Overview
Adult-onset overlap myositis (AOM) refers to a complex clinical syndrome characterized by the presence of autoantibodies that interfere with interferon-gamma (IFN-γ) signaling, leading to immunodeficiency and myositis. This condition predominantly affects previously healthy adults over 18 years of age, with notable prevalence in Asian populations, particularly in Thailand, Taiwan, and China 1. Patients often present with recurrent or disseminated infections caused by intracellular pathogens such as non-tuberculous mycobacteria (NTM), Talaromyces marneffei, Salmonella species, and varicella-zoster virus (VZV), alongside myopathic symptoms 1. The presence of neutralizing anti-IFN-γ autoantibodies (nAIGAs) is a hallmark of this condition, significantly impacting macrophage activation and immune defense mechanisms 1. Early recognition and management are crucial due to the potential for severe and resistant infections, underscoring the importance of accurate diagnostic tools and timely intervention in day-to-day clinical practice 1.Pathophysiology
The pathophysiology of adult-onset overlap myositis (AOM) involves a multifaceted interplay of immunological dysregulation and cellular dysfunction. At its core, the condition is marked by the development of neutralizing anti-interferon-gamma autoantibodies (nAIGAs) that target and inhibit IFN-γ signaling pathways 1. IFN-γ plays a pivotal role in activating macrophages and enhancing their ability to combat intracellular pathogens, thereby maintaining immune surveillance against infections such as those caused by mycobacteria and fungi 1. When nAIGAs are present, they block this critical signaling cascade, leading to impaired macrophage function and a heightened susceptibility to opportunistic infections 1. Additionally, the myopathic component of AOM suggests involvement of muscle tissue, potentially through direct autoimmune attack or secondary effects of systemic immune dysregulation 3. The exact mechanisms linking nAIGAs to myositis are not fully elucidated but likely involve complex interactions between immune dysregulation and muscle cell damage, contributing to the characteristic clinical presentation of muscle weakness and inflammation 3.Epidemiology
Adult-onset overlap myositis (AOM) exhibits a notable geographic and demographic distribution, particularly prevalent in Asian populations. Incidence and prevalence data are limited but suggest a higher occurrence in regions such as Thailand, Taiwan, and China 1. The condition predominantly affects adults over 18 years of age, with no significant sex predilection observed in reported cohorts 1. Age-wise, patients typically present in their mid-adulthood, ranging from their 20s to 70s, though the peak incidence may vary geographically 1. Risk factors remain largely undefined, but the association with certain genetic predispositions and environmental triggers is an area of ongoing investigation 1. Trends over time indicate a stable prevalence with sporadic case reports, suggesting no marked increase or decrease without broader epidemiological studies 1.Clinical Presentation
Patients with adult-onset overlap myositis (AOM) present with a combination of immunodeficiency symptoms and myopathic features. Common clinical manifestations include recurrent or disseminated infections by intracellular pathogens such as non-tuberculous mycobacteria (NTM), Salmonella species, and varicella-zoster virus (VZV) 1. These infections often involve multiple organ systems and can be severe and treatment-resistant 1. Myopathic symptoms typically manifest as asymmetric muscle weakness, predominantly affecting distal upper extremity muscles and proximal lower extremity muscles, leading to difficulties in activities of daily living and gait disturbances 3. Additional red-flag features may include dysphagia, which can indicate involvement of cranial muscles, and systemic symptoms like fatigue and weight loss 3. The overlap between immunodeficiency and myositis necessitates a thorough clinical evaluation to distinguish AOM from other myopathies and immunodeficiencies.Diagnosis
The diagnosis of adult-onset overlap myositis (AOM) involves a comprehensive approach integrating clinical history, physical examination, and specific laboratory tests. Key steps include:Clinical Evaluation: Detailed history focusing on recurrent infections, myopathic symptoms, and absence of HIV infection.
Laboratory Tests:
- Detection of nAIGAs:
- Competitive ELISA (cELISA): Utilize monoclonal antibody B27 (B27 mAb) as a surrogate competitor to detect neutralizing anti-IFN-γ autoantibodies. Positive cutoff typically defined by comparison with healthy controls, often with a threshold indicating significant competition for IFN-γ binding 1.
- Immunochromatographic Strip Test (IC Strip Test): Offers rapid detection with high specificity and sensitivity, showing percent positive agreement of 91.30% compared to cELISA 2.
- Functional Assays:
- MHC Class II Expression: Measure IFN-γ-induced surface MHC class II expression on cells to assess functional impact of nAIGAs 1.
Differential Diagnosis:
- Primary Immunodeficiencies: Distinguish by genetic testing and specific antibody deficiencies.
- Autoimmune Myopathies: Rule out through muscle biopsy and specific autoantibody profiles (e.g., anti-Jo1, anti-Mi2).
- Chronic Infections: Exclude through comprehensive microbiological testing (e.g., PCR, cultures).(Evidence: Strong 12)
Management
First-Line Treatment
Immunoglobulin Replacement Therapy:
- Intravenous Immunoglobulin (IVIG): Administer at doses typically ranging from 400 to 600 mg/kg every 3-4 weeks to bolster immune function 1.
- Subcutaneous Immunoglobulin (SCIG): Alternative dosing based on individual patient needs, often similar to IVIG but adjusted for frequency and volume 1.
Antimicrobial Prophylaxis:
- Trimethoprim-Sulfamethoxazole (TMP-SMX): Consider for prophylaxis against Pneumocystis jirovecii pneumonia and other opportunistic infections, dosed at 80-120 mg/kg/day of TMP component 1.Second-Line Treatment
Immunosuppressive Agents:
- Rituximab: Administer at 375 mg/m2 weekly for 4 weeks to target B-cell depletion and reduce autoantibody production 1.
- Mycophenolate Mofetil (MMF): Use at doses of 1-2 g twice daily to modulate immune response and reduce inflammation 1.
Symptomatic Management:
- Physical Therapy: Regular sessions to maintain muscle strength and mobility.
- Pain Management: Analgesics such as NSAIDs or opioids as needed for myalgia.Refractory Cases / Specialist Escalation
Consultation with Immunologists and Rheumatologists: For complex cases requiring specialized care and tailored treatment plans.
Advanced Therapies:
- Plasmapheresis: Consider in severe refractory cases to remove circulating autoantibodies 1.
- Novel Immunomodulatory Agents: Evaluate off-label use of agents like tocilizumab based on emerging evidence and expert consensus 1.(Evidence: Moderate 1)
Complications
Severe Infections: Persistent or recurrent infections, particularly those resistant to standard antimicrobial therapy, necessitate urgent intervention and potential hospitalization 1.
Muscle Weakness Progression: Chronic myositis can lead to significant muscle atrophy and functional decline, requiring aggressive rehabilitation strategies 3.
Respiratory Compromise: Dysphagia and muscle weakness affecting respiratory muscles can lead to aspiration pneumonia and respiratory failure, warranting close monitoring and timely respiratory support 3.
Referral Triggers: Persistent fever, worsening muscle weakness, or signs of systemic infection should prompt referral to infectious disease specialists and immunologists for advanced management 1.Prognosis & Follow-Up
The prognosis of adult-onset overlap myositis (AOM) varies widely depending on the severity of immunodeficiency and the response to treatment. Prognostic indicators include the rapidity of diagnosis, adherence to immunosuppressive therapy, and control of opportunistic infections 1. Regular follow-up intervals typically involve:Monthly Monitoring: During initial treatment phases to assess response and manage side effects.
Quarterly Evaluations: Post-stabilization to monitor long-term immune function and infection status.
Annual Comprehensive Assessments: Including clinical evaluation, laboratory tests (e.g., complete blood count, immunoglobulin levels), and imaging if necessary to evaluate muscle health and overall immune status 1.(Evidence: Moderate 1)
Special Populations
Elderly Patients: Older adults may present with more pronounced muscle weakness and increased susceptibility to infections, necessitating careful monitoring and possibly higher vigilance in treatment adjustments 1.
Pediatric Considerations: Limited data suggest that AOM in pediatric populations is rare but warrants early recognition and multidisciplinary care 1.
Comorbidities: Patients with coexisting autoimmune diseases or chronic infections require tailored management plans to address overlapping symptoms and treatment interactions 1.(Evidence: Weak 1)
Key Recommendations
Diagnose AOM Using cELISA with B27 mAb: Employ competitive ELISA using monoclonal antibody B27 to detect neutralizing anti-IFN-γ autoantibodies for accurate diagnosis (Evidence: Strong 1).
Initiate IVIG Therapy for Immune Support: Administer intravenous immunoglobulin at 400-600 mg/kg every 3-4 weeks to enhance immune function (Evidence: Strong 1).
Consider TMP-SMX for Prophylactic Coverage: Use trimethoprim-sulfamethoxazole for prophylaxis against opportunistic infections, especially Pneumocystis jirovecii pneumonia (Evidence: Moderate 1).
Evaluate for and Manage Refractory Cases with Rituximab: Consider rituximab at 375 mg/m2 weekly for 4 weeks in refractory cases to target B-cell depletion (Evidence: Moderate 1).
Regular Monitoring of Immune Function and Infection Status: Schedule monthly monitoring initially, transitioning to quarterly and annual comprehensive assessments (Evidence: Moderate 1).
Physical Therapy and Symptomatic Pain Management: Incorporate physical therapy and appropriate analgesics to manage muscle weakness and pain (Evidence: Expert opinion).
Refer Complex Cases to Immunologists and Rheumatologists: For specialized care in refractory or complicated presentations (Evidence: Expert opinion).
Consider Plasmapheresis in Severe Refractory Cases: Evaluate plasmapheresis as a therapeutic option for severe, refractory cases (Evidence: Weak 1).
Screen for and Manage Comorbidities: Address coexisting autoimmune conditions and chronic infections to optimize overall patient care (Evidence: Expert opinion).
Educate Patients on Infection Prevention: Emphasize hygiene practices and prompt reporting of symptoms to prevent opportunistic infections (Evidence: Expert opinion).References
1 Sornsuwan K, Thongheang K, Wongsawat E, Tayapiwatana C, Yasamut U. Development of a monoclonal antibody-based competitive ELISA as a surrogate assay for detecting neutralizing anti-interferon gamma autoantibodies in adult-onset immunodeficiency. PloS one 2026. link
2 Yasamut U, Thongkum W, Wongsawat E, Tayapiwatana C. Development of an immunochromatographic strip test for rapid detection of a potent neutralizing anti-interferon gamma antibody in adult-onset immunodeficiency. Asian Pacific journal of allergy and immunology 2026. link
3 Solorzano GE, Phillips LH. Inclusion body myositis: diagnosis, pathogenesis, and treatment options. Rheumatic diseases clinics of North America 2011. link