Summary
Anti-CD20 therapies are a class of monoclonal antibodies that bind to CD20 on the surface of B cells. They work by depleting peripheral B-cells. Four anti-CD20 antibodies are available for treating MS and are administered by intravenous or subcutaneous injection. The three licensed agents for treating relapsing forms of MS are ocrelizumab (Ocrevus), ofatumumab (Kesimpta) and ublituximab (Briumvi). In addition, ocrelizumab is the only anti-CD20 therapy with a license to treat primary progressive MS. In many countries, rituximab (MabThera) is used off-label. Rituximab will be increasingly used as it has recently been included on the WHO’s essential medicines list as a treatment for MS.
Most B-cell killing due to anti-CD20 is done through immunological processes that burst or lyse the cells, releasing their contents. This can cause a cell lysis syndrome or infusion reaction, which in the case of anti-CD20 therapies tends to be mild to moderate. The infusion reactions are typically managed by predosing with steroids, antihistamines and/or antipyretics (paracetamol/acetaminophen or a non-steroid anti-inflammatory such as ibuprofen). The doses and dosing schedules of the anti-CD20 therapies differ.
Ocrelizumab (600 mg), ublituximab (450 mg) and rituximab (1000 mg) are given as 6-monthly intravenous infusions and ofatumumab (20 mg) as monthly subcutaneous injections.
The anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity (NEIDA), slowing down disability worsening and brain volume loss. A recent real-world study suggests that ocrelizumab is more effective than rituximab. However, as these agents have yet to be compared head-to-head in a clinical trial, it is difficult to claim one is more or less effective than the others.
Rituximab and ublituximab are the least humanised of the anti-CD20s and are associated with a higher rate of antidrug antibodies (ADAs), which are usually neutralising antibodies (NAbs). It is reported that 6.4% of ublituximab-treated subjects and even more rituximab-treated patients develop ADAs. In comparison, 1 ̶ 2% of ocrelizumab-treated patients and fewer than 0.5% of ofatumumab-treated patients develop ADAs as these therapeutic antibodies are more humanised than the others and less likely to induce an antidrug immune response. The ADAs are important considerations when choosing between these products.
The most common adverse effects of anti-CD20 therapies are mild infusion-like reactions (generally not seen with subcutaneous ofatumumab), infections, low antibody levels in the blood (hypogammaglobulinaemia), blunted vaccine responses and (rarely) delayed neutropenia. In the ocrelizumab trials, the number of malignancies (including breast cancers) was increased. The incidence was, however, within the background rate expected for an MS population, and post-marketing studies have not shown an increased rate of malignancies.
Anti-CD20 therapies are generally available first line to treat DMT-naive patients. As a class, anti-CD20 therapies have transformed the management of MS by allowing the adoption of a treatment strategy of using high-efficacy DMTs as the first treatment, which I refer to as ‘flipping the pyramid’. Importantly, ocrelizumab has also ushered in the era in which we can treat some patients with primary progressive MS.
Trade names
Ocrevus (ocrelizumab), Kesimpta/Bonspri (ofatumumab), Briumvi (ublituximab), MabThera (rituximab). Please note rituximab is off patent and many biosimilars are available globally; hence the treatment you receive may have a different tradename.
Mode of action
Anti-CD20 therapies work via peripheral B-cell depletion. It is unknown how B-cell depletion works as a treatment for MS. However, it is hypothesised that anti-CD20 therapies work via several mechanisms involving the B cell and possibly through a small population of CD20-expressing T cells:
- preventing autoantigen presentation via the B cell
- reducing B-cell-derived proinflammatory cytokines
- reducing B-cell production of autoantibodies
- depleting pro-inflammatory effector CD20-expressing T cells
- as an anti-EBV agent: EBV (Epstein-Barr virus) resides in memory B cells, and depleting these cells decreases EBV viral loads. However, it is currently unknown what role EBV plays in the pathogenesis of MS.
Efficacy
High. Compared with active comparators (interferon-beta and teriflunomide), anti-CD20 therapies reduce the annual relapse rate by ~50% and 3-month disability progression by one-third. The no evident disease activity (NEDA) rates across 2 years of the pivotal trials are ~50%, and these drugs slow down accelerated brain volume loss to ~0.3 ̶ 0.4% per annum. This rate of brain volume loss, however, is still considered to be above what is expected when compared to the rate of <0.2% per annum in age-matched healthy subjects.
Class
Maintenance therapy – continuous B-cell depletion.
Immunosuppression
Yes, long-term.
Dosing and availability
Ocrevus (ocrelizumab) dosing
The initial 600 mg dose is administered as two separate intravenous infusions, first as a 300 mg infusion, followed 2 weeks later by a second 300 mg infusion. These initial infusions are given over 2.5 hours. Subsequent doses of ocrelizumab are administered as a single 600 mg intravenous infusion every 6 months. The infusion rate will vary from 2.0 to 3.5 hours, depending on how well it is tolerated. It is recommended that a minimum interval of 5 months should be maintained between each dose of ocrelizumab.
Kesimpta/Bonspri (ofatumumab) dosing
The recommended dose is 20 mg ofatumumab administered by subcutaneous injection with initial dosing at weeks 0, 1 and 2, followed by monthly dosing, starting at week 4.
Kesimpta is sold in an autoinjector, and Bonspri is sold as a vial for self-administration. Bonspri is only available in some middle-income and low-middle-income countries, where it is sold at a discount to Kesimpta.
Briumvi (ublituximab) dosing
The first dose is administered as a 150 mg intravenous infusion over 4 hours (first infusion), followed 2 weeks later by a 450 mg intravenous infusion over one hour (second infusion). All subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks over one hour.
Ublituximab is the latest anti-CD20 therapy to be shown to be effective in MS and it may not yet be available in your country.
MabThera (rituximab) dosing
Please note rituximab is off patent, and many biosimilars are now available across the world. The most common dose is 1000 mg of intravenous rituximab on days 1 and 15 and then 1000 mg intravenously every 6 months. There are variations to this dosing scheme, with many neurologists reducing the dose or extending the interval between doses to try and reduce the risk of long-term adverse effects.
Pre-treatment and prophylaxis treatment
For the anti-CD20 therapies, 100 mg of methylprednisolone (or an equivalent corticosteroid) is administered intravenously approximately 30 minutes before each infusion to reduce the frequency and severity of infusion reactions. This can be combined with chlorpheniramine 10 mg. Paracetamol 1g and/or ibuprofen 400 mg is given on an ‘as-required’ basis for pyrexia, myalgias or pain, which can rarely occur as part of the infusion reaction. As the infusion reactions are only a problem with the first and second courses, many centres now omit methylprednisolone and antihistamines once patients are B-cell depleted and established on the treatment. The infusion reactions are due to a cell lysis syndrome. Once B-cell depletion is established, there are too few circulating B cells to cause a cell lysis syndrome. Prophylactic antivirals or antibiotics are not required with the anti-CD20 therapies.
Please note premedication is not necessary with subcutaneous ofatumumab.
Off-label rituximab
Rituximab is off patent and is relatively cheap, which explains why it is one of the drugs on the MS-Selfie off-label essential DMT list for treating MS in resource-poor environments. It is also worth noting that rituximab is one of three DMTs added to the WHO List of Essential Medicines to treat MS.
Main adverse events
Infusion-related reactions
Infusion-related reactions (IRRs) are relatively common and are experienced by about one in three subjects with the first and second infusions. Typical IRRs include pruritus, rash, urticaria, erythema, flushing, low blood pressure, pyrexia, fatigue, headache, dizziness, throat irritation, oropharyngeal pain, nausea, tachycardia, shortness of breath and throat or laryngeal swelling. The risk of anaphylaxis is very low.
Infection
Infections, particularly of the respiratory tract, are the most common adverse event with anti-CD20 therapies. Infections tend to be minor, but occasional severe infections occur. Herpes infections, including herpes zoster and oral or genital herpes simplex virus infection, are reported more frequently in patients treated with anti-CD20 therapies than in those receiving other DMTs.
Laboratory abnormalities
Anti-CD20 treatment decreases total immunoglobulins (antibodies), mainly driven by reduced IgM (immunoglobulin M) and IgA levels. Decreased levels of IgG tend to occur later and are associated with a higher risk of infection and severe infections. Not all patients treated with anti-CD20s develop hypogammaglobulinaemia.
A minority of people with MS treated with anti-CD20 therapies develop mild lymphopaenia; a small number (<1%) develop grade 3 lymphopaenia (<500 cells/mm3). An increased rate of serious infections has been seen during episodes of lymphopaenia.
A small number of patients treated with anti-CD20s develop neutropaenia, generally mild and transient; fewer than 1% developed grade 3 (500 ̶ 1000 cells/mm3) or grade 4 neutropaenia (<500 cells/mm3) in the trials. Please note that neutropaenia can occur several months after starting anti-CD20 therapy and has been associated with infections.
To minimise infectious complications, we recommend all patients have a vaccine review and ensure they are up to date with their seasonal flu and COVID-19 vaccines. In addition, we recommend all patients have the pneumococcal vaccine (Pneumovax) and the varicella zoster virus (VZV) vaccine (Shingrex) before starting anti-CD20 therapy (please see our derisking guide and article on reducing side effect risk). Some people with MS may want to consider additional vaccines before starting an anti-CD20 therapy.
As anti-CD20 therapies are immunosuppressive, they increase the likelihood of infections. To derisk infections, we recommend routine baseline screening for human immunodeficiency virus (HIV), syphilis, hepatitis B and C and tuberculosis. In addition, we screen for exposure to VZV and if seronegative we strongly recommend VZV vaccination before starting therapy.
Malignancy
An increased number of malignancies (including breast cancer) were seen in ocrelizumab-treated subjects in clinical trials. However, the incidence appears to be within the background rate expected for an MS population. Patients must follow standard breast cancer screening guidelines, i.e. monthly self-examination, and women between 50 and 70 years of age should have a mammogram every 3 years. Other potential cancers linked to anti-CD20 therapies include basal cell carcinoma.
Pharmacovigilance monitoring requirements
Baseline
Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (VZV, HIV 1 and 2, hepatitis B and C, TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, a pregnancy test and baseline blood pressure are done.
Follow-up
No routine follow-up blood tests are mandated. However, we now monitor the full blood count and serum immunoglobulin levels every 6 ̶ 12 months when patients come for their infusions or annual follow-up appointments. The latter is particularly relevant for patients on subcutaneous ofatumumab.
Rebaselining
A rebaseline MRI scan needs to be done after starting an anti-CD20 therapy. I recommend that an MRI is done at ~6 months after starting treatment and that Gd-enhancement is ideally included as part of the rebaselining MRI. A monitoring MRI is then done annually after that (resources permitting).
Women of childbearing potential and pregnancy
The SmPCs recommend that women of childbearing age should use contraception while receiving anti-CD20 treatment and, in the case of ocrelizumab, for up to 12 months after the last infusion. However, I tend to give women who want to start or extend their families the option of starting an anti-CD20 and falling pregnant in their own time. There are several reasons for this. Most women don’t fall pregnant immediately; it takes, on average, four ovulation cycles and often much longer. Anti-CD20 therapies do not affect fertility and are not teratogenic (i.e. it does not affect the developing baby). In addition, the placenta does not mature until towards the end of the second trimester, when it allows antibodies (anti-CD20 is an antibody) to cross from the maternal circulation into the developing baby’s circulation. So once a woman falls pregnant, we delay the next infusion until after the baby’s delivery. Even if small amounts of anti-CD20 cross over into the baby’s circulation, it tends to cause a transient B-cell depletion in the baby.
Breastfeeding
In general, monoclonal antibodies, including the anti-CD20 therapies, are safe during breastfeeding because little drug gets into the breast milk; the small amounts that reach the breast milk will be metabolised in the baby’s gastrointestinal tract. The exception is in the first 2 ̶ 3 weeks post-partum when a woman’s breasts produce colostrum, and the newborn’s intestinal tract is immature and can transfer antibodies across the intestinal surface.
Colostrum, or first milk, is produced immediately after the newborn’s delivery and for about 2 ̶ 3 weeks after delivery. Colostrum is exceptionally high in antibodies and other factors to protect the newborn against disease and infection. As the newborn’s gastrointestinal tract is immature, many of the proteins in colostrum are absorbed and will have systemic immune effects.
Most of the antibodies in colostrum are IgA and IgM produced by plasma cells in the breast. Therefore, I suspect that circulating IgG, including the anti-CD20, is transferred into breast milk in small amounts. However, the breast epithelial cells express the so-called neonatal Fc-receptor, the molecular shuttle for transporting antibodies into milk. In addition, this neonatal Fc receptor shuttle is also expressed in the newborn intestine. So, the molecular mechanisms are in place potentially to increase your developing baby’s exposure to anti-CD20.
Neonatal Fc-receptors expressed on breast epithelial cells transport small amounts of antibodies into breast milk.
If you plan to breastfeed, which I recommend, you will want to avoid ocrelizumab while your breasts produce colostrum. There are no black-and-white answers to any problem in MS. Delaying recommencing ocrelizumab treatment for a few weeks post-partum outweighs the chances of rebound disease activity.
Fertility
Animal studies and experience in humans reveal no issues concerning fertility in women receiving anti-CD20 treatment.
Vaccination
It is recommended that anti-CD20-treated patients are immune to the VZV before starting treatment. Patients should also be offered the pneumococcal (Pneumovax) and VZV (Shingrex) component vaccines to boost immunity before treatment. Antibody response, but not T-cell responses, to neoantigens (new vaccines) is blunted in patients on anti-CD20 therapies. Therefore, patients on such therapies can receive inactivated vaccines and mount a partial response to them. Live attenuated vaccines are not recommended for these patients.
Travel
People with MS need to be aware that being on an anti-CD20 may affect travel; for example, some countries require you to be vaccinated against yellow fever, a live attenuated vaccine. Therefore, the yellow fever vaccine must be given before starting anti-CD20 treatment.
High-dose versus low-dose anti-CD20
To move our treatment target in MS beyond NEIDA, the new focus must be on preventing end‑organ damage and the processes driving smouldering MS; that target therefore includes:
- stopping disability progression
- normalising brain volume loss
- flattening the area under the neurofilament level curve
- stopping slowly expanding lesions from getting bigger
- clearing the cerebrospinal fluid of oligoclonal IgG bands
- if possible, promoting repair and recovery of the nervous system.
What good is it to be free of relapses and focal MRI activity if your MS gets worse? This is why the concept of using low-dose anti-CD20 therapy seems flawed. Trial participants exposed to lower doses of ocrelizumab in the phase 3 trials, owing to greater body size, do as well as those exposed to higher doses in relation to relapses and MRI activity, but not in relation to worsening disability or smouldering disease.
The phase 3 ocrelizumab trials in both relapsing and primary progressive MS used a fixed dose of 600 mg of ocrelizumab intravenously every 6 months.1,2 Therefore, smaller people with MS got a larger dose of ocrelizumab than larger people. For example, someone weighing 60 kg got 10 mg/kg of ocrelizumab 6-monthly compared to 5 mg/kg for someone with MS weighing 120 kg. By measuring drug concentrations, trial subjects could be divided into four groups or quartiles representing four dosing levels. Although the treatment effect of ocrelizumab on relapses and MRI activity showed no difference between the four groups in these pivotal studies, post-hoc analyses showed that subjects who received higher doses and had more significant B-cell depletion were less likely to exhibit disease progression than those on low doses. This higher-dose treatment effect on smouldering MS, i.e. beyond NEIDA, was seen in both the relapsing and primary progressive populations.3
It is clear from these post-hoc analyses that higher, not lower, doses of anti-CD20 therapy may be needed to tackle smouldering MS. Currently, these observations apply only to the initial 2 years of treatment. Hence, we don’t know if people with MS will only need higher doses as an induction strategy to purge the various B-cell compartments of pathogenic (disease-causing) cells.
Once you have purged these B-cell compartments after 2 years of high-dose anti-CD20 treatment, you may not need to maintain people with MS on such high doses, which would continue suppressing normal B-cell biology and immune responses – with long-term complications.
Two large phase 3 trials are ongoing, testing high-dose ocrelizumab (1200 and 1800 mg every 6 months) compared with standard-dose ocrelizumab (600 mg every 6 months) in both relapsing and primary progressive MS. The results of these trials should answer some of the lingering questions about dosing of anti-CD20 therapies.
Please note that lower dose anti-CD20 therapies are a moving target. Anti-CD20 dosing should not be based on B-cell counts in the peripheral blood, which are a poor surrogate for what is happening in the deep tissues and central nervous system. We need better and more accessible biomarkers to study these B-cell compartments. Receiving ocrelizumab less frequently than the licensed 6-monthly dose and rituximab, ofatumumab or ublituximab could potentially be considered as low-dose anti-CD20 therapy.
Summaries of Product Characteristics (SmPC)
Ocrevus (ocrelizumab), Kesimpta (ofatumumab), Briumvi (ublituximab), MabThera (rituximab).
Switching-2-anti-CD20 therapy
Interferon and glatiramer acetate
An anti-CD20 therapy can be started immediately after discontinuing interferon-beta or glatiramer acetate. All the recommended baseline screening tests and vaccination reviews must be done before starting one of the anti-CD20s.
Natalizumab
Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended. Most often, switching from natalizumab to an anti-CD20 or another DMT is to reduce the risk of carry-over progressive multifocal leukoencephalopathy from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we typically initiate the anti-CD20 as soon as possible after the last natalizumab infusion. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20.
S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)
Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks, before switching to another DMT; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of lymphopaenia following S1P modulator administration. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting an anti-CD20.
Fumarates
All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If lymphopaenia is the main reason for switching from fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting an anti-CD20.
Teriflunomide
All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. I recommend the total peripheral lymphocyte counts are above 800/mm3 before starting an anti-CD20. We don’t routinely do an accelerated washout of teriflunomide before starting an anti-CD20.
Anti-CD20 therapies (selective cell depleting DMTs)
If patients switch between formulations of anti-CD20 therapies out of choice (patient preference), it can be done without safety concerns or needing to wait for B-cell counts to recover. If patients are switching for loss of efficacy, I suggest checking for antidrug antibodies and reviewing the diagnosis of MS to try and understand why the individual has not responded to the specific anti-CD20 and/or its formulation.
Mitoxantrone/alemtuzumab/cladribine/AHSCT
Before starting an anti-CD20 therapy, I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1000/mm3 and 800/mm3, respectively. An exception to this would be the cases of severe rebound that are rarely seen after alemtuzumab. In these circumstances, the anti-CD20 therapy is given to treat very active, often pseudotumoral or tumefactive, MS. All the recommended baseline screening tests must be done before starting an anti-CD20 therapy.
References
- Hauser SL, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376: 221 ̶ 34. doi: 10.1056/NEJMoa1601277.
- Montalban X, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376: 209 ̶ 20. doi: 10.1056/NEJMoa1606468.
- Hauser SL, et al. Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2023; 10:e200094. doi:10.1212/NXI.0000000000200094.
