Risk of Serious Infections in Multiple Sclerosis Patients
MS patients face significantly elevated infection risks compared to the general population, with the magnitude varying substantially by disease-modifying therapy—rituximab carries the highest risk of serious infections requiring hospitalization, while natalizumab and fingolimod show intermediate risk, and interferon-beta/glatiramer acetate demonstrate the lowest risk among DMTs.
Baseline Infection Risk in MS Patients
MS patients have an inherently increased infection risk independent of treatment. Untreated MS patients demonstrate a 2.97-fold increased risk of serious infections and a 39% increased risk of outpatient infections compared to matched controls without MS 1. This baseline elevation persists even with first-line therapies, as interferon-beta/glatiramer acetate-treated patients show a 2.31-fold increased risk of serious infections and 60% increased risk of outpatient infections versus controls 1.
DMT-Specific Infection Risks
High-Risk Therapies
Rituximab and Anti-CD20 Therapies carry the highest serious infection burden. Rituximab demonstrates a 70% increased risk of serious infections compared to interferon-beta/glatiramer acetate (adjusted HR 1.70,95% CI 1.11-2.61) 2. The crude incidence rate reaches 19.7 serious infections per 1000 person-years with rituximab versus 8.9 per 1000 person-years with interferon-beta/glatiramer acetate 2. Rituximab also shows a 19% increased risk of outpatient infections compared to interferon-beta/glatiramer acetate 1.
Natalizumab presents a 40% increased risk of serious infections versus interferon-beta/glatiramer acetate (adjusted HR 1.40,95% CI 0.96-2.04) 1. The crude incidence rate is 11.4 serious infections per 1000 person-years 2. Natalizumab demonstrates an 82% increased risk of outpatient herpetic infections specifically (HR 1.82,95% CI 1.34-2.46) 2. Progressive multifocal leukoencephalopathy (PML) represents the most devastating opportunistic infection risk with natalizumab, particularly in JCV-seropositive patients with treatment duration ≥18 months 3, 4, 5.
Fingolimod shows a 22% increased risk of outpatient infections compared to interferon-beta/glatiramer acetate 1. Fingolimod demonstrates a 71% increased risk of outpatient herpetic infections (HR 1.71,95% CI 1.27-2.32) 2. Long-term use of fumarates associates with higher severe infection rates, particularly in patients with poorer baseline health 6.
Lower-Risk Therapies
Interferon-beta and glatiramer acetate represent the lowest infection risk profile among DMTs, though still elevated compared to the general population 1, 2.
Critical Risk Factors Beyond DMT Choice
Independent predictors of serious infections include:
- Higher Charlson Comorbidity Index significantly increases serious infection risk regardless of DMT 1
- Previous hospitalization for infections substantially elevates future serious infection risk 1
- Advanced disability status (requiring walking aids or wheelchair-bound) markedly increases infection risk 1, 6
- Progressive MS phenotype associates with higher severe infection rates 6
- Longer DMT duration predicts increased mild infection rates 6
Notably, hospitalization for urinary tract infection-related pseudorelapses accounts for 24-48% of serious infections in MS patients, highlighting the importance of optimizing bladder care 1.
Specific Opportunistic Infection Risks
Progressive Multifocal Leukoencephalopathy (PML)
For natalizumab-treated patients, PML risk stratification is mandatory 4, 5:
- JCV-seronegative patients: PML risk approximately 1 in 10,000 4
- JCV-seropositive with index ≤1.5: PML risk approximately 1 in 5,882 4
- JCV-seropositive with index >1.5: PML risk approximately 1 in 855 4
Brain MRI screening every 3-4 months is required for high-risk natalizumab patients (JCV-seropositive, treatment duration ≥18 months) using FLAIR, T2-weighted, and diffusion-weighted imaging 3, 4. Low-risk patients (JCV-seronegative) require annual brain MRI 3, 4.
Herpes Virus Infections
Natalizumab increases risk of herpes simplex and varicella zoster encephalitis and meningitis, with serious, life-threatening, and sometimes fatal cases reported 5. Acute retinal necrosis (ARN) caused by herpes viruses occurs at higher rates with natalizumab, potentially leading to blindness 5. In real-world practice, HSV-1 reactivation with detectable plasma DNA occurred in natalizumab-treated patients, along with VZV reactivation in cladribine-treated patients 7.
Hepatitis B Reactivation
HBV reactivation can occur in anti-HBc positive patients during DMT treatment, documented in ocrelizumab-treated patients 7. All anti-HBc positive patients require HBV-DNA monitoring before and during DMT 7.
Carry-Over Infection Risk When Switching DMTs
"Carry-over opportunistic infections" represent a critical risk when switching therapies, occurring at treatment discontinuation or several months after starting new treatment 3. This phenomenon is particularly concerning when switching from natalizumab to fingolimod, alemtuzumab, or dimethyl fumarate 3.
Enhanced pharmacovigilance with brain MRI every 3-4 months for up to 12 months is required when switching from natalizumab to other therapeutics 3. Brain MRI should be obtained at the time current treatment is discontinued and after new treatment is started in patients at high risk of opportunistic infections 3.
Post-AHSCT Infection Risk
Following autologous hematopoietic stem cell transplantation (AHSCT), infection risk at 12 months is comparable to non-induction DMTs 3. However, risk of adverse events may be increased by previous high-dose immunosuppression due to cumulative lower immune competence 3.
Multiple factors influence post-AHSCT infection risk including epidemiological factors (influenza season, household contacts), previous recurrent infections, immunosuppressive treatment received before AHSCT, type of chemotherapy used, and use of B cell-depleting antibodies 3.
Pre-Treatment Screening Requirements
Mandatory screening before DMT initiation includes 7:
- Anti-HBc and HBV-DNA testing for hepatitis B
- QuantiFERON-TB Gold testing for tuberculosis
- JCV antibody testing before natalizumab 4, 5
- Varicella zoster immunity assessment
Among screened patients, latent tuberculosis infections and active tuberculosis require one month of prophylaxis or treatment, respectively, before starting DMTs 7. All anti-HBc positive patients without detectable HBV-DNA can start DMT with appropriate monitoring 7.
Risk Mitigation Strategies
To minimize serious infection risk 1:
- Optimize bladder care to prevent UTI-related pseudorelapses (which account for up to 48% of serious infections)
- Implement comorbidity prevention strategies
- Ensure varicella vaccination before starting DMT
- Consider discontinuing or avoiding DMT use in patients with advanced disability (EDSS >6.0) and/or previous hospitalizations for infections
- Perform regular infectious disease assessments during DMT treatment 7
For patients on natalizumab, strict pharmacovigilance includes 3, 4:
- Brain MRI every 3-4 months for high-risk PML patients
- Annual brain MRI for low-risk patients
- MRI protocol must include FLAIR, T2-weighted, and diffusion-weighted imaging
Clinical Implications for Treatment Selection
The infection risk profile should fundamentally inform DMT selection. Patients with multiple comorbidities, previous serious infections, advanced disability, or progressive MS phenotype should preferentially receive interferon-beta/glatiramer acetate when disease activity permits 1, 6. Conversely, younger patients with highly active disease and minimal comorbidity burden can tolerate higher-risk DMTs with appropriate monitoring 1.
Hepatotoxicity monitoring is essential, as clinically significant liver injury including acute liver failure requiring transplant has occurred with natalizumab, with signs appearing as early as six days after first dose 5. Natalizumab must be discontinued in patients with jaundice or laboratory evidence of significant liver injury 5.