Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis

INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system that is a leading cause of disability in young adults. Disease-modifying therapies (DMTs) for MS are drugs that effectively reduce the relapse rate and the development of new lesions for patients with MS.

The indications, efficacy, dose, administration, monitoring, and adverse effects of the monoclonal antibody DMTs for MS are discussed in this topic review. Other DMTs for MS are reviewed elsewhere:

●Oral DMTs (see "Clinical use of oral disease-modifying therapies for multiple sclerosis")

●Platform injection therapies (see "Overview of disease-modifying therapies for multiple sclerosis", section on 'Platform therapies')

CHOOSING THERAPY — There are multiple disease-modifying therapies (DMTs) for MS, including older platform injection therapies, monoclonal antibodies, and oral agents.

Monoclonal antibodies for MS include natalizumab, ocrelizumab, rituximab, ofatumumab, alemtuzumab, and ublituximab. These DMTs are highly efficacious for reducing the relapse rate in patients with MS, but serious safety issues, including infections, are possible adverse effects of several of these medications. Thus, monoclonal antibody DMTs may be preferred for patients with more active disease and for those who place a high value on efficacy and are risk-tolerant.

However, there is no uniform method for choosing the best DMT for an individual patient. The choice of a specific agent for patients with MS should be individualized according to disease activity, comorbid conditions, and patient values and preferences (algorithm 1).

The use of DMT for specific clinical situations is discussed in detail elsewhere:

●(See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)

●(See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

●(See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis".)

●(See "Treatment of secondary progressive multiple sclerosis in adults".)

●(See "Treatment of primary progressive multiple sclerosis in adults".)

●(See "Multiple sclerosis: Pregnancy planning".)

●(See "Multiple sclerosis: Pregnancy and postpartum care".)

The treatment of acute MS exacerbations is also reviewed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults".)

INTEGRIN ANTAGONIST THERAPY

Natalizumab — Natalizumab is a recombinant monoclonal antibody directed against the alpha-4 subunit of integrin molecules, thereby blocking integrin association with vascular receptors and limiting adhesion and transmigration of leukocytes. In patients with MS, natalizumab treatment is associated with a diminished migratory capacity of immune cells and a prolonged decrease in lymphocyte counts in the cerebrospinal fluid (CSF) [1,2].

Natalizumab-sztn is a biosimilar product that has no clinically meaningful differences from natalizumab [3].

Indications — Natalizumab is indicated as monotherapy for the treatment of relapsing forms of MS, including clinically isolated syndromes (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

Natalizumab is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) and in patients with a previous hypersensitivity reaction to natalizumab. Because of the risk of PML, natalizumab should not be used for patients who may have impaired immunity, such as hematologic or rheumatologic conditions associated with compromised cell-mediated immunity [4,5].

Dose and administration — Natalizumab is given as a 300 mg intravenous (IV) infusion over one hour, every four weeks. In the United States, infusions are given in centers registered under the TOUCH program. Patients should be observed for any signs or symptoms consistent with hypersensitivity reaction during the infusion and for one hour after the infusion is complete. Natalizumab should be discontinued in patients who develop hypersensitivity reactions.

Extended interval dosing — Among patients treated with natalizumab who are seropositive for JC polyomavirus (JCV) antibody, observational data suggest that dosing natalizumab every five to eight weeks rather than every four weeks may reduce the risk of PML without reducing efficacy [6-12], but this approach is not yet optimized.

In a retrospective cohort study that analyzed over 35,000 patients from the TOUCH database who were seropositive for the anti-JCV antibody, natalizumab extended interval dosing was associated with a lower risk of PML than standard interval dosing [10]. A later study from the same investigators, published in abstract form, updated data from the TOUCH program and also found that extended interval dosing was associated with a lower risk of PML [8]. In the open-label, randomized NOVA trial, which enrolled 499 patients, extended interval dosing compared with standard interval dosing of natalizumab was associated with a higher estimated number of new or enlarging T2 hyperintense lesions at week 72; the difference reached statistical significance in one of the two prespecified analysis methods, and, notably, most of the new magnetic resonance imaging (MRI) activity was driven by two outliers in the extended interval dosing group [13]. The safety profiles of the two dosing groups were similar. Several small studies found that extended interval dosing was not associated with an increase in neurofilament light serum levels, a proposed biomarker of MS disease activity [9,14].

In a subsequent prospective study of 61 patients with RRMS who were free of disease activity on natalizumab for at least one year, natalizumab treatment intervals were personalized according to natalizumab trough levels [7]. The dosing interval was increased by one week if the natalizumab trough level was ≥15 mcg/mL, targeting a natalizumab trough level of 10 mcg/mL. This method extended the dosing interval to five to seven weeks for 51 patients and retained the standard four-week dosing interval for 10 patients. For patients on extended interval dosing who completed one year of follow-up (n = 48) and a one-year extension phase (n = 24), none developed relapses or new or enlarging MRI lesions.

The utility of extended interval dosing needs confirmation, ideally in a larger clinical trial, but such extended interval dosing is a potential option when natalizumab is continued despite conversion to seropositivity for the JCV.

Adverse effects — Natalizumab treatment is associated with a risk of developing PML, a rare, potentially fatal neurologic disease caused by reactivation of JCV infection. (See 'Surveillance for PML' below and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

The most frequent adverse events associated with natalizumab treatment include infusion-related symptoms (headache, flushing, erythema, nausea, and dizziness), fatigue, infections (mainly urinary tract and lower respiratory tract infections), arthralgia, gastroenteritis, vaginitis, extremity pain, depression, and rash [15,16]. Other than PML, opportunistic infections are rarely associated with natalizumab therapy; they have included cases of herpes zoster, herpes meningitis, herpes simplex virus encephalitis, and tuberculosis [15,17,18]. Hepatoxicity, including clinically significant liver injury, and thrombocytopenia have been reported in postmarketing data [19,20]. Neonatal thrombocytopenia has been reported in newborns exposed to natalizumab in utero [16].

As of July 2022, there were 892 cases of natalizumab-associated PML reported worldwide [21]. The risk of natalizumab-associated PML for an individual patient varies according to the following factors (table 1) [22-26]:

●Anti-JCV antibody status

●Prior immunosuppressant treatment

●Duration of natalizumab exposure

Detailed PML risks are provided in the figure (figure 1) [27]. The estimated risk of PML is low (<1:10,000) for patients who are seronegative for anti-JCV antibodies but increases with seroconversion, the strength of the seropositive response, and the duration of natalizumab exposure for seropositive patients. (See 'Surveillance for PML' below.)

In postmarketing data as of June 2017, the number of natalizumab doses received before the diagnosis of PML ranged from 8 to 136 (mean approximately 49) [28]. In the United States, the number of prior natalizumab infusions for an individual patient can be determined by contacting the TOUCH program.

Screening and monitoring — When there is suspicion for PML, natalizumab should be discontinued [22]. Thus, surveillance for PML is a critical aspect of natalizumab treatment. (See 'Surveillance for PML' below.)

The management of natalizumab-related PML is discussed elsewhere. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'Natalizumab-associated PML'.)

●Before starting – Whenever possible, leukocyte and neutrophil counts should be within or close to the normal range. We suggest stopping glucocorticoids and most other immunosuppressive medications, including cladribine and monoclonal antibody disease-modifying therapies (DMTs), for at least one month prior to starting natalizumab, but a prolonged washout may not be necessary for beta interferons, glatiramer acetate, or oral DMTs other than cladribine. Cholestyramine may be used to accelerate the removal of teriflunomide. A longer washout period (up to three months or more) is suggested for azathioprine, methotrexate, mycophenolate, mitoxantrone, and cyclophosphamide [4]. A baseline brain MRI scan should be obtained prior to initiating therapy with natalizumab, since it is useful in comparison with later MRI scans for detecting changes suggestive of PML.

However, this goal may not be feasible for people switching from a sphingosine 1-phosphate receptor (S1PR) modulator, where waiting for normalization of lymphocyte count is associated with increased risk of rebound disease; similarly, people switching from a fumarate may need to be individually counseled about the pros and cons of waiting for normalization of lymphocytes prior to switching to natalizumab (or any other MS therapy). In most cases, active MS is the indication for switching (escalation) to a higher efficacy medication (natalizumab); waiting for normalization of lymphocytes increases the risk of further MS activity.

●Antibodies to natalizumab – Antibodies to natalizumab are not routinely obtained in clinical practice, but limited data suggest they may be useful in select patients with infusion reactions or poor response to natalizumab. However, it is more common in these scenarios to switch to a different DMT rather than obtain natalizumab antibody studies. Antibodies to natalizumab developed in approximately 9 percent of patients in the AFFIRM and SENTINEL trials and were persistently positive in approximately 6 percent [29]. When compared with antibody negativity, persistent anti-natalizumab antibody positivity was associated with reduced clinical effectiveness of natalizumab treatment and with an increased incidence of infusion reactions.

Surveillance for PML — PML is rare in the first year of natalizumab therapy even among those who are seropositive at baseline for anti-JCV antibodies. In patients with a negative or low JCV antibody level, most studies suggest that approximately 97 percent remain low over an 18-month period. However, the risk increases in patients who are seropositive for anti-JCV antibodies and with longer duration of natalizumab therapy.

●Risk management program – For patients treated with natalizumab, rigorous clinical and neuroimaging follow-up is essential to detect the onset of symptoms and signs related to PML as opposed to those related to MS [22]. Natalizumab is available in the United States through a risk management program (the TOUCH risk minimization action plan) that requires enrollment by prescribers, specialty pharmacies, and infusion centers that dispense the drug [30]. Clinicians must evaluate patients at three and six months after natalizumab treatment is started, and at least every six months thereafter. Patients receiving natalizumab must enroll in a mandatory registry and complete a checklist that asks about medications and new symptoms suggestive of PML prior to monthly infusions. Monitoring programs and registries for natalizumab prescribing are in place in several other countries as well.

●JCV antibody testing – We strongly suggest testing for anti-JCV antibodies at baseline and every six months while on natalizumab therapy (table 2). For patients who are seropositive and without prior immunosuppressive treatment, determination of anti-JCV antibody levels, as measured by the anti-JCV antibody index, may improve the accuracy of PML risk stratification [25]. The index allows quantification of anti-JCV antibody levels for individual patients and is calculated by normalizing the optical density of the anti-JCV antibody serum sample with a calibrator [31].

In contrast to testing for anti-JCV antibodies, testing for JCV deoxyribonucleic acid (DNA) in blood or urine appears to have no utility for determining the risk of PML. The authors have noted with some frequency that despite ordering JCV antibody testing, some commercial laboratories have erroneously run the JCV polymerase chain reaction (PCR) instead. Therefore, it is important to verify that the correct test (the anti-JCV antibody assay) was done when results come in.

●JCV antibody status – The JCV antibody status, JCV antibody index, history of prior immunosuppressant exposure, and duration of natalizumab exposure can be used to estimate the risk of PML and to guide decisions concerning natalizumab therapy (figure 1) [25,31,32].

•For patients who remain seronegative for anti-JCV antibodies, the estimated risk of PML is <1:10,000, suggesting relative safety of continuing natalizumab as indicated for MS. However, vigilance for PML is still required, as illustrated by a case report of a patient who had a negative anti-JCV antibody test two weeks prior to being diagnosed with PML [27]. Suggested monitoring involves repeating the anti-JCV antibody test every six months and a brain MRI every 12 months of natalizumab exposure. Although a negative JCV antibody test is often used to signify safety of therapy for indefinite periods of time, there is limited documented experience with long-term (more than six years) natalizumab therapy [33-36]. In one retrospective report of patients treated with natalizumab for more than six months, the median time from a negative JCV index value at baseline to JCV seroconversion based upon survival analysis was 103 months; the annualized seroconversion rate was 5.8 percent [37].

•For patients who are seropositive or seroconvert to positive anti-JCV status, and who have no prior use of immunosuppressant medications, the estimated risk of PML varies with the strength of the seropositive response or the antibody index; higher antibody levels are associated with a higher risk.

-With an anti-JCV antibody index <0.9, the estimated risk of PML is <1:10,000 for months 1 to 24 and 1:748 for >24 months of natalizumab exposure (table 2) [25,31,32]. Suggested monitoring involves repeating the anti-JCV antibody index every six months and a brain MRI every 12 months of natalizumab exposure. At a minimum, clinicians should counsel the patient about the risks of continuing natalizumab therapy beyond 24 months, although it should be cautioned that PML risk is cumulative rather than only beginning at the 24-month period.

-With an anti-JCV antibody index of ≥0.9, the estimated risk of PML is <1:1062 for months 1 to 24 and 1:101 for >24 months of natalizumab exposure (table 2). Suggested monitoring involves repeating the MRI scan at 12 months and then every six months beginning at 18 months of natalizumab exposure. For patients with an index of ≥0.9, we suggest stopping natalizumab after 24 months of treatment and transitioning to another DMT because of the mounting risk of PML, or extending the dosing interval of natalizumab even before 24 months. (See 'Extended interval dosing' above.)

-With an anti-JCV antibody index of ≥1.5, a conservative approach is to avoid natalizumab and use an alternate DMT for initial or escalation therapy.

Some experts, including one author of this topic (EM), do not routinely use natalizumab for patients who are anti-JCV antibody positive at baseline. They also favor switching from natalizumab to another DMT as soon as possible if patients seroconvert to positive anti-JCV antibody status during natalizumab treatment, particularly if they have a high titer, with appropriate counseling about the pros and cons of doing so.

The rationale for switching to another DMT immediately upon seroconversion is that the risk of PML is cumulative with natalizumab treatment; continued natalizumab exposure drives up risk, which may theoretically be compounded by the potential for a short period of heightened PML risk when switching to the next DMT. However, reducing PML risk by simply stopping natalizumab for a washout period carries an unacceptable risk of MS rebound. It is reasonable to obtain a brain MRI scan prior to starting the next therapy (to exclude signs of PML) and to discuss the utility of CSF JCV PCR testing.

Extended interval dosing of natalizumab, which has been associated with a reduced risk of PML in observational studies, is an alternative to switching DMT for patients who seroconvert. (See 'Extended interval dosing' above.)

•For patients with a history of prior immunosuppressant use (eg, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, mycophenolate, or a combination) who are seropositive for anti-JCV antibodies, or who seroconvert from negative to positive during subsequent testing, the estimated risk of PML is relatively high even in the first 24 months (1:330) and increases thereafter to 1:31. Therefore, we suggest stopping natalizumab and transitioning to another DMT after 12 months of treatment (or sooner) for most of these patients because of the mounting risk of PML. It is unknown if prior use of newer DMTs (anti-CD20 agents, S1PR modulators, etc) confers an elevated PML risk similar to that of traditional immunosuppressants, as these agents were not yet available when the risk of prior immunosuppressants was first reported.

Importantly, the JCV antibody status may change over time among natalizumab-treated patients with MS [38-41]. In a retrospective study of German patients with serologic follow-up over approximately eight months, conversion from anti-JCV seronegative to seropositive status occurred in 19 of 194 (10 percent), while conversion from seropositive to seronegative status occurred in 13 of 276 (5 percent) [38]. Anti-JCV antibody levels were low in both groups, suggesting that fluctuations around the cut points of the assay could lead to alternating positive and negative test results. A study of 165 patients from France reported a higher rate of seroconversion after one year of treatment with natalizumab, but the study used a more sensitive anti-JCV assay, which complicates the analysis [39].

●Neurologic assessment – Clinical vigilance and neurologic follow-up is an important aspect of monitoring for the signs and symptoms of PML. In general, MS relapses are characterized by subacute onset, typically occurring over hours to days, with eventual stabilization and resolution, and typical presentations that include diplopia, optic neuritis, and myelopathy. By contrast, PML is characterized by even slower onset over several weeks to months, progressive disease, and presentations that include aphasia, behavioral and neuropsychiatric abnormalities, cortical visual deficits, hemiparesis, and seizures.

●MRI monitoring – Some PML cases have been discovered prior to any symptoms, and imaging (ie, brain MRI) follow-up is very important. A baseline brain MRI scan should be obtained prior to initiating therapy with natalizumab. For patients who are JCV antibody-positive, screening for PML with brain MRI more frequently (as often as every three to four months) may be advised, although practice preferences vary widely among MS experts. For patients who are negative for JCV antibodies at baseline and at one year, we suggest repeating the MRI scan every 12 months for PML monitoring (table 2).

●New MRI lesion – Any anti-JCV seropositive patient on natalizumab who develops a new MRI lesion should be evaluated for the possibility of PML. Important issues are the specific characteristics of the lesion and the length of time on natalizumab. Radiologists must be informed that patients are on natalizumab and at risk for PML, as the initial lesions of PML may be indistinguishable from a new demyelinating lesion due to MS. PML lesions usually begin in the subcortical white matter of the parieto-occipital or frontal lobes but may also involve the corpus callosum, brainstem, pyramidal tracts, and cerebellum. However, the presence of punctate or confluent hyperintense T2 lesions and cortical gray matter involvement suggest PML rather than new MS-related lesions, while periventricular location and focal appearance (as opposed to a diffuse, confluent irregular, or infiltrative appearance) suggest new MS-related lesions rather than PML [42]. Cerebrospinal fluid analysis for JCV PCR DNA is mandatory in these patients, though different laboratories have different sensitivities, and the PCR may be negative in early cases of PML. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Efficacy — In a 2011 systematic review of trials evaluating natalizumab for relapsing forms of MS, pooled efficacy data from two randomized controlled trials, AFFIRM [43] and SENTINEL [44], showed that natalizumab significantly reduced the risk for having a relapse during two years of treatment (relative risk [RR] 0.57, 95% CI 0.47-0.69) [45]. In addition, natalizumab significantly reduced the risk for experiencing progression at two years (RR 0.74, 95% CI 0.62-0.89). The number needed to treat (NNT) to prevent one new exacerbation at two years was 4 (95% CI 3-5) and the NNT to prevent progression at two years was 10 (95% CI 7-23).

In the AFFIRM trial, 942 patients with relapsing MS were randomly assigned to receive either monotherapy with natalizumab 300 mg (n = 627) or placebo (n = 315) by IV infusion every four weeks for two years [43]. Natalizumab treatment was associated with a statistically significant 68 percent reduction in annualized relapse rate compared with placebo treatment at one year (0.26 versus 0.81), a reduction that was maintained at two years, and with a significant reduction in the cumulative probability of sustained disability progression at two years (17 versus 29 percent).

In the SENTINEL trial, 1171 patients with relapsing MS who continued to experience disease activity despite interferon beta-1a treatment were randomly assigned to also receive natalizumab 300 mg (n = 589) or placebo (n = 582) by IV infusion every four weeks [44]. All patients continued to receive interferon beta-1a throughout the trial. The study was stopped approximately one month early because two patients developed progressive multifocal leukoencephalopathy. Combination therapy (natalizumab plus interferon beta-1a) was associated with a statistically significant 54 percent reduction in annualized relapse rate compared with placebo at one year (0.38 versus 0.82), a difference that was maintained at two years, and with a significant reduction in the risk of sustained disability progression at two years (23 versus 29 percent).

Natalizumab was beneficial in all analyses of primary and secondary endpoints in both the AFFIRM and SENTINEL trials, indicating the robust nature of the results [43,44]. As an example, natalizumab treatment as monotherapy (in AFFIRM) or combination therapy (in SENTINEL) was associated with an 83 percent reduction in the number of new or enlarging hyperintense lesions on T2-weighted MRI. Finally, natalizumab treatment was associated with improved health-related quality of life compared with placebo [46].

ANTI-CD20 THERAPIES — The anti-CD20 monoclonal antibodies for MS work by targeting B cells that express CD20, which leads to depletion of circulating B cells via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity [47].

Ocrelizumab — Ocrelizumab is a recombinant humanized anti-CD20 (a B cell marker) monoclonal antibody that binds to a different, but overlapping, CD20 epitope than rituximab, another anti-B cell monoclonal antibody. It was designed to optimize B cell depletion by modification of the Fc region, which enhances antibody-dependent cell-mediated cytotoxicity and reduces complement-dependent cytotoxicity compared with rituximab; the latter has shown efficacy in small trials (see 'Rituximab' below) and has been widely used in some MS centers for years.

Indications — Ocrelizumab is indicated for relapsing forms of MS including relapsing-remitting multiple sclerosis (RRMS), clinically isolated syndromes (CIS), and active secondary progressive multiple sclerosis (SPMS); it is also indicated for primary progressive MS [48]. Ocrelizumab is contraindicated in patients with active hepatitis B virus infection and those with a history of life-threatening infusion reaction to ocrelizumab [49].

Dose and administration — The initial dose of ocrelizumab is a 300 mg intravenous (IV) infusion, followed two weeks later by a second 300 mg IV infusion [49]. Subsequently, ocrelizumab is given as 600 mg IV infusion every six months, beginning six months after the first 300 mg dose. The drug should be given under close medical supervision with access to medical support should severe infusion reactions develop. Premedication is recommended, with both methylprednisolone 100 mg IV (or equivalent IV or oral glucocorticoid, although sometimes this premedication is not used) approximately 30 to 60 minutes prior to each ocrelizumab infusion to reduce the frequency and severity of infusion reactions; an antipyretic (eg, acetaminophen) is often added as well. Infusions should be delayed if there is active infection until the infection resolves. Some mild infusion reactions can be treated with additional doses of methylprednisolone and/or antihistamine.

Adverse effects — The most common adverse effects of ocrelizumab are infusion reactions, upper and lower respiratory tract infections, and skin infections [49].

In the postmarketing setting, the following infections and immune-mediated conditions have been reported in patients treated with ocrelizumab [49-51]:

●Serious infections caused by herpes simplex virus and varicella zoster virus (VZV)

●Hepatitis B reactivation

●Progressive multifocal leukoencephalopathy (PML) that developed in patients on ocrelizumab who had not received natalizumab or prior immunomodulatory medications, and who did not have conditions resulting in compromised immune system function

●Immune-mediated colitis

There may be an increased risk of malignancy, including breast cancer, with ocrelizumab. In randomized trials, ocrelizumab treatment was associated with infusion reactions in 34 percent, serious infections in 1 percent, and neoplasms in 0.5 percent of patients [52,53].

Longer-term risks associated with rituximab use (see 'Rituximab' below) are theoretically also similar for ocrelizumab, and we suggest counseling patients accordingly [54].

There are no data regarding the risk of fetal harm associated with ocrelizumab treatment during pregnancy, but animal data suggest harm with observations of increased perinatal mortality and renal, bone marrow, and testicular toxicity [49].

Screening and monitoring

●Infections – Patients must be screened for hepatitis B virus before starting ocrelizumab (see "Hepatitis B virus: Screening and diagnosis in adults") [49]. We also screen at baseline for hepatitis C, tuberculosis, human immunodeficiency virus (HIV), and VZV, and we obtain a complete blood count with differential, lymphocyte subsets, and a metabolic panel including liver enzymes. Repeat screening for these factors depends upon individual patient characteristics, such as hepatitis risk factors, prior vaccination, and level of hepatitis B surface antibody (anti-HBs) as a positive response to vaccination. (See "Hepatitis B virus immunization in adults".)

●Immunoglobulin levels – Quantitative levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) should be obtained at baseline; the label recommends consulting with immunology experts for patients with low immunoglobulin levels before starting ocrelizumab [49].

●Vaccination status – Patients should receive all necessary live or live-attenuated vaccines at least four weeks before starting ocrelizumab and non-live vaccines at least two weeks before starting ocrelizumab [49]. Live-attenuated and live vaccines are not recommended during ocrelizumab treatment or after discontinuation until B-cell repletion occurs.

●Other concerns – Standard breast cancer screening guidelines should be followed. (see "Screening for breast cancer: Strategies and recommendations"), and patients should be monitored for immune-mediated colitis.

Efficacy — Two identical randomized, controlled trials (OPERA I and OPERA II) of 821 and 825 adults with relapsing MS compared IV ocrelizumab (600 mg every 24 weeks) with subcutaneous interferon beta-1a (44 micrograms three times weekly) for 96 weeks [52]. All patients were pretreated with one dose of IV methylprednisolone (100 mg) before each infusion. In both trials, treatment with ocrelizumab compared with interferon beta-1a significantly reduced the annualized relapse rate (0.16 versus 0.29, absolute risk reduction [ARR] 0.13). Ocrelizumab treatment also reduced the mean number of gadolinium-enhancing lesions per MRI scan in OPERA I (0.02 versus 0.29, ARR 0.27) and in OPERA II (0.02 versus 0.42, ARR 0.40). In a prespecified pooled analysis, ocrelizumab led to a significant reduction in the proportion of subjects with confirmed disability progression at 24 weeks (6.9 versus 10.5 percent, hazard ratio 0.60, 95% CI 0.43-0.84, ARR 3.6 percent).

In the placebo-controlled ORATORIO trial, which enrolled 732 adult patients with primary progressive MS, ocrelizumab modestly reduced confirmed disability progression at 12 and 24 weeks. The evidence for ocrelizumab in primary progressive MS is reviewed in greater detail elsewhere. (See "Treatment of primary progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)

Rituximab — Rituximab is a chimeric mouse-human monoclonal antibody also directed against the CD20 antigen on B lymphocytes that causes B cell reduction; its mechanism of action is similar to that of ocrelizumab.

Indications — Rituximab has been widely used off-label to treat relapsing forms of MS (RRMS and active SPMS) in some centers for years.

Dose and administration — Rituximab dosing varies among UpToDate MS experts, with the following different regimens employed [55,56]:

●Induction with two 1 g infusions separated by a two-week interval, followed by 1 g infusion given every six months

●1 g infusion given every six months with a reduction in the dose and/or infusion frequency after one or two years

●500 mg infusion given every six months

Rituximab should be given under close medical supervision with access to medical support to manage possible severe infusion reactions. Premedication is recommended using both methylprednisolone 100 or 125 mg IV (or equivalent glucocorticoid) approximately 30 minutes prior to each rituximab infusion, and with an antihistamine (eg, diphenhydramine) approximately 30 to 60 minutes prior to each rituximab infusion, to reduce the frequency and severity of infusion reactions; an antipyretic (eg, acetaminophen) can be added as well. Infusions should be delayed if there is active infection until the infection resolves.

Adverse effects — Potential adverse effects include infusion reactions, hypogammaglobulinemia, infection, reactivation of hepatitis B, and neutropenia.

Rare cases of PML have been reported in patients treated with rituximab for other indications. However, it is unknown if rituximab increases the risk of PML, since rituximab is often used to treat patients who have an underlying risk factor for PML. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

A registry-based cohort study of over 6400 patients with RRMS from Sweden examined the risk of infection associated with exposure to rituximab, natalizumab, fingolimod, interferon beta, and glatiramer acetate [54]. Among these, treatment with rituximab was associated with the highest rate of serious infections, particularly after a few years of exposure.

Screening and monitoring

●Infections – Patients must be screened for hepatitis B virus before starting rituximab (see "Hepatitis B virus: Screening and diagnosis in adults"). We also screen at baseline for hepatitis C, tuberculosis, and HIV, and we obtain a complete blood count; lymphocyte subsets; levels of IgG, IgA, and IgM; and a metabolic panel.

●Immunoglobulin levels – Immunoglobulin levels (IgG, IgA, and IgM) should be obtained at baseline and monitored prior to each infusion cycle.

●Vaccination status – Patients should ideally receive all necessary immunizations at least four weeks prior to starting rituximab. Live-attenuated vaccines are not recommended during rituximab treatment or after discontinuation of rituximab treatment until B cell repletion occurs.

Efficacy — Data from randomized controlled trials supporting the effectiveness of rituximab for RRMS are limited but convincing, and nonrandomized studies and the positive trials for ocrelizumab increase confidence that rituximab is beneficial [55].

In a rater-blind trial, adult patients (n = 200) in Sweden with RRMS or CIS were randomly assigned in a 1:1 ratio to treatment with IV rituximab (1000 mg, followed by 500 mg every six months) or oral dimethyl fumarate (240 mg twice daily) [57]. At 24 months of follow-up, relapses were less frequent in the rituximab group compared with the dimethyl fumarate group (3 versus 16 percent, risk ratio [RR] 0.19, 95% CI 0.06-0.62). In an earlier randomized trial of 104 adult patients with RRMS, treatment with IV rituximab (1000 mg) given on days 1 and 15 reduced both total and new gadolinium-enhancing lesions on brain MRI at 24 weeks when compared with placebo [58]. In addition, rituximab treatment reduced the proportion of patients who had a clinical relapse by week 24.

Observational studies largely support the efficacy of rituximab, although they are limited by the greater potential for bias and confounding compared with randomized controlled trials. In an observational study of 256 patients with stable RRMS who switched to rituximab or fingolimod after stopping natalizumab due to JC polyomavirus (JCV) antibody positivity, the rituximab group had lower rates of clinical relapse, adverse events, and treatment discontinuation compared with the fingolimod group [59]. In another observational study of 494 patients diagnosed with RRMS identified from a Swedish MS registry, rituximab treatment was associated with a lower discontinuation rate compared with other disease-modifying therapies (DMTs), including interferons, glatiramer acetate, dimethyl fumarate, fingolimod, and natalizumab [60]. Rituximab treatment was also associated with a lower rate of clinical relapses and MRI measures of disease activity compared with interferons, glatiramer acetate, and dimethyl fumarate.

Ofatumumab — Ofatumumab is a human monoclonal antibody that also targets CD20 on B lymphocytes and causes selective B cell depletion.

Indications — Ofatumumab was approved in August 2020 by the US Food and Drug Administration (FDA) for the treatment of adults with relapsing forms of MS, including CIS, RRMS, and active SPMS. Ofatumumab is contraindicated in patients with active hepatitis B virus infection.

Dose and administration — Ofatumumab is given by subcutaneous injection, starting with 20 mg administered at weeks zero, one, and two. Subsequently, the dose is 20 mg per month starting at week four [61]. Administration should be delayed in patients with active infection until the infection resolves.

Adverse effects — The most common adverse effects observed with ofatumumab are upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions [61]. The potential for reduction in immunoglobulins may increase the risk of recurrent infections or opportunistic infections.

Animal data suggest a risk of fetal harm. The label recommends use of an effective method of contraception during ofatumumab treatment and for six months after discontinuation [61].

Screening and monitoring

●Infections – Before the first dose of ofatumumab, patients should be screened for hepatitis B virus. We also screen at baseline for hepatitis C, tuberculosis, HIV, and VZV, and we obtain a complete blood count with differential, lymphocyte subsets, and a metabolic panel including liver enzymes. Repeat screening for these factors depends upon individual patient characteristics, such as hepatitis risk factors, prior vaccination, and level of anti-HBs as a positive response to vaccination.

●Immunoglobulin levels – Quantitative serum levels of IgG, IgA, and IgM should be obtained at baseline and monitored during treatment and after discontinuation of ofatumumab treatment until B cell repletion occurs [61].

●Vaccination status – Patients should receive all recommended immunizations at least four weeks before starting ofatumumab. Live or live-attenuated vaccines are not recommended during treatment and after stopping treatment until B cell repletion occurs.

Efficacy — Efficacy of ofatumumab was established in two controlled trials (ASCLEPIOS I and II) of identical design that enrolled a combined total of over 1800 adults with relapsing MS [62]. Patients were randomly assigned in a 1:1 ratio to treatment with subcutaneous ofatumumab and oral placebo or oral teriflunomide and subcutaneous placebo for up to 30 months. At a median follow-up of 1.6 years, ofatumumab compared with teriflunomide reduced the annualized relapse rate in ASCLEPIOS I (0.11 versus 0.22, ARR -0.11, 95% CI -0.16 to -0.06) and ASCLEPIOS II (0.10 versus 0.25, ARR -0.15, 95% CI -0.20 to -0.09). In pooled data from the two trials, ofatumumab reduced the number of patients with disability worsening confirmed at six months (8.1 percent, versus 12.0 with teriflunomide, hazard ratio 0.68, 95% CI 0.50-0.92, ARR 4.1 percent). In both trials, ofatumumab reduced the mean number of gadolinium-enhancing lesions per T1-weighted MRI scan and the annualized rate of new or enlarged lesions on T2-weighted MRI.

Ublituximab — Ublituximab is a recombinant mouse-human chimeric monoclonal antibody that binds to a CD20 epitope distinct from those targeted by ocrelizumab, rituximab, and ofatumumab. Ublituximab was glycoengineered with a low sugar content in its Fc segment to achieve a high affinity for Fc gamma RIIIa (CD16) receptors [63]. This enhances its ability to activate natural killer cell-mediated antibody-dependent cellular cytotoxicity, leading to B cell depletion.

Indications — Ublituximab was approved by the FDA in December 2022 for the treatment of adults with relapsing forms of MS, including CIS, RRMS, and active SPMS [64].

Dose and administration — Ublituximab is administered intravenously [64]:

●150 mg for the first infusion

●450 mg for the second infusion, approximately two weeks after the first

●450 mg for subsequent infusions beginning 24 weeks after the first infusion and every 24 weeks thereafter

Premedication with methylprednisolone 100 mg IV (or an equivalent glucocorticoid) and an antihistamine (eg, diphenhydramine) is recommended before each dose. Patients should be monitored during infusions and for at least one hour after completing the first two infusions. Thereafter, postinfusion monitoring is at the discretion of the treating clinician.

Administration should be delayed in patients with active infection until the infection resolves.

Adverse effects — The most common adverse effects of ublituximab seen in clinical trials are infusion reactions, with an incidence of approximately 50 percent, and upper respiratory tract infections, with an incidence of approximately 45 percent [64]. Other adverse effects include:

●Potentially life-threatening bacterial and viral infections

●Reduction in immunoglobulins

●Potential for fetal harm

Ublituximab is contraindicated for patients with active hepatitis B virus infection and for those with prior life-threatening infusion reaction to ublituximab [64]. The label recommends use of an effective method of contraception during ublituximab treatment and for six months after discontinuation.

Screening and monitoring

●Infections – Patients should be screened at baseline for hepatitis B virus; we also screen for hepatitis C, tuberculosis, HIV, and VZV, and we obtain a complete blood count, lymphocyte subsets, and a metabolic panel. Repeat screening for these factors depends upon individual patient characteristics, such as hepatitis risk factors, prior vaccination, and level of anti-HBs as a positive response to vaccination.

●Immunoglobulin levels – Quantitative levels of IgG, IgA, and IgM should be obtained at baseline; the label recommends consulting with immunology experts for patients with low immunoglobulin levels before starting ublituximab [64].

●Vaccination status – As with other B cell depleting agents, patients should receive all recommended immunizations at least four weeks before starting ublituximab. Live or live-attenuated vaccines are not recommended during treatment and after stopping treatment until B cell repletion occurs.

Efficacy — The efficacy of ublituximab for patients with relapsing MS was demonstrated in two identical randomized trials, ULTIMATE I (n = 549) and ULTIMATE II (n = 545) [65]. Patients in these trials were randomly assigned in a 1:1 ratio to IV ublituximab (150 mg on day one, followed by 450 mg on day 15 and at weeks 24, 48, and 72) plus oral placebo, or to oral teriflunomide (14 mg daily) plus IV placebo. At a median follow-up of 95 weeks, the annualized relapse rate was lower with ublituximab compared with teriflunomide in ULTIMATE I (0.08 versus 0.19; rate ratio [RR] 0.41, 95% CI 0.27-0.62) and ULTIMATE II (0.09 versus 0.18; RR 0.51, 95% CI 0.33-0.78). The mean number of gadolinium-enhancing brain lesions on MRI was also lower with ublituximab compared with teriflunomide in ULTIMATE I (0.02 versus 0.49; RR 0.03, 95% CI 0.02-0.06) and ULTIMATE II (0.01 versus 0.25; RR 0.04, 95% CI 0.02-0.06).

In a pooled analysis of the two trials, worsening of disability at 12 weeks was similar with ublituximab and teriflunomide (5.2 versus 5.9 percent, hazard ratio 0.84; 95% CI 0.50-1.41) [65].

ANTI-CD52 THERAPY

Alemtuzumab — Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, B cells, natural killer cells, and monocytes [66].

Indications — Alemtuzumab is indicated for the treatment of relapsing forms of MS, including relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS). Because of its safety profile (see 'Adverse effects' below), alemtuzumab is not recommended for the treatment of clinically isolated syndromes (CIS).

Alemtuzumab is generally reserved in the United States for patients with highly active RRMS who have had an inadequate response to two or more disease-modifying therapies (DMTs), or where other DMTs cannot be used. Furthermore, the European Medicines Agency (EMA) recommends that alemtuzumab should only be used for the treatment of RRMS if the disease is highly active despite treatment with at least one DMT or if the disease is worsening rapidly [67].

Alemtuzumab is contraindicated in patients with HIV infection, active infection, or known hypersensitivity to alemtuzumab [68].

Dose and administration — Alemtuzumab is administered via IV infusion at 12 mg daily for five consecutive days (total 60 mg) at the start of treatment, followed 12 months later by 12 mg daily for three consecutive days (total 36 mg) [68]. Subsequent treatments (12 mg daily for three consecutive days, total dose 36 mg) are given as needed at least 12 months after the last dose of a previous treatment course.

Premedication with glucocorticoids (1 g of methylprednisolone) for the first three days of therapy is indicated. Infusions should be administered in a medical setting capable of managing anaphylaxis, serious infusion reactions, and myocardial, cerebrovascular, or pulmonary adverse reactions, and patients should be observed for at least two hours after each infusion.

Antiviral prophylaxis for herpetic viral infections (eg, oral acyclovir 200 mg given twice daily) is recommended, starting on the first day of each treatment course and continuing for at least two months following treatment with alemtuzumab or until the CD4+ lymphocyte count is at least 200 cells per microliter, whichever occurs later [68].

Adverse effects — The main side effects of alemtuzumab are infusion reactions, infections, and autoimmune disorders [69-72]. Infusion reactions occur in approximately 90 percent of patients and are characterized by headache, rash, nausea, and fever. Infections, though generally not severe, were observed in two-thirds or more of the patients treated with alemtuzumab. Herpes viral infections occurred in 16 to 18 percent, leading to a change in the protocol of the in-progress CARE-MS trials with the addition of prophylactic acyclovir treatment during alemtuzumab infusion and for 28 days after infusion [70,71]. Thyroid autoimmunity was seen in 16 to 18 percent of patients at two years after alemtuzumab treatment [70,71], and in 30 percent with longer follow-up [72]. Immune thrombocytopenia (ITP) developed in 1 percent of patients at two years [70,71] and in 3 percent at three years [69,72]. This included one patient who suffered a fatal intracerebral hemorrhage in a phase II study of alemtuzumab. All subsequent ITP cases were detected through a monitoring program and successfully treated [73].

The prescribing label warns of an increased risk of autoimmunity (ITP, thrombotic thrombocytopenic purpura [TTP], antiglomerular basement membrane disease, autoimmune encephalitis), infusion reactions, thyroid disorders, hemophagocytic lymphohistiocytosis, adult-onset Still disease, acquired hemophilia A, infections, and malignancies (thyroid cancer, melanoma, lymphoproliferative disorders) [68].

Other reports described three cases of acute acalculous cholecystitis [74] and two cases of neutropenia [75] during treatment with alemtuzumab for RRMS. Announcements from the US Food and Drug Administration (FDA) and EMA have warned of cases of ischemic stroke, hemorrhagic stroke, arterial dissection, and myocardial infarction that occurred shortly after starting treatment with alemtuzumab [67,76,77].

Screening and monitoring — Alemtuzumab therapy requires monitoring (for infusion reactions, symptoms of ITP, and symptoms of nephropathy) and prophylaxis for herpes virus infections (oral acyclovir 200 mg twice daily) during treatment and continuing for at least two months after completion of a treatment course, or until the CD4+ count is >200 cells/microL, whichever occurs later [68]. Prolonged surveillance (for 48 months after the last dose) for bone marrow suppression, infections, and autoimmune disorders such as ITP is also necessary. Patients should be educated about the symptoms of ITP and should report them immediately if they develop.

●Infections – Patients should be screened for tuberculosis and advised to avoid potential sources of Listeria monocytogenes. (See "Treatment and prevention of Listeria monocytogenes infection", section on 'Prevention of foodborne infection'.)

●Vaccination status – Necessary immunizations must be completed at least six weeks before the start of treatment with alemtuzumab [68]. Patients without a history of varicella zoster virus (VZV) infection or vaccination for VZV should be tested for antibodies to VZV. Vaccination for VZV should be considered for patients who are antibody-negative, postponing alemtuzumab treatment for six weeks after VZV vaccination.

●Laboratory tests – To monitor for early signs of potentially serious adverse events, laboratory testing is recommended at baseline and periodically thereafter until 48 months after the last treatment course of alemtuzumab for the following [68]:

•Urine protein to creatinine ratio prior to initiation of treatment

•Complete blood count with differential prior to treatment and at monthly intervals thereafter

•Serum creatinine levels prior to treatment and at monthly intervals thereafter

•Urinalysis with urine cell counts prior to treatment and at monthly intervals thereafter

•Thyroid function testing (eg, thyroid-stimulating hormone [TSH] level) prior to treatment and every three months thereafter

•Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels prior to initiation and periodically thereafter

●Malignancy – Baseline and yearly skin examination are recommended to monitor for melanoma [68].

●Risk management program – Treatment with alemtuzumab in the United States requires special registration through a restricted distribution program (the LEMTRADA Risk Evaluation and Mitigation Strategy or REMS) for both the center and patient to ensure adequate follow-up [78].

Efficacy — Data from randomized controlled trials show that alemtuzumab is more effective than interferon beta-1a for reducing the relapse rate in RRMS [79]. This benefit is associated with a small increased risk of potentially serious infections and autoimmune disorders, including ITP [69-71].

CARE-MS I was a rater-blind trial that evaluated over 550 adults with RRMS, low disability levels, and no prior DMT [70]. Subjects were randomly assigned to either alemtuzumab or subcutaneous interferon beta-1a (44 mcg three times per week) in a 2:1 ratio. Alemtuzumab was infused intravenously at 12 mg daily for five days at the start of treatment and for three days at 12 months. At two years, alemtuzumab reduced the proportion of patients with any relapse (22 percent, versus 40 percent for interferon beta-1a, rate ratio 0.45, 95% CI 0.23-0.63) and the annualized relapse rate (0.18 versus 0.39). However, there was no significant difference between groups for sustained accumulation of disability (8 versus 11 percent). Imaging outcomes were mixed; there was no significant difference between groups for median change in volume of T2-hyperintense brain lesions, but the alemtuzumab group had fewer new or enlarging T2-hyperintense lesions and fewer gadolinium-enhancing lesions.

The similar CARE-MS II trial evaluated nearly 800 adults with RRMS and at least one relapse while on treatment with interferon beta-1a or glatiramer acetate [71]. At two years, alemtuzumab reduced the proportion of patients with any relapse (35 percent, versus 53 percent for interferon beta-1a, rate ratio 0.51, 95% CI 0.39-0.65) and the annualized relapse rate (0.26 versus 0.52). Unlike CARE-MS I, the alemtuzumab group in CARE-MS II had a significantly lower rate of sustained accumulation of disability (13 versus 20 percent, hazard ratio 0.58, 95% CI 0.38-0.87). Like CARE-MS I, the imaging outcomes in CARE-MS II showed no significant difference between groups for median change in volume of T2-hyperintense brain lesions, but the alemtuzumab group had significantly fewer new or enlarging T2-hyperintense lesions, and fewer gadolinium-enhancing lesions. Notably, the CARE-MS II trial design may have magnified the treatment effect of alemtuzumab, as some patients were randomly assigned to the same treatment (interferon beta-1a) on which they had disease activity prior to enrollment. Modern treatment paradigms usually do not continue a therapy that has been associated with breakthrough disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY

●Role of monoclonal antibody treatment – Disease-modifying therapies (DMTs) for multiple sclerosis (MS) include several categories of medications. Monoclonal antibody DMTs are highly efficacious and may be preferred for patients with more active disease and for those who place a high value on efficacy and are risk-tolerant. However, serious safety issues, including infections, are possible adverse effects of several of these medications. The choice of DMT for patients with MS should be individualized according to disease activity and patient values and preferences (algorithm 1). (See 'Choosing therapy' above.)

The use of DMT for specific clinical situations is discussed in detail elsewhere:

•(See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)

•(See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

•(See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis".)

•(See "Treatment of secondary progressive multiple sclerosis in adults".)

•(See "Treatment of primary progressive multiple sclerosis in adults".)

•(See "Multiple sclerosis: Pregnancy planning".)

•(See "Multiple sclerosis: Pregnancy and postpartum care".)

●Natalizumab – Natalizumab, an integrin receptor antagonist, is indicated as monotherapy for the treatment of relapsing forms of MS, including clinically isolated syndromes (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). It is administered by intravenous (IV) infusion every four weeks. Natalizumab treatment is associated with the risk of opportunistic infections, including progressive multifocal leukoencephalopathy (PML), and hepatoxicity. The risk of PML is related to the JC polyomavirus (JCV) antibody level. Screening and monitoring recommendations, including JCV antibody status, and PML surveillance, are discussed above. (See 'Natalizumab' above.)

●Ocrelizumab – Ocrelizumab is a recombinant humanized anti-CD20 monoclonal antibody that depletes B cells. It is indicated for relapsing forms of MS (CIS, RRMS, active SPMS) and for primary progressive MS. It is given by IV infusion as described in detail above. Potential serious adverse effects include infections, infusion reactions, immune-mediated colitis, hypogammaglobulinemia, and an increased risk of malignancy. Screening and monitoring recommendations are discussed above. (See 'Ocrelizumab' above.)

●Rituximab – Rituximab is a chimeric mouse-human anti-CD20 monoclonal antibody that causes B cell reduction. It is widely used off-label to treat relapsing or active forms of MS. It is given by IV infusion as described in detail above. Potential adverse effects include infections, infusion reactions, reactivation of hepatitis B, and hypogammaglobulinemia. Screening and monitoring recommendations are discussed above. (See 'Rituximab' above.)

●Ofatumumab – Ofatumumab is a human monoclonal antibody that also targets CD20 on B lymphocytes and causes selective B cell depletion. It is indicated for relapsing forms of MS (CIS, RRMS, and active SPMS). It is administered by subcutaneous injection, with dosing as described above. Potential adverse effects include infections, infusion reactions, reactivation of hepatitis B, and hypogammaglobulinemia. Screening and monitoring recommendations are discussed above. (See 'Ofatumumab' above.)

●Ublituximab – Ublituximab is a chimeric monoclonal antibody with a glycoengineered Fc segment (to enhance antibody-dependent cell-mediated cytotoxicity) that targets a different CD20 epitope than the other anti-CD20 monoclonal antibodies and causes B cell depletion. It is indicated for relapsing forms of MS (CIS, RRMS, and active SPMS). It is given by IV infusion, with premedication and dosing as described above. Potential adverse effects include infections, infusion reactions, reactivation of hepatitis B, and hypogammaglobulinemia. Screening and monitoring recommendations are discussed above. (See 'Ublituximab' above.)

●Alemtuzumab – Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, B cells, natural killer cells, and monocytes. It is indicated for the treatment of relapsing MS, including RRMS and active SPMS. However, alemtuzumab is not recommended for the treatment of CIS because of its safety profile. Alemtuzumab is given by IV infusion, with premedication and dosing described above. Potential adverse effects include infections, thyroid disorders, immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, nephropathy, autoimmune encephalitis, adult-onset Still disease, acquired hemophilia A, autoimmune hepatitis, hemophagocytic lymphohistiocytosis, infusion reactions, ischemic and hemorrhagic stroke, myocardial ischemia, and malignancies. Screening and monitoring recommendations are discussed above. (See 'Alemtuzumab' above.)