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

ABSTRACT For patients with autoimmune diseases, the risks and benefits of immunosuppressive or immunomodulatory treatment are a matter of continual concern. Knowledge of the follow-up routine for each drug is crucial, in order to attain better outcomes and avoid new disease activity or occurrence of adverse effects. To achieve control of autoimmune diseases, immunosuppressive and immunomodulatory drugs act on different pathways of the immune response. Knowledge of the mechanisms of action of these drugs and their recommended doses, adverse reactions and risks of infection and malignancy is essential for safe treatment. Each drug has a specific safety profile, and management should be adapted for different circumstances during the treatment. Primary prophylaxis for opportunistic infections and vaccination are indispensable steps during the treatment plan, given that these prevent potential severe infectious complications. General neurologists frequently prescribe immunosuppressive and immunomodulatory drugs, and awareness of the characteristics of each drug is crucial for treatment success. Implementation of a routine before, during and after use of these drugs avoids treatment-related complications and enables superior disease control.

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.

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.
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 hypothalamicpituitary-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.
Corticosteroid-induced osteoporosis is usually multifactorial 5 . 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    Once a year *Those must be tested also before initiation of long-term use. 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 .
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 antiproliferative 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-(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][33][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, immunemediated 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 barrier 47 . 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 antigenpresenting 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 10 9 /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 antiinflammatory 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 flulike 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 postinjection 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; immunemediated 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 .
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 .

ReCOMMendaTiOnS FOR VaCCinaTiOn and PROPHYLaXiS FOR PaTienTS UndeRGOinG TReaTMenT wiTH iMMUnOSUPPReSSiVe dRUGS
Regular evaluation of immunization schedules is an essential part of consultations for immunosuppressed patients. Safety and immunogenicity are the major concerns regarding vaccination. The immunization schedule should be updated four weeks before immunosuppression is started 70 . When the therapy cannot be delayed, the minimum interval from vaccine dose to treatment start is two weeks [71][72][73] .
Live-agent vaccines (e.g. yellow fever, oral polio and measles-mumps-rubella) have higher risk of severe adverse effects in patients under immunosuppression. Patients under mild to moderate immunosuppression can be considered for live-agent vaccine if their clinical and epidemiological profile is favorable 71 . Patients with a controlled autoimmune disease who are at higher risk of becoming infected (e.g. through living in yellow fever endemic areas) might be considered to be candidates to receive the vaccine. Contacts of immunosuppressed patients should not receive oral polio vaccine due to the risk of viable virus transmission. Maternal exposure to biological agents during pregnancy is a contraindication for application of rotavirus vaccine and BCG vaccination until the child is six months of age 71 . Table 4 summarizes a routine for immunization of patients before, during and after immunosuppression.

OPPORTUniSTiC inFeCTiOnS, SCReeninG and PROPHYLaXiS FOR PaTienTS UndeRGOinG TReaTMenT wiTH iMMUnOSUPPReSSiVe dRUGS
Patients on immunosuppressive therapy are highly susceptible to opportunistic infections. Identification of risk factors, clinical and laboratory monitoring, vaccination and patient education are key to preventing opportunistic infections in these patients.
Corticosteroids have been associated with invasive fungal infections, especially Candida sp. and Pneumocystis jirovecii (PJP). Administration of sulfamethoxazole-trimethoprim 2-3 times a week (or dapsone when a patient is allergic) is known to prevent PJP infection in patients with ANCA-positive vasculitis (especially granulomatosis with polyangiitis during induction treatment) and those receiving corticosteroids with other agents such as azathioprine, cyclophosphamide and methotrexate 74 . Use of thiopurines, MTX and infliximab has been associated with increased risk of C. difficile-associated disease 75 . Vaccination is able to prevent pneumonia and meningitis caused by Streptococcus pneumoniae (revaccination is recommended because antibody levels decrease over time) 76 .
All patients should be evaluated to determine the risk of latent or active TB (especially those on corticosteroids, cladribine, teriflunomide and anti-TNF) through tuberculin skin testing or interferon-gamma-release assays (IGRAs). A definitive diagnosis of latent TB is established through identifying risk factors and through positive screening tests, even without clinical or radiographic evidence of active TB. The European Crohn' s and Colitis Organization (ECCO) guidelines recommend delaying anti-TNF therapy for TB patients for at least three weeks after starting chemoprophylaxis with isoniazid or rifampicin 77 .
Patients should be screened for hepatitis B virus (HBV) (HBsAg, anti-HBc and anti-HBs) before immunosuppression because of the risk of reactivation of HBV replication 78 . It is also recommended to test for HIV infection. Corticosteroids increase the CD4 population and decrease the HIV viral load, while AZA therapy is associated with increased viral replication 79 . Varicella-zoster virus can cause encephalitis, pneumonia, hepatitis and death, particularly among older patients and those using anti-TNF, fingolimod and corticosteroids. Thus, active vaccination is recommended 80 . Over 90% of the world's population is infected with Epstein-Barr virus (EBV), and seropositivity increases with age 81 . AZA has been associated with EBV hepatitis, mucocutaneous ulcers and hemophagocytic syndrome, and IFX has been linked to severe complications or atypical presentations 82 . All patients should be vaccinated against human papillomavirus (HPV), and women require more frequent gynecological examinations and cervical screening 83 .
In conclusion, the follow-up for patients with autoimmune diseases is a complex task, and correct management of immunosuppressive or immunomodulatory drugs is crucial for ensuring better outcomes. Knowledge of doses, adverse effects and follow-up details for each drug used is essential for attaining a balance between the risks and benefits of immunosuppression. Vaccination, prophylaxis for infections and adverse effect screening are important issues to be considered before, during and after the treatment. This review may serve as a guide for general neurologists, to help in management of patients under treatment with immunosuppressive or immunomodulatory drugs.