Immunosuppressors and immunomodulators in Neurology - Part I: a guide for management of patients underimmunotherapy

Abrantes, Fabiano Ferreira; Moraes, Marianna Pinheiro Moraes de; Albuquerque Filho, José Marcos Vieira de; Alencar, Jéssica Monique Dias; Lopes, Alexandre Bussinger; Pinto, Wladimir Bocca Vieira de Rezende; Souza, Paulo Victor Sgobbi de; Oliveira, Enedina Maria Lobato de; Oliveira, Acary de Souza Bulle de; Pedroso, José Luiz; Barsottini, Orlando Graziani Povoas

doi:10.1590/0004-282X-ANP-2020-0593

Fabiano Ferreira Abrantes

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-3813-5993

Marianna Pinheiro Moraes de Moraes

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0003-1273-9083

José Marcos Vieira de Albuquerque Filho

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-4533-2637

Jéssica Monique Dias Alencar

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-6354-4043

Alexandre Bussinger Lopes

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0001-5466-2155

Wladimir Bocca Vieira de Rezende Pinto

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-0150-525X

Paulo Victor Sgobbi de Souza

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-7416-7108

Enedina Maria Lobato de Oliveira

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-4939-7200

Acary de Souza Bulle de Oliveira

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-6986-4937

José Luiz Pedroso

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-1672-8894

Orlando Graziani Povoas Barsottini

Universidade Federal de São Paulo, Departamento de Neurologia, Divisão de Neurologia Geral, São Paulo SP, Brazil.

https://orcid.org/0000-0002-0107-0831

Correspondence:
Fabiano Ferreira Abrantes; Email: fabianofabrantes@hotmail.com

Conflict of interest:

There is no conflict of interest to declare.

Authors’ contributions:

FFA, MPMM, MVAF, OGB: conception, organization, and execution of the article project, writing, review, and critique of the first draft; JMDA, ABL, WBVRP, PVSS: execution of article project, review and critique of the manuscript; EMLO, ABSO: execution of article project, writing, review and critique of the manuscript; JLP: conception and execution of article project, writing, review and critique of the manuscript.

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 (7^th-14^th 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 (7^th-14^th 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 1^st 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 1^st 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

	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

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

Vaccination pre-immunosuppression:	Vaccination on immunosuppression:	After immunosuppression:
Non-live vaccines should be administered at least two weeks prior to treatment; Live vaccines should be given at least one month prior to treatment; Pneumococcal vaccine should be given to all immunosuppressed patients; Influenza vaccine should be given yearly for patient and household.	Generally, no live vaccines should be given; All patients should receive HPV vaccine if age-appropriate and a yearly influenza vaccine (inactivated); Meningococcal vaccines should be repeated every five years if immunosuppression is ongoing.	After 4 months off therapy, check baseline serology (VZV, measles, mumps, rubella, hepatitis A and B, diphtheria, tetanus and H. influenzae b), if antibodies are present, polio/pertussis vaccines do not need to be re-administered; If lymphocyte count > 1,000, initiate re-immunization schedule; IVIg interferes with antibody response to live vaccines. These should be delayed until 9 months (if 1 g/kg/dose given) or 11 months (if 2 g/kg/dose given).

[1] Correspondence:
Fabiano Ferreira Abrantes; Email: fabianofabrantes@hotmail.com

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Immunosuppressors and immunomodulators in Neurology - Part I: a guide for management of patients underimmunotherapy

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ABSTRACT