Infections in Idiopathic Inflammatory Myopathies: Do Asians Need a Different Dose of Immunosuppression?

Abstract

Day et al. highlight the intricate challenges in managing rare rheumatic diseases like idiopathic inflammatory myopathies (IIMs), particularly when aggressive immunosuppression is complicated by opportunistic infections [1]. This rare disease-rare complication scenario is further complicated by the hypothesis that infections may trigger autoimmunity, creating a paradoxical management dilemma. Opportunistic infections, which often present atypically in myositis patients and may mimic active IIM, pose a significant clinical challenge [2]. Furthermore, infections are the leading cause of death in myositis patients, suggesting that clinicians need to manage the prevention and early detection of infection. Moreover, immunosuppressive drugs (ISDs) may lead to other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs), particularly in patients treated with methotrexate [3]. The absence of well-defined guidelines for these complex scenarios underscores the urgent need for comprehensive research to inform evidence-based management strategies in these challenging cases.

In patients with IIM and other autoimmune diseases, infection risk is influenced by a complex interplay of disease characteristics and treatment. A dysregulated immune response, disease severity, and the use of immunosuppressive medications significantly increase infection risk in conditions such as systemic lupus erythematosus (SLE) with an infection rate of 29.2%–43.9% [4]. Opportunistic infections in myositis patients also present a significant clinical challenge, with a reported 33%–54% overall infection rate and 6%–12% classified as opportunistic, particularly within the first year of high-dose corticosteroid treatment [5-7]. Dermatomyositis patients, especially those with anti–MDA5-antibody positivity, face heightened infection risks independent of immunosuppressive therapy [7-9]. Other factors, such as methylprednisolone pulse therapy, combination therapy, disease onset after age 50 years, a lymphocyte count below 1200/mm³, high serum KL-6 levels, and the presence of interstitial lung disease (ILD), also contribute to higher infection risk [10, 11]. This issue is particularly acute in developing regions like Asia, where environmental factors and healthcare disparities, including inadequate vaccination protocols for immunosuppressed patients, exacerbate outcomes. The prevalence and impact of these infections underscore the urgent need for improved prevention strategies and management guidelines, especially in resource-limited settings.

Significant regional disparities in infection prevalence among myositis patients demand tailored management strategies. Asia reports higher mycobacterial infection rates (5.86%) compared to Europe (2.36%) and Latin America (2.47%) in IIM patients [12]. These patients show increased susceptibility to tuberculosis, often presenting with extrapulmonary forms and experiencing slower treatment responses [13]. Environmental factors in tropical regions further complicate management, with studies highlighting respiratory and opportunistic infections (e.g., aspergillosis, Pneumocystis jirovecii, cytomegalovirus) as major concerns [14]. These regional variations underscore the critical need for locale-specific approaches in managing opportunistic infections in myositis, emphasizing tailored prevention and treatment protocols aligned with local epidemiological patterns and resources.

While infections remain a concern for IIM patients globally, their prevalence and types differ between developed and developing regions. Studies in the United States and France report infection rates of 28%–37% in IIM patients, primarily bacterial pneumonia and bacteremia, with opportunistic infections being less common [15, 16]. Viral infections, particularly varicella-zoster, affect IIM patients at similar rates globally [17, 18]. However, rare infections like pneumatosis coli are increasingly reported in Western countries, likely due to superior diagnostic capabilities. The absence of such reports from Asian countries suggests potential underdiagnosis due to diagnostic challenges and inadequate infrastructure, particularly in rural areas. This disparity highlights the urgent need for improved diagnostic and treatment strategies in resource-limited settings.

The paucity of myositis-specific studies on infection risks associated with immunosuppressive therapies necessitates extrapolation from other rheumatic diseases. Evidence from lupus nephritis patients indicates increased herpes zoster reactivation with higher steroid doses and cumulative immunosuppressant exposure [19]. Myositis patients, requiring similar treatments, likely face comparable risks.

Initial corticosteroid dosing in IIM-ILD is typically higher (0.75–1 mg/kg/day prednisolone) with slower tapering compared to other rheumatic diseases, reflecting limited evidence and lack of standardized guidelines [20]. Critically, immunosuppressant dosing protocols are predominantly based on Western population studies, potentially overlooking genetic and metabolic differences in Asian patients. This discrepancy may inadvertently increase infection susceptibility among Asian populations when standard Western doses are applied. Furthermore, the underrepresentation of Asian patients in clinical trials limits the generalizability of these dosing regimens [21]. To mitigate these risks, there is an urgent need for stratified profiling of immunosuppressant dosing based on body mass and fat index, optimizing for individual patient requirements. This approach could help balance effective disease control with minimized infection risk. Additionally, increased representation of Asian populations in clinical trials is crucial to develop more universally applicable treatment protocols. The 2022 EULAR recommendations provide guidance for managing chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases (AIIRDs) [22]. While emphasizing that national guidelines and endemic disease factors should be considered, the recommendations did not specify interventions for Asia, considering it beyond their scope. This highlights the need for region-specific adaptations, particularly in areas like Asia where infections significantly impact AIIRD mortality.

Limited studies on glucocorticoid (GC) pharmacokinetics in obesity reveal partial distribution in excess body weight, suggesting that dosing adjustments based on total or excess body weight may lead to inappropriately high initial plasma concentrations [23]. Contradictory findings on GC exposure and clearance, coupled with observed increased GC sensitivity in obese patients even at lower exposures, indicate that weight-based dosing may be not only unnecessary but potentially harmful, underscoring the urgent need for further pharmacokinetic studies to guide appropriate GC dosing in this population. A systematic literature review indicates that genetic polymorphism, although frequently cited, may be overemphasized in explaining inter-ethnic pharmacokinetic differences [24]. The findings suggest that interindividual variability, stemming from factors such as diet, weight, body composition, and environmental influences, plays a more significant role in both interindividual and inter-ethnic variations in drug pharmacokinetics than previously recognized [24].

The heterogeneous Asian population exhibits diverse life expectancies, ranging from the lowest in South Asia to the highest globally in Japan's blue zones. Aging significantly impacts drug pharmacokinetics and introduces immunosenescence, necessitating precision-based dose optimization to mitigate infection and toxicity risks, as evidenced in renal transplant patients [25]. A study of Asian renal transplant recipients suggests that body-weight-adjusted mycophenolate mofetil (MMF) dosing at lower dose of 12 mg/kg twice daily may achieve therapeutic mycophenolic acid exposure than the standard 2 g/day, although significant interindividual variability indicates the need for therapeutic drug monitoring for optimal dose adjustment [26]. A recent study demonstrated that low-dose rituximab (100 mg weekly for 4 weeks) was effective in treating skin rash and ILD, including rapidly progressive ILD, in anti-MDA5 antibody-positive dermatomyositis, with potential cost and safety benefits [27]. Another study developed a physiologically based pharmacokinetic model for cyclosporine A in Asian children with renal impairment, enabling the assessment of ethnicity, age, and renal function impacts on drug pharmacokinetics, thus highlighting the importance of population-specific modeling in pediatric pharmacology [28].

Recently, a clinical panel of gastroenterologists developed guidance for autoimmune hepatitis (AIH) management in the Asia-Pacific region, recommending lower steroid doses and early azathioprine initiation due to the distinctive metabolic profiles and body fat composition of Asian populations [29]. This approach aims to optimize efficacy while minimizing steroid-related adverse events, emphasizing the importance of tailored therapy in this demographic.

Current guidelines for juvenile and adult myositis lack demographic-specific immunosuppression recommendations, primarily due to limited attention to regional outcome differences and missing data from certain Asia-Pacific areas [30]. This oversight fails to account for the varying immunosuppression requirements across diverse populations, potentially leading to suboptimal treatment strategies in regions with distinct genetic, metabolic, and environmental factors.

While IIMs are traditionally viewed as autoimmune conditions, emerging evidence suggests roles for autoinflammatory and immunodeficiency mechanisms. Notably, antibody-negative amyopathic dermatomyositis may represent an autoinflammatory phenotype potentially responsive to interleukin-1 blockade [31]. Similarly, VEXAS syndrome manifests myositis features in older adults [32]. Immunodeficiency processes, including MSN-deficient EBV-associated dermatomyositis and CVID-associated IIM, alongside complement deficiencies (C4A in DR3 positive individuals) in juvenile dermatomyositis, highlight alternative pathogenic mechanisms [33-35]. These insights suggest tailored therapeutic approaches, such as targeting innate immunity and addressing underlying immune defects, may be warranted in select cases.

In conclusion, the stark regional variations in infection patterns and the challenges experienced by patients with IIM demand urgent attention, particularly in Asia, where infections account for a staggering one-third of the mortality. This compelling statistic underscores the critical need for region-specific strategies in immunosuppressed patients. Addressing this unmet need through optimized immunosuppression dosing protocols, enhanced healthcare infrastructure, and increased awareness among both healthcare professionals and patients could significantly reduce infection-related mortality.

Groups such as the APLAR Myositis Special Interest Group and global initiatives like MIHRA, with their core values of inclusivity, diversity, and equity, are uniquely positioned to address these gaps. Their collaborative efforts can drive the development of tailored, evidence-based strategies for immunosuppression management in Asia, potentially transforming patient outcomes across the region. By leveraging these organizations' expertise and commitment to equitable healthcare, we can prioritize enhanced diagnostic capabilities, infrastructure development, and targeted research on rare infections in myositis. This approach not only promises to improve outcomes for IIM patients but also generates valuable insights for the broader immunocompromised population. The time for action is now; through these collaborative efforts, we can dramatically reduce infection risk and revolutionize the care of IIM patients in Asia and beyond.

Conceptualization: L.G. Data curation and formal analysis: All authors. Funding acquisition: N/A. Investigation: All authors. Methodology: J.P, L.G. Validation: All Authors, Visualization: L.G, Writing – original draft: Jasmine Parihar. Writing – review and editing: All authors.

T.G., H.S., and L.G. are members of the APLAR myositis special interest group.

The authors declare no conflicts of interest.

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