When I highlighted the risk of hypogammaglobulinaemia and infection in MSers receiving anti-CD20 therapy after ECTRIMS I go a very long email from someone from Roche playing down the risks. The following study is therefore very timely and shows that when comparing interferon-beta, glatiramer acetate, natalizumab, fingolimod and rituximab with each other it is rituximab that comes out worst in relation to infectious complications.
You also need to remember that not all anti-CD20 therapies are made equal and that ocrelizumab is a more potent B-cell depleter than rituximab. We know this based on the infectious complications seen in study subjects with rheumatoid arthritis and lupus and the observation that there is a clear varicella-zoster signal in the ocrelizumab phase 3 programme. In this context, an interesting observation was that there was a lower rate of anti-herpes/anti-virals in the rituximab-treated MSers compared to the other DMTs. This is interesting and raises questions of why this should be? Could it be because rituximab only reduces the CD8+ T-cell counts by about 15% after the first infusion and his little impact thereafter?
So don’t let anyone pull the wool over your eyes that anti-CD20 therapies are not immunosuppressive and are not associated with an infection signal. It is becoming clear to me that continuous dosing with anti-CD20 therapy will result in a cumulative increase in infections and at some stage we are as an MS community are going to have to derisk this problem by using (1) anti-CD20 therapy as an immune-reconstitution therapy (IRT) or as (2) an induction agent or (3) by correcting the immune deficiency by giving immunoglobulin replacement therapy when our patients develop hypogammaglobulinaemia.
I think we need to do the ADIOS study sooner than later. Don’t you?
Gustavo et al. Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies. JAMA Neurol. Published online October 7, 2019. doi:10.1001/jamaneurol.2019.3365
Question: What is the risk of infections in association with different disease-modifying treatments for multiple sclerosis?
Findings: This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment. The rate of infections was lowest with injectable therapies; among newer treatments, use of rituximab was associated with the highest rate of serious infections but less use of herpes antiviral medications compared with fingolimod and natalizumab.
Meaning: Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies.
Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.
Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.
Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.
Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon-beta and GA.
Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.
Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).
Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
POST-SCRIPT
In response to a comment, the following figures put the serious infection (requiring hospitalisation) risk on ocrelizumab in context; i.e. how common is this complication. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months 1 patient will be admitted to hospital with a serious infection.
However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months 1 patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.
Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-Label Extensions. ECTRIMS 2019,
MD Here I add this to the bottom of ProfGs post
Evaluating the efficacy and safety of ZytuxTM (Rituximab, AryoGen pharmed) in Iranian multiple sclerosis patients: An observational study. Naser Moghadasi A, Darki A, Masoumi P, Hashemi SN, Ghadiri F. Mult Scler Relat Disord. 2019 Sep 27;36:101419
BACKGROUND:Anti-CD20 monoclonal antibodies such as ocrelizumab, rituximab, and ofatumumab target B-cell lineage. Clinical trials have demonstrated their effect on reducing both magnetic resonance imaging (MRI) active lesion burden as well as clinical activity. Zytux™ (Rituximab, AryoGen Pharmed) used in the present study for multiple sclerosis (MS) patients is basically a biosimilar rituximab. In this observational study, a total of 100 patients receiving Zytux™ were collected to see its effect on the clinical course of the disease.
RESULT: A total of 100 MS patients including 36 males and 64 females participated in the present study. The patients included 20 relapsing remitting MS (RRMS), 20 primary progressive MS (PPMS), and 60 secondary progressive MS (SPMS) patients. Totally, the mean of EDSS score before and after the administration of drug was 5.50 ± 1.04 (ranging from 1 to 7) and 5.11 ± 1.59 (ranging from 0 to 7), respectively, with the difference between them being very significant (p-value: 0.000). Also, the mean of ARR before and after the initiation of the medication was 0.47 and 0.10, respectively, whose difference was also significant (p-value: 0.000). In our study, the greatest effect of Zytux™ was observed in RRMS patients. At the time of injection, 70 patients indicated some reactions including limb pain, skin sensitivity, and throat irritation. One month after the injection, one of the patients suffered from pneumonia and two patients had a urinary tract infection.
CONCLUSION:The observed results revealed that the Zytux™ could have a positive and significant effect on all types of MS
CoI: multiple
How is it @95% CL that natal is safer (infection wise) than fingolimod yet significantly more effective?
Why would any JCV- choose fingol instead of natal in that case?
Surely not for a preference of taking the pill to IV ?
I am obviously excluding women wanting children, etc…
Tony
Natalizumab is licensed for RES (rapidly-evolving severe) MS and fingolimod for highly-active MS. The EMA forces us to use fingolimod in some MSers who would clearly be better off on natalizumab.
I have been saying for years that we should have the option of using natalizumab 1st-line in JCV-ve patients. Biogen are you listening? We need you to go back to the EMA and request a label change and don’t worry about the possibility of cannibalizing your DMF market.
Interesting, thank you.
For a lay-person please can you quantify this risk in a way I can grasp?
Life is full of risks and how most of us manage them is to form an understanding, however bats it may be, to reduce day to day cognitive dissonance an (presently) existential threat presents, in order to assess the likelihood of the event and decide on what, if any, precautionary measures we need to take.
For example: is this serious enough that I make a point of leading with my concern when I next see my Neurologist (CoI – I am on Ocrelizumab)? Or, is it something there and to be aware of but on balance it is far less likely to harm me than say driving, going to the gym, cooking and so on.
As a pwMS on a potent drug then managing potential risks is a greater part of daily life so posts like this cause me to sit-up and wonder and I look to experts to help me understand my options.
Thank you.
Dominic
Dominic, the figures above (post-script) put the serious infection (requiring hospitalisation) risk on ocrelizumab in context; i.e. how common is this complication. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months 1 patient will be admitted to hospital with a serious infection.
However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months 1 patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.
Hi Dominic, hi Prof. G
I have exactly the same thought than you, Dominic. That’s why it is for me (and I think for a lot of patients who have not a very active MS) very difficult to decide to flip the pyramid or wait for the classic escalating strategy. On the one hand, it’s very tempting to go for highly effective DMT first line (because of end-organ damages), but on the other hand, articles like this are pretty frightening. To my mind, the meaning of “flipping the pyramid” is about going for highly effective DMTs as first-line without being forced to do so because of signs of active MS despite first-line DMT. So what NEDA-3 patients should do? Fliping the pyramid or wait?
I ain’t no Prof G nor any of his esteemed colleagues, I am an utter layman.
I disagree with your analysis. I asked the question because I want to manage the risk appropriately. The question as whether to or not take a highly effective DMT is not influenced.
I think of it like this: i used to ride motorcycles a lot, teach Advanced Motorcycle Riding. Sure, it is more dangerous transport method on paper. It is definitely a more effective way to get somewhere sooner than a car. If that is the absolute priority, for some groups of transport users, as it sometimes is, then understanding and managing the risks involved ought to be the key pastime.
MS makes the adoption of a higher risk strategy non-optional to me. I had better accept the risk but understand it, engage with it and manage it.
Having MS is binary to me. I am convinced that mild/inactive/benign MS is not a thing and I am convinced by medics and medical evidence that there is value in treating early and effectively.
The risk of not being on a highly effective DMT is a much longer term one and is what I understand to underpin the flipping the pyramid approach.
Given I am on Ocrelizumab already I need to understand what the ontological reality is so I can plan for it, discuss it with my clinicians, and react appropriately should it happen.
You can ask about your IGG levesl as an indication of B cell activity.
Thank you, MD.
That standalone number doesn’t mean much to me.
Are there parameters of IGG in relation to B Cells that puts the figure into a useful context – for a lay person?
To hear it is one thing – am routinely screened for it every 6mo at the JR before each Oc infusion – but to know what it means and what the implications(s) is/are is what interests me.
Maybe ProfG can post on this
Risks associated with immunosuppression (hypogammaglobulinaemia) cumulate over time and related to intensity and duration. That is the longer you are immunosuppressed the greater the risk. And the intensity feeds into that. So there is no simple answer. This is why IRT (immune reconstitution therapies) are so much more appealing that continous immunosuppressive therapies. Once your immune system has reconstituted there is very little or no risk.
And now I am on Ocrelizumab there is a much lower chance of presenting with an active lesion via Gad enhanced MRI thereby being an eligible candidate for IRT.
I saw a colleague of yours only last week to request IRT. That was the summation of their reply. Even if I had the funds to pursue privately this active lesion on MRI is becoming a more common criteria apparently.
Feel trapped between devil and deep blue sea. Do I come off an effective therapy for at least 6 mo, have an MRI and hope it provides the necessary result? If not, it was a fools errand.
No easy answer.
When I spoke to my haematologist about the long term risks of continual rituximab they were perplexed- they have people/children on it for years and just give them immunoglobulin. Surely this is something that has been anticipated?
Re: “….just give them immunoglobulin.”
Yes, that is one solution and probably the easiest solution and can be done at the same time ocrelizumab or rituximab is infused. It will a bit more complicated for ofatumumab-treated patients.
Yes, I definitely think the study is needed earlier! I started on Ocrevus shortly after it was approved in the U.S., and after my last infusion in June, my neutrophil count went down to .1 and I developed several infections all at once, including 3 areas of staph with cellulitis on my skin. Thanks to your blog, I was on the lookout for hypogammaglobulinemia, knowing that infections were possible, and got help right away. The infections happened so fast, it was pretty scary.
Will the ADIOS study (if positive) establish ocrelizumab as a reconstitution treatment or will it still be the company (Roche) that has to apply to change the official dosing regime?
Thanks for getting this out there Prof G – you’re a brave, courageous, hardworking v clever man.
If anyone is going to formulate a cure, it’s you and your v wise fellow contributors.
Anyway, I wonder how many patients would think twice about taking these drugs if they were more fully briefed about the slightly increased risk of infections?
I have thought twice, or maybe 100 times, of a dmd; but a very bad experience in hospital and an antibiotic resistant infection that nearly killed me, still has me dithering.
Is there anything that can be done to minimise the risk of an infection, or are they opportunistic and random?
And how does this work with the antibiotic crisis …and the cost and feasibility of closely monitoring patients, while also being mindful of not handing out too many antibiotics?
To get the licence changed it will be the licence holder that needs to do this I suspect. Roche should fund and do the study ASAP and then they will be in control, but if the academics do it then they may loose control. I believe there is already anecdote for ADIOS and a reduced dosing frequency is happening because some people in the USA can’t afford to do it every 6 months. Then there is the Swedish and US experience and rituximab and we have now seen extended dosing used in rituximab presented at ECTRIMS. It is only a matter of time before we see the Swedish experience. I have heard of the experience. Ocrelizumab is more potent than rituximab, we can look at the B cell repopulation speeds which is about twice as slow as rituximab.
Ocrevus patients suffer far worse complications than RTX ones, and this will hopefully be apparent soon.
If you have no experience of rituximab. How would you guage this?
No direct comparison unfortunately, but from the Sweden and US trial and clinical experience this might show. The patient reports are quite different between the two.
I agreed and I also know who has the information
Very interesting, I didn’t know about this concept of IRT. The conclusion is that immune reconstitution therapies with anti-CD-20 are clearly more appealing than maintenance therapies. But why is it not more common if so ‘better’ than maintenance strategies? Is IRT with anti-CD-20 something we can ask for to our neurologist or it’s only something very experimental at the moment?
There is no evidence base for the IRT activity so the licensed 6 monthly dose is the standard. A trial needs to be done to ensure the safety and efficacy.
The IRT potential is based on the biology we have created, some published trial data with rituximab the hidden ocrelizumab trial data which we don’t know how good the data is, Also off label use of rituximab. We have to hope that is written up
Thank you MouseDoctor. And thank you for this blog in general. Such a goldmine for me.