Serious infections on anti-CD20 therapies
Most serious infections on ocrelizumab happen in people with MS with normal immunoglobulin levels
This newsletter is in response to some questions I received regarding my Q&A post about recurrent infections on ocrelizumab (14-Oct-2024).
Any one of the following criteria defines what is a severe infection:
An infection that requires or prolongs hospitalisation
It causes persistent or significant disability or incapacity
Is life-threatening, e.g. the infection is associated with septic shock or requires ITU admission with ventilation.
Results in death
The following is the ocrelizumab data on serious infections. In summary, 7 out of every 100 people with MS (pwMS) on ocrelizumab have severe infections. This data excluded COVID-19, so this risk is likely slightly higher than this. Contrary to expectations, there has been no increase rate over time. Saying this, older pwMS on ocrelizumab and with more disability are at higher risk. The effect of age is likely due to the impact of immunosenescence, i.e. an ageing immune system does not cope well with chronic immunosuppression. Disability contributes to risk as it predisposes you to aspiration pneumonia, urinary tract infections, and skin infections caused by being less mobile. Disability is also closely linked to age, so the association with disability is likely to include immunosenescence as well.
People with primary progressive MS (PPMS) were at greater risk than those with relapsing MS. This is not surprising as pwPPMS are older and more disabled. PwPPMS with severe walking difficulties were 4x more likely to have serious infections. Similarly, having comorbidities, low levels of immunoglobulin M, or being overweight also increases the risk of serious infections.
As expected, pneumonia and urinary tract infections were the most common severe infections. Most people with serious infections recover (>90%), i.e., the risk of dying or being left incapacitated is low. In this study, most pwMS with severe infections continued treatment with ocrelizumab (>80%), which is also my clinical experience.
People with relapsing MS are at increased risk of serious infection if they have had a recent relapse, are disabled with walking difficulties, or have comorbidities, in particular, diabetes and bladder dysfunction. I suspect the use of steroids to treat relapses contributes to the risk of serious infections associated with relapses. This is one of the reasons why I prefer not to use steroids to treat relapses.
This data on serious infections on ocrelizumab needs to be balanced against the long-term benefits of being on ocrelizumab. We presented the long-term follow-up data at ECTRIMS, i.e. after 11 years of continuous ocrelizumab treatment, ocrelizumab effectively controlled long-term disease activity and prevented disability accumulation. Three-quarters of pwRMS were progression-free, and >90% did not need a walking aid. A third of pwPPMS were progression-free, and 80% did not need a wheelchair. Although these results only represent the results of pwMS staying on ocrelizumab, they are impressive and indicate how anti-CD20 therapies have changed the long-term outcome for people with MS. You can download the poster from ECTRIMS-2024 here.
How should these results affect clinical practice?
Firstly, they are reassuring that the problem of serious infections is manageable. However, I would warn older pwMS (>55 years) who are disabled and have comorbidities about the increased risk of serious infections. The dangers of anti-CD20 therapy in this group of patients may outweigh the benefits, and they may be better off on immunomodulatory or an immune reconstitution therapy, i.e. cladribine.
PwMS on immunosuppressive therapies must be made aware of infections and the potential for serious infections and, therefore, must seek medical attention when they develop an infection. Derisking infections is essential, i.e. having vaccines done before starting treatment and having the boosters when they become available. The latter is relevant regarding influenza, COVID, Shingrex and RSV vaccines, which are all available via the NHS for people on immunosuppressive therapies. For more information on vaccines, please read ‘Q&A 48 - RSV and other vaccines: to vaccinate or not’ (03-Sep-2024) and ‘The rationale for derisking DMTs’ (20-Aug-2022).
The question I can’t answer is if someone with MS on ocrelizumab has a severe infection, should they stop the treatment and switch to another less risky therapy? This scenario differs from recurrent infections and depends on many factors discussed above, i.e., risk factors for serious infections, lifestyle factors, family planning, and other therapeutic options available to treat MS. One severe infection is not necessarily a sufficient reason to switch treatments. However, this decision should be a shared decision, and some people with MS may prefer a less risky option.
Please note that most serious infections in pwMS on ocrelizumab happen in pwMS with normal immunoglobulin levels. Low immunoglobulin levels are only a minor risk factor for serious infection. Although this data is for ocrelizumab, the most potent depleter of the anti-CD20 therapies licensed for MS, I would treat this information as a class effect, i.e. if you are on rituximab, ofatumumab or ublituximab you should take similar precautions.
I would like to know if any of you had a severe infection while on anti-CD20 therapy and how this has affected your treatment. Did you stay on treatment or did you switch?
Paper
Plain language summary: Is continued treatment with ocrelizumab associated with a higher risk of infections and serious infections in patients with multiple sclerosis? Patients with multiple sclerosis (PwMS) are at an increased risk of infections compared with the general population. Infections are also among the most frequently reported side effect in PwMS treated with ocrelizumab. Initial analyses have shown that serious infection (SI) rates in PwMS treated with ocrelizumab were stable over 6 years, but there is concern that this rate may increase with continued treatment. This study aimed to describe infections and SIs in PwMS treated with ocrelizumab and look into factors that increase patients’ susceptibility to infections. We analyzed the largest population of PwMS ever treated with ocrelizumab, including 6155 patients from 13 clinical trials. Some of these patients received ocrelizumab for as long as 14 years. Approximately 7 out of every 100 patients experienced SIs, excluding COVID-19 infections, with no increase in yearly rates of SIs over time. Pneumonia and urinary tract infections were the most common SIs. Almost all patients recovered from their infections (>9 out of 10 cases), and continued treatment with ocrelizumab (>8 out of 10 cases). When looking at factors that made PwMS more prone to SIs, we found that patients with relapsing MS had an increased risk if they had experienced recent MS relapses, severe walking difficulties, or other health conditions like diabetes and bladder problems. Patients with primary progressive MS (PPMS) with severe walking difficulties were four times more likely to have SIs. Having other health conditions like heart or bladder problems, low levels of immunoglobulin M, or excess weight also increased the risk of SIs in patients with PPMS. In conclusion, continued treatment with ocrelizumab did not increase the risk of SIs, and most of those infections resolved without stopping ocrelizumab treatment. Addressing certain health conditions and achieving a good control of the MS disease may help to reduce the risk of SIs.
Background: Patients with multiple sclerosis (PwMS) have an increased risk of infections.
Objectives: To characterize incidence, clinical characteristics, outcomes and risk factors of infections, and serious infections (SIs) in ocrelizumab (OCR)-treated PwMS.
Design: Post-hoc analysis of pooled data from 6155 patients in 13 clinical trials.
Methods: Descriptive analyses of clinical characteristics and outcomes were reported over ⩽14 years. A Poisson Generalized Estimating Equation model was constructed to examine risk factors in a subgroup of patients with longer exposure to OCR (n = 2092).
Results: Over a median (max) treatment period of 3.7 (13.9) years, 420/6155 patients (6.8%) experienced 583 SIs, excluding coronavirus disease 2019. Incidence rates in relapsing multiple sclerosis (RMS; 1.50 per 100 patient years [95% confidence interval (CI): 1.34-1.68]) and progressive multiple sclerosis (PMS; 3.70 [95% CI: 3.27-4.17]) remained stable over this period. Lower respiratory tract, urinary tract, abdominal and gastrointestinal, and skin infections were the most commonly reported SIs. Most SIs (~90%) resolved, and treatment with OCR was continued in >80% of cases. The presence of 1 or ⩾2 comorbidities (rate ratio = 1.66, 2.73, respectively), recent relapse activity (2.06), and Expanded Disability Status Scale (EDSS) score ⩾6.0 (2.02) were significant risk factors for SIs in patients with RMS treated over a median (max) period of 8.3 (11.2) years. In patients with primary PMS treated over a median (max) period of 7.1 (11.8) years, an EDSS score ⩾6.0 was associated with the greatest risk of SIs, a 4-fold increase (rate ratio, 4.31), followed by abnormal immunoglobulin (Ig)M levels (1.89), the presence of ⩾2 comorbidities (1.80), and having overweight/obesity (1.46). Time on OCR and abnormal IgG levels were not significantly associated with an increased SI risk.
Conclusion: Continuous long-term treatment with OCR is associated with a manageable infection risk profile. Optimal disease control and addressing modifiable risk factors may reduce the risk of infections.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
It looks like my pneumonia wasn't severe, at least according to your criteria :-)
I was bedridden for 2 months, had 20 days of oral and 14 days of IV antibiotics; and after I got better, my MS started to slowly get worse (from EDSS 1 to EDSS 4 in 1,5 years).
Regardless of the statistics shown in your article, I am glad that I switched to Mavenclad, after 6 years of Rituximab/Ocrevus.
🌹🌻🌸💐💚💛💜❤️🌼😍🥰