Immunotherapy & MS Pharmacology
Immunotherapy & MS Pharmacology
What You'll Learn
- 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), ravulizumab (anti-C5, FDA April 2024 for AQP4+ NMOSD), inebilizumab (anti-CD19), satralizumab (anti-IL-6R); meningococcal vaccination required for C5 inhibitors; 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
HighYield Pearls
- NMOSD ≠ MS: interferon-β, fingolimod, and natalizumab worsen NMOSD → always check AQP4-IgG before starting an MS DMT in atypical demyelination
- Eculizumab and ravulizumab (FDA April 2024 for AQP4+ NMOSD) require meningococcal vaccination (ideally ≥ 2 weeks before first dose) → terminal complement blockade → Neisseria risk
- Rituximab + HBV: screen HBsAg + anti-HBc before every course; entecavir prophylaxis if positive → fulminant reactivation can occur months after infusion
- Natalizumab PML risk stratified by JCV index (> 1.5), prior immunosuppression, and duration > 24 months → consider switching at this threshold
- ICI neurotoxicity: myasthenia + myocarditis + myositis overlap syndrome carries ≥ 30% mortality → high-dose steroids + IVIG/PLEX, hold ICI, check troponin and CK on every case
- Check TPMT before azathioprine and avoid live vaccines (MMR, VZV, yellow fever) on B-cell depletion, S1P modulators, or high-dose steroids
- Mycophenolate and methotrexate are teratogens → contraception required; glatiramer + interferon-β are the safest MS DMTs in pregnancy
- PJP prophylaxis (TMP-SMX) for prolonged high-dose steroids (≥ 20 mg prednisone ≥ 4 weeks) and cyclophosphamide
- Stress-dose steroids for major illness or surgery in any patient on > 5 mg prednisone > 3 weeks → adrenal suppression
- NEDA-3 (no relapses, no MRI activity, no disability progression) is the modern treatment target in MS
🔍 Quick ReferenceMechanism · Adverse effects · Use / monitoring
Mechanism
- Rituximab / ocrelizumab / ofatumumab / ublituximab → anti-CD20 B-cell depletion (chimeric, humanized, fully human SQ, glycoengineered)
- Inebilizumab → anti-CD19 (broader B-cell + plasmablast depletion) for NMOSD
- Eculizumab / ravulizumab → anti-C5 complement inhibitor (NMOSD, AChR+ MG, PNH)
- Satralizumab / tocilizumab → anti-IL-6R (NMOSD maintenance)
- Efgartigimod / rozanolixizumab → FcRn antagonist → accelerated IgG catabolism (MG)
- Azathioprine → 6-MP → purine synthesis inhibition (TPMT-dependent)
- Mycophenolate → IMPDH inhibitor → selective lymphocyte purine block
- Methotrexate → dihydrofolate reductase inhibitor
- Cyclophosphamide → alkylating agent (DNA cross-linking)
- Tacrolimus / cyclosporine → calcineurin inhibitors
Adverse effects / monitoring
- Anaphylaxis on first IVIG dose → selective IgA deficiency (use IgA-depleted product)
- Aseptic meningitis + thromboembolism + AKI → IVIG
- Hemorrhagic cystitis + bladder cancer + infertility → cyclophosphamide (MESNA + hydration)
- Pulmonary fibrosis + hepatotoxicity + stomatitis → methotrexate (folate rescue)
- PRES + nephrotoxicity + tremor + hirsutism + Mg wasting → calcineurin inhibitors
- HBV reactivation + late hypogammaglobulinemia + rare PML → rituximab / anti-CD20
- Citrate-induced hypocalcemia + hypotension + line complications → PLEX
- Secondary autoimmunity (ITP, Graves, anti-GBM) → alemtuzumab
- Severe TPMT deficiency → profound myelosuppression → azathioprine
- Meningococcal sepsis risk → eculizumab / ravulizumab (mandatory vaccination)
Use / pregnancy / pearls
- Methylprednisolone 1 g IV × 3–5 d → acute MS relapse, NMOSD attack, ADEM, transverse myelitis, autoimmune encephalitis
- PLEX (5–7 exchanges) → MG crisis, GBS, steroid-refractory NMOSD/MS, tumefactive/Marburg MS, autoimmune encephalitis
- Rituximab first-line → MuSK MG, refractory AChR MG, NMOSD, PCNS vasculitis, IgG4-related disease
- Mycophenolate / azathioprine → long-term maintenance for MG, NMOSD, AIE, sarcoid neuropathy
- Glatiramer acetate + interferon-β → safest MS DMTs in pregnancy; avoid teriflunomide, fingolimod, fumarates
- Anti-CD20 antibody crosses placenta → infant B-cell suppression up to 6 months postpartum → delay live vaccines
- Autologous HSCT → highly active / treatment-refractory relapsing MS, severe SSc, refractory SLE
- ICI-related myasthenia → methylprednisolone 1 g + IVIG/PLEX + hold ICI + screen for myocarditis (troponin) and myositis (CK)
- Live vaccines (MMR, VZV, yellow fever) contraindicated on B-cell depletion, S1P modulators, high-dose steroids; Shingrix (recombinant) is OK
- NEDA-3 = no relapses + no MRI activity + no disability progression → modern MS treatment target
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 methylprednisolone | 1250 mg PO × 3–5 days | Non-inferior to IV in the COPOUSEP trial (Le Page et al., Lancet 2015); 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, while low-dose oral prednisone (1 mg/kg/day) increased the rate of new optic neuritis attacks vs placebo — this finding applies to LOW-dose oral prednisone, NOT to high-dose oral methylprednisolone (1250 mg), which is an accepted alternative to IV.
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 considered low risk in pregnancy based on accumulated registry data and is the safest DMT during pregnancy; 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 | Contraindicated in pregnancy (boxed warning — teratogenic in animals); 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
- Monomethyl fumarate (Bafiertam): bioequivalent active metabolite of dimethyl fumarate; oral; similar efficacy with improved GI tolerability
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: *1/*3 or *2/*3 → maintenance 1 mg daily (vs standard 2 mg); *3/*3 contraindicated | CYP2C9 genotype before starting; first-dose cardiac monitoring; ophthalmology |
| Ozanimod (Zeposia) | Selective S1P1/S1P5 modulator | PO daily (with dose titration) | Similar to fingolimod; no genotyping needed but titration required; MAO-related dietary cautions | First-dose monitoring per titration; ophthalmology; LFTs |
| Ponesimod (Ponvory) | Selective S1P1 modulator | PO daily (with 14-day titration) | Similar to fingolimod; shorter half-life (~33 h) → faster washout; no genotyping | Titration kit; first-dose monitoring per protocol; ophthalmology; LFTs |
| 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, hypogammaglobulinemia; early OPERA/ORATORIO trials suggested a possible breast cancer signal, but subsequent post-marketing data have NOT consistently confirmed increased risk | 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. Anti-CD20 therapies (ofatumumab, ocrelizumab, ublituximab) — label advises contraception during and for 6 months after last dose; not taught as absolute pregnancy contraindication; individualize in high-activity MS, particularly because fetal/neonatal B-cell depletion is the key concern with late pregnancy exposure | HBV screen; immunoglobulin levels |
| Ublituximab (Briumvi) | Anti-CD20 monoclonal Ab; glycoengineered (low-fucose) → enhanced antibody-dependent cellular cytotoxicity (ADCC), allowing lower dose and shorter infusion | IV infusion q6 months (FDA Dec 2022 for RRMS); ULTIMATE I/II trials | Infusion reactions, ↑ infections, HBV reactivation, hypogammaglobulinemia | HBV screen; immunoglobulin levels; CBC |
| 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 B cells more than T cells; B-cell recovery slower than T-cell recovery | 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. Extend monitoring overnight if HR <45 bpm at hour 6, new ≥2nd-degree AV block, or QTc >500 ms. Patients on beta-blockers or calcium channel blockers are at higher risk. VZV vaccination should be done at least 1 month before starting fingolimod.
Autologous Hematopoietic Stem Cell Transplantation (aHSCT)
- Indication: considered for aggressive RRMS with breakthrough disease on high-efficacy DMT; younger patients with active inflammatory disease (relapses, Gd-enhancing lesions) and limited disability accrual respond best
- Procedure: mobilization of autologous HSCs → immunoablative conditioning (e.g., cyclophosphamide-based) → reinfusion of stem cells to “reset” the immune system
- Evidence: MIST trial (Burt et al., JAMA 2019) showed superiority of aHSCT to DMT for relapsing-remitting MS with breakthrough activity
- Risks: infection during aplastic phase, secondary autoimmunity, infertility, transplant-related mortality (<1% in experienced centers)
- Not typically effective in progressive MS without ongoing inflammatory activity
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 | Generally discontinued before conception; no longer considered absolutely contraindicated | Stop before conception ideally; may be continued if disease activity warrants | Increasing registry data (EMA label update; EFPIA cohorts) suggest relative safety if exposure occurs during pregnancy |
| Natalizumab | Use with caution | Typically stopped at conception | May continue through pregnancy in high-activity disease to prevent rebound; neonatal hematologic abnormalities reported |
| Teriflunomide | Contraindicated in pregnancy (boxed warning — teratogenic in animals) | Accelerated elimination: cholestyramine 8 g TID × 11 d OR activated charcoal 50 g BID × 11 d, then verify plasma teriflunomide concentration <0.02 mg/L (NOT just "undetectable"), generally on two tests separated by ≥14 days | MUST verify drug elimination (plasma level <0.02 mg/L on 2 tests ≥14 d apart) before conception; active metabolite persists for months without washout |
| Dimethyl fumarate | Limited pregnancy data; generally discontinued before conception | Stop before conception ideally | Short half-life allows relatively quick washout if needed mid-pregnancy |
| Fingolimod | Contraindicated | 2 months before conception | Teratogenic in animal studies; rebound disease risk during washout period |
| Ocrelizumab | Label advises contraception during treatment and for 6 months after the last infusion; NOT taught as absolute contraindication — individualize | Contraception during therapy and 6 months after last dose | B-cell depleting; key concern is neonatal B-cell depletion if exposed in 3rd trimester — timing is individualized in high-activity MS |
| 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 |
MS Symptomatic Management
| Symptom | Pharmacologic Options | Key Points |
|---|---|---|
| Spasticity | Baclofen (oral or intrathecal), tizanidine, dantrolene, gabapentin, botulinum toxin (BoNT) | Intrathecal baclofen for severe refractory cases; tizanidine causes sedation and hepatotoxicity; BoNT for focal spasticity |
| Bladder dysfunction | Oxybutynin, tolterodine, mirabegron, sacral neuromodulation, intermittent catheterization | Antimuscarinics (oxybutynin/tolterodine) for detrusor overactivity; mirabegron (β3 agonist) avoids anticholinergic side effects; CIC for retention |
| Fatigue / cognition | Amantadine, modafinil, methylphenidate | Amantadine first-line for MS fatigue; modafinil for excessive daytime sleepiness; address sleep, mood, and thyroid first |
| Gait impairment | Dalfampridine (Ampyra, 4-aminopyridine) — 10 mg PO BID | K+ channel blocker; improves walking speed in ~35%; contraindicated in seizure history and CrCl ≤50 mL/min |
| Neuropathic pain / paroxysmal symptoms | Gabapentin, pregabalin, carbamazepine, oxcarbazepine, duloxetine, amitriptyline | Carbamazepine for trigeminal neuralgia and tonic spasms; SNRIs for chronic neuropathic pain |
| Depression | SSRIs, SNRIs, CBT | Prevalent (~50% lifetime); screen routinely; avoid interferons in active depression |
| Pseudobulbar affect | Dextromethorphan/quinidine (Nuedexta) | FDA-approved for PBA in MS and ALS |
Infection Prophylaxis & Bone Health on Immunotherapy
- PCP (Pneumocystis jirovecii) prophylaxis: TMP-SMX (or atovaquone or dapsone as alternatives) for patients on prednisone ≥20 mg/day for ≥4 weeks, cyclophosphamide, or combinations involving high-dose chronic immunosuppression. Routine PCP prophylaxis is generally NOT needed with rituximab or ocrelizumab as monotherapy in MS or NMOSD; reserve for patients on combination immunosuppression (e.g., concurrent chronic steroids, cyclophosphamide, or other lymphocyte-depleting therapy) or with significant lymphopenia
- Bone health on chronic steroids: calcium + vitamin D supplementation, baseline and serial DEXA, bisphosphonate consideration for sustained steroid exposure (especially ≥7.5 mg/day prednisone-equivalent for ≥3 months)
- HBV reactivation prophylaxis: entecavir or tenofovir for HBsAg+ patients receiving rituximab/ocrelizumab/ublituximab/inebilizumab
- TB screening: consider IGRA (QuantiFERON) before starting long-term immunosuppression in patients with TB risk
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, ravulizumab (Ultomiris), zilucoplan (Zilbrysq) | NMOSD (AQP4+), MG (AChR+) | Meningococcal vaccination required for all C5 inhibitors |
| IL-6 receptor | Satralizumab, tocilizumab | NMOSD (AQP4+) | Blocks IL-6 → ↓ plasmablast survival and antibody production |
| FcRn (neonatal Fc receptor) | Efgartigimod (Vyvgart), rozanolixizumab (Rystiggo) | MG (AChR+ and MuSK+); efgartigimod SC also for CIDP | Accelerates IgG catabolism → lowers IgG; does NOT affect IgM or IgA — selective antibody class effect |
💎 Board Pearl — Anti-CD19 vs Anti-CD20
| Target | Cells Depleted | Key Clinical Implication |
|---|---|---|
| CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) | Mature B cells (pre-B through memory B); spares plasmablasts and plasma cells | Effective for B-cell–mediated disease; preserves established antibody production by plasma cells; first-line in MS, off-label in NMOSD |
| CD19 (inebilizumab) | Mature B cells PLUS plasmablasts (CD19+/CD20−) that produce pathogenic antibodies like AQP4-IgG | Broader B-cell depletion; rationale for use in NMOSD where short-lived plasmablasts drive AQP4-IgG production — explains why inebilizumab may outperform anti-CD20 here |
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