Smoking in Multiple Sclerosis (MS), NMSOD and MOGAD

Smoking is one of the few modifiable environmental risk factors for multiple sclerosis (MS) and other autoimmune diseases of the central nervous system (CNS). In MS, tobacco use increases the risk of developing the disease, accelerates disability accumulation and promotes earlier transition to secondary progressive MS. In NMSOD - neuromyelitis optica spectrum disorder (hereafter NMSOD) and MOGAD, current evidence suggests that smoking does not increase the risk of disease onset, but it worsens recovery after attacks and is associated with higher disability.

Importantly, smoking cessation at any stage — from clinically isolated syndrome (CIS) to long-standing MS or NMSOD/MOGAD — is associated with slower disease progression, and in some patients, after several years of abstinence, the risk of disability approaches that of never-smokers.

Contents

• How smoking affects the risk of developing MS
• Impact of smoking on MS course, progression and prognosis
• Mechanisms of tobacco smoke effects on the CNS and immune system
• Passive smoking, pack-years and other nuances
• Smoking in NMSOD and MOGAD
• E-cigarettes, vaping and heated tobacco
• Benefits of smoking cessation in MS, NMSOD and MOGAD
• How to quit smoking (brief overview)
• Key messages for patients
• References

How smoking affects the risk of developing multiple sclerosis

Smoking is a well-established environmental risk factor for MS. Large meta-analyses show that smokers have approximately a 1.5-fold higher risk of developing MS compared with never-smokers, with a clear dose–response relationship: the greater the lifetime exposure and intensity of smoking, the higher the risk.

Contemporary estimates suggest that at least 13 % of MS cases could be prevented if exposure to tobacco smoke (active and passive smoking) were eliminated. This is a very substantial contribution of a single risk factor in a chronic neurological disease.

Importantly, the risk is increased not only in active smokers, but also in people with long-term exposure to passive smoking. Studies have shown that living or working in an environment with constant tobacco smoke also increases the likelihood of developing MS.

Why does smoking increase MS risk?

The main hypotheses include:

• inhalation of toxic combustion products from tobacco, which cause chronic inflammation in the lungs and trigger a systemic immune response;
• activation of innate and adaptive immunity, with a shift towards proinflammatory T-helper and B-cell responses;
• damage to vascular endothelium and disruption of the blood–brain barrier, which facilitates penetration of immune cells into the CNS;
• epigenetic changes (primarily DNA methylation changes) that interact with genetic MS risk factors (HLA alleles and others).

Taken together, these mechanisms make the immune system more “inclined” to autoimmunity and promote an autoimmune attack on myelin in genetically susceptible individuals.

Impact of smoking on MS course, progression and prognosis

In people with established MS, smoking is associated not only with higher inflammatory activity, but also with faster disability accumulation and earlier transition to secondary progressive MS.

• More frequent relapses and higher MRI lesion burden (new and enlarging lesions, more contrast-enhancing lesions).
• Faster conversion from clinically isolated syndrome (CIS) to clinically definite MS.
• Earlier transition to the secondary progressive phase and faster attainment of disability milestones on the EDSS (e.g. 4.0 and 6.0).
• More pronounced brain atrophy and a combination of neurodegenerative and vascular damage to CNS tissue.

In a large cohort study, current smokers reached significant disability milestones more rapidly than never-smokers, while ex-smokers had an intermediate risk and, over time, approached the never-smoker group.

Effect of smoking on MS treatment efficacy

There is evidence that smoking may reduce the effectiveness of some disease-modifying therapies (DMTs). In particular, for natalizumab, a higher frequency of neutralizing antibody formation has been reported in smokers.

Smoking has also been associated with a poorer response to interferon-beta and likely exacerbates overall vascular risk (hypertension, dyslipidemia, diabetes), which is important given the growing recognition of vascular factors in long-term MS prognosis.

Mechanisms of tobacco smoke effects on the immune system and CNS

Tobacco smoke contains thousands of chemical compounds, including nicotine, nitrogen oxides, carbon monoxide, free radicals and heavy metals. Their effects are multi-component:

1. Immune activation and neuroinflammation

• activation of innate immunity (macrophages, dendritic cells, neutrophils);
• shift towards Th1/Th17 responses and increased production of proinflammatory cytokines (IL-6, TNF-α and others);
• enhanced B-cell activity and antibody production;
• increased trafficking of activated lymphocytes across the blood–brain barrier.

2. Oxidative stress and neuronal damage

• increased production of free radicals and reactive oxygen species;
• mitochondrial damage and impaired neuronal energy metabolism;
• greater vulnerability of demyelinated axons and acceleration of neurodegeneration.

3. Epigenetic changes

Large studies have demonstrated that smoking induces widespread DNA methylation changes in patients with MS. The magnitude of these changes increases with cumulative smoking exposure and is partially reversible after cessation. Many affected loci are involved in immune regulation and overlap with MS risk genes (for example, AHRR and the HLA region).

Passive smoking, long-term exposure and other nuances

Passive smoking (living or working in environments with constant tobacco smoke) is also associated with a higher risk of MS and likely with a more severe disease course.

Several exposure parameters are important:

• lifetime smoking exposure (pack-years) — the greater it is, the higher the cumulative risk of MS and progression;
• age at smoking initiation — early onset (adolescence) is particularly unfavorable from an autoimmune risk perspective;
• type of product — cigarettes, cigars, waterpipe, roll-your-own and others differ in toxic profiles, but there is no evidence of a “safe” option.

To date, no safe level of smoking has been identified for people with MS: even “occasional” or “social” smoking adds up to a significant immune and vascular burden over time.

Smoking in NMSOD and MOGAD

In NMSOD (opticospinal spectrum disorder) and MOGAD, the situation differs somewhat from MS.

Risk of disease onset

Available data do not support a significant increase in the risk of developing NMSOD among smokers compared with non-smokers, in contrast to the clear smoking–MS association. Similarly, for MOGAD there is currently no robust evidence that smoking increases disease susceptibility.

Impact on attack outcomes and disability

Recent multicenter studies have shown that current smoking is associated with worse attack outcomes and higher disability in both AQP4-positive NMSOD and MOGAD:

• in MOGAD, current smokers had roughly three-fold higher odds of residual disability after the initial attack and after the first episode of optic neuritis compared with never-smokers;
• in AQP4-positive NMSOD, the odds of disability after onset attacks were even higher, with odds ratios around 7.5 for current smokers;
• smokers more frequently demonstrated incomplete MRI lesion resolution, and poor lesion resolution correlated strongly with worse clinical recovery.

Thus, even if smoking does not clearly increase the risk of developing NMSOD or MOGAD, it significantly worsens attack outcomes and long-term prognosis. Smoking cessation is therefore just as relevant for these patients as it is for those with MS.

E-cigarettes, vaping and heated tobacco: is there a “safe” alternative?

E-cigarettes and heated tobacco products are often marketed as “less harmful” alternatives to conventional smoking. However, data specifically in patients with MS, NMSOD and MOGAD are extremely limited. Most studies have been conducted in the general population and in experimental models.

Experimental work suggests that aerosols from e-cigarettes can damage vascular endothelium and disrupt blood–brain barrier integrity, enhance neuroinflammation and lead to cognitive impairment in animal models. Several components (for example, acrolein and certain flavorings) induce pulmonary inflammation and could, in theory, amplify autoimmune cascades.

Large reviews of biological barriers conclude that vapes are not “harmless”: they can cause endothelial dysfunction, impair lung barrier function and likely promote neuroinflammation.

Professional societies (including national MS societies) stress that e-cigarettes may be considered only as a temporary tool on the pathway to complete nicotine cessation in cases where other methods have failed. Evidence-based strategies such as nicotine replacement therapy (patches, gum, lozenges, sprays) and behavioral programmes are preferred over long-term vaping.

In summary, for patients with MS, NMSOD and MOGAD the ultimate goal should be complete cessation of tobacco and nicotine. If vaping is used, it should be only a short-term step within a structured cessation plan, under medical supervision.

Benefits of smoking cessation in MS, NMSOD and MOGAD

The good news is that the benefits of smoking cessation in MS and related demyelinating diseases are measurable.

MS: slowing progression and “convergence” with never-smokers

• Cohort studies have shown that after smoking cessation, the rate of disability accumulation decreases, and over time (approximately 5–10 years) the risk of reaching key EDSS milestones approaches that of never-smokers.
• In the study by Tanasescu et al., each year of abstinence was associated with a further reduction in the risk of disability progression.
• Smoking cessation is also associated with reduced clinical and MRI disease activity, particularly when combined with effective DMTs.

Importantly, regardless of MS stage (CIS, early relapsing–remitting MS, established secondary progressive MS), quitting smoking is always better than continuing: at any baseline level of disability, the slope of further decline becomes less steep.

NMSOD and MOGAD

Long-term studies specifically addressing the effects of smoking cessation on NMSOD and MOGAD prognosis are still limited. However, it is already clear that:

• current smokers have a higher risk of residual disability after attacks and a higher frequency of incompletely resolving MRI lesions;
• based on these data and general knowledge about tobacco’s impact on the immune and vascular systems, it is reasonable to assume that smoking cessation should improve prognosis, although the magnitude of this effect needs to be quantified in longitudinal studies.

At present, the practical recommendation is straightforward: patients with NMSOD and MOGAD should be considered a priority group for active smoking cessation support, just like patients with MS.

How to quit smoking: main approaches (brief overview)

Smoking cessation strategies in patients with MS and other demyelinating diseases generally follow standard guidelines but must take into account disease-specific features such as fatigue, depression and cognitive difficulties.

• Discussion with a neurologist — assessment of current MS/NMSOD/MOGAD activity, comorbidities, medications and potential interactions.
• Nicotine replacement therapy (patches, gum, lozenges, sprays, etc.) — helps reduce withdrawal symptoms.
• Prescription smoking cessation medications (e.g. varenicline, bupropion) — prescribed by a physician with attention to neurological and psychiatric status.
• Behavioral support — individual or group counselling, cognitive-behavioral therapy, self-help programmes and mobile apps.
• Managing stress and mood — stress management and treatment of depression/anxiety; in MS/NMSOD/MOGAD this is particularly important since stress and depression may themselves worsen disease course.
• Weight management and physical activity — light, regular exercise may help patients cope with cessation and improves overall wellbeing.

The key principle is an individualized plan that takes into account the neurological status, cognitive profile and life circumstances of each patient.

Key messages for patients

• Smoking increases the risk of developing MS and accelerates progression in people who already have the disease.
• In NMSOD and MOGAD, smoking does not appear to increase the risk of onset, but it worsens recovery after attacks and increases disability.
• Smoking enhances neuroinflammation, damages the blood–brain barrier and induces epigenetic changes that interact with genetic risk factors.
• Smoking cessation at any stage is one of the most effective available interventions to improve long-term outcomes.
• E-cigarettes and vapes are not a safe alternative; they may be used only as a short-term tool on the way to complete nicotine cessation.
• The optimal approach combines pharmacological support, behavioral interventions and lifestyle modification.

References

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