Smoking a potential drug interaction in IFNB

Are you a smoker? This is an important post if you are.




Neurology. 2018 Jan 17. pii: 10.1212/WNL.0000000000004949. doi: 10.1212/WNL.0000000000004949. [Epub ahead of print]

Smoking affects the interferon beta treatment response in multiple sclerosis.

Petersen ER, Oturai AB, Koch-Henriksen N, Magyari M, Sørensen PS, Sellebjerg F, Søndergaard HB.

Abstract

OBJECTIVE:

To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A.

METHODS:

DNA from 834 IFN-β-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.

RESULTS:

We found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant.

CONCLUSION:

In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.

No ifs ands or butts, cigarette smoking is a health hazard. Together with vitamin D, smoking in MS has been well documented as a risk factor for disease susceptibility. It has also been linked to genes implicated in MS risk, including human leukocyte antigen (HLA) DRB1*15:01 and A*02:01 and N-acetyltransferase-1 (NAT1, gene involved in the metabolism of tobacco smoke constituents that modifies MS risk in smokers).

Here, the authors study the influence of smoking on relapse activity in IFN-B treated RRMS, including whether treatment response was influenced by interaction between smoking and gene variants listed above. A total of 834 PwMS were examined.

They found after adjusting for confounding factors such as gender, age at start of IFN-β and the number of relapses in the 2 years prior to commencing treatment that smoking was associated with an increased relapse rate (by ~27%) during the course of treatment. IFN-β treatment efficacy has been linked to the presence of neutralizing antibodies (Nabs), which may negate its action by as much as 50%. Therefore, they excluded those with persistent Nabs in this study. Passive smoking was not examined in this study.

They did not find any association with the genetic variants tested. Previously, another study had reported that the NAT1 genetic variant (rs7388368A) interacted with smoking as a risk factor for MS (Briggs FB, Acuna B, Shen L, et al. Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants. Epidemiology 2014;25:605–614).

The question therefore, is to what extent smoking affects the efficacy of other MS therapies if at all?...

Comorbidties and smoking, what can we do about them?

The elephant in the room is comorbidities such as hypertension, diabetes, obesity, metabolic syndrome and smoking. How can we get pwMS to take their general health seriously? 

In the study below physical comorbidity was not only associated with disability but with each additional comorbidity, there was a mean increase in the EDSS score of 0.18. By optimising your general health you will reduce your chances of getting worse. 

When last have you been to your family doctor, or GP, to have your blood pressure, weight, blood sugar and lipids checked? If you haven't had these done in the last 12 months you should go and get them done. 

Are you still a smoker? If yes, you need to read the second paper below that shows smoking reduces the effectiveness of interferon-beta. I wouldn't be surprised if this observation extends to other DMTs. We know that pwMS who smoke do worse than non-smokers. So if you want to improve your outcome you need to stop smoking. Please note you don't have to necessarily give up your nicotine habit. You can get your daily fix of nicotine from several other safer options (gum, skin patches, tablets, e-cigarettes, etc.). 

COMORBIDITIES

Zhang et al. Effects of physical comorbidities on disability progression in multiple sclerosis. Neurology. 2018 Jan 3. pii: 10.1212/WNL.0000000000004885.

OBJECTIVE: To examine the association between physical comorbidities and disability progression in multiple sclerosis (MS).

METHODS: We conducted a retrospective cohort study using linked health administrative and clinical databases in 2 Canadian provinces. Participants included adults with incident MS between 1990 and 2010 who entered the cohort at their MS symptom onset date. Comorbidity status was identified with validated algorithms for health administrative data and was measured during the 1 year before study entry and throughout the study period. The outcome was the Expanded Disability Status Scale (EDSS) score as recorded at each clinic visit. We used generalized estimating equations to examine the association between physical comorbidities and EDSS scores over time, adjusting for sex, age, cohort entry year, use of disease-modifying drugs, disease course, and socioeconomic status. Meta-analyses were used to estimate overall effects across the 2 provinces.

RESULTS: We identified 3,166 individuals with incident MS. Physical comorbidity was associated with disability; with each additional comorbidity, there was a mean increase in the EDSS score of 0.18 (95% confidence interval [CI] 0.09-0.28). Among specific comorbidities, the presence of ischemic heart disease (IHD) or epilepsy was associated with higher EDSS scores (IHD 0.31, 95% CI 0.01-0.61; epilepsy 0.68, 95% CI 0.11-1.26).

CONCLUSIONS: Physical comorbidities are associated with an apparent increase in MS disability progression. Appropriate management of comorbidities needs to be determined to optimize outcomes.

SMOKING

Petersen et al. Smoking affects the interferon beta treatment response in multiple sclerosis. Neurology. 2018 Jan 17. pii: 10.1212/WNL.0000000000004949.

OBJECTIVE: To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A.

METHODS: DNA from 834 IFN-β-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.

RESULTS: We found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant.

CONCLUSION: In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.

ProfG    

Why does smoking increase your risk of MS?

We don’t understand yet why people get MS. The accepted view is that there is an interaction between risk genes and environmental factors like EBV, smoking, and vitamin D status. Epidemiological studies have helped to identify these risk factors for developing MS, but it is unclear how these factors actually contribute to disease evolution and progression.

There is strong evidence that smoking increases your risk of developing MS. There is also strong evidence that in pwMS, smoking is bad for both disease activity and long-term disability progression. The effect of smoking is long-lived: it takes about 10 years after quitting for disease activity to return to the level of people who don’t smoke. As well as being harmful in terms of overall health, smoking increases your risk of Crohn’s disease and Rheumatoid Arthritis - other autoimmune diseases similar in some respects to MS.

Why smoking influences MS is unclear. One explanation is that the chemicals in cigarette smoking alter the tagging and folding of DNA in our cells, and thereby change the way that the genetic code is read out.

A brief interlude on this theme. For many years the central dogma of biology was that information flowed as a one-way street (excuse mixed metaphor) from our genetic code. Crick and Watson, the scientists credited with discovering the structure of DNA, suggested that the genetic material (DNA) tells the cell which proteins to make, but that this information does not flow the other way. Classically, DNA was thought to be used to generate messenger molecules (mRNA), which then formed the recipe for making the proteins required for cellular processes:

We now recognise that this is not the whole story. While the vast majority of our cells carry the same DNA, they do not all make the same proteins. In fact any one cell only reads out from a tiny fraction of its DNA at any one time. In addition, the parts of DNA that a cells reads out from changes dynamically from moment to moment.

How does this phenomenon take place? Well, although the backbone of DNA is a simple double-stranded helix, each molecule of DNA is folded into a complicated 3D structure in the cell. To read out from a particular portion of DNA, that portion needs to be accessible to the reading machinery. We now understand that cells have various ways of ‘tagging’ parts of the DNA molecule which can effectively turn genes on and off. These modifications essentially change the way the genetic code is read out without changing the DNA itself: they are therefore dubbed ‘epigenetic’ rather than genetic.

One of the best-understood epigenetic modifications is called methylation. A methyl group is a carbon with 3 hydrogen atoms attached. Addition of a methyl group to a part of DNA normally has the effect of switching off nearby genes. Studying DNA methylation is very interesting because it tells us how genes may be switched on and off in both health and disease.

Against this backdrop, a new Swedish study asked whether DNA methylation might be the link between smoking and MS. They looked at 2 cohorts from a huge case-control study of MS. First, they picked people who had a particular genetic signature known to interact with smoking: they were positive for HLA-DRB1*15:01 – the main risk gene - and negative for HLA-A*02 – the main protective gene. The second group were people with MS without any genetic criteria.

For each participant, they analysed the entire epigenome: the map of all methylated sites in the DNA. They then categorised people into three groups according to when they last smoked:

-          Within 5 years

-          Beyond 5 years

-          Never-smokers

… and compared the epigenomes between these groups.

Interestingly, they found several positions in the genome at which the methylation status differed between never-smokers and recent smokers. There was no difference between never-smokers and ex-smokers who quite >5 years previously. Surprisingly, the effect of smoking on DNA methylation is greater in those with MS than those without. Whether this is due to synergistic effects of disease-modifying therapy or related to the underlying disease is not clear.

This study identifies a possible mechanistic link between smoking and the risk of developing MS. The authors prove that smoking leads to epigenetic changes in pwMS. It is therefore plausible that smoking has widespread effects on the expression of various genes which may facilitate the development of MS. The fact that these effects were only seen in the recent smokers supports the idea that smoking might promote MS through changes in gene expression, as this fits with the epidemiological data: the harms of smoking for MS dissipate 5 – 10 years after quitting. So, the timescale of the epigenetic modifications reported here is consistent with a causal link between smoking and MS.

While these data are very interesting, they do not really show how smoking exacerbates MS. Smoking influenced the methylation status of several genes, but only one of these was shown to be expressed differently as a downstream consequence. This gene was not obviously involved in the development of MS. It seems likely to me that smoking influences the expression of lots of genes; it also promotes lung inflammation, can introduce mutations into the underlying DNA, and promotes cardiovascular disease. The mechanism by which smoking influences MS is likely very complicated and is unlikely to be just due to a direct effect on gene expression. There are also important confounders like activity level, socio-economic status, and overall health which may influence smoking status and epigenetic modifications.

The bottom line is that this study shows one possible mechanism – epigenetic modification - through which smoking might influence the risk of MS.

***

Abstract

Cigarette smoking is an established environmental risk factor for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease, although a mechanistic basis remains largely unknown. We aimed at investigating how smoking affects blood DNA methylation in MS patients, by assaying genome-wide DNA methylation and comparing smokers, former smokers and never smokers in two Swedish cohorts, differing for known MS risk factors. Smoking affects DNA methylation genome-wide significantly, an exposure-response relationship exists and the time since smoking cessation affects methylation levels. The results also show that the changes were larger in the cohort bearing the major genetic risk factors for MS (female sex and HLA risk haplotypes). Furthermore, CpG sites mapping to genes with known genetic or functional role in the disease are differentially methylated by smoking. Modeling of the methylation levels for a CpG site in the AHRR gene indicates that MS modifies the effect of smoking on methylation changes, by significantly interacting with the effect of smoking load. Alongside, we report that the gene expression of AHRR increased in MS patients after smoking. Our results suggest that epigenetic modifications may reveal the link between a modifiable risk factor and the pathogenetic mechanisms.