Immunotherapy & MS Pharmacology
Immunotherapy & MS Pharmacology
What Do You Need to Know?
- MS acute relapse treatment — IV methylprednisolone 1 g × 3–5 days speeds recovery but does NOT change long-term outcome; PLEX for steroid-refractory relapses
- MS DMT efficacy tiers — moderate (interferon-beta, glatiramer, teriflunomide, dimethyl fumarate) vs high (natalizumab, ocrelizumab, alemtuzumab, cladribine, S1P modulators)
- PML risk with natalizumab — stratify by JCV antibody index (>1.5 = high risk), prior immunosuppression, and duration of therapy (>24 months); also monitor lymphopenia with dimethyl fumarate
- NMOSD-specific therapies — eculizumab (anti-C5), inebilizumab (anti-CD19), satralizumab (anti-IL-6R); do NOT use MS DMTs (interferon, fingolimod, natalizumab) — they worsen NMO
- Autoimmune encephalitis — first-line (steroids, IVIG, PLEX), second-line (rituximab, cyclophosphamide), tumor removal if paraneoplastic
- General immunosuppressants — know mechanisms and monitoring: azathioprine (check TPMT), mycophenolate (teratogen), rituximab (HBV screen), cyclophosphamide (hemorrhagic cystitis)
- IVIG — Fc receptor/complement modulation; side effects include aseptic meningitis, thrombosis, renal failure, hemolysis in non-O blood types
MS Acute Relapse Management
Treatment Options
| Treatment | Regimen | Key Points |
|---|---|---|
| IV methylprednisolone | 1 g/day × 3–5 days | First-line; speeds recovery but does NOT alter long-term disability; no taper required for short courses |
| Oral prednisone | 1250 mg PO × 3–5 days | Bioequivalent to IV in the TREAT trial; alternative when IV access is impractical |
| PLEX (plasmapheresis) | 5–7 exchanges over 10–14 days | For steroid-refractory relapses; most effective for severe attacks with prominent demyelination |
| ACTH (Acthar gel) | 80 units IM/SC daily × 5 days | Alternative to IV steroids; stimulates endogenous cortisol + possible direct immunomodulatory effects; expensive |
- Treat only true relapses — new or worsening neurological symptoms lasting >24 hours, in the absence of fever or infection (pseudo-relapses)
- Rule out pseudo-relapse: UTI, other infections, heat exposure (Uhthoff phenomenon) can mimic relapse
- Steroid side effects in MS: insomnia, mood disturbance, hyperglycemia, GI upset, avascular necrosis (with repeated courses), transient worsening before improvement
Board Pearl
IV steroids speed recovery from MS relapses but do NOT change the degree of long-term recovery or prevent future relapses. The Optic Neuritis Treatment Trial (ONTT) showed IV methylprednisolone shortened recovery but oral prednisone alone (low dose) actually increased recurrence — never use low-dose oral prednisone alone for MS relapse.
MS Disease-Modifying Therapies
Treatment Approach & Escalation Strategy
- Escalation approach: start with moderate-efficacy agent, escalate if breakthrough disease (relapses, new MRI lesions, disability progression)
- Early high-efficacy treatment (EHET): increasingly favored — start with high-efficacy DMT (e.g., natalizumab, ocrelizumab, alemtuzumab) in patients with poor prognostic features (high relapse rate, high lesion burden, spinal cord lesions, young age)
- Breakthrough disease on DMT: ≥1 relapse/year, new/enlarging T2 lesions, new Gd-enhancing lesions, or sustained disability worsening → switch to higher-efficacy agent
- Pregnancy planning: most DMTs require washout before conception; glatiramer acetate is safest during pregnancy (Category B equivalent); natalizumab may be continued until conception in high-activity disease
Platform / Moderate-Efficacy DMTs
| Drug | Mechanism | Route / Frequency | Key Side Effects | Monitoring |
|---|---|---|---|---|
| Interferon beta-1a (Avonex, Rebif) | Immunomodulatory; ↓ T-cell activation, ↓ BBB permeability, shifts Th1→Th2 | IM weekly (Avonex) or SC 3×/week (Rebif) | Flu-like symptoms, injection site reactions, hepatotoxicity, depression, leukopenia | CBC, LFTs q3–6 months; neutralizing antibodies (reduce efficacy) |
| Interferon beta-1b (Betaseron, Extavia) | Same as above | SC every other day | Same as above | Same as above |
| Glatiramer acetate (Copaxone) | Synthetic polypeptide; mimics MBP; shifts Th1→Th2; induces regulatory T cells | SC daily or 3×/week (40 mg) | Injection site reactions, lipoatrophy, immediate post-injection systemic reaction (chest tightness, flushing — benign, self-limited) | None required routinely |
| Teriflunomide (Aubagio) | Inhibits dihydroorotate dehydrogenase (DHODH) → ↓ pyrimidine synthesis → ↓ lymphocyte proliferation | PO daily | Teratogenic (Category X), hepatotoxicity, hair thinning, diarrhea, peripheral neuropathy | LFTs monthly × 6 months then periodically; pregnancy test before starting; cholestyramine washout if pregnancy desired |
| Dimethyl fumarate (Tecfidera) | Activates Nrf2 pathway → antioxidant/anti-inflammatory; depletes memory T cells | PO BID | Flushing, GI upset (nausea, diarrhea), lymphopenia → PML risk if sustained ALC <500 | CBC q6 months; hold if ALC <500 for >6 months |
- Interferon neutralizing antibodies: develop in 2–40% depending on formulation; reduce drug efficacy; check if breakthrough disease occurs on interferon therapy
- Glatiramer acetate lipoatrophy: subcutaneous fat loss at injection sites; rotate injection sites to minimize; cosmetically distressing
- Teriflunomide washout: extremely long half-life (>2 weeks); cholestyramine 8 g TID × 11 days or activated charcoal for accelerated elimination (required before pregnancy)
- Dimethyl fumarate flushing: managed with aspirin 325 mg taken 30 minutes before dose; taking with food reduces GI symptoms
- Diroximel fumarate (Vumerity): same active metabolite as dimethyl fumarate but better GI tolerability; equivalent efficacy
High-Efficacy DMTs
| Drug | Mechanism | Route / Frequency | Key Side Effects | Monitoring |
|---|---|---|---|---|
| Natalizumab (Tysabri) | Anti-α4-integrin (VLA-4) monoclonal Ab → blocks lymphocyte migration across BBB | IV infusion q4 weeks | PML (JCV reactivation), infusion reactions, hepatotoxicity, rebound disease activity on discontinuation | JCV antibody & index q6 months; MRI for PML surveillance; LFTs |
| Fingolimod (Gilenya) | S1P receptor modulator → traps lymphocytes in lymph nodes → prevents CNS infiltration | PO daily | First-dose bradycardia/AV block (6-hour cardiac monitoring), macular edema, ↑ infections, PML (rare), rebound on discontinuation | First-dose 6h ECG monitoring; ophthalmology at 3–4 months; CBC; VZV titer (vaccinate if negative before starting) |
| Siponimod (Mayzent) | Selective S1P1/S1P5 modulator | PO daily (with dose titration) | Similar to fingolimod; requires CYP2C9 genotyping (contraindicated in *3/*3 homozygotes) | CYP2C9 genotype before starting; first-dose cardiac monitoring; ophthalmology |
| Ocrelizumab (Ocrevus) | Anti-CD20 monoclonal Ab → depletes B cells (spares plasma cells and pro-B cells) | IV infusion q6 months | Infusion reactions, ↑ infections, HBV reactivation, possibly slightly ↑ breast cancer risk, hypogammaglobulinemia | HBV screen before starting; immunoglobulin levels; CBC |
| Ofatumumab (Kesimpta) | Anti-CD20 monoclonal Ab (fully human) | SC monthly (self-injection) | Injection site reactions, ↑ infections, HBV reactivation | HBV screen; immunoglobulin levels |
| Alemtuzumab (Lemtrada) | Anti-CD52 → pan-lymphocyte depletion (T and B cells, monocytes, NK cells) | IV infusion: 5 days year 1, 3 days year 2 | Secondary autoimmunity: thyroid disease (30–40%), ITP, anti-GBM disease (Goodpasture); infusion reactions; ↑ infections | CBC, TSH, creatinine, urinalysis monthly for 4 years after last dose; monitor for autoimmune disease |
| Cladribine (Mavenclad) | Purine analog → selective lymphocyte depletion (preferentially depletes T and B cells) | PO: 2 short courses/year × 2 years, then no treatment needed | Lymphopenia, herpes zoster, ↑ malignancy risk (theoretical), teratogenic | CBC before each course; lymphocyte count must recover before re-dosing |
- Natalizumab rebound: discontinuation can lead to severe rebound disease activity (tumefactive lesions, IRIS-like) within 3–6 months; bridge therapy needed when switching
- Fingolimod rebound: similar rebound risk; do not abruptly stop; plan transition to next DMT carefully
- Alemtuzumab autoimmunity timeline: thyroid disease typically occurs 1–5 years after treatment; ITP peaks at ~2 years; anti-GBM nephritis is rare but can be fatal — monitor urinalysis for hematuria
Board Pearl
Fingolimod requires 6 hours of cardiac monitoring after the first dose because it can cause symptomatic bradycardia and AV block. This effect is mediated by S1P1 receptor agonism on atrial myocytes. Patients on beta-blockers or calcium channel blockers are at higher risk. VZV vaccination should be done at least 1 month before starting fingolimod.
DMTs and Pregnancy
| DMT | Pregnancy Category | Washout Before Conception | Notes |
|---|---|---|---|
| Glatiramer acetate | Generally considered safe | None required | Safest DMT in pregnancy; can continue until positive pregnancy test; often used as bridge therapy |
| Interferon beta | Contraindicated | Stop before conception | Theoretical risk of miscarriage/low birth weight; limited human data |
| Natalizumab | Use with caution | Typically stopped at conception | May continue through pregnancy in high-activity disease to prevent rebound; neonatal hematologic abnormalities reported |
| Teriflunomide | Category X — teratogenic | Cholestyramine washout + confirm undetectable levels | MUST verify drug elimination before conception; active metabolite persists for months without washout |
| Dimethyl fumarate | Contraindicated | Stop before conception | Limited data; short half-life allows relatively quick washout |
| Fingolimod | Contraindicated | 2 months before conception | Teratogenic in animal studies; rebound disease risk during washout period |
| Ocrelizumab | Contraindicated | 6–12 months before conception | B-cell depleting; neonatal B-cell depletion if exposed in 3rd trimester |
| Alemtuzumab | Contraindicated | 4 months after last dose | Risk of neonatal thyroid disease (from maternal anti-TSH receptor antibodies) |
| Cladribine | Teratogenic | 6 months for women; 6 months for men | Both male and female patients must use contraception during and after treatment |
Monoclonal Antibody Targets in Neuroimmunology — Summary
| Target | Drug(s) | Indication(s) | Key Consideration |
|---|---|---|---|
| α4-integrin (VLA-4) | Natalizumab | MS | PML risk (JCV stratification) |
| CD20 | Ocrelizumab, ofatumumab, rituximab | MS, NMOSD, MG, autoimmune encephalitis | HBV screening; hypogammaglobulinemia with prolonged use |
| CD19 | Inebilizumab | NMOSD (AQP4+) | Broader B-cell depletion than anti-CD20 (includes plasmablasts) |
| CD52 | Alemtuzumab | MS | Secondary autoimmunity (thyroid, ITP, anti-GBM) |
| C5 complement | Eculizumab | NMOSD (AQP4+), MG (AChR+) | Meningococcal vaccination required |
| IL-6 receptor | Satralizumab, tocilizumab | NMOSD (AQP4+) | Blocks IL-6 → ↓ plasmablast survival and antibody production |
| FcRn (neonatal Fc receptor) | Efgartigimod, rozanolixizumab | MG (AChR+) | Accelerates IgG catabolism → lowers pathogenic antibody levels |
JCV & PML Risk Stratification
PML Risk Factors with Natalizumab
| Risk Factor | Details | Clinical Significance |
|---|---|---|
| JCV antibody status | Positive = prior JCV exposure; ~55–60% of MS patients are seropositive | JCV-negative patients have very low PML risk (~0.1/1000); recheck q6 months as seroconversion occurs |
| JCV antibody index | Quantitative measure of anti-JCV antibody level | Index >1.5 = significantly higher PML risk; index <0.9 = lower risk even if seropositive |
| Prior immunosuppression | Previous use of azathioprine, mitoxantrone, cyclophosphamide, etc. | Approximately doubles PML risk at any JCV antibody level |
| Duration of natalizumab | Risk increases substantially after >24 months | Risk stratification: <24 months + JCV negative = very low; >24 months + JCV+ + index >1.5 = highest risk (~1/90) |
PML Surveillance & Switching Strategies
- MRI surveillance: q3–6 month brain MRI looking for new non-enhancing lesions not consistent with MS (subcortical U-fiber involvement, no mass effect initially)
- PML presentation: subacute cognitive/behavioral changes, visual deficits, or motor weakness; lesions involve subcortical white matter, cross vascular territories, and initially do NOT enhance
- PML vs MS lesion: PML lesions involve U-fibers (juxtacortical), have ill-defined borders, no mass effect, and do not enhance early; MS lesions enhance with gadolinium in acute phase and are periventricular/ovoid
- CSF JCV PCR: confirmatory test; sensitivity ~80% (can be false negative in early PML); ultrasensitive PCR may detect earlier
- PML-IRIS: immune reconstitution inflammatory syndrome after stopping natalizumab — paradoxical worsening with new enhancement as immune system recovers; treat with steroids
- Switching off natalizumab: washout period of 4–8 weeks before starting new DMT, but prolonged washout risks severe rebound disease activity; bridge with short steroid course or start new DMT as soon as feasible
- Extended-interval dosing (EID): natalizumab q6 weeks instead of q4 weeks reduces PML risk in JCV+ patients while maintaining efficacy (NOVA study data)
Board Pearl
The three factors for PML risk on natalizumab are: JCV antibody status/index, prior immunosuppression, and treatment duration >24 months. A JCV-negative patient has near-zero PML risk. If JCV+ with index >1.5 and >2 years on therapy, strongly consider switching. PML lesions do NOT enhance initially (unlike MS) and involve subcortical U-fibers.
NMOSD-Specific Therapies
FDA-Approved NMOSD Treatments
| Drug | Mechanism | Route / Frequency | Key Points |
|---|---|---|---|
| Eculizumab (Soliris) | Anti-C5 complement monoclonal Ab → blocks terminal complement activation | IV infusion q2 weeks | PREVENT trial; must vaccinate against Neisseria meningitidis ≥2 weeks before starting; for AQP4-IgG+ NMOSD |
| Inebilizumab (Uplizna) | Anti-CD19 monoclonal Ab → broader B-cell depletion than anti-CD20 (includes plasmablasts) | IV infusion: days 1 & 15, then q6 months | N-MOmentum trial; for AQP4-IgG+ NMOSD; HBV screening required |
| Satralizumab (Enspryng) | Anti-IL-6 receptor monoclonal Ab → blocks IL-6 signaling | SC q4 weeks (after loading doses at weeks 0, 2, and 4) | SAkuraSky/SAkuraStar trials; for AQP4-IgG+ NMOSD; can be used as monotherapy or add-on |
Off-Label NMOSD Treatments
| Drug | Mechanism | Notes |
|---|---|---|
| Rituximab | Anti-CD20 → B-cell depletion | Most widely used off-label; infusion q6 months; monitor CD19/CD20 counts and immunoglobulins |
| Azathioprine | Purine analog → ↓ lymphocyte proliferation | Often used in resource-limited settings; check TPMT before starting; slower onset (3–6 months) |
| Mycophenolate mofetil | Inosine monophosphate dehydrogenase inhibitor | Alternative maintenance therapy; teratogenic; GI side effects common |
- Rationale for complement inhibition: AQP4-IgG is pathogenic via complement-dependent cytotoxicity; eculizumab directly blocks this pathway
- Anti-CD19 vs anti-CD20: CD19 is expressed on a broader range of B lineage cells including plasmablasts that produce AQP4-IgG; anti-CD20 spares these cells
- IL-6 in NMOSD: IL-6 promotes plasmablast survival and AQP4-IgG production; elevated in CSF during NMOSD attacks
Board Pearl
Do NOT use MS-specific DMTs in NMOSD — interferon-beta, fingolimod, and natalizumab can all WORSEN NMO attacks. Always confirm AQP4-IgG status. FDA-approved NMOSD therapies (eculizumab, inebilizumab, satralizumab) are all for AQP4-IgG seropositive patients. Eculizumab requires meningococcal vaccination before starting.
MOGAD Treatment
Acute Treatment
- IV methylprednisolone 1 g × 5 days with slow oral taper (often over 3–6 months — MOGAD is steroid-dependent with high relapse rates during taper)
- IVIG for steroid-refractory cases or as initial therapy in children
- PLEX for severe steroid-refractory presentations (e.g., severe transverse myelitis, bilateral optic neuritis)
- Key difference from MS: MOGAD relapses occur frequently during steroid taper, necessitating slower tapers than in MS relapse treatment
Maintenance Treatment
| Treatment | Notes |
|---|---|
| Chronic IVIG | Emerging as a preferred first-line maintenance therapy; monthly infusions; well-tolerated; reduces relapse rate |
| Azathioprine | Steroid-sparing agent; slower onset (3–6 months); check TPMT; bridge with steroids |
| Mycophenolate mofetil | Alternative steroid-sparing agent; teratogenic; also requires steroid bridge |
| Rituximab | Used off-label; less robust evidence than in NMOSD; some patients relapse despite B-cell depletion |
- No FDA-approved DMTs for MOGAD — treatment is based on expert consensus and observational data
- MOGAD is highly steroid-responsive but steroid-dependent — relapses often occur during steroid taper
- Unlike MS, many patients with MOGAD have monophasic disease (especially children); maintenance therapy reserved for relapsing MOGAD
- Do NOT use MS DMTs for MOGAD — fingolimod and natalizumab are not effective and may worsen outcomes
Autoimmune Encephalitis Treatment
Treatment Algorithm
| Line | Treatments | Key Details |
|---|---|---|
| First-line | Corticosteroids, IVIG, PLEX | Start empirically while awaiting antibody results; often used in combination; improvement within 2–4 weeks |
| Second-line | Rituximab, cyclophosphamide | For patients who fail first-line therapy; rituximab preferred in younger patients (less toxicity than cyclophosphamide) |
| Tumor removal | Resect underlying neoplasm | Ovarian teratoma in anti-NMDAR encephalitis — removal is essential for recovery; screen all young women with pelvic imaging |
| Chronic immunotherapy | Rituximab, mycophenolate, azathioprine | For relapse prevention in antibody-mediated (LGI1, CASPR2, NMDAR) subtypes with relapsing course |
Antibody-Specific Considerations
- Anti-NMDAR encephalitis: most responsive to immunotherapy; ~80% have good outcomes with aggressive treatment; young women — always look for ovarian teratoma; recovery can take months
- LGI1 encephalitis: responds well to steroids and immunotherapy; faciobrachial dystonic seizures (FBDS) may respond to immunotherapy better than AEDs alone; associated with hyponatremia
- CASPR2 encephalitis: associated with Morvan syndrome (peripheral nerve hyperexcitability + encephalitis); screen for thymoma
- Paraneoplastic with intracellular antibodies (Hu, Yo, Ri, CV2): often less responsive to immunotherapy; tumor treatment is primary; neurological damage is frequently irreversible
- Timing matters: earlier immunotherapy initiation (<4 weeks from onset) is associated with better outcomes in anti-NMDAR encephalitis
- GAD65 antibodies: associated with stiff-person syndrome, cerebellar ataxia, and limbic encephalitis; these conditions respond variably to immunotherapy; high titers are more clinically significant than low titers
Surface vs Intracellular Antibody — Treatment Implications
| Feature | Cell-Surface Antibodies | Intracellular Antibodies |
|---|---|---|
| Examples | NMDAR, LGI1, CASPR2, AMPAR, GABA-B | Hu (ANNA-1), Yo (PCA-1), Ri (ANNA-2), CV2/CRMP5, amphiphysin |
| Pathogenicity | Directly pathogenic (antibody-mediated) | Marker of T-cell mediated cytotoxicity |
| Response to immunotherapy | Good — often reversible with treatment | Poor — neuronal damage often irreversible |
| Tumor association | Variable (teratoma in NMDAR; thymoma in CASPR2) | Strong (SCLC with Hu; ovarian/breast with Yo) |
| Primary treatment strategy | Immunotherapy + tumor removal if present | Tumor removal is primary; immunotherapy often limited benefit |
Clinical Pearl
In anti-NMDAR encephalitis, always screen for ovarian teratoma with pelvic ultrasound or CT/MRI. Teratoma removal is a critical part of treatment and dramatically improves outcomes. Up to 50% of young women with anti-NMDAR encephalitis have an underlying teratoma.
General Immunosuppressants in Neurology
Commonly Used Agents
| Drug | Mechanism | Key Uses in Neurology | Important Side Effects | Monitoring |
|---|---|---|---|---|
| Azathioprine | Purine analog → inhibits DNA/RNA synthesis → ↓ lymphocyte proliferation | MG, NMOSD, MOGAD, neuroimmunology | Myelosuppression, hepatotoxicity, GI, pancreatitis, ↑ lymphoma risk | Check TPMT before starting (low TPMT = severe myelosuppression); CBC, LFTs regularly |
| Mycophenolate mofetil | Inosine monophosphate dehydrogenase (IMPDH) inhibitor → selective lymphocyte antiproliferative | MG, NMOSD, MOGAD, CNS vasculitis | GI upset (diarrhea), myelosuppression, teratogenic (Category X), ↑ infections, PML (rare) | CBC monthly initially; pregnancy test; LFTs |
| Rituximab | Anti-CD20 monoclonal Ab → B-cell depletion | NMOSD, MG, autoimmune encephalitis, CIDP, CNS vasculitis | Infusion reactions, HBV reactivation, hypogammaglobulinemia, PML (rare), late-onset neutropenia | HBV serologies before starting; immunoglobulin levels; CD19/CD20 counts |
| Cyclophosphamide | Alkylating agent → cross-links DNA → kills proliferating lymphocytes | CNS vasculitis, refractory autoimmune encephalitis, severe NMOSD, neurosarcoidosis | Hemorrhagic cystitis, bladder cancer, myelosuppression, infertility, secondary malignancies, SIADH | CBC; urinalysis; hydration + MESNA to prevent bladder toxicity; fertility preservation discussion |
IVIG (Intravenous Immunoglobulin)
| Feature | Details |
|---|---|
| Mechanism | Fc receptor blockade, complement modulation, anti-idiotype antibodies, cytokine modulation, ↓ pathogenic antibody production |
| Key neurologic uses | GBS, CIDP, MG exacerbation, MOGAD, autoimmune encephalitis, MMN, dermatomyositis |
| Dosing | Typically 2 g/kg divided over 2–5 days (induction); 1–2 g/kg q3–4 weeks (maintenance) |
| Side effects | Headache, aseptic meningitis, fever/chills, thrombosis (VTE, stroke, MI), renal failure (especially sucrose-containing formulations), hemolysis in non-type-O blood (anti-A/anti-B isohemagglutinins) |
| Contraindications | IgA deficiency (anaphylaxis risk — use IgA-depleted product); severe renal insufficiency |
| Pre-treatment | Check IgA level, renal function, blood type; premedicate with acetaminophen, diphenhydramine; slow infusion rate initially |
Plasmapheresis (PLEX / Therapeutic Plasma Exchange)
| Feature | Details |
|---|---|
| Mechanism | Removes pathogenic antibodies, immune complexes, complement, and cytokines from circulation |
| Key neurologic uses | GBS, MG crisis, NMOSD acute attacks, CIDP, steroid-refractory MS relapse, autoimmune encephalitis |
| Regimen | Typically 5–7 exchanges over 10–14 days (every other day) |
| Side effects | Hypotension, hypocalcemia (from citrate anticoagulant → paresthesias, tetany), coagulopathy (removes clotting factors), line infections, electrolyte derangements |
| Key pearl | Do NOT give IVIG immediately before PLEX — PLEX will remove the infused immunoglobulin (give IVIG after PLEX if using both) |
FcRn Inhibitors — Emerging Agents
- Mechanism: block neonatal Fc receptor (FcRn) → accelerate IgG catabolism → rapidly lower pathogenic IgG antibody levels
- Efgartigimod (Vyvgart): FDA-approved for generalized MG (AChR-Ab positive); IV infusion in 4-week cycles; rapid onset of action
- Rozanolixizumab: SC injection; also approved for generalized MG (AChR-Ab positive)
- Advantage over PLEX: selectively reduces IgG without removing other immunoglobulins, clotting factors, or albumin; no central line required
- Side effects: headache, nasopharyngitis, URIs, UTIs; potential infection risk from reduced IgG
IVIG vs PLEX — Comparison
| Feature | IVIG | PLEX |
|---|---|---|
| Mechanism | Immunomodulation (multiple mechanisms) | Antibody/immune complex removal |
| Access required | Peripheral IV | Central venous catheter (usually) |
| Speed of effect | Days to weeks | Rapid (within days of first exchange) |
| Key advantage | Easier access; no coagulopathy; outpatient possible | Faster onset; directly removes pathogenic antibodies |
| GBS | Equivalent to PLEX (preferred in many centers for ease) | Equivalent to IVIG; start within 4 weeks of onset |
| MG crisis | Equivalent to PLEX | Equivalent to IVIG |
| CIDP | First-line maintenance | Alternative if IVIG fails |
| MS relapse | Not standard | Second-line for steroid-refractory relapse |
Clinical Pearl
Check TPMT enzyme activity before starting azathioprine. Homozygous TPMT deficiency (~0.3% of patients) causes life-threatening myelosuppression. Heterozygotes (~11%) need dose reduction. Screen HBV serologies before rituximab — reactivation can cause fulminant hepatitis.
Clinical Pearl
IVIG causes hemolysis most commonly in patients with blood types A, B, or AB (non-type-O). The pooled immunoglobulin contains anti-A and anti-B isohemagglutinins. Monitor hemoglobin after infusion, especially with high-dose IVIG, and check a DAT (direct antiglobulin test) if hemolysis is suspected.
Vaccination Considerations with Immunotherapy
- Live vaccines are contraindicated in patients on immunosuppressive therapy (fingolimod, ocrelizumab, rituximab, alemtuzumab, mycophenolate, azathioprine, cyclophosphamide, chronic corticosteroids)
- VZV vaccination: must be given ≥1 month BEFORE starting fingolimod or other S1P modulators; check VZV IgG titer and vaccinate if negative
- Meningococcal vaccination: REQUIRED ≥2 weeks before starting eculizumab (complement inhibitor increases risk of Neisseria infections)
- Hepatitis B screening: required before all anti-CD20 therapies (ocrelizumab, ofatumumab, rituximab) and inebilizumab; HBV reactivation risk
- Timing of inactivated vaccines: ideally administer ≥2 weeks before starting DMT or ≥6 months after last anti-CD20 infusion for optimal immune response
- COVID-19 vaccination: blunted humoral response in patients on anti-CD20 therapies and fingolimod; T-cell response may still be partially preserved; time vaccination ≥12 weeks after last anti-CD20 dose if possible
- Influenza and pneumococcal vaccines: recommended for all immunosuppressed patients (inactivated formulations are safe)
Quick Reference Table
Immunotherapy & MS Pharmacology — At a Glance
| Topic | Key Point | Board-Yield Detail |
|---|---|---|
| MS relapse | IV methylprednisolone 1 g × 3–5 days | Speeds recovery; does NOT change long-term outcome; PLEX for steroid-refractory |
| Natalizumab & PML | Anti-VLA-4; highest efficacy but PML risk | JCV index >1.5 + >24 months + prior IS = highest risk; extended-interval dosing reduces risk |
| Fingolimod | S1P modulator; first-dose bradycardia | 6-hour cardiac monitoring; macular edema at 3–4 months; VZV vaccination before starting |
| Ocrelizumab | Anti-CD20; first DMT approved for PPMS | HBV screening mandatory; infusion reactions; ORATORIO trial; monitor immunoglobulins |
| Alemtuzumab | Anti-CD52; highly effective but autoimmunity | Thyroid (30–40%), ITP, anti-GBM — monitor monthly for 4 years after last dose |
| Dimethyl fumarate | Nrf2 pathway; moderate efficacy | Lymphopenia → PML if ALC <500 sustained >6 months; GI/flushing common |
| Teriflunomide | DHODH inhibitor; Category X | Teratogenic; cholestyramine washout; hepatotoxicity; hair thinning |
| NMOSD | Do NOT use MS DMTs — they worsen NMO | Use eculizumab (anti-C5), inebilizumab (anti-CD19), satralizumab (anti-IL-6R) |
| MOGAD | Steroid-responsive but steroid-dependent | No FDA-approved DMT; IVIG emerging as preferred maintenance; slow steroid taper |
| Autoimmune encephalitis | First-line: steroids, IVIG, PLEX | Second-line: rituximab, cyclophosphamide; tumor removal in paraneoplastic (teratoma in NMDAR) |
| IVIG | Aseptic meningitis, thrombosis, renal failure | Hemolysis in non-type-O blood; contraindicated in IgA deficiency (anaphylaxis) |
| Azathioprine | Check TPMT before starting | Homozygous deficiency → fatal myelosuppression; purine analog |
| Cyclophosphamide | Alkylating agent; hemorrhagic cystitis | Give MESNA + hydration; risk of bladder cancer; fertility preservation |
| PLEX | Removes antibodies; hypocalcemia from citrate | Do NOT give IVIG before PLEX (will be removed); used in GBS, MG crisis, NMOSD |
Board Pearl
Siponimod is the only S1P modulator approved specifically for active SPMS (secondary progressive MS). It requires CYP2C9 genotyping before starting — patients homozygous for CYP2C9*3 cannot receive siponimod due to markedly reduced metabolism and increased drug exposure.
Board Pearl
Ocrelizumab is the first and only FDA-approved DMT for primary progressive MS (PPMS) based on the ORATORIO trial. All other DMTs are approved only for relapsing forms of MS. Anti-CD20 agents require HBV screening (HBsAg, anti-HBc, anti-HBs) before initiation due to risk of fatal HBV reactivation.
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