This document is intended to provide a guide to safety monitoring for practitioners caring for patients with multiple sclerosis (MS) who are candidates for initiation of disease modifying therapy (DMT), are being maintained on long-term treatment, or are being monitored after cessation of therapy by summarizing the approach of the Cleveland Clinic Mellen Center staff. Recommendations for pre-treatment testing, monitoring on maintenance therapy, and post-treatment surveillance are outlined for each DMT class, and additional recommendations pertaining to individual DMTs have been included where appropriate.

For newly diagnosed patients in whom several or all DMT classes are being considered, a standard set of pre-treatment studies is often obtained which includes a complete blood count (CBC) with differential, complete metabolic panel (CMP), tuberculosis (TB) screen (PPD or Quantiferon), John Cunningham virus (JCV) serology with titer, Varicella Zoster virus (VZV) serology, remote Hepatitis serology panel, and baseline immunoglobulin G (IgG) and immunoglobulin M (IgM) levels. Human immunodeficiency virus (HIV) and serum human chorionic gonadotropin (HCG) screening may also be considered based on clinician preference and patient-specific risk factors. All patients should have an established primary care provider with whom preventative care (including age- and risk-appropriate cancer screening) can be coordinated.

It is also important for clinicians to discuss family planning, pregnancy, and use of contraception with women being treated with or planning to start DMT at each visit (see Management of Multiple Sclerosis during Pregnancy). Recommendations are summarized in Table 1.

Interferon β products: interferon β-1a,1, 2 interferon β-1b3, peginterferon β-1a4

For interferon beta produces, pre-treatment testing includes a CBC with differential, CMP, and thyroid stimulating hormone (TSH) level. Clinicians should inquire about history of cardiac disease (including congestive heart failure), stroke, seizure, and liver disease prior to treatment initiation.

Routine laboratory monitoring consists of CBC with differential, CMP, and TSH at months 1, 3, and 6 after treatment initiation, and every 6-12 months thereafter. Should the patient have evidence of ongoing disease activity (either clinically or radiologically), neutralizing antibodies may be checked 1-2 years after treatment initiation. Persistent high-titer neutralizing antibodies warrant a change in therapy. Patients should be clinically monitored for treatment side effects, particularly injection site reactions and worsening depression.

Glatiramer acetate5, 6

Glatiramer acetate does not require any pretreatment testing, including testing for pregnancy (both FDA and EMA warnings for pregnancy have been removed). There is also no routine laboratory monitoring required.

Patients should be counseled on the risk of systemic post-injection reaction symptoms (including chest pain, shortness of breath, flushing, rash, swelling, or itching) and injection site reaction (including redness, pain, swelling, or itching at the injection site). It is recommended that patients lay down / rest if they experience these symptoms, and to call 911 / seek emergent care if symptoms are prolonged.

Fumarate Products: dimethyl fumarate7, monomethyl fumarate8, diroximel fumarate9

Pretreatment testing for all fumarate medications includes CBC with differential and CMP. Long-term laboratory monitoring consists of CBC with differential every 6 months while treatment is continued. Dimethyl fumarate causes a progressive decline in lymphocyte count over the first year of treatment, after which the absolute lymphocyte count (ALC) remains suppressed. Liver function tests may be repeated as clinically indicated for any signs or symptoms concerning for liver injury.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported. Should a patient develop lymphopenia, more frequent monitoring may be indicated. For counts 500 – 750/µL, CBC with differential should be monitored, and JCV serology should be obtained. If the ALC is persistently below 500/µL and/or the patient is JCV seropositive, an alternative treatment should be considered. Patients with an ALC between 200 and 750/µL who are JCV negative may be continued on fumarate therapies with continued monitoring of ALC and JCV status. In cases of suspected PML, treatment should be paused, and confirmatory tests should be performed (see section on natalizumab below). As part of routine clinical monitoring, patients should be asked about infection history (including occurrence of severe infections), flushing, and gastrointestinal side effects.


Prior to initiation of teriflunomide treatment a CBC with differential, CMP, TB screen, and a serum pregnancy test (in women of childbearing age) should be performed. Baseline blood pressure should also be documented. Patients must be counseled on the teratogenic effect of teriflunomide, and that contraceptive measures are needed for both men and women on teriflunomide.

Long-term laboratory monitoring consists of LFT testing once monthly for 6 months after treatment initiation, and then every 6 months thereafter. If pregnancy occurs while a patient is taking teriflunomide, a rapid elimination protocol should be implemented.11 Cholestyramine may be administered orally, 8g every 8 hours for 11 days (if tolerated) until plasma concentration reaches < 0.02 mg/L. Teriflunomide plasma levels may be evaluated using a LabCorp assay (acquisition form may be obtained from If the patient is unable to tolerate this regimen a 4g dose may be used. Alternatively, activated charcoal powder may be administered orally, 50g every 12 hours for 11 days. Special attention should be paid to development of recurrent infections, and blood pressure should be documented at each clinical visit.

Sphingosine 1-posphate receptor (S1Pr) modulators: fingolimod12, siponimod13, ozanimod14, ponesimod15

Prior to starting treatment with an S1Pr modulator a CBC with differential, electrocardiogram (ECG), CMP, VZV serology (to ensure sufficient response to prior exposure or vaccination), and optical coherence tomography (OCT) or ophthalmologic examination (to screen for macular edema and/or asymptomatic uveitis) should be completed. Patients that are VZV IgG negative should be vaccinated against VZV prior to initiation of treatment. For siponimod, the CYP2C9 genotype must also be checked prior to treatment initiation, as the initiation titration strategy varies based on genotype (see Mellen Center approach titled “Siponimod”). For all patients planning to start S1Pr modulators in whom screening ECG is abnormal or who have a history of cardiac disease, a Cardiology consultation should be obtained. Similarly, for patients complaining of shortness of breath, chronic cough, or who have a history of abnormal pulmonary function tests, a Pulmonary Medicine consultation may also be considered. The ozanimod package insert recommends that a Sleep Medicine consultation be obtained for patients with obstructive sleep apnea, though this is not done routinely at the Mellen Center.

In patients starting fingolimod, a first-dose observation (FDO) period is required. After administration of the initial dose, heart rate and blood pressure should be monitored hourly, and an ECG should be checked after 6 hours. Patients developing heart rate < 45 beats per minute (bpm) or AV conduction slowing in adults should be monitored until bradycardia resolves, and patients developing symptomatic bradycardia or AV conduction slowing should be monitored with ECG until symptoms resolve. Patients developing symptomatic bradycardia with the initial dose should also be monitored after taking the second dose. FDO is only necessary for patients with pre-existing cardiac conditions when starting siponimod or ponesimod. There is no recommended FDO for patients starting ozanimod, though Cardiology evaluation is recommended for patients with pre-existing cardiac history. If one or more doses of medication are missed, FDO and/or dose titration may need to be repeated based on the medication being used and the duration of therapy prior to the missed dose, as outlined below.

Drug 0-2 weeks after initiation 3-4 weeks after initiation > than 4 weeks after initiation
Fingolimod FDO if missed 1 day of treatment FDO if missed > 7 days FDO if missed > 14 days
Siponimod Reinitiate titration per genotype indicated dosing if dose missed for > 24 hours during initiation Reinitiate titration per genotype indicated dosing if 4 or more consecutive daily doses are missed
Ozanimod Reinitiate titration regimen if 1 dose missed Continue 0.92 mg daily if dose missed
Ponesimod Reinitiate titration if 4 consecutive doses are missed Reinitiate titration if 4 or more consecutive daily doses are missed

Long-term laboratory monitoring consists of CBC with differential and CMP at 3 and 6 months after treatment initiation, after which liver function tests (LFTs) and CBC with differential are checked every 6 months while treatment is continued. Approximately a 30-45% reduction in ALC from baseline is expected following treatment initiation (depending on medication). ALC suppression has not been associated with development of PML in patients treated with S1Pr modulators. For patients with ALC <200/µL, repeat CBCs should be performed monthly. When concurrent leukopenia is present or recurrent infections have occurred, alternative therapy should be considered. We recommend discontinuation of S1Pr modulator therapy if alanine transaminase (ALT) levels exceed three times the upper limit of normal, and close interval monitoring for patients developing transaminitis, hyperbilirubinemia, or signs or symptoms of hepatic dysfunction.

Blood pressure monitoring at routine clinical visits is recommended. Patients receiving fingolimod and siponimod should have a repeat ophthalmologic examination or OCT at 3 months following treatment initiation to monitor for development of macular edema. Only patients at high risk for macular edema (patients with diabetes or uveitis) receiving ponesimod or ozanimod require repeat OCTs at 6 months after treatment initiation. All patients receiving S1Pr modulator therapy should remain up to date on routine cancer screening, including Papanicolaou (Pap) testing per routine guidelines, and yearly full-body dermatologic examinations performed by a dermatologist (self-examination of skin every 3 months) to monitor for development of skin cancer.

If treatment is discontinued, patients should be monitored closely for signs and symptoms of rebound disease activity, both clinically and radiologically (with repeat MRI as needed for worsening disability). Rebound disease activity may occur within 2-4 months after discontinuation of S1Pr modulators, particularly in those with highly active MS prior to initiation. It is recommended that when switching therapies, the gap between cessation of the S1Pr modulator and the new therapy be as short as possible, and that patients are informed of the risks associated with discontinuation.


Pretreatment testing for natalizumab includes CBC with differential, CMP, and JCV serology with index. Patients should also have a dermatologic evaluation prior to initiation of treatment to screen for any signs of skin cancer. All patients receiving natalizumab must be enrolled in the TOUCH prescribing program. Patients should be monitored during all infusions for evidence of hypersensitivity reaction, and for at least one hour following infusion for the first 12 doses.

Routine laboratory monitoring for patients on maintenance therapy consists of a CBC with differential and CMP at months 3 and 6, and then every 6 months thereafter. Natalizumab is typically not initiated in patients that are JCV positive. If a patient becomes JCV positive while on treatment, we consider an alternative therapy. JCV serology with index should be monitored every 3 months in patients receiving natalizumab that are JCV negative. If a patient is JCV seropositive with a low-titer and there is a clinical reason to continue natalizumab, repeat JCV serology can be considered every 3 months to monitor for conversion to high-titer positivity. JCV serology is typically not monitored or re-checked in patients that are high-titer positive. Neutralizing antibodies should be checked at 6 months after treatment start, and for any evidence of ongoing disease activity (either clinically or radiologically). Presence of neutralizing antibodies warrants a change in therapy. Interval MRIs should be performed every 6 months while patients remain JCV negative on active treatment. Patients who are JCV positive should receive MRIs every 3 months to monitor for changes suggestive of PML.

Patients should be seen clinically at least once every 6 months, at which time detailed history and neurological examination should be performed to evaluate for potential signs and symptoms of PML (see Mellen Center approach titled “PML Diagnosis & Management”).

B-Cell Depleting Therapies: ocrelizumab17, rituximab18, ofatumumab19, ublituximab-xiiy20

Pretreatment testing for B-cell depleting therapies includes CBC with differential, CMP, TB screen, remote Hepatitis serology panel, and baseline serum IgG and IgM levels. All necessary vaccinations should be administered at least four weeks prior to the first scheduled infusion.

Routine laboratory monitoring consists of CBC, CD19 count, IgG and IgM levels, and serum HCG in women of childbearing age within the two weeks prior to each maintenance infusion for ocrelizumab and rituximab. CBC, CD19 count, and IgG and IgM levels are obtained every six months for patients treated with ofatumumab. The frequency of which immunoglobulin levels are checked may be adjusted on an individual basis, based on the rate of infection occurrence, as the clinical relevance of changes in immunoglobulin levels is unknown. Lower baseline IgG levels have been associated with subsequent hypogammaglobulinemia (IgG < 700 mg/dL), which is often persistent while B-cell depleting therapy is continued (though there does not appear to be a cumulative effect).21 In one recent study, rituximab-treated patients (all indications) with recurrent infections treated with immunoglobulin replacement had reduced rates of non-severe infections compared to those who were untreated, though rates of serious infections (requiring intravenous antibiotic treatment or hospitalization) did not differ between groups. 22 At the Mellen Center, our practice is to consider referring patients on B-cell depleting therapy with persistent hypogammaglobulinemia and recurrent infections, or patients who are at high risk for infections, to Immunology for consideration of replacement therapy. Alternative therapy may also be considered in these cases. See Figure 1 for additional information.


Pretreatment testing includes CBC with differential, CMP, TSH, VZV serology, remote Hepatitis serology panel, TB screen, and serum pregnancy test (in women of childbearing age). Patients should also have completed all age-appropriate cancer screening, including baseline dermatologic (through dermatology) and gynecologic examinations, prior to starting treatment. A normal lymphocyte count and serum creatinine clearance > 60 mL/min is required prior to treatment initiation. All necessary vaccinations should be completed prior to the first dose of treatment.

Routine and post-treatment laboratory monitoring consists of monthly CBC with differential through 24 months after the last administered dose, CMP every 6 months, and maintenance of regular malignancy screening at standard intervals. There is an increased risk for dermatomal herpes zoster outbreaks when ALC levels fall below 500/µL, and anti-viral prophylaxis is recommended for counts < 200/µL. If the ALC remains below 500/µL, active monitoring should continue until there is recovery to a level > 800/µL. If the ALC has not recovered prior to the second cycle of treatment (year two), administration should be delayed by up to six months. Should the ALC remain depleted by six months, further treatment should not be administered. A repeat serum pregnancy test should also be repeated prior to the second cycle of treatment. As part of routine clinical monitoring both men and women treated with cladribine should be reminded to continue contraception for at least 6 months after the last dose.


Pretreatment testing includes CBC with differential, CMP, TSH, VZV serology, remote Hepatitis serology panel, serum pregnancy test (in women of childbearing age), urinalysis (with cell counts), TB screen. Patients must also complete all age-appropriate cancer screenings including a full-body dermatologic examination (through dermatology) and gynecologic examination (where appropriate) prior to initiation of therapy. Initiation of a listeria-free diet prior to treatment may also be considered to mitigate the risk of listeria meningitis.

Long-term / post-treatment laboratory monitoring consists of monthly CBC with differential and urinalysis through month 48 after the last administered dose. TSH levels should be monitored every 3 months through 48 months after the last administered dose. Prophylaxis for herpes zoster is recommended starting from day 1 of treatment, through two months after treatment initiation or until the CD4 count reaches > 200.

Patients should be monitored for development of recurrent and/or severe infections (including listeria meningitis and PML), vascular complications (including stroke and acute cardiac events), signs/symptoms of secondary autoimmunity (including thyroid disease, hepatitis, anti-glomerular basement membrane disease, cytopenias, and autoimmune encephalitis), acute acalculous cholecystitis, hemophagocytic lymphohistiocytosis, and other rare and life-threatening conditions. It is imperative that prescribers be aware of the many potential complications of this treatment (see Table 1). All patients should remain up to date on all age-appropriate cancer screenings with yearly dermatologic and gynecologic examinations. Clinical monitoring typically consists of visits every 3 months to evaluate for complications of therapy. Additional details may be found in the Mellen Center approach titled “Lemtrada (alemtuzumab)”.


  1. Biogen Avonex (interferon beta-1a). 2021.
  2. EMD Serono, Inc. Rebif (interferon beta-1a).
  3. Bayer Pharmaceuticals Co. Betaseron (interferon beta-1b). 2021.
  4. Biogen Plegridy (peginterferon beta-1a). 2014.
  5. Teva Pharmaceuticals Industries Ltd. Copaxone (glatiramer acetate). 2020.
  6. Novartis Pharmaceuticals Corp. Glatopa (glatiramer acetate). 2018.
  7. Biogen Tecfidera (dimethyl fumarate). 2013.
  8. Banner Life Sciences Bafiertam (monomethyl fumarate). 2021.
  9. Biogen Vumerity (diroximel fumarate). 2021.
  10. Genzyme Corp. Aubagio (teriflunomide). 2012.
  11. Genzyme Corp. (2021). For RMS patients on Aubagio, elimination can be accelerated: A step-by-step guide to the accelerated elimination procedure for your Aubagio (teriflunomide)patients and your office.
  12. Novartis Pharmaceuticals Corp. Gilenya (fingolimod). 2010.
  13. Novartis Pharmaceuticals Corp. Mayzent (siponimod). 2021.
  14. Bristol Meyers Squibb Zeposia (ozanimod). 2021.
  15. Janssen Pharmaceuticals Ponvory (ponesimod). 2021.
  16. Biogen Tysabri (natalizumab). 2020.
  17. Genentech Ocrevus (ocrelizumab). 2021.
  18. Pfizer Ruxience (rituximab-pvrr). 2020.
  19. Novartis Pharmaceuticals Corp. Kesimpta (ofatumumab). 2020.
  20. TG Therapeutics Briumvi (ublituximab-xiiy). 2022.
  21. Boleto G, Avouac J, Wipff J, Forien M, Dougados M, Roux C, Kahan A, Dieude P, Allanore Y. Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: A 12-year longitudinal multi-center study. Semin Arthritis Rheum. 2018 Oct;48(2):149-154. doi: 10.1016/j.semarthrit.2018.02.010. Epub 2018 Feb 21. PMID: 29548542.
  22. Tieu J, Smith RM, Gopaluni S, Kumararatne DS, McClure M, Manson A, Houghton S, Jayne DRW. Rituximab Associated Hypogammaglobulinemia in Autoimmune Disease. Front Immunol. 2021 May 12;12:671503. doi: 10.3389/fimmu.2021.671503. PMID: 34054846; PMCID: PMC8149951.
  23. EMD Serono Inc. Mavenclad (Cladribine). 2019.
  24. Genzyme Corp. Lemtrada (alemtuzumab). 2001.