Immune disease of the central nervous system - Immune-mediated neuropathies Flashcards
What is the incidence of chronic inflammatory demyelinating neuropathy (CIDP)?
2.8/100.000 person-years
What are the clinical features of CIDP?
- Similar to GBS, but less severe
- Symptoms progress >8 weeks
- Chronic-progressive/repalsing disease course
- No apparent association with infection
- 2-16% = acute onset
What is typical CIDP?
Neuropathy with motor and sensory involvement
What are atypical forms of CIDP? (2)
- Pure sensory CIDP
- Lewis-Sumner syndrome (LSS)
What is the pathogenesis of CIDP?
Combined cellular & humoral auto-immune response to Schwann cells & myelin antigens, leading to demyelination
What is the animal model for CIDP?
Experimental auto-immune neuritis (EAN)
What are the treatment options of CIDP? Which is most used?
- IVIG = most used
- Corticosteroids
- Plasma exchange
What is the difference in IVIG regimen for CIDP compared to GBS?
GBS = one high dose
CIDP = lower dose maintenancy therapy
How many % of CIDP patients don’t respond to IVIG?
20%
What is an alternative to maintenance IVIG therapy in CIDP patients?
SCIg
What is the advantage of cortocosteroid treatment of CIDP?
Has a 25% chance of long-term remission
What are histological features of CIDP? (5)
- Demyelination of peripheral nerves
- Onion bulbs = demyelinated myelin sheath
- Schwann cell proliferation
- Myelin phagocytosis
- Remyelination
What are immunological features of CIDP? (5)
- Clonally expanded T-cells in the nerve
- Increased active CD8+ T-cells in the CSF
- Elevated BAFF-levels
- Expanded B-cell clones in blood
- IgM & IgG to diverse glycolypids, causing complement deposition
What is immune-mediated nodopathy?
CIDP subtype characterized by antibodies targeting the paranodal loops
What is the effect of antibodies targeting the paranodal loops in immune-mediated nodopathy?
Disruption of the adhesion molecules responsible for a tight connection between axon & myelin -> space between axon & the myelin sheath
How many % of CIDP patients have antibodies against paranodal loops?
7%
What disease features is the presence of antibodies targeting the paranodal loop in CIDP/immune-mediated nodopathy associated with?
- Ataxia
- Tremor
- Aggressive onset
- Poor response to IVIG
Of which subtype are the auto-antibodies in immune-mediated nodopathy?
IgG4
What are the properties of the IgG4 loop-targeting auto-antibodies in immune-mediated nodopathy? (4)
- No complement activation
- Reduced FcR-activation
- Can perform half-molecule exchange
- Related to chronic immune activation
What is half-molecule exchange of antibodies? How is it possible?
IgG4 lacks a disulfide bridge between its chains, allowing for dissociatoin & recombination of IgG4 chains in the serum
What is the treatment of immune-mediated nodopathy?
Anti-CD20 (rituximab) to decrease the paranodal antibody titres
What is the prevalence of multifocal motor neuropathy (MMN)?
0.6/100.000
What is MMN?
Multifocal motor neuropathy
What are the characteristics of MMN?
- Focal, assymetric distal weakness
- Muscle atrophy
- No apparent association with infection
- Presence of anti-GM1 IgM in ~50% of cases
With which HLA type is MMN especially associated?
HLA-DR1*15
Of what isotype are antibodies of MMN? What is their most frequent target antigen?
IgM, targeting GM1
With which disease does MMN share strong similarities? How can they be differentiated?
MMN is similar to early ALS
Can be differentiated by detection of causative auto-antibodies -> points to MMN
MMN is more common in biological [females/males]
MMN is more common in biological males
What is the mean age of onset of MMN?
40 years
What are properties of anti-GM1 IgM in MMN? (5)
- Complement activation
- Most likely monoclonal -> either kappa or lambda in most patients
- IgM paraprotein found in 7% of MMN patients
- Antibodies contain mutations -> suggestive of germinal centre reaction
- Low-affinity
What is paraprotein indicative of?
A monoclonal expansion of B-cells
Which type of neurons is targeted by anti-GM1 antibodies?
Motor neurons (hence: multifocal motor neuropathy)
What suggests that the pentameric structure of IgM likely plays a role in the pathogenesis of MMN?
IgG against the same epitope needs to be present in far higher concentrations to cause disease -> pentameric structure of IgM likely plays a role in causing disease
What is the treatment of MMN?
High-dose IVIG, followed by low-dose maintenance therapy IVIG
What is the response rate of MMN patients to IVIG?
70-94%
What is the downside of MMN treatment with IVIG?
It does not prevent slow developent of axonal degeneration, even if it does suppress symptoms
Why are corticosteroids and/or plasma exchange not used for MMN?
They are ineffective or even exacerbate symptoms
What is an alternative to IVIG treatment in IVIG? What is its downside?
High dose cyclophosphamide
Downside: severe side effects
Can rituximab be used for MMN treatment? Why (not)?
No; it has been successful in small studies, but no RCT has been performed
What are the characteristics of anti-MAG neuropathy? (2)
- Distal asymmetric neuropathy, predominantly sensory
- IgM paraprotein, either kappa or lambda
What are the antigens of anti-MAG neurpathy?
Carbohydrates on MAG
What is the prevalence of anti-MAG neuropathy?
1/100.000
What is the typical age of onset of anti-MAG neuropathy?
> 50
What is MAG? What is its function?
Myelin-associated protein; stabilizes axon-myelin interactions & prevents axon-myelin spacing + prevents neurite outgrowth
What kind of molecule is MAG?
Sialic acid receptor
What is an alternative name of MAG?
Siglec-4
MAG is a sialic acid receptor. What are its ligands? (2)
- GD1a
- GT1b
Where is MAG mostly expressed?
Non-compact myelin
Where can non-compact myelin (where MAG is expressed) be found?
Outer myelin & paranodes
What is the effect of MAG knockout in animals?
Peripheral hypomyelination
How do anti-MAG antibodies cause damage?
Complement deposition
What are features of the B-cells producing auto-antibodies in anti-MAG neuropathy?
- Clonal B-cells in bone marrow
- Predominantly IGHV-34 rearrangement
- 60% of patients have L265P mutations in MyD88
With which diseaes is L265P mutation of MyD88 associated? (4)
- Anti-MAG neuropathy
- Waldenstrom’s macroglobulinaemia
- IgM monoclonal gammopathy of undetermined significance (MGUS)
- Diffuse large B-cell lymphoma (DLBCL)
What are the effects of L265P mutation in MyD88?
- Increased NF-κB signalling
- Increased cytokine signalling
What is the treatment of anti-MAG neuropathy?
Currently no treatment available
Why is rituximab not used for anti-MAG neuropathy?
Low succes rate
Why is there a need for improved GBS treatment?
Chance of severe disease despite treatment
Why is there a need for new CIDP treatment?
Current treatment require life-long administration & does not cure disease
What is the incidence of GBS?
1,3-1,5/100.000/year
What are the diagnostic criteria of GBS? (4)
- Acute onset
- Limb weakness
- Areflexia
- Progress <4 weeks
How many % of GBS patients has a known preceding infection?
70%
How many % of GBS patients has sensory disturbances in addition to their motor problems?
85%
How many % of GBS patients has cranial nerve involvement?
60%
How many % of GBS patients has autonomic dysfunction?
20-50%
What is the treatment for GBS?
Optimal supportive care with timely ICU admission
IVIG or plasma exchange
Corticosteroids are [effective/ineffective] for GBS
Ineffective
How many % of GBS patients require artificial ventilation?
20-25%
How many % of GBS patients is unable to walk after 6 months?
20%
What is GBS mortality?
5%
What was the argument to explore adding a second IVIG course to GBS treatment?
Lower increase of serum IgG after IVIG is correlated with slow recovery -> apparently higher levels of IgG are needed to deplete disease-causing antibodies
What were the results of a trial exploring a second IVIG course for GBS? (2)
- No significant difference in disability score
- More serious adverse effects
What is often the strategy of IVIG-non responsive GBS treatment?
25% get a second course of IVIG, 75% only receive supportive treatment
What were the results of studies with complement inhibitors in GBS?
No significant difference in disease outcome
Why is imlifidase not a routine GBS treatment?
It has not been tested in an RCT
What is most often the treatment stategy for CIDP?
IVIG
What are the follow-up steps if first-line treatment of IVIG fails?
- Re-evaluate diagnosis and restart treatment with one of the other first line options (IVIG/corticosteroids, plasmapheresis)
- If that fails: re-evaluate diagnosis & restart with the last first-line option
- If that fails: re-evaluate diagnosis & start with second-line options
What are second-line treatment options of CIDP?
- Rituximab
- Cyclophosphamide
- Cyclosporine
What are important ongoing studies for GBS treatment? (3) What are their results?
- C1 blocker (large phase 3 RCT): results not yet published
- C5 blocker (small phage 3 RCT): ineffective
- Imlifidase: phase 2 study, awaiting publication
What are the important ongoing studies for CIDP treatment? (2) What ere their results?
- FcRn antagonist (large RCT): effective
- C1 blocker (small phase 2): effective, moving into phase 3 trial
What are the phases of clinical trials? (5) What are their primary goals?
- Pre-clinical trials: indication of effect in laboratory studies
- Phase I: safety in healthy volunteers
- Phase II: safety & effectiveness in patients
- Phase III: safety, effectiveness & dosing in patients
- Phase IV: long-term/side-effects after introduction into clinical use
What is the average duration of a phase I study for drugs?
1-6 months
How many drugs move on from phase I to phase II?
70%
How many participants does a phase I trial for a new drug typically have?
10-50 healthy volunteers
What is the average duration of a phase II study for drugs?
3-18 months
How many participants does a phase II trial for a new drug typically have?
10-50 patients
How many drugs move on from phase II to phase III?
33%
What is the average duration of a phase III study for drugs?
12-18 months
How many participants does a phase III trial for a new drug typically have?
30-100 (up to several thousands) patients
What is the typical study design of a phase III study?
Randomized-controlled trial (RCT)
How many drugs move on from phase III trial to regulatory approval?
25%
When do phase IV studies of drugs take place?
After regulatory approval and introduction into clinical use
