Did you know that a third of relapses are triggered by infections, typically non-specific viral infections?
The observation that a relapse is more likely to occur in the so-called ‘at risk’ period, typically 5-6 weeks after infection than at other times predates the disease-modifying therapy era of MS. The mechanism is thought to be that infection boosts the immune system non-specifically, which then trigger relapses. This observation was extrapolated to vaccinations, but most vaccine studies now show that vaccines in general, with the possible exception of the yellow fever vaccine*, are safe and are not associated with an increased risk of relapses nor MRI activity.
* Please note recent data on the live yellow fever vaccine shows that it doesn’t trigger MS relapses.
Once people are on an effective DMT the link between infections and relapses is not observed. This is another, albeit minor, reason to be on a DMT. However, there is an emerging field in basic science and clinical evidence to support it that recurrent infections drive some of the pathological processes that are responsible for smouldering MS. Systemic inflammation activates CNS microglia that then produce cytokines and inflammatory mediators that have a negative effect on neuronal function. This is why people with MS handle infections so poorly and often don’t get back to baseline after a severe systemic infection.
Therefore as part of the holistic management of MS, it is a good idea to prevent chronic or recurrent infections. So if you have recurrent or chronic bladder infections, periodontitis (gum disease), chronic sinusitis or recurrent chest infections you need to do something about it. Don’t just accept recurrent infections as your lot in life ask your MS team for advice and help.
It is clear that many MSers on continuous anti-CD20 therapy are concerned about the risk of developing hypogammaglobulinaemia and subsequent infections. Yesterday, I spoke to several neurologists at the O’HAND investigators meeting in Barcelona who informed me that they are considering giving their ocrelizumab-treated patients hyperimmune globulin replacement therapy (HYPE-Ig-RT) when they develop hypogammaglobulinaemia to prevent serious and potentially fatal infections.
The problem I have with this is that HYPER-Ig-RT is expensive and for it to be covered by the NHS we will need to show that it is cost-effective. In response to these discussions Owen Pearson, an MSologist from Swansea, and I came up with the design of the HYPE study below.
The HYPE study
This is a randomised placebo-controlled trial to assess whether or not HYPE-Ig-RT will work, i.e. reduce the risk of serious infection, infections and mortality in MSers on continuous anti-CD20 therapy. Please note we don’t think this study should be limited to ocrelizumab-treated MSers but should be open to any patient on anti-CD20 therapy, including those on rituximab and ofatumumab.
What do you think of the HYPE study? Do we have clinical equipoise?
Please remember for the payers, i.e. NHS England and insurance companies, to pay for HYPER-Ig-RT we need class 1 evidence to make the financial case to them. This study will test the hypothesis that HYPE-Ig-RT will derisk continuous anti-CD20 therapies and prevent some of the infectious complications related to hypogammaglobulinaemia.
What is the risk of serious infections on anti-CD20 therapies?
The following figures put the serious infection risk, i.e. infections requiring hospitalisation, on ocrelizumab in context. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months one 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 one 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.
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?
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.
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
An important highlight of ECTRIMS this year was the data on the safety of the anti-CD20 therapies as a class. It is clear that prolonged, and sustained, B-cell depletion is not safe. Hypogammaglobulinaemia will become a problem with the risk of both common and opportunistic infections.
Stephen Hauser presented the 7-year ocrelizumab safety data and there is a clear uptick in infections in year 7. His poster also included a probable opportunistic infection signal. As of January 2019, there were six potential serious opportunistic infections that had been reported from the ocrelizumab clinical trials.
Systemic Pasteurella infection in a patient with RMS following a cat bite (resolved)
Multisegmental herpes zoster infection in a patient with RMS, treated with intravenous (IV) acyclovir (resolved)
Enterovirus-induced fulminant hepatitis in a diabetic patient with RMS, resulting in liver transplant
Candida sepsis in a patient with PPMS who had stopped OCR treatment 11 months previously and was receiving cancer chemotherapy (resolved)
Viral meningitis in a patient with RMS, cerebrospinal fluid positive for varicella-zoster, treated with IV acyclovir (resolved)
Herpes zoster (monodermatomal) in a patient with RMS treated for a neutropenic fever (not assessed as an opportunistic infection) (resolved)
Continuous anti-CD20 therapy prevents you from forming germinal centres (where B-cells get educated and selected to make antibodies) in lymph nodes and the spleen. In other words, the anti-CD20 therapies result in what I refer to as a functional splenectomy. This causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted.
I highlighted in my hot topics talk on ‘DMTs in RRMS 2019: what remains to be achieved’ about the problems of having a functional splenectomy on anti-CD20 therapies. I recommended that all MSers be vaccinated with the polyvalent pneumococcal vaccine (Pneumovax) and possibly the vaccines for Haemophilus influenzae type B and Meningococcus. In addition, all MSers should have the annual flu vaccine, but with the inactivated component flu vaccine and not the live flu vaccine. In fact, MSers on anti-CD20 therapy should avoid coming into contact with recipients of the live flu vaccine in case it becomes more virulent and infects them. Please note the live flu vaccine is used in the UK in young children and it is recommended that children who have parents or family members at home on immunosuppressive therapies should not have this vaccine.
Another option open to people on longterm anti-CD20 therapy is antibiotic prophylaxis against infections with these encapsulated bacteria. I suspect this may be necessary when MSers develop hypogammaglobulinaemia and recurrent infections, similar to the NMO cases described below. It is clear that anti-CD20 therapies will need annual immunoglobulin levels measured so that if hypogammaglobulinaemia develops MSers can we warned. I suspect immunoglobulin replacement therapy will only be required in the case of recurrent infections, for example, sinus or chest infections; for example, the NMO patient on longterm rituximab who developed bronchiectasis.
I would also recommend that MSers on immunosuppressive therapies wear a medic-alert bracelet that states they are on an anti-CD20 therapy. This would help HCP in an emergency if you are too sick to provide a history. An American colleague told me about one of his ocrelizumab-treated patients, who was fit and well, who died suddenly in the emergency department after presenting with a high temperature and not feeling well. I suspect the cause of death was probably septic shock from one of the encapsulated bacteria discussed above.
The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections and excessive number of deaths, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels explains why there are infectious complications on ocrelizumab.
So if you are on rituximab, ocrelizumab, ofatumumab or any othe anti-CD20 please be vigilant and take care. On the other side of the coin are the benefits of these treatments and their ease of use and low monitoring burden. As with all DMTs the risks need to be balanced against the benefits.
B-cell depleting anti-CD20 monoclonal antibody therapies have demonstrated promising clinical efficacy in suppressing relapses in individuals with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, uncertainties remain about the optimum treatment schedule. In rheumatological disease, anti-CD20 agents are most often employed for short-term induction therapy and are subsequently replaced by longer-term maintenance therapy. In contrast, repeated cycles of anti-CD20 monoclonal antibody therapy are proposed as maintenance therapy for CNS neuro-inflammatory disorders. Post-marketing surveillance will be essential to fully uncover the long-term safety profile of repeated B-cell depletion. Hypogammaglobulinaemia is a recognised consequence in a proportion of patients treated with medium- to long-term B-cell therapy and may play a role in the increased incidence of infection observed in the anti-CD20 arms of treatment trials. We report 5 cases of serious infection associated with hypogammaglobulinaemia occurring in patients receiving rituximab for NMO. The cases were all female, all had low IgG with variable reductions in IgM and IgA. The cases had a mean treatment duration of 3.1 years, but not all cases had had extensive exposure (treatment duration range 0.5 – 6.2y). We review the evidence relating to hypogammaglobulinaemia following anti-CD20 treatment for neuroinflammatory disorders and propose an algorithm for monitoring and treatment of this recognised complication.
Should your vaccine status be checked and updated before you start treatment?
As part of our programme to derisk disease-modifying therapies (DMTs) for pwMS in our service, we are reviewing our vaccination policy. One issue that has emerged is the possible need to boost immunity to certain types of bacteria that are known to pose a risk in patients on long-term immunosuppression, in particular B cell depleters, such as rituximab, ocrelizumab and ofatumumab. Why?
Chronic B-cell depletion essentially prevents B-cells mounting an adequate antibody response to new antigens. It does this by preventing the formation of so-called germinal centres in the spleen and/or lymph nodes. In other words patients on longterm anti-CD20 therapy behave, from an immunological perspective, if they have had a functional splenectomy. This put patients with longterm B cell depletion at risk of hypogammaglobulinaemia (low immunoglobulin levels) in the future and predisposes them to infections caused by so-called encapsulated bacteria; these include pneumococcus, meningococcus and Haemophilus Influenzae.
When you review the rheumatoid arthritis literature in relation to longterm rituximab (anti-CD20) therapy both these problems have been documented. How do the rheumatologists deal with these problems? They appear to routinely monitor immunoglobulin levels and they proactively vaccinate their patients prior to starting long-term anti-CD20 therapy.
It seems pretty obvious to me, reading the rheumatology literature, that before you start long-term anti-CD20 therapy you should have your vaccination status checked and we should start vaccinating patients against pneumococcus, meningococcus and Haemophilus Influenzae B. In fact, pneumococcal vaccine is already recommended, if possible, for all patients before starting immunosuppressive treatments. It is clear for anti-CD20 therapies that the vaccines will need to be given prior to starting treatment (see Nguyen paper below).
We also recommend doing baseline immunoglobulin levels on all patients before starting treatment as a reference and then to start checking levels from year 3 onwards. I say year 3 because in the ocrelizumab trials we only saw a significant drop in IgM and IgA levels over 2 years and IgG levels were stable. Based on the rituximab data a drop in IgG levels is, therefore, only likely to emerge after 2 years of treatment.
I would be interested to know if any of you had your vaccine status discussed before you started maintenance immunosuppression?
BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.
METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out.
RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.
CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.
OBJECTIVE: To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations.
METHODS: Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations.
RESULTS: Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76-0.94) and 94% (95% CI 0.77-0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action.
CONCLUSION: The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.
PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA.
RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals.
SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA.
