INTRODUCTION
Significant developments within Immunology over the last decades have led to marked
improvement in diagnosis and management of autoimmune disorders. A close relationship
between Neurology and Immunology has been demonstrated by the large number of neurological
disorders for which the pathophysiological explanation relates to immune-mediated
mechanisms. Discoveries of new autoantibodies and new therapies have been increasing.
Considering all the developments at the interface of Neurology and Immunology, Autoimmune
Neurology has been emerging as a new subspecialty[1]. In order to improve knowledge of and care for patients with autoimmune and demyelinating
disorders, there is a large need for updates on management of these disorders. In
line with this, drug management of autoimmune disorders requires understanding of
accurate drug dosing, infusion schedules and the most suitable infection screening
and follow-up.
We searched the PubMed and Scientific Electronic Library Online (SciELO) databases
for published studies in Portuguese and English over the period 1990-2020. Through
the search process, articles that described drug pharmacology, administration schemes,
adverse effects and other safety issues were included. Articles and guidelines describing
the major points relating to opportunistic infections and vaccination in patients
under immunosuppression or immunomodulation were also included. The aim of this review
of the literature was to provide a practical approach and guidance for general neurologists
with regard to drug management for patients with different forms of autoimmune disorders
that affect the nervous system.
IMMUNOSUPPRESSIVE AND IMMUNOMODULATORY DRUGS
Several types of immunosuppressive drugs are commonly used for patients with immune-mediated
neurological disorders, and the most commonly used types within daily practice are
discussed in the following topics and are summarized in [Table 1].
Table 1
Main immunosuppressive and immunomodulatory drugs used in Neurology.
|
Drug
|
Dose
|
Special issues
|
Interactions
|
Follow-up
|
Pregnancy and breastfeeding
|
|
Azathioprine (AZA)
|
Initial: 50 mg/day Dose increase: 25-50 mg/week or two weeks Aimed dose: 2-3 mg/kg/day
|
Extremes of weight, old age, hepatic insufficiency and renal insufficiency give rise
to higher risk of toxicity Low levels of TPMT: increased risk of myelosuppression
|
Xanthine oxidase inhibitors increases toxicity (e.g. allopurinol) ACEi increases the
chance of leukopenia AZA reduces warfarin effect
|
CBC, Cr, AST, ALT on starting and weekly after dose changes, until stable dose is
reached; and then every 12 weeks thereafter
|
Can continue to be given during pregnancy but should not be started during it. Safe
in breastfeeding.
|
|
Methotrexate (MTX)
|
Initial: 7.5-15 mg/day Dose increase: 5-10 mg per 2 weeks or 4 weeks Aimed dose: 20-25
mg/day
|
Supplementation of folic acid 5 mg one day after MTX administration
|
Other drugs that deplete folate (e.g. sulfamethoxazole-trimethoprim) increase myelosuppression risk
|
CBC, Cr, AST, ALT on starting and weekly after dose changes, until stable dose is
reached; and then every 12 weeks thereafter
|
Contraindicated during pregnancy and lactation
|
|
Mycophenolate mofetil (MMF)
|
Initial: 500 mg daily for several days Target dose: 1.5 and 3 grams divided twice
daily
|
Do not exceed 2 grams daily if GFR < 25 ml/min
|
Proton pump inhibitors can decrease MMF absorption. Rifampin decrease MMF serum concentration
and acyclovir can increase it. MMF may decrease serum concentrations of hormonal contraceptives
(pills, patches and vaginal rings)
|
Prior to MMF therapy: CBC, liver function tests, Cr, urinalysis, serological tests
for HBV and HCV, screening for latent tuberculosis (TST or IGRA). New CBC 1-2 weeks
after the start of therapy and if no evidence of bone marrow suppression, check every
6-8 weeks
|
Contraindicated during pregnancy and lactation
|
|
Cyclosporin
|
Initial dose: 2.5 mg/kg every 12 hours Adjustment of dose according to serum level,
to achieve 100-150 mcg/liter
|
Increased risk of lymphoproliferative disorders
|
Selective serotonin reuptake inhibitors, statins, azole antifungals, non-dihydropyridine
calcium channel blockers and angiotensin receptor blockers raise cyclosporin level
Rifampicin, carbamazepine, phenytoin and phenobarbital decrease cyclosporin level
|
Serum cyclosporin electrolytes, Cr, AST, ALT, coagulation tests, hemolysis biomarkers
Annual dermatoscopic evaluation
|
This should be given during pregnancy if the benefits outweigh the risks Breastfeeding
is contraindicated
|
|
Cyclophosphamide (CYP)
|
Initial: 500-750 mg/m2 every 4 weeks Dose adjustment: According to leukocyte nadir (7th-14th day of infusion). Less than 3500 leukocytes or less than 1500 neutrophils reduces
the next dose by 20-25%. If leukocytes are higher than 4000, consider an increase
of 20-25% at the next dose.
|
Attention regarding hydration on the day of the infusion. Consider mesna in children
and patients with cardiopathy or nephropathy. Higher doses increase chances of cancer
(leukemia, bladder and skin cancer). Male and female infertility (risk increases with
an accumulated dose higher than 10 g). Dose adjusted with GFR < 10 ml/min.
|
Ondansetron, clopidogrel, paroxetine and sertraline could reduce the CYP effect. Phenytoin,
carbamazepine and rifampicin could increase the toxicity.
|
CBC, Cr, AST, ALT and urinalysis monthly (7th-14th day after the infusion)
|
Contraindicated during pregnancy and lactation
|
|
Infliximab
|
IV 3-7 mg/kg at 0, 2 and 6 weeks, with maintenance infusions every 4 to 8 weeks.
|
In heart failure, individualize risk and benefit: NYHA Class I/II no adjustment necessary,
monitor closely; NYHA Class III or IV: ≤ 5 mg/kg. No renal adjustment. If hepatotoxicity
during treatment (jaundice and/or increase in liver enzymes (≥ 5 times ULN), discontinue
treatment. Consider antihistamines, acetaminophen and/or corticosteroids to prevent
infusion-related reactions. Caution in patients with history of seizures.
|
Enhances the risk of T-cell non-Hodgkin’s lymphoma and increases serum concentration
of active metabolite when used with azathioprine.
|
Active and latent TB screening prior and during therapy; HBV screening prior to initiating
(all) and during and for several months after therapy (HBV carriers); AST, ALT. Attention
for signs and symptoms of malignancy (hepatosplenomegaly, persistent fever, weight
loss)
|
Live vaccines should be avoided for the first 6 months of life if the exposure occurs
after the 1st trimester of pregnancy. Compatible with breastfeeding but should be discussed (potential
transfer into breast milk 2-3 days after dose).
|
|
Adalimumab
|
40 mg every other week subcutaneously
|
No dosage adjustments for renal or hepatic impairment. No dose particularity for geriatric
patients. No contraindications reported.
|
Concurrent use with azathioprine, methotrexate and prednisone increases risk of serious
infection.
|
Active and latent TB screening prior to and during therapy; HBV screening prior to
initiating (all) and during and for several months after therapy (HBV carriers); AST,
ALT. Attention for signs and symptoms of malignancy (hepatosplenomegaly, persistent
fever, weight loss)
|
Live vaccines should be avoided for the first 6 months of life if the exposure occurs
after the 1st trimester of pregnancy. Compatible with breastfeeding but should be discussed (potential
transfer into breast milk 2-3 days after dose).
|
|
Rituximab
|
375 m2/week for 4 consecutive weeks 1000 mg on day 1 and day 15 Premedication with 100 mg
of methylprednisolone is recommended before every infusion
|
Consider Ig reposition if the patient presents with recurrent infections and IgG levels
lower than 6 g/L.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, CD19+ assays (4-6 weeks), IgG, IgA and IgG levels (at beginning and if recurrent
infections occur) Active and latent TB screening prior and during therapy; HBV screening
prior to initiating; Malignancy screening.
|
Contraindicated during pregnancy. Compatible with breastfeeding but should be discussed
(potential transfer into breast milk 2-3 days after dose).
|
|
Ocrelizumab
|
300 mg, IV, on days 1 and 15. 600 mg, IV, every 6 months at the following doses. Premedication
with 100 mg of methylprednisolone is recommended before every infusion.
|
High incidence of herpes virus infections.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, CD19+ assays, IgG, IgA and IgG levels (if recurrent infections) Malignancy screening.
|
Contraindicated during pregnancy and lactation
|
|
Ofatumumab
|
20 mg, SC, on days 1, 7 and 14, and every 4 weeks after loading doses.
|
Injection-site reactions
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, CD19+ assays, IgG, IgA and IgG levels (if recurrent infections) Malignancy screening.
|
Contraindicated during pregnancy and lactation
|
|
Alemtuzumab
|
12 mg, IV, 5 days in year 1. 12 mg IV, 3 days in years 2, 3 and 4. The infusion has
to be done for 4 hours to prevent infusion-associated reactions, combined with antipyretics,
antihistamines and corticosteroids prior to the infusion.
|
Herpes zoster prophylaxis. Baseline thyroid hormones, platelets, creatinine levels
and urine analysis.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, TSH, T4, Cr, urinalysis. Every 3 months and 48 months after the last dose, testing
for autoantibodies (anti-GBM, anti-thyroperoxidase, thyrotropin receptor antibodies)
must be done.
|
Contraindicated during pregnancy and lactation
|
|
Natalizumab
|
300 mg, IV, every 4 weeks for 24 weeks, or longer periods in extended interval doses.
|
PML in JCV-positive patients.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC. JCV every 6 months
|
This should be given during pregnancy if the benefits outweigh the risks Breastfeeding
is contraindicated
|
|
Cladribine
|
3.5 mg/kg, orally, via 10 mg tablets, four to five days in weeks 1 and 5 for two subsequent
years. Maximal dose: 100 mg.
|
Total blood count, herpes zoster serology, tuberculosis screening. Vaccines should
be updated.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC every 6 months
|
Contraindicated during pregnancy and lactation
|
|
Dimethyl fumarate
|
120 mg orally, twice a day, after 7 days start a maintenance dose of 240 mg orally
twice a day.
|
Administered with food for TGI effects. Aspirin should be taken if flushing.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, AST, ALT, bilirubin levels, urine analysis.
|
Contraindicated during pregnancy and lactation
|
|
Fingolimod
|
0.5 mg, orally, daily
|
The first dose must be taken in a hospital facility due to cardiological risk.
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, AST, ALT Annual dermatological and ophthalmological evaluation
|
Contraindicated during pregnancy and lactation
|
|
Teriflunomide
|
14 mg, orally, daily.
|
Hair thinning
|
Anti-neoplastic, immunomodulatory and immunosuppressive drugs.
|
CBC, ALT, AST
|
Contraindicated during pregnancy and lactation
|
|
Interferon β
|
Interferon β 1a, 22 and 44 mcg, SC, 3 times a week
|
Association with depression.
|
No interactions
|
CBC, AST, ALT
|
No contraindications
|
|
Interferon β 1a, 30 mcg, IM, weekly
|
|
Interferon β 1b, 300 mcg, SC, every other day
|
|
Pegylated Interferon β 1a, 125 mcg, SC, every 14 days
|
|
Glatiramer acetate
|
20 mg, SC, daily or 40 mg, SC, 3 times a week.
|
Short-term infusion reaction (palpitation, flushing and chest tightness)
|
No interactions
|
CBC
|
No contraindications
|
|
PLEX
|
3-7 sessions, every other day
|
Hypocalcemia risk during sessions
|
No interactions
|
Blood pressure, calcium, coagulation tests.
|
No contraindications
|
|
Intravenous immunoglobulin (IVIg)
|
Initial dose: Up to 2 g/kg per cycle (most cases 0.4 g/kg per day for 5 days Infusion:
starting at 0.01 mL/kg/min; in situation of clinical stability, increase it every
15-30 minutes up to 0.08 mL/kg/min *Mean of at least 1 hour per flask (5 g/flask)
is recommended in the presentation widely available from SUS
|
IgA level dosage is recommended before start Attention to increased risk of thromboembolic
events
|
No interactions
|
No need for routine examinations
|
Can be used safely during pregnancy and breastfeeding if the benefits surpass the
risks.
|
|
Subcutaneous immunoglobulin
|
Dosage: Convert current monthly intravenous immunoglobulin dosage to weekly subcutaneous
infusions of 1-2 mL/kg per week (total dosage is the same for the period: total in
grams multiplied by 5 = volume in mL); infusion rate: 15-20 mL/hour/infusion site
(high infusion rates during further treatment stages: up to 25-50 mL/hour/infusion
site).
|
IgA level assay is recommended before start Attention to increased risk of thromboembolic
events
|
No interactions
|
No need for routine examinations
|
Not assigned by FDA yet
|
ACEi: angiotensin-converting enzyme inhibitors; TPMT: thiopurine methyltransferase;
CBC: complete blood count; AST: aspartate transaminase; ALT: alanine transaminase;
Cr: serum creatinine; GFR: glomerular filtration rate; HBV: hepatitis B virus; HCV:
hepatitis C virus; TST: tuberculin skin test; IGRA: interferon gamma release assay;
NYHA: New York Heart Association; TB: tuberculosis; ULN: upper limit of normal; TSH:
thyroid-stimulating hormone; T4: thyroxine; GBM: glomerular basement membrane; PML:
progressive multifocal leukoencephalopathy; JCV: John Cunningham virus.
Corticosteroids
Corticosteroids are synthetic hormones that mimic the action of endogenous cortisone
and modify metabolism and immune function through protein expression at DNA level.
Also, corticosteroids reduce inflammatory responses and decrease lymphocyte, eosinophil
and basophil counts[2].
Prednisone is four times as potent as hydrocortisone. The usual dose of prednisone
for immunosuppressive effects is 30 mg per day[3]. Other corticosteroids include dexamethasone, methylprednisolone and deflazacort.
[Table 2] summarizes the relative activity and length of action of different corticosteroids.
Table 2
Relative activity and length of action of the corticosteroids most used in Neurology.
|
|
Dosage equivalency (mg)
|
Relative activity (hydrocortisone)
|
Relative mineralocorticoid activity
|
Duration of activity (h)
|
Neurological conditions
|
|
Prednisone
|
5
|
4
|
0.3
|
12-36
|
MG, NMOSD and others
|
|
Prednisolone
|
5
|
4
|
0.3
|
12-36
|
Sarcoidosis, NMOSD and others
|
|
Methylprednisolone
|
4
|
5
|
0
|
12-36
|
MS, NMOSD and others
|
|
Deflazacort
|
7.5
|
3
|
Minimal
|
24
|
Duchenne dystrophy
|
|
Dexamethasone
|
0.75
|
30
|
0
|
36-72
|
CNS tumor edema
|
Corticosteroids are used for a variety of different neurological conditions, and not
only autoimmune disorders: inflammatory processes relating to infections (e.g., tuberculosis
or bacterial meningitis), primary refractory headaches (e.g., cluster headache), Duchenne
muscular dystrophy and autoimmune or autoinflammatory diseases (e.g. Behçet’s syndrome,
Still’s disease, sarcoidosis, multiple sclerosis relapses, neuromyelitis optica spectrum
disorder [NMOSD] relapses, acute disseminated encephalomyelitis [ADEM], etc.).
Side effects relating to use of corticosteroids are common, and include insomnia and
mood changes (euphoria); increased risk of sepsis; venous thromboembolism; bone fractures;
obesity; glucose intolerance; diabetes; myopathy; osteoporosis; peptic ulcer; skin
lesions; and infections[4],[5].
Pulse therapy is defined as treatment with doses higher than 250 mg of prednisone
or its equivalent[6]. Methylprednisolone is more widely used than prednisone for pulse therapy because
of its lower mineralocorticoid activity. Pulse therapy with dexamethasone has shown
similar results in patients with MS and optic neuritis[7]. The usual dose of methylprednisolone is 1 g administered as an infusion diluted
with 0.9% saline solution over 1-3 hours (to avoid hemodynamic instability) for 3
to 5 days. Before starting to administer pulse therapy, it is recommended that an
evaluation should be conducted through routine laboratory tests (glucose, urea, creatinine
and blood count), with prophylaxis for disseminated strongyloidiasis using antiparasitic
drugs (e.g. ivermectin at 200 mcg/kg). During drug infusion, vital sign monitoring
is essential. Long-term corticosteroid use requires gradual tapering to avoid hypothalamic-pituitary-adrenal
axis suppression. For short-term use (less than 14 to 21 days) (including pulse therapy
schemes), this tapering is not necessary[8].
An initial metabolic profile, including screening for diabetes, dyslipidemia and vitamin
D levels, should be assessed prior to starting administration of corticosteroid. [Table 3] shows the basic monitoring during treatment with corticosteroids.
Table 3
Monitoring routine for long-term corticosteroid use.
|
Side effects
|
Investigation
|
Periodicity
|
|
Systemic hypertension
|
Blood pressure
|
Every 6 months*
|
|
Diabetes
|
Blood glucose/ glycated hemoglobin
|
Before start*
|
|
Dyslipidemia and metabolic syndrome
|
Weight, height, BMI and lipids
|
Every 6 months*
|
|
Osteoporosis and fractures
|
BMD
|
Once a year * If stable, every two years
|
|
|
Spine X-ray
|
Once a year
|
|
Glaucoma and cataracts
|
Ophthalmological consultation
|
Once a year
|
*Those must be tested also before initiation of long-term use.
Corticosteroid-induced osteoporosis is usually multifactorial5. Assessment of bone mineral density (BMD) is required before treatment and within
one year. If BMD remains stable, this assessment can be repeated within 2-3 years[3]. Both calcium and vitamin D supplementation is recommended, in order to prevent
BMD reduction[9]. The Fracture Risk Assessment Tool (FRAX) is a tool for evaluating patients’ risk
of fractures and it can help in deciding when to start treatment with common bisphosphonates[10]. Hip pain needs to be assessed by means of x-rays and/or magnetic resonance imaging
(MRI) because of the risk of spontaneous osteonecrosis. Patients on high-dose GLC
should be evaluated for ophthalmological complications (e.g. glaucoma and cataracts)
after an interval of 6-12 months.
One practical approach for corticosteroid dosage reduction to prevent serious side
effects is to reduce the dose by 10-20% every 2-4 days. After reaching a dose of 5
mg of prednisone or equivalent, the adrenal axis should be tested (serum ACTH and
morning cortisol levels). If test results are normal, corticosteroids can be discontinued[11]. We recommend that patients with abnormal test results should be referred to an
endocrinologist for evaluation of signs and symptoms of adrenal insufficiency and
steroid withdrawal.
Azathioprine
Azathioprine belongs to the group of thiopurines. It undergoes metabolization to 6-mercaptopurine
(6-MP), a metabolite that has immunosuppressive effects and inhibits purine synthesis,
reduces leukocyte proliferation and impairs immune response[12].
The main indications of azathioprine for neurological disease treatment are myasthenia
gravis, NMOSD, primary central nervous system (CNS) vasculitis, immune-mediated myopathies,
neuro-Behçet’s disease (NBD) and chronic inflammatory demyelinating polyneuropathy
(CIDP).
Hematological toxicity and the risk of myelosuppression are primary concerns associated
with use of azathioprine, mostly related to low levels of thiopurine methyltransferase.
Minor blood cell changes, including mild lymphopenia and increased mean corpuscular
volume, may occur during treatment, but do not necessarily require drug discontinuation[13]. Other side effects include hepatotoxicity, nausea, vomiting and skin rash. Azathioprine
has been associated with a low risk of malignancies[13].
Methotrexate
Methotrexate (MTX) is a folic acid antagonist that inhibits purine and pyrimidine
synthesis, thus affecting DNA and RNA synthesis[14]. It disrupts inflammatory and neoplastic cell division, reduces the levels of some
cytokines (thereby leading to reactive oxygen species (ROS) accumulation in T-cells)
and inhibits inflammatory transcription factors[15].
MTX is widely used for managing several autoimmune disorders including sarcoidosis,
immune-mediated myopathies and granulomatosis with polyangiitis (GPA). Patients on
MTX may present incapacitating gastrointestinal side effects, mostly nausea and vomiting,
and switching from oral to subcutaneous MTX may increase tolerance[16]. Other side effects include hepatotoxicity, stomatitis, pulmonary fibrosis, neurotoxicity
(e.g., leukoencephalopathy), nodulosis, renal insufficiency and cytopenia[17]. Use of MTX has been associated with increased risk of lymphoproliferative disorders[18].
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is a drug with immunosuppressive properties that acts
in purine synthesis and has anti-proliferative effects on T- and B-lymphocytes, with
depletion of lymphocytic and monocytic cells and inhibition of interleukin production[19]. MMF is used in MG, NMOSD, autoimmune neuropathies and immune-mediated myopathies.
It is also effective for treating systemic lupus erythematosus (SLE), vasculitis,
rheumatoid arthritis and Takayasu arteritis[20].
The side effects of MMF are usually mild, mostly consisting of gastrointestinal complaints
(e.g. diarrhea, vomiting and mild abdominal pain), and mild lymphocytopenia can also
occur. MMF increases the risk of lymphoproliferative disorders, especially in patients
infected by Epstein-Barr virus[21],[22].
Cyclosporine (or cyclosporine A)
Cyclosporine reduces the cytosolic activity of calcineurin and proinflammatory cytokines
(mainly IL-2) produced by T-lymphocytes. It is a corticosteroid-sparing drug used
in management of inflammatory autoimmune neuromuscular disorders including generalized
MG Class II-IV, dermatomyositis and idiopathic inflammatory myopathies and autoimmune
neuropathies. It is usually reserved for refractory cases that have been treated with
other agents (e.g. methotrexate, mycophenolate and azathioprine).
The common side effects of cyclosporine include arterial hypertension, hyperlipidemia,
nephrotoxicity, hypomagnesemia, hyperkalemia and hypophosphatemia. Posterior reversible
encephalopathy syndrome (PRES) induced by cyclosporine is rare.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that interferes in DNA synthesis and disrupts
cell replication. Because of its effect, rapidly proliferating cells such as leukocytes
are more susceptible to cyclophosphamide[23].
Cyclophosphamide is used for treatment of neurological conditions including autoimmune
encephalitis, primary CNS vasculitis, immune-mediated myopathies, neuropsychiatric
SLE and neurological manifestations of systemic vasculitis.
There are three major safety concerns relating to this drug: hematological toxicity,
infertility and hemorrhagic cystitis[24]. Cyclophosphamide may cause neutropenia, leukopenia and bone marrow suppression
at high doses, generally occurring within 7 to 14 days of administration[23]. Female infertility and premature menopause are associated with cumulative doses
and advanced age[25]. Hemorrhagic cystitis may occur due to exposure of the bladder to acrolein, a metabolite
of cyclophosphamide[26]. Increased water ingestion and normotonic saline administration before and during
infusion can increase urinary dilution and reduce exposure to acrolein, thus preventing
occurrence of acrolein-induced hemorrhagic cystitis. Mesna can be used as an alternative
agent, as it metabolizes acrolein to a less toxic compound and protects against hemorrhagic
cystitis. Other side effects include alopecia, mucositis, nausea, vomiting, hyponatremia,
nephrotoxicity, cardiac toxicity and hepatotoxicity[24]. Cyclophosphamide increases the risk of neoplasia, especially bladder cancer, and
lymphoproliferative disorders[27].
Anti-tumor necrosis factor-
Tumor necrosis factor-α (TNF) is essential for macrophage and phagosome activation,
differentiation of monocytes into macrophages, neutrophil and macrophage recruitment
and granuloma formation and maintenance[28]. TNF inhibitors (anti-TNF) are used to manage inflammatory conditions (e.g. rheumatoid
arthritis, sarcoidosis and Behçet’s disease).
Injection site reactions (ISR) are common side effects associated with anti-TNF therapies.
They typically occur within the first month of treatment and last 3-5 days. Infusion
reactions to infliximab are classified as acute (those that occur within 24 hours
in 90% of infusions) or delayed (those that develop within 1-14 days of infusion),
and they can be IgE-mediated (anaphylactic) including hypotension, bronchospasm, wheezing
and urticaria or anaphylactoid (nonallergic)[29],[30]. Neutropenia and infectious complications, including bacterial infections (particularly
pneumonia), herpes zoster infection, tuberculosis and opportunistic infections, are
adverse effects of this drug. Reactivation of hepatitis B virus can occur in chronic
carriers. Although a causal relationship remains uncertain, this drug class should
not be given to patients with demyelination[31]. Other adverse effects include heart failure, sarcoid-like pulmonary disease or
fibrotic/interstitial pulmonary disease, hepatic involvement (acute liver failure,
hepatitis and cholestasis) and cutaneous involvement (psoriasiform eczema, eczema,
xerosis cutis, palmoplantar pustulosis and psoriasis)[32]
-
[34]. Rare cases of autoimmune disorders, such as lupus-like syndrome and positive antinuclear
antibody titers in patients who were negative at baseline, have been reported.
Anti-CD20
Rituximab, ocrelizumab and ofatumumab are monoclonal antibodies that selectively target
CD20, a cell surface antigen expressed in a broad range of B-cells. These drugs preferentially
bind to CD20 on the cell surface of B-cells, which consequently leads to cell death
through numerous mechanisms, including complement-dependent cytotoxicity, antibody-dependent
cellular cytotoxicity and antibody-dependent cellular phagocytosis[35].
Anti-CD20 therapies are used for managing several neurological disorders, including
MS, NMOSD, MG, immune-mediated myopathies, autoimmune encephalitis, CNS vasculitis
and sarcoidosis. They are associated with high infection rates, especially of herpes
virus infection, but most cases are mild. Patients on long-term anti-CD20 therapy
are at risk of hypogammaglobulinemia with resultant higher risk of recurrent infections.
They should be followed up with regular cancer screening examinations, and any suspicious
lesions must be further assessed to rule out malignancies[36].
Alemtuzumab
Alemtuzumab is a humanized monoclonal antibody that is specific to CD52, a lymphocytic
cell surface glycoprotein of unknown function. This drug causes profound depletion
of peripheral lymphocytes and leads to long-lasting changes in adaptive immune response,
and mild reduction of innate immune system cells (neutrophils and NK cells)[37]. It has been approved for treating patients with highly active MS.
Severe autoimmune-related adverse events have been reported from use of alemtuzumab.
The most relevant adverse effects are thyroid diseases (17% after three years of exposure),
immune thrombocytopenia (ITP) (2.3%) and nephropathies (0.2%)[38]. Before treatment, baseline assessments should be performed, including thyroid hormone
levels, platelet count, serum creatinine and urine analysis. A specialist should be
consulted for advice on managing immune-related adverse events[39].
Infections (commonly herpes simplex or zoster infection) may also occur. Prophylaxis
is necessary until normal lymphocyte counts have been restored[40].
Natalizumab
Natalizumab is a humanized antibody that binds to a specific cell adhesion molecule
called integrin. Integrins are expressed on the cell surface of all leukocytes, except
neutrophils. This drug binds to integrin a4ß1 and a4ß7 subunits and blocks leukocytes
from crossing the blood-brain barrier[41].
Natalizumab is approved for treatment of patients with highly active relapsing-remitting
MS (RRMS). Anti-JC virus (JCV) antibody serological status is used to determine treatment
duration. Treatment can be discontinued after 24 infusions; however, new data has
recently shown that treatment can be extended over 24 months with dosing intervals
of 6 weeks[42].
Progressive multifocal leukoencephalopathy (PML) is a major adverse event associated
with continuous natalizumab therapy. The risk factors for PML include the number of
infusions, anti-JCV status and index and prior use of immunosuppressants[43].
Patients should be tested for anti-JCV antibody status before treatment is started
and should be retested during treatment every 6 months to detect seroconversion or
index augmentation[41]. Nevertheless, regular 24-month treatment with natalizumab in patients testing positive
for anti-JCV antibodies appears to be safe[43].
Cladribine
Cladribine is an agent that causes profound lymphopenia due to cytotoxicity, particularly
in lymphocytes. It disrupts cellular metabolism, inhibits DNA synthesis and repair
and induces lymphocyte apoptosis[44]. Recently, an oral formulation of cladribine has been approved for treatment of
highly active relapsing MS in Europe, USA and Brazil[45].
Cladribine has a good overall safety profile but, as expected, severe lymphopenia
can occur[46]. However, lymphocyte counts tend to recover after discontinuation of treatment.
The malignancy rate in cladribine-treated patients is almost the same as the rate
in the overall population[46].
SPHINGOSINE 1-PHOSPHATE RECEPTOR MODULATORS
Fingolimod and siponimod are sphingosine-1-phosphate (S1P) receptor modulators that
acts as functional receptor antagonists. They inhibit the S1P1 receptor and block
lymphocyte migration from lymph nodes to peripheral blood and through endothelial
barriers such as the blood-brain barrier47. Fingolimod is used for treatment of RRMS.
S1P receptors are present in different organs. It is thus recommended that cardiac
and ophthalmological evaluations should be performed before treatment is started,
in order to rule out preexisting conditions that may increase the risk of cardiovascular
events and macular edema through continuous use of fingolimod[47].
Patients should be given the first dose of fingolimod in a hospital setting and should
be monitored for severe bradycardia and atrioventricular block over a six-hour period.
Monitoring of lymphocyte counts should be performed, as fingolimod can cause lymphopenia
and sometimes severe lymphopenia (≤ 200/μL). Fingolimod-treated patients are at higher
risk of herpes zoster infection and also other opportunistic infections such as TB
and cryptococcosis[48]. Gradual withdrawal of fingolimod over a four-week period, in order to prevent rapid
lymphocyte release and severe disease activation, has been suggested[49].
Dimethyl fumarate
Dimethyl fumarate (DMF) has been approved for treatment of RRMS. It has immunomodulatory
and neuroprotective effects and acts by shifting the balance between pro-inflammatory
and anti-inflammatory immune responses and altering the composition of lymphocyte
subpopulations, thus resulting in induction of T-cell apoptosis, inhibition of activation
of antigen-presenting cells and downregulation of vascular cell adhesion molecule
expression in brain endothelium and of transmigration across the blood-brain barrier[50].
Real-life data and data from pivotal studies have shown that adverse events are usually
mild to moderate, including flushing, diarrhea and nausea, and seldom require drug
discontinuation. Flushing can be managed with prophylactic use of aspirin and gastrointestinal
events can be improved through food and initial-dose titration[51].
DMF can cause severe and persistent lymphopenia, proteinuria and hematuria. Despite
its safety, common infections such as nasopharyngitis and upper respiratory tract
infections have been reported. PML has been described in a few older patients with
prolonged lymphopenia (0.5 x 109/L)[52].
Teriflunomide
Teriflunomide is an active metabolite of leflunomide with immunosuppressive activity
that selectively inhibits dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme
that is essential for the de novo pyrimidine nucleotide synthesis pathway and is expressed
at high levels in proliferating lymphocytes. This drug reduces T-cell and B-cell activation
and decreases their ability to cross the blood-brain barrier[53].
Teriflunomide has been approved for treatment of RRMS and clinically isolated syndrome
(CIS). It is a sustainable, safe drug. Common adverse events include hair thinning,
nausea, diarrhea and alanine aminotransferase alterations[54].
This drug is contraindicated for use in pregnant women and child-bearing women who
are not using reliable contraception methods, since it can cause embryo-fetal developmental
toxicity and malformations[54]. If pregnancy occurs during treatment, the patient must undergo an accelerated drug
elimination procedure, with administration of cholestyramine or charcoal powder[55].
Interferon beta
Interferon beta (IFNβ) acts on the immune system through a variety of mechanisms including
inhibition of pro-inflammatory cytokines, inhibition of T-cell activation, stimulation
of anti-inflammatory cytokine production and restriction of leukocyte migration across
the blood-brain barrier[56].
IFNβ-derived drugs are indicated for RRMS. The treatment has proven safety. Common
adverse events include flu-like symptoms, which can be managed with dose titration
and symptomatic medication administered before injection. Lymphopenia and increased
aminotransferase (AST and ALT) levels may occur and may eventually lead to drug withdrawal[57]. A previous history of depression is a known risk factor for developing new depressive
episodes within the first six months of treatment and it is a contraindication for
use of IFNβ[58]. IFNβ has been proved safe during pregnancy and lactation[59].
Glatiramer acetate
Glatiramer acetate (GA) comprises four amino acids (L-glutamic acid, L-lysine, L-alanine
and L-tyrosine) that form a synthetic analog of myelin basic protein (MBP). Its precise
mechanism of action is not fully understood but involves immunomodulatory effects
(Th1-Th2 shift and increased regulatory T-cells) and neuroprotective effects[60].
GA is indicated for treating RRMS. Common adverse events associated with GA include
mild injection site reactions (e.g. pain, erythema, edema and nodules) and mild immediate
post-injection reactions (e.g. vasodilatation, chest pain, tachycardia and palpitation)[61]. Patients on GA treatment are not at increased risk of malignancies or infections
and do not require monitoring[62]. It is a safe therapy during pregnancy and lactation[63].
Intravenous immunoglobulin
Intravenous immunoglobulin (IVIg) is a pool of functionally and structurally distinct
human immunoglobulin G (IgG) from different individuals. It acts through various immune
mechanisms to reduce autoreactive antibodies and causes indirect reduction of TNF-α
and IL-10 and decreased macrophage activation[64].
IVIg is indicated for treatment of acute inflammatory demyelinating polyneuropathy
(Guillain-Barré syndrome) and its variants, except typical Miller-Fisher syndrome;
multifocal motor neuropathy (MMN) with conduction block; small-fiber neuropathy with
autoimmune dysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP);
myasthenia gravis; relapsing myelin oligodendrocyte glycoprotein antibody-associated
disease in both children and adults; immune-mediated myopathies (dermatomyositis,
immune-mediated necrotizing myopathy and overlapping syndromes) and dysphagia in sporadic
inclusion body myopathy; idiopathic and paraneoplastic autoimmune encephalitis; and
stiff-person syndrome and its variants.
Mild to moderate adverse reactions to IVIg therapy can occur. Patients who suffer
from serum IgA deficiency are at higher risk, especially during the first administration
of IVIg. These reactions include skin rash, headache, fever, thrombophlebitis, thromboembolic
events, anaphylactic reactions, anaphylactoid reactions, aseptic meningitis, vestibular
symptoms, myalgia, cramps, diarrhea, hypertensive crisis, hypotension, cardiac arrhythmias,
chest pain, hemolytic anemia, transient neutropenia, acute renal failure, pseudohyponatremia
and transfusion-related acute lung injury (TRALI). A slow infusion rate and pre-hydration
with 500 mL of 0.9% saline solution for adults can minimize these reactions[65].
Subcutaneous immunoglobulin
Subcutaneous immunoglobulin (SCIg) and IVIg have similar mechanisms of action and
clinical indications. SCIg is indicated for treatment of patients with serious adverse
effects from IVIg or when venous access is unavailable; and in situations of CIDP,
MMN, immune-mediated myopathies and autoimmune MG (during acute exacerbations).
SCIg is well tolerated in general and safer than IVIg, but it can cause local granuloma-like
reactions, fever, skin rash, cellulitis, anaphylaxis due to inadvertent vascular injection,
skin eruptions, pruritus and joint pain[65],[66].
Therapeutic plasma exchange
Therapeutic plasma exchange (TPE or PLEX) is a therapeutic procedure using an apheresis
device in which the plasma is separated from whole blood, removed and replaced with
a substitution fluid (albumin or saline). PLEX requires adequate venous access (a
central venous catheter). It usually involves 3-7 sessions with time intervals of
24-48 h between sessions, and typically 1-1.5 plasma volumes are removed per procedure[67].
PLEX is a well-established treatment for MG, Guillain-Barré syndrome, CIDP, paraproteinemic
demyelinating polyneuropathies, chronic focal encephalitis (Rasmussen encephalitis),
Lambert-Eaton myasthenic syndrome, MS (acute exacerbation) and NMOSD (during acute
exacerbations).
Occurrences of adverse events in PLEX are associated with several factors including
preexisting conditions. Severe symptoms are mostly associated with addition of infusion
fluid or anticoagulants (citrate) during the procedure. Citrate can cause symptomatic
hypocalcemia, and patients may develop allergic reactions due to the infusion fluid[68]. Hypotension, arrhythmias and tetany may occur; therefore, patient monitoring is
required during the procedure[69].
