Simply Stated: Understanding Idiopathic Inflammatory Myopathies

The idiopathic inflammatory myopathies (IIMs) are a group of rare autoimmune muscle diseases that include dermatomyositis, polymyositis, immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome, and inclusion body myositis (IBM). These disorders cause progressive muscle weakness, can affect multiple organs, and often impact quality of life. Together, the IIMs affect an estimated 2 to 25 per 100,000 people.

Subtypes and symptoms of IIMs

The IIM subtypes have many similarities in presentation and the classification of the different subtypes is rapidly changing in clinical practice. Currently, the main IIM subtypes are characterized as follows:

Dermatomyositis (DM) – Dermatomyositis is characterized by a combination of muscle weakness and distinctive skin rashes. Many people with DM have specific autoantibodies that help understand their subtype and guide prognosis, such as anti–TIF-1γ (linked to a higher cancer risk) or anti–MDA5 (linked to lung involvement).

Polymyositis (PM) – Polymyositis involves muscle weakness without a rash, but true PM is rare. Many cases once diagnosed as polymyositis are now understood to be different conditions, such as IMNM, early or misdiagnosed IBM, or other related diseases such as overlap myositis or antisynthetase syndrome without a rash.

Antisynthetase Syndrome – This form of IIM is marked by antibodies against tRNA synthetases, which are essential for making new proteins inside cells. People with this condition often develop a recognizable pattern of symptoms, including muscle inflammation, lung disease, “mechanic’s hands” (rough, cracked skin on the fingers), joint pain, and Raynaud’s phenomenon (episodes where fingers or toes turn white or blue in response to cold or stress due to reduced blood flow). This condition typically develops more suddenly than classic dermatomyositis.

Immune-Mediated Necrotizing Myopathy (IMNM) – IMNM causes severe muscle weakness but usually little inflammation as seen by muscle biopsy. Rather, the muscle cells show signs of active injury. Some people have anti-HMGCR antibodies (sometimes linked to statin exposure), while others have anti-SRP antibodies. IMNM often looks like polymyositis, but behaves differently and requires its own treatment approach.

Inclusion Body Myositis (IBM) – IBM is different from the other myopathies. It tends to affect older adults, especially men, and causes a slow, uneven muscle weakness, often making it hard to grip objects or climb stairs. Doctors may see specific changes called “inclusion bodies,” by muscle biopsy, though these structures are not always found. IBM has a different underlying cause than other myopathies and does not respond well to standard immune-suppressing treatments.

Sometimes the IIMs occur alongside another autoimmune disease, such as lupus, scleroderma, or mixed connective tissue disease. In these cases, muscle symptoms may be mild, and specific antibodies (like anti-RNP or anti–PM-Scl) can help clarify the diagnosis.

For more information about the characteristic symptoms of the IIM subtypes, as well as diagnostic and management concerns, a recent overview can be found here.

Cause of IIMs

The IIMs are autoimmune diseases, which means that the immune system mistakenly attacks the body’s own muscle tissue during the course of disease. Although the exact causes are still unknown, researchers believe these conditions develop through a combination of genetic susceptibility and environmental triggers. Certain inherited genetic variations can increase a person’s risk, while factors such as infections, medications, or UV exposure may activate the abnormal immune response. In many cases, specific autoantibodies, such as anti-MDA5, anti-TIF-1γ, anti-HMGCR, or anti-Jo-1, help define the IIM subtype and may contribute to how the disease develops. Ultimately, IIMs arise from an overactive immune system that leads to inflammation, muscle weakness, and damage to other tissues.

Current management of IIMs

While there is currently no cure for the IIMs, many of the symptoms can be treated with immunosuppressive therapy, physical therapy, and/or rest. Not all subtypes of IIM respond to immunosuppressive therapy, however, so the ability to accurately diagnose the IIM subtype is important to guide appropriate management. Therapeutic development in the IIM space is also accelerating, leading to promising new clinical trial opportunities for patients.

Treatment for IIMs depends on the specific subtype and the person’s symptoms. Most forms respond to immune-based treatments, while IBM typically does not. Care is tailored based on muscle weakness, how long the disease has been present, other organ involvement, cancer risk, age, and other health conditions.

For most people with IIM, initial treatment starts with broad-spectrum steroids (glucocorticoids) plus a long-term steroid-sparing medication such as methotrexate, mycophenolate, azathioprine, or rituximab. Intravenous immunoglobulin (IVIG) is FDA-approved for DM and is often an effective option. Supportive care is also essential and may include physical therapy, steps to prevent swallowing problems and aspiration, and measures to protect bone health.

People with DM skin disease may need additional treatments, including sun protection, antimalarial agents, or other immunosuppressive or immunomodulating therapies if the rash is hard to control.

Evolving research and treatment landscape

The most promising therapies in development for IIMs focus on using more precise methods to modulate the immune system. These treatments are designed to target specific disease pathways and offer better options for people who do not respond well to traditional broad-spectrum steroids. Some promising new therapies in clinical trials for IIMs include:

JAK inhibitors (Janus kinase inhibitors): This class of oral small molecules is a major area of research due to its ability to suppress multiple immune signaling pathways implicated in DM.

• Baricitinib is being investigated in a phase 3 trial (BIRD) for people with new or refractory DM. This study is currently recruiting participants.
• Brepocitinib, a TYK2/JAK1 inhibitor, recently met the primary endpoint in its phase 3 trial (VALOR) for adults with DM, demonstrating the ability to reduce steroid use in patients. An FDA filing (submission of trial and safety data for review and potential approval) is expected in the first half of 2026, moving brepocitinib closer to becoming a new treatment option.

FcRn inhibitors (Neonatal Fc receptor inhibitors): These monoclonal antibodies are designed to reduce the levels of disease-causing autoantibodies in the bloodstream.

• Efgartigimod is in a phase 3 trial for IIM to study long-term safety and efficacy, with positive phase 2 data showing clinical improvement across disease activity measures.
• Nipocalimab is also being investigated in a phase 2 trial (SPIREA) for DM, anti-synthetase syndrome, and IMNM.

CAR T-cell therapy (Chimeric antigen receptor T-cell therapy): This innovative cellular therapy approach targets specific B cells to potentially reset the immune system and achieve long-term, drug-free remission in severe, refractory cases. Multiple studies are underway for various IIM subtypes.

Anti-interferon agents: Many people with DM show increased activity of the type I interferon (IFN-a) immune signaling pathway, so therapies targeting this pathway show promise as potential therapies.

• Anifrolumab (Saphnelo), an agent targeting the type I interferon receptor, is being studied in a phase 3 trial that is currently recruiting participants with DM or PM.

B-cell depletion therapy: This therapeutic strategy has proven effective in other autoimmune diseases, highlighted by the recent FDA approval of Uplizna for treatment of myasthenia gravis. Several next-generation B-cell depletion agents are in development to provide stronger or more targeted effects, especially for people who do not respond to standard therapies.

• Obinutuzumab, a stronger B-cell-targeting antibody is being tested in patients who have not responded well to prior B-cell depletion therapy, such as rituximab.

Interferon-gamma targeting agents: While type I interferon (IFN-a) plays a role in skin manifestations in dermatomyositis, type II interferon (known as interferon-gamma (IFN-γ)) appears more relevant for muscle inflammation. Interferon-gamma–targeting therapies are therefore in development to address muscle inflammation in IIMs.

• Dazukibart (PF-06823859) is an anti-IFN-γ antibody under investigation in people with IIM. It is being studied in a phase 3 trial that is currently recruiting participants.

Inclusion body myositis (IBM) treatments: IBM has been particularly challenging to treat, but several agents are in development to slow disease progression or manage symptoms.

• Sirolimus (rapamycin), an mTOR inhibitor, is designed to preserve muscle function. The therapy is in a phase 3 trial for IBM patients.
• Ulviprubart (ABC008), an anti-KLRG1 antibody, aims to selectively remove the specific immune cells that damage muscle tissue in IBM. It is being studied in a phase 2/3 trial.

To learn more about clinical trial opportunities in IIM, visit clinicaltrials.gov and search for the specific disease name (e.g., “inclusion body myositis”) in the condition or disease field.

MDA’s work to further cutting-edge IIM research

Since its inception, MDA has invested more than $22.3 million in IIM research. Through strategic investments from MDA, partner advocacy groups, and the National Institutes of Health (NIH), IIM research is advancing, offering hope for breakthroughs and a better future for those living with these complex conditions.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about idiopathic inflammatory myopathies (IIMs), open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.