositis is even more pronounced when a patient presents with subtle or nonspecific findings or other organ involvement such as within the lungs or joints. Patients with anti-synthetase syndrome are often misdiagnosed with undifferentiated connective tissue disease or idiopathic pulmonary fibrosis when they initially present with the clinical features of non-specific connective tissue disease such as Raynaud’s symptoms or interstitial lung disease (ILD), respectively.
Identifying one of the eight anti-synthetase antibodies can provide a confirmatory classification for these patients as an anti-synthetase syndrome, and should lead to appropriate treatment with immunosuppressive drugs. For those with rapidly progressing ILD, who are often amyopathic, the situation is even more critical, as cutaneous features such as palmar papules may be missed in a sick patient in the intensive care unit.
In the absence of anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody testing, either due to test availability or lack of clinical suspicion, these patients can be misdiagnosed with acute interstitial pneumonitis of infectious or drug-induced origin, resulting in high mortality risk. Therefore, myositis-specific autoantibodies play a critical role when the presentation is limited to “formes frustes” of a systemic autoimmune disease, which may be particularly difficult to recognize clinically as myositis subset.
The high specificity of myositis autoantibodies has recently been recognized in the new 2017 EULAR/ACR classification criteria for idiopathic inflammatory myositis, where myositis antibody (Jo-1) has the highest weightage towards meeting classification if positive.
Unfortunately, levels of most myositis antibodies lead neither to a high titre, nor do they provide a distinctive immunofluorescence pattern on ANA testing. ANA positivity may be as low as 50% in some myositis cohorts. It is important to note that many myositis antibodies, including anti-synthetase antibodies, yield a cytoplasmic rather than a nuclear staining pattern on ANA testing, which is unfortunately overlooked by immunology labs.
Myositis autoantibodies are almost always mutually exclusive and fairly specific, adding value as a useful biomarker for diagnosis. Although individual autoantibodies aren’t sensitive enough to detect the full spectrum of myositis, the sensitivity of a collective myositis panel is increasing as more autoantibodies are discovered, and as better assays become available.
Role in identifying a unique clinical phenotype of myositis
Each myositis-specific antibody is associated with homogeneous patterns of disease phenotype within the myositis spectrum of conditions. Being a morbid disease, myositis entails risks of future organ involvement or associated complications, which need to be monitored and managed over time. Myositis autoantibodies can help in organ involvement prediction as well as stratifying risk of serious complications, leading to early identification and proactive management.
One antibody that deserves particular mention is anti-transcription intermediary factor 1 gamma (anti-TIF1γ) antibodies, which have been linked to a 10-fold increased risk for malignancy. In fact, it is now known that possession of either anti-TIF1γ or antinuclear matrix protein 2 (anti-NXP2) antibodies represents a significant risk factor for cancer-associated dermatomyositis. Patients with either of these antibodies should undergo more aggressive cancer screening with early computerized axial tomography scans, or even positron emission tomography in some cases, to allow discovery of underlying occult malignancy. It has also been seen that patients who test negative to routine myositis antibody panels have a higher risk for malignancy. The combination of these two approaches is 94% sensitive, with 100% sensitivity and negative predictive value in dermatomyositis. However, this risk association is specific to adults; children with anti-TIF1γ or anti-NXP2 are at risk for severe skin disease including calcinosis, but not cancer.
Similarly, antibodies to the aminoacyl t-RNA synthetases (ARS) (see Table 1) identify a cohort of anti-synthetase syndrome patients where ILD is the most common and severe manifestation. Other clinical features such as myositis, arthritis, fever, mechanic’s hands, and Raynaud’s phenomenon are seen in much less frequency. In particular, non-Jo-1 ARS are associated with more severe ILD, often occurring in the absence of muscle disease.
More recently, the concept of pure polymyositis has largely been subsumed by the separately defined entities such as inclusion body myositis, necrotizing myopathy, and overlap myositis syndromes. The argument of degenerative versus autoimmune origin of inclusion body myositis has, perhaps, slightly tilted in favor of an autoimmune disorder, with the discovery of autoantibodies to cytosolic 5'-nucleotidase 1A (cN-1A) present in 30–70% of cases. Necrotizing myopathy has two main profiles of myositis specific antibodies: anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibody, which is highly associated although not exclusively so with statin use, and anti-signal recognition particle (anti-SRP) which is often found in young patients with severe refractory muscle disease. Clinically amyopathic dermatomyositis, on the other hand, embraces several myositis specific antibody profiles including the anti-MDA-5, anti-TIF1 γ and anti-small ubiquitin-like modifier activating enzyme (anti-SAE).
Role in prognosis of myositis
Myositis autoantibodies have also been highly valuable in identifying probable disease course and outcome. Anti-Mi-2 positive myositis is associated with cutaneous disease with mild muscle involvement and overall excellent prognosis, whereas anti-SRP is associated with rapidly progressive myositis refractory to multiple immunosuppressants, and severe morbidity consequent to disabling weakness.
It is therefore useful to know the myositis-specific autoantibody profile at the outset in myositis patient so that glucocorticoid use can be minimized in anti-Mi-2 positive disease, whereas aggressive immunosuppression can be pursued in an anti-SRP positive patient. ARS positivity ascribes to intermediate prognosis, being the harbinger of chronicity and relapsing disease.
ILD is the major cause of attributable mortality (40%) although many patients succumb to infections. Given the strong association of ARS positivity with ILD, these patients have poor survival outcomes as compared with other subsets, including refractory myositis patients with anti-SRP antibody.
Among ARS positive patients, non-anti-Jo-1 positive patients fare worse than anti-Jo-1 positive patients due to delay in diagnosis and higher prevalence of ILD. A newly described entity of anti-MDA-5-associated ILD portend grave prognosis given the rapidly progressive nature of lung disease in certain ethnic groups. In patients with anti-TIF1 γ, survival is reduced due to underlying cancer in most patients.
Not only are different serological subsets associated with unique prognostic patterns, but levels of some myositis-specific autoantibodies such as anti-Jo-1, anti-TIF1γ and anti-MDA-5, are associated with disease activity and flare up.
Role in treatment of myositis
Patients who are positive for myositis-specific autoantibodies linked to treatment resistance should receive glucocorticoids combined with any one of several immunosuppressive drugs, such as azathioprine, methotrexate, mycophenolate mofetil (MMF), intravenous immunoglobulin and rituximab. Reports show that the therapeutic response to rituximab is more favorable in patients who are autoantibody positive, particularly those with ARS positivity or anti-Mi-2, than in those without any myositis specific antibody.
Patients with an ARS phenotype have a glucocorticoid-responsive disease but have a high tendency to relapses, which are detrimental to associated ILD. ARS-positive patients are best managed with MMF or tacrolimus followed by rituximab in refractory cases.
Among patients with anti-SRP antibodies, the odds of refractory disease are high. Thus, traditional agents should be switched quickly in the absence of timely response. Initial treatment can be methotrexate in combination with glucocorticoids, with intravenous immunoglobulin (IVIg) and rituximab being good second line therapies. In those with anti-HMGCR antibodies, IVIg has more favorable outcomes over traditional immunosuppressants. Anti-MDA-5 positive ILD can be particularly refractory to all forms of therapy, and recent evidence suggests a rapid step up to second- and third-line therapies, including high dose intravenous glucocorticoids, cyclophosphamide, rituximab, cyclosporine and tacrolimus in various combinations can be lifesaving.
There is emerging evidence that suggests Janus Kinase inhibitors might be particularly useful in this subset of myositis, especially in rapidly progressive ILD. Due to the high likelihood of underlying malignancy, patients with anti-TIF1γ and anti-NXP2 are advised to undergo cancer surveillance and close follow up. In the event of malignancy, treatment of the associated cancer is paramount for improvement of myositis, and often glucocorticoids and/or IVIG can be used for symptomatic improvement.
Summary
In summary, the discovery of several newer autoantibody specificities in addition to those more traditionally known to be associated with inflammatory myopathy has changed the landscape in terms of diagnostic utility, prognostication, and approach to the management of idiopathic inflammatory myopathies.
Key messages
- Myositis-specific antibodies are highly specific and useful to classify patients as having clinico-serologic syndromes with distinct clinical features and prognosis.
- Patients with ARS or anti-MDA5 antibodies have a high risk for ILD, entailing the need for aggressive management.
- Anti-TIF1γ, anti-NXP2 and myositis-specific autoantibody negativity predicts a high risk of malignancy, and the need for more intensive cancer screening up to three years of diagnosis.
- Anti-SRP and anti-HMGCR antibodies are associated with necrotizing myopathies.
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