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© 2014 Direct One Communications, Inc. All rights reserved. 1
Infectious Complications of Multiple Sclerosis Therapies
Carrie M. Hersh, DO
Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio
A REPORT FROM THE 28TH ANNUAL MEETING OF THE CONSORTIUM OF MULTIPLE SCLEROSIS CENTERS AND THE 19TH ANNUAL MEETING OF THE AMERICAS COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS
© 2014 Direct One Communications, Inc. All rights reserved. 2
Growing Field of Therapies for MS
There are currently 10 approved disease-modifying therapies (DMTs) for relapsing forms of MS.
Several more DMTs are in experimental phases or in approval stages in the United States.» Ocrelizumab
» Ofatumumab
» Ocaratuzumab
» Daclizumab
» Alemtuzumab
Newer agents have various immune-mediated effects that may increase the risk of opportunistic infections.
© 2014 Direct One Communications, Inc. All rights reserved. 3
Interferon b-1a and b-1b
Mechanism of action:» Increase HLA class 1 and reduce HLA class 2
antigens
» Increase NK cell activity
» Increase tumor suppressor lymphocytes
» Increase antibody-dependent cytotoxicity
Possible antiviral properties:» Decrease expression of human herpesvirus 6 and
replication of herpes simplex virus 1 replication in vivo
» Potential efficacy in hepatitis C and varicella zoster virus infections
May cause lymphopenia and neutropenia (rarely of clinical significance)Carr DJ et al. J Neuroimmunol. 2003;141:40
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Glatiramer Acetate
Mechanism of action:» Shifts pro-inflammatory T-helper 1 (Th1)
lymphocytes to regulatory Th2 lymphocytes
» Blocks tumor necrosis factor-alpha (TNF-) from interferon- and endotoxin-stimulated macrophages
There are no reports to suggest that glatiramer acetate is linked to an increased risk of infection when used in the treatment of MS.
© 2014 Direct One Communications, Inc. All rights reserved. 5
Mitoxantrone Mechanism of action:
» Disrupts DNA synthesis and repair by intercalation between DNA base pairs
» Causes leukopenia with a reduction in the number of B and T lymphocytes and macrophages
Rarely used in treating MS owing to potential long-term serious complications, including cardiac injury and lymphoproliferative disorders
Increased risk of infections with severe leukopenia:» Urinary tract infections» Pneumonia» Varicella zoster virus infections» Herpes simplex virus infections (0.6% of treated
patients)
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Natalizumab Mechanism of action:
» 41 and 47 integrin antagonist
» Blocks binding to VCAM-1 prevents transmigration of lymphocytes into the CNS potentially impairs immune surveillance for CNS infections
Progressive multifocal leukoencephalopathy (PML):» Association with natalizumab is well documented
» As of May 2014, approximately 464 natalizumab-treated patients developed PML
» Risk factors that increase the risk of PML:• Positive JCV antibody status (further defined by index value)• Treatment duration (risk increases > 24 months of therapy)• Prior immunosuppression (mitoxantrone, azathioprine,
methotrexate, cyclophosphamide, mycophenolate mofetil)Biogen Idec (https://medinfo.biogenidec.com); Plavina T et al. Eur Neurol Soc 2013, Abstract O228
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Natalizumab:
Risk of PML
Global natalizumab PML risk estimates (May 2014):
Biogen Idec (https://medinfo.biogenidec.com)
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Natalizumab:
Relation to JCV Antibody Index
Risk of PML based upon JCV antibody index
Plavina T et al. Eur Neurol Soc 2013, Abstract O228
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Natalizumab:
Treatment of PML
Standard of care for natalizumab-related PML is rapid withdrawal of the drug» May precipitate immune reconstitution
inflammatory syndrome (IRIS), a potentially serious complication with severe morbidity
Observational studies show potential efficacy against PML with:» Mirtazapine
» Mefloquine
» Cidofovir
» Risperidone
Cettomai D, McArthur JC. Arch Neurol. 2000;66:255; Lanzafame M et al. Infez Med. 2009;17:35; Marra CM et al. AIDS. 2002;16:1791; Gasnault J et al. J Neurovirol. 2001;7:375; Focosi D et al. Antiviral Res. 2007;74:156
© 2014 Direct One Communications, Inc. All rights reserved. 10
Natalizumab:
Herpesvirus Infections
Twenty confirmed cases of herpes simplex and varicella zoster virus infections in the brain and spinal cord of MS patients treated with natalizumab» Patients received a median of 21 monthly infusions
» Seven patients had no prior immunosuppression
» Two fatal cases
» Four patients had residual neurological sequelae, including neuropsychiatric impairments
Overall good response with early detection and treatment with antiviral therapy: acyclovir, valacyclovir, or famciclovir
Fine AJ et al. Clin Infect Dis. 2013;57, 849
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Natalizumab:
Other Infections
CNS toxoplasmosis» One case of encephalitis
» One case of ocular infection
Cryptosporidium gastroenteritis CNS cytomegalovirus infection Cryptococcal meningitis in a patient
previously treated with mitoxantrone
Fine AJ et al. Clin Infect Dis. 2013;57, 849
© 2014 Direct One Communications, Inc. All rights reserved. 12
Fingolimod
Mechanism of action:» Sphingosine-1-phosphate agonist
» Reversible sequestration of lymphocytes in lymph nodes
• Lymphocyte counts return to normal within 2 months of fingolimod discontinuation
» Effector memory T-lymphocytes are spared (important for immune surveillance)
Phase 2 and 3 studies show similar rates of infectious complications in fingolimod and control groups» Modestly higher risk of herpesvirus infections in
fingolimod-treated patients (0.5 mg, 6.3; 1.25 mg, 5.9) than in control groups (placebo, 5.7; interferon b-1a, 3.0)
Cohen JA et al. ECTRIMS 2012, Abstract P983
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Fingolimod:
Other Infections
Two reported cases of PML:» One case in a patient previously exposed to
natalizumab
» One case with suspicious brainstem lesions suggestive of PML, later reclassified as neuromyelitis optica
Overall, lymphopenia is not a compelling risk factor for infections
Novartis (http://www.novartis.com/downloads/newsroom/product-related-info-center/statement-PML.pdf)
© 2014 Direct One Communications, Inc. All rights reserved. 14
Teriflunomide
Mechanism of action:» Inhibits de novo synthesis of pyrimidine nucleotides
by inhibiting dihydroorotate dehydrogenase
» Inhibits T-lymphocyte activation and cytokine production
» Promotes cytostatic effects on proliferating B and T lymphocytes
Pooled data from three phase 2 and phase 3 studies (TOWER, TEMSO, and TENERE) show no increase in infectious rates compared with placebo or deaths from opportunistic infections.
O'Connor P et al. N Engl J Med. 2011;365:1293; Confavreux C et al. Lancet Neurol. 2014;13:247; Vermersch P et al. Mult Scler. 2014;20:705
© 2014 Direct One Communications, Inc. All rights reserved. 15
Dimethyl Fumarate
Mechanism of action:» Activates nuclear factor (erythroid-derived 2)-like 2
(Nrf2)
» Inhibits expression of adhesion molecules and pro-inflammatory cytokines
» Decreases circulating T lymphocytes
» Promotes shift from T-helper 1 to T-helper 2 lymphocytes
Phase 2 and 3 studies show no dimethyl fumarate-related increases in opportunistic infections
Two reported cases of PML in patients who used dimethyl fumarate for psoriasis for 3–5 years» One had no prior exposure to immunosuppressive
agents
van Oosten BW et al. N Engl J Med. 2013;368:1658; Ermis U et al. N Engl J Med. 2013;368:1657
© 2014 Direct One Communications, Inc. All rights reserved. 16
Rituximab
Mechanism of action:» Anti-CD20 monoclonal antibody
» Induces rapid depletion of B lymphocytes for 4–12 months
» Naïve B cells return to normal before memory B cells
Rituximab therapy associated with: » Increased risk of PML, reactivation of hepatitis B,
and possibly Pneumocystis carinii pneumonia in patients receiving rituximab for lymphoma and rheumatoid arthritis.
» Approximately 80 rituximab-related cases of PML have been reported in patients with chronic lymphocytic leukemia and other lymphoproliferative disorders.
» Patients with autoimmune disorders also developed PML.
Nived O et al. Lupus. 2008;17:1036; Carson KR et al. Blood. 2009;113:4834
© 2014 Direct One Communications, Inc. All rights reserved. 17
Alemtuzumab
Mechanism of action:» Anti-CD52 humanized monoclonal antibody
» Causes rapid depletion of circulating B and T lymphocytes
» Repopulation leads to a distinctive lymphocyte profile
Increased rate of mild to moderate infections in patients receiving alemtuzumab (16%) vs 2%–4% in control patients receiving interferon b-1a» Infections consisted primarily of nasopharyngitis,
urinary tract infections, upper respiratory tract infections, and herpesvirus infections.
Serious opportunistic infections in the setting of lymphopenia were absent in all clinical trials.
Coles A, Group CS. N Engl J Med. 2008;359:1786; Cohen JA et al. Lancet. 2012;380:1819; Coles AJ et al. Lancet. 2012;380:1829
© 2014 Direct One Communications, Inc. All rights reserved. 18
Vaccination of Patients with MS
Several small cohort studies have shown increased relapse rates in MS patients during “at risk” periods (2 weeks before and 5 weeks after infectious event).» Adenovirus and rhinovirus were implicated in
particular.
» Infections were not well defined and usually self-diagnosed.
Institute of Medicine (2012) report:» No convincing evidence that any of eight common
vaccines caused MS or induced relapses in MS patients
Similar findings have been made in other reviews and one large case-crossover study.
Sibley WA et al. Lancet. 1985;1:1313; Panitch HS. Ann Neurol. 1994;36:S25; Rutschmann OT et al. Neurology. 2002;59:1837; Stratton K et al, eds. Adverse Effects of Vaccines: Evidence and Causality; 2012; Loebermann M et al. Nat Rev Neurol. 2012;8:143; Confavreux C et al. N Engl J Med. 2001;44:319
© 2014 Direct One Communications, Inc. All rights reserved. 19
Vaccine Recommendations
Inactivated vaccines are generally considered safe in patients with MS, even during treatment with DMTs.
The safety of live attenuated vaccines is less certain.
American Academy of Neurology’s MS Council for Clinical Practice Guidelines recommendations:» MS patients should not be vaccinated during or
immediately following a clinical relapse, typically 4–6 weeks from the onset of a relapse.
» Recommended vaccines: seasonal killed influenza vaccine, hepatitis B virus, pneumococcal vaccine, and tetanus, as well as varicella vaccine prior to fingolimod therapy in patients who were not previously exposed to varicella virus
Rutschmann OT et al. Neurology. 2002;59:1837
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Summary
Early recognition and treatment of MS are key in minimizing neurologic morbidity.
Natalizumab-related PML remains the infectious complication of greatest concern.
IRIS is a common, potentially serious complication of treating PML.
Herpesvirus infections have been implicated in MS patients receiving certain DMTs (notably, natalizumab, fingolimod, and alemtuzumab)
While inactivated vaccines are generally considered safe, the safety of live attenuated vaccines in MS patients receiving DMTs is less certain.