Myasthenia Gravis and Other Disorders of the NMJ 1

Question 1

MG Pathophysiology

Answer 1

antibodies are targeted against the nicotinic acetylcholine
receptor (AChR) at the neuromuscular junction, resulting
in an overall reduction in the number of AChRs and damage
to the postsynaptic membrane

Question 2

Sensitivity of diagnostic tests in MG

Answer 2

Question 3

AchR receptor ab in MG: mechanism and percentage

Answer 3

AChR antibodies cause dysfunction at the neuromuscular junction by
- blocking ACh binding to the AChR
- cross-linking and internalizing AChRs
- activating complement-mediated AChR destruction

Generalized MG up to 90% of patients
purely ocular MG only about 50% of patients

Question 4

anti MUSK ab in MG: mechanism and percentage

Answer 4

MuSK antibodies have been shown to disrupt neuromuscular junction function by adversely affecting the maintenance of AChR clustering at the muscle endplate, thus leading to reduced numbers of functional AChRs.

about 40% of generalized MG patients who do not have AChR antibodies

Question 5

In which patients there is a higher prevalence of MUSK antibodies?

Answer 5

• females
• Meditteranen decent
• younger at time of disease onset

Question 6

LRP4 antibodies percentage in MG

Answer 6

7% of patients that have neither AChR nor MuSK antibodies

Question 7

Role of titin and ryanodine autoantibodies in MG diagnosis

Answer 7

Titin is a large skeletal and cardiac muscle protein, and ryanodine is an intracellular protein within the sarcoplasmic reticulum.

Autoantibodies to titin and/or ryanodine receptors may be found in some patients with MG.

They have been associated with the presence of thymoma and may predict a more severe disease and an unsatisfactory outcome after thymectomy

Question 8

anti MUSK MG: clinical findings

Answer 8

Patients with anti-MuSK MG:
* often have a more severe phenotype compared with other forms of MG with early involvement of bulbar, respiratory, and neck muscles.
* experience quicker progression of weakness,
* have a higher incidence of myasthenic crisis
* have a reduced likihood of a pure ocular MG phenotype

Continuum 2022

Question 9

Hallmark features of MG

Answer 9

Fluctuating and fatigable nature

ptosis
diplopia
dysarthria
dysphagia
respiratory and limb muscle weakness

Question 10

Myasthenic crisis symptoms and percentage in MG patients

Answer 10

• weakness of diaphragmatic and intercostal muscles
• severe bulbar symptoms (dysphagia)

15-20% of MG patients

Question 11

Risk of MG exacerbation in pregnancy

Answer 11

In one third of pregnant women, MG is exacerbated by the pregnancy, with the greatest risk during the first trimester.

In some patients, symptoms and signs improve during the second and third trimesters coincident with the relative immunosuppression that occurs during this phase of pregnancy.

A high risk then returns during the postpartum period.

Question 12

MG age of onset

Answer 12

MG occurs at any age, but there tends to be a bimodal distribution to the age and sex predominance of onset, with an early peak in the second and third decades (female predominance) and a late peak in the sixth to eighth decade (male predominance).

Question 13

Most common presenting symptom in MG
Most common muscles affected

Answer 13

ptosis and diplopia
ανελκτήρας του βλεφάρου/ άνω ορθός μυς

50%

2/3 of patients continue to developed generalized MG
while one-third will have pure OMG

Most (78 percent) of those who will develop generalized MG (GMG) will do so within the first year, and 94 percent will do so within three years.

Question 14

Serum antibody studies in occular myasthenia

Answer 14

The sensitivity of AChR-Ab testing in OMG may be as low as 45 to 60 percent.
However, this is the most specific test for MG; no false positives have been reported (100 percent specificity)

Once thought to be unassociated with OMG, MuSK antibodies have been detected in patients with OMG in a few case reports
In case reports also LRP4 antibodies

Question 15

Ptosis in MG characteristics

Answer 15

• may be present continually or it may develop within 60 seconds of sustained upward gaze
• It may also be identified by holding up the opposite eyelid with the examiner’s finger (curtain sign)
• may improve with testing after the application of an ice pack to the closed lid

Question 16

MG presenting symptoms percentage

Answer 16

Question 17

In which phase of MG does myasthenic crisis occur more often

Answer 17

Active phase

An active phase characterized by the most fluctuations and the most severe symptoms typically occurs in the five to seven years after onset.

Question 18

MG clinical testing

Answer 18

Ice pack test

Cold is thought to decrease cholinesterase activity and promote the efficiency of acetylcholine at eliciting depolarizations at the end plate.

Question 19

Myasthenia gravis diagnosis

Answer 19

Question 20

MG antibodies and thymus

Answer 20

Question 21

How is RNS performed

Answer 21

• The test is performed by placing the recording electrode over the endplate region of a muscle and stimulating the motor nerve to that muscle.
• The muscles tested should be warm, and acetylcholinesterase inhibitors should be held for 12 hours before the study.
• Proximal muscles and clinically weak muscles should be tested in addition to distal muscles.
• The nerve is electrically stimulated 6 to 10 times at low rates (2 or 3 Hz).
  The CMAP amplitude is recorded from the electrode over the muscle after electrical stimulation of the nerve. In normal muscles, there is no change in CMAP amplitude with RNS.
  In MG, there may be a progressive decline in the CMAP amplitude with the first four to five stimuli (a decremental response).

An RNS study is considered positive (ie, abnormal) if the decrement is greater than 10 percent.

Electrical stimulation is also performed after exercise to identify postactivation facilitation (improvement) in CMAP amplitude.

In the exercise protocol, the patient is asked to exercise the muscle maximally for 30 to 60 seconds.
A train of stimuli is performed immediately after exercise. A repair of the CMAP decremental response (a smaller percent decrement compared with the decrement seen at rest) indicates postexercise or postactivation facilitation.
An additional train of stimuli is delivered at one, three, and five minutes after exercise. This delayed stimulation may result in a larger decrement than seen at rest, termed postexercise or postactivation exhaustion.
The exercise protocol may increase the sensitivity of RNS by an additional 5 to 10 percent.

Question 22

Single fiber EMG: how does it work

Answer 22

SFEMG is performed with a specialized needle electrode that allows simultaneous recording of the action potentials of two muscle fibers innervated by the same motor axon.
The variability in time of the second action potential relative to the first is called “jitter.”

Increased jitter occurs when neuromuscular transmission is impaired because the physiologic excess (safety factor) in the amount of neurotransmitter required to produce an action potential is reduced. A reduced safety factor leads to variable timing of nerve impulse transmission and increased jitter in MG.

Question 23

MG pharmacological testing

Answer 23

The edrophonium (“Tensilon”) test has fallen out of use due to suboptimal sensitivity and specificity as well as associated adverse risks.

Edrophonium chloride is an acetylcholinesterase inhibitor with rapid onset (30 to 45 seconds) and short duration of action (5 to 10 minutes). This agent prolongs the presence of acetylcholine in the neuromuscular junction and results in an immediate increase in muscle strength in many of the affected muscles.

The injection of edrophonium is associated with adverse risks due to the potentiated muscarinic effects of acetylcholine. Patients frequently develop increased salivation and mild gastrointestinal cramping. More seriously, symptomatic bradycardia or bronchospasm can also occur.

Question 24

Percentage of MG and thymoma who are positive for AchR abs

Answer 24

All patients
(98-100%)

Question 25

Percentage of patients with AChR antibody-positive MG who have thymic abnormalities

Answer 25

More than 75 percent

thymic hyperplasia is most common (85 percent), but other thymic tumors (primarily thymoma) are present in up to 15 percent

Question 26

Percentage of MG patients who have thymoma
Percentage of patient with thymoma who have MG

Answer 26

15%
40%

Question 27

Percentage of patients with MG who have autoimmune thyroid disease

Answer 27

3 to 10 percent %

Question 28

Do patients with MG have increased risk for other autoimmune diseases?

Answer 28

Autoimmune rheumatic disorders, including Sjögren’s disease, rheumatoid arthritis, and systemic lupus erythematosus, occur with increased frequency in patients with MG compared with age- and sex-matched patients without MG.

The reported incidence of a comorbid rheumatic disorder ranges from 1.25 to as high as 8 percent

Question 29

Which MG patients should have CT or MRI of the thorax

Answer 29

seronegative and most seropositive patients with MG

Patients with muscle-specific tyrosine kinase (MuSK)-positive MG do not typically require chest imaging because thymic abnormalities and thymomas are not associated with MuSK-positive MG, and thymectomy has not been shown to be effective in this group

seronegative = AChR, MuSK antibody and LRP4 negative

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Question 30

MG treatment (four primary therapies)

Answer 30

●Symptomatic treatment (acetylcholinesterase inhibition) to increase the amount of acetylcholine (ACh) available at the neuromuscular junction

●Chronic immunotherapies (glucocorticoids and nonsteroidal immunosuppressive and immunomodulatory agents) to target the underlying immune dysregulation

●Rapid but short-acting immunomodulating treatments (therapeutic plasma exchange and intravenous immune globulin [IVIG])

●Surgical treatment (thymectomy)

Question 31

Can AchR antibodies titer be used as a marker for response to treatment

Answer 31

following acetylcholine receptor (AChR) or other antibody levels as a marker for treatment response in MG is not recommended

Question 32

Drugs to avoid in MG

Answer 32

1) Fluoroquinolones (such as ciprofloxacin and levofloxacin) and macrolides (such as azithromycin and erythromycin), Aminoglycosides, Macrolides

2) Botox

3) Neuromuscular blocking agents (rocuronium, vecuronium, succinylcholine) may be necessary for anesthesia or intubation, but their use delays emergence from anesthesia, recovery of muscle strength, and weaning from mechanical ventilation

4) Magnesium sulfate

5) Penicillamine

6) Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, are used as immunotherapy in certain cancers (eg, metastatic melanoma and nonsmall cell lung cancer). These drugs enhance immune responses and have been reported to trigger autoimmune MG

7) Certain cardiac drugs, such as all beta blockers, procainamide, and quinidine

8) statins have occasionally been reported to unmask or exacerbate MG
(However, statins are not contraindicated in patients with MG and should be used in those with appropriate cardiovascular indications)

9) lithium

10) phenothiazines (eg, chlorpromazine, prochlorperazine)

11) certain antiepileptics (eg, gabapentin, phenytoin)

12) calcium channel blockers

Question 33

Risk of patients with occular MG to develop generalized MG

Answer 33

patients with stable ocular MG of three or more years duration are much less likely to develop generalized disease

(and therefore are not considered to be at increased risk of myasthenic exacerbations or respiratory compromise)

Question 34

Immunization in MG patients

Answer 34

• Current guidelines recommend annual seasonal influenza vaccination for all individuals receiving immunosuppressive therapy, and for those with neurologic conditions, including neuromuscular disorders such as generalized MG, or ocular MG within three years of onset
• inactivated vaccines (eg, pneumococcal and intramuscular influenza vaccines) generally are considered safe in adults or children with immunocompromising conditions or on immunosuppressive drugs.
• Most live-attenuated vaccines should be avoided in patients with MG taking immunosuppressive medications such as prednisone, azathioprine, or mycophenolate mofetil. These patients should not receive the live-attenuated (intranasal) influenza vaccine
• guidelines support the administration of the live-attenuated zoster vaccine for varicella-positive patients aged 50 to 59 years and all patients aged ≥60 years who are receiving therapies that induce low levels of immunosuppression, including the following:
  1) Low-dose prednisone (<2 mg/kg; maximum ≤20 mg/day) or equivalent
  2) Azathioprine (≤3 mg/kg/day)

Question 35

MG initial symptomatic therapy

Answer 35

Pyridostigmine

Question 36

Indications for immunotherapy in MG and choice of treatment

Answer 36

Patients who remain significantly symptomatic on pyridostigmine, or who become symptomatic again after a temporary response to pyridostigmine

Glucocorticoids are typically used initially, and many patients with generalized MG require addition of a nonsteroidal immunotherapeutic agent such as azathioprine or mycophenolate for maintenance and to spare long-term glucocorticoid toxicities.

Question 37

What can cause worsening of MG symptoms

Answer 37

1) infection
2) surgery
3) pregnancy
4) childbirth
5) certain medications
6) tapering of immunotherapeutic medications
7) spontaneously as part of the natural history of the disease

Question 38

Flares of MG management

Answer 38

In the mildest flares (eg, recurrent ptosis or diplopia, mild facial or limb weakness, or mild dysarthria), the choice may be to:

• increase the dose of pyridostigmine
• initiate or increase the dose of glucocorticoids
• monitor closely without medication changes while treating a secondary cause of the exacerbation

On the other end of the spectrum, if there are increasing dysphagia or dyspnea and concerns for the ultimate development of a myasthenic crisis, the patient may be admitted to an ICU setting for close respiratory monitoring.
Treatment in this circumstance is the same as with a myasthenic crisis.

Question 39

Which period in pregnancy has the highest risk for MG exacerbation

Answer 39

The first trimester and the month postpartum are the periods of highest risk of exacerbation.

Question 40

Nonsteroidal immunotherapy indications

Answer 40

1) insufficient response to glucocorticoids
2) patients who cannot taper glucocorticoids below a reasonably acceptable level without return of symptoms
3) as a steroid-sparing therapy in patients with toxicities of chronic glucocorticoid use

Question 41

Nonsteroidal immunotherapy drugs in AChR positive and seronegative MG (which is the first line)

Answer 41

First line: Azathioprine and mycophenolate mofetil

Alternative agents: efgartigimod alfa, ravulizumab, cyclosporine, tacrolimus, and rozanolixizumab, zilucoplan and methotrexate

Efgartigimod, ravulizumab, rozanolixizumab or zilucoplan may be used as a glucocorticoid-sparing therapy with a more rapid onset of effect than other available agents.

Cyclosporine and tacrolimus have activity in MG and may achieve results faster than azathioprine or mycophenolate, but concerns about kidney toxicity and drug interactions limit their use as first-line steroid-sparing agents.
In rare patients with contraindications to both drugs (eg, active liver disease for azathioprine and lymphopenia for either azathioprine or mycophenolate), cyclosporine or tacrolimus may be used as an initial oral glucocorticoid-sparing agent

Question 42

Nonsteroidal immunotherapy in MusK positive MG

Answer 42

Rituximab has emerged as a preferred early therapy in these patients, especially if there is an unsatisfactory response to initial glucocorticoids
If cost or access to rituximab is prohibitive, azathioprine and mycophenolate mofetil remain reasonable to use as first-line steroid-sparing therapies

(Most patients with MuSK-positive disease are poorly responsive to anticholinesterase agents. While many patients respond to glucocorticoids, they are more likely to remain steroid dependent despite the addition of other immunotherapeutic agents such as azathioprine or mycophenolate mofetil)

Rozanolixizumab was approved by the US FDA, including for patients with MuSK-positive MG, but its place in MG treatment has not yet been defined

Question 43

MG management in pregnancy

Answer 43

Pyridostigmine is a first-line therapy for MG during pregnancy, and prednisone is the immunotherapy of choice in patients who are not adequately controlled by symptomatic therapy alone.

In patients who cannot be adequately controlled on prednisone, selective use of azathioprine during pregnancy is warranted when the benefits of immunosuppression with this agent appear to outweigh the risks.
There is a consensus that azathioprine is safer in pregnancy than other immunosuppressant drugs, including mycophenolate mofetil, cyclosporine, and tacrolimus.

Question 44

MG management in older adults

Answer 44

We use glucocorticoids in older individuals who need a relatively quick response to immunotherapy and then try to add another agent (most often azathioprine or mycophenolate) to replace the glucocorticoids for the long term.

Question 45

Paraneoplastic syndromes associated with thymic neoplasms

Answer 45

Question 46

Should patients with thymoma screened for MG?

Answer 46

Clinical evaluation for MG, including assessment of acetylcholine receptor (AChR) antibody status, is indicated for all patients with confirmed or suspected thymoma.

Question 47

Thymectomy timing

Answer 47

Thymectomy in patients with MG is an elective procedure and should not be performed in the setting of myasthenic crisis or otherwise poorly controlled symptoms.

Symptoms of MG should be under good control if possible, with minimal bulbar and respiratory symptoms.

Question 48

Pyridostigmine: dosage, mechanism of action, time of action

Answer 48

Oral: Initial: 30 to 60 mg 3 times daily; may increase in increments of 30 mg/dose every 2 to 3 days based on response and tolerability to 60 to 120 mg every 3 to 4 hours while awake

Inhibits destruction of acetylcholine by acetylcholinesterase which facilitates transmission of impulses across neuromuscular junction

Pyridostigmine has a rapid onset of action (15 to 30 minutes) with peak action at approximately two hours, and its effects last for three to four hours

Question 49

Pyridostigmine: adverse effects, contraindications

Answer 49

Adverse effects:
1) Cardiac effects
bradycardia, atrioventricular block, and syncope

2) Gastrointestinal effects
abdominal cramps, diarrhea, increased peristalsis, nausea, sialorrhea, and vomiting

3) Respiratory effects
increased bronchial secretions and bronchoconstriction

4) fasciculations and muscle cramping

5) cholinergic crisis (rare)

Contraindication:
mechanical intestinal or urinary obstruction

Question 50

How effective is pyridostigmine in MuSK positive MG

Answer 50

most patients with muscle-specific tyrosine kinase (MuSK)-positive disease have a poor response to anticholinesterase agents

Question 51

Which symptoms respond better to treatment with pyridostigmine

Answer 51

limb and bulbar symptoms (dysphagia, fatigable chewing, and dysarthria) respond better to anticholinesterase drugs than the ocular manifestations (ptosis and diplopia).

Diplopia is particularly resistant to these medications in many patients

Question 52

Role of thymectomy in MG

Answer 52

●Patients with thymoma – In the approximately 10 to 15 percent of patients with MG associated with a thymoma, surgery is indicated for patients in whom a complete resection is considered feasible.
Management includes complete resection of the thymus and sometimes involves chemotherapy and radiation therapy in cases of potentially resectable or unresectable disease.

● Patients without thymoma – Thymectomy in the absence of thymoma is recommended in patients with generalized MG and acetylcholine receptor (AChR) antibodies who are ≤50 years of age. The benefit of thymectomy is delayed and accrues over several years postoperatively. The role of thymectomy in other patient groups, such as those without AChR antibodies, older patients, and those with ocular MG, is more controversial, and treatment decisions are individualized.

Question 53

Plasmapheresis in MG time of action, course of treatment and complications

Answer 53

The beneficial clinical effect of plasmapheresis is usually seen within days, but the benefit typically lasts only three to six weeks

A typical course of treatment consists of five exchanges (3 to 5 L of plasma each) over 7 to 14 days.

• Significant chronic catheter complications can result, such as infection and thrombosis
• bleeding
• hypotension
• cardiac arrhythmias
• muscle cramps
• toxic reaction to the citrate used in the procedure

Question 54

Therapies for MG time of onset

Answer 54

Question 55

IVIG for MG: time of action, course of treatment, adverse effects

Answer 55

the effect of IVIG is seen typically in less than a week, and the benefit can last for three to six weeks

The total dose of IVIG is 2 g/kg, usually over two to five days

The side effects of IVIG are most commonly mild and are related to the infusion rate. These include headache, chills, dizziness, and fluid retention.

Other uncommon complications include:
aseptic meningitis
acute renal failure (related to the high sucrose content of some preparations of IVIG)
thrombotic events (myocardial infarction, stroke, and pulmonary embolism)
anaphylaxis (associated with immunoglobulin A (IgA) deficiency)

Question 56

Biologic therapies for MG

Answer 56

1) Efgartigimod alfa
2) ravulizumab
3) rozanolixizumab
4) Zilucoplan

++ eculizumab only for refractory MG

The time to onset of effect for these agents is one to two weeks, so they may also be used as bridge therapy to slower-acting immunotherapies for patients in whom it is especially desirable to avoid or minimize glucocorticoid use.

Question 57

Refractory MG: management

Answer 57

treatment is individualized and may include strategies such as maintenance intravenous immune globulin (IVIG), rituximab, eculizumab, and pulsed cyclophosphamide

Question 58

Prednisolone in MG: How to prescribe

Answer 58

We typically start prednisone at 20 mg daily and then increase by 5 mg every three to five days to a usual target dose of 60 mg per day (or 1 mg/kg per day, maximum 80 mg daily). This often takes four to eight weeks.
By that time, it is generally clear if there is a response to glucocorticoids. Tapering of the dose can then begin after a month or so at this dose.

If the patient has responded completely with resolution of the symptoms at a lower dose, then the dose does not need to go any higher.
However, it is probably wise to hold the dose at that level for a month or so to be certain that the response is sustained, before beginning a tapering schedule.

Once an effective response is obtained, it is important not to taper the glucocorticoids too quickly, or else relapse is likely. Also, it should be remembered that worsening due to a reduction in dose typically takes at least two weeks.

Glucocorticoid tapering can be done with the final goal of achieving either a daily or alternate-day regimen

With either regimen, the daily dose may be reduced by 5 to 10 mg each month until below 30 mg, then more slowly thereafter (eg, 5 mg per month or slower).

(Tapering: After the minimum time to onset of clinical response for the added immunotherapeutic agent has passed (eg, as long as 12 months on azathioprine), we begin to slowly taper prednisone to as low a dose as can be achieved, preferably none at all.)

Question 59

Prednisolone: mechanism of action, common side effects and contraindications

Answer 59

suppresses the immune system by reducing activity and volume of the lymphatic system

Common side effects:
weight gain, Cushingoid facies, easy bruising and skin fragility, cataracts, aseptic necrosis of the femoral or humeral heads, hypertension, diabetes, and osteoporosis

Οι σημαντικότερες από τις αντενδείξεις είναι οι εξής:
- Γαστροδωδεκαδακτυλικό έλκος
- απλούς οφθαλμικός έρπητας
- γλαύκωμα
- οστεοπόρωση
- σακχαρώδης διαβήτης
- ψυχώσεις
- αμέσως πριν και μετά από προφυλακτικό εμβολιασμό
- καρδιοπάθεια ή υπέρταση με συμφορητική καρδιακή ανεπάρκεια
- συστηματική μυκητίαση
- φυματίωση
- βαρειά νεφροπάθεια
- λοιμώδη νοσήματα
- αιμορραγική διάθεση

Question 60

Prednisone monitoring

Answer 60

Patients should be advised of the potential weight gain and provided an appropriate diet if necessary.

Calcium (1500 mg per day) and vitamin D (400 to 800 international units per day) supplementation should be used to reduce bone mineral loss, especially postmenopausal patients. For those most at risk for osteoporosis, bone density should be measured at the start of treatment and then periodically. If bone mineral loss has occurred, patients are generally given a bisphosphonate or an alternative agent

A histamine-2 blocker does not need to be used routinely, but it should be given in patients with a history of peptic ulcer disease or those who develop symptoms of gastritis.
Blood pressure and serum glucose levels should be routinely monitored.
Yearly checks for cataracts and glaucoma are also recommended.

Pneumocystis pneumonia prophylaxis should be considered for patients who are treated with significant doses of glucocorticoids (eg, ≥20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug.

Question 61

In which patients Pneumocystis pneumonia prophylaxis should be considered

Answer 61

Pneumocystis pneumonia prophylaxis should be considered for patients who are treated with significant doses of glucocorticoids (eg, ≥20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug.

Question 62

Azathioprine: mechanism of action, dosage

Answer 62

Azathioprine is an imidazolyl derivative of mercaptopurine; metabolites are incorporated into replicating DNA and halt replication; also block the pathway for purine synthesis

Oral: Initial: 50 mg once daily; increase daily dose by 50 mg every 1 to 4 weeks as tolerated to a target dose of 2 to 3 mg/kg once daily

Question 63

Azathioprine: adverse effects, contraindications

Answer 63

AEs
1) GI effects
nausea, vomiting, and diarrhea

2) Hematologic toxicity
leukopenia, thrombocytopenia, and anemias, including macrocytic anemia and/or pancytopenia
(Azathioprine should be discontinued if the white blood cell count falls below 3000 cells/mm3!!)

3) Infections
Bacterial infections, viral infections, fungal infections, protozoal infections, and opportunistic infections, including reactivation of latent infections.
Viral infections reported with the use of azathioprine include JC virus infection resulting in progressive multifocal leukoencephalopathy, cytomegalovirus (CMV) disease, herpes simplex virus infection, human papillomavirus infection, and reactivation of hepatitis B and tuberculosis

4) Liver dysfunction

5) Malignancy
lymphoproliferative disorders and/or neoplasms (including skin carcinoma) in adult and pediatric patients. Malignancies reported have included malignant lymphoma, hepatosplenic T-cell lymphoma (HSTCL), hemophagocytic lymphohistiocytosis (HLH), acute myelocytic leukemia, myelodysplastic syndrome, and malignant neoplasm of skin, among others

6) Pancreatitis

contraindications:
* Μυελική απλασία ή υποπλασία
* Κύηση

Question 64

Azathioprine monitoring

Answer 64

CBC with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly thereafter

total bilirubin, LFTs (every 3 months),

CrCl

monitor for signs/symptoms of infection and malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).

Azathioprine has been associated with skin cancer with long-term use after kidney transplantation.
Patients taking azathioprine for a prolonged time period should avoid sun exposure and be monitored for skin cancer regularly.

Question 65

Azathioprine pretreatment screening

Answer 65

Before starting azathioprine, it is prudent to screen patients for variants in the thiopurine methyltransferase (TPMT) gene that causes TPMT deficiency.

One in 300 individuals is homozygous for a genetic variant and has very low or absent enzyme levels.
Such patients should not receive azathioprine because they cannot metabolize the drug and may develop life-threatening bone marrow suppression.

Patients who are heterozygous for a genetic variant generally have low enzyme activity but can tolerate azathioprine at lower than usual doses.

Question 66

Mycophenolate mofetil: mechanism of action, dosage

Answer 66

MPA exhibits a cytostatic and reversible effect on T and B lymphocytes.

Oral: Initial: 500 mg twice daily; increase after 1 to 4 weeks based on response and tolerability to a maintenance dose of 1 to 1.5 g twice daily

Question 67

Mycophenolate mofetil: adverse effects, contraindications

Answer 67

AEs
1) Acute inflammatory syndrome
fever, arthralgias, arthritis, myalgias, and increased inflammatory markers without evidence of infection or disease recurrence

2) Bone marrow suppression
anemia, leukopenia or thrombocytopenia

3) GI effects

4) Infection
bacterial, viral, fungal, and protozoal infections, including opportunistic infections.
Viral infections reported with the use of mycophenolate include polyomavirus infection (which may result in polyomavirus associated nephropathy [PVAN]), JC virus-associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) disease, COVID-19, and reactivation of hepatitis B (HBV) or hepatitis C (HCV).

5) Lymphoproliferative disorders and/or neoplasms (including skin carcinoma)

6) Pure red cell aplasia

CIs
- δεν θα πρέπει να δίνεται σε γυναίκες σε αναπαραγωγική ηλικία, οι οποίες δεν χρησιμοποιούν αντισύλληψη υψηλής αποτελεσματικότητας
- δεν θα πρέπει να ξεκινά σε γυναίκες σε αναπαραγωγική ηλικία, χωρίς να προσκομίζουν αποτέλεσμα δοκιμασίας κύησης, προκειμένου να αποκλειστεί η ακούσια χρήση στην κύηση
- δεν θα πρέπει να χρησιμοποιείται στην κύηση, εκτός εάν δεν υπάρχει κατάλληλη εναλλακτική θεραπεία
- δεν θα πρέπει να δίνεται σε γυναίκες που θηλάζουν

Question 68

Mycophenolate mofetil: monitoring

Answer 68

Complete blood count (weekly for first month, twice monthly during months 2 and 3, then monthly thereafter through the first year);

renal and liver function

signs and symptoms of bacterial, fungal, protozoal, new or reactivated viral (including reactivation of HBV or HCV), or opportunistic infections

neurological symptoms (eg, hemiparesis, confusion, cognitive deficiencies, ataxia) suggestive of progressive multifocal leukoencephalopathy

in patients with hepatitis B or hepatitis C, monitor for signs of viral reactivation;

monitor for signs/symptoms (eg, fever, arthralgias, arthritis, muscle pain, proinflammatory markers) suggestive of acute inflammatory syndrome;

pregnancy test (sensitivity of ≥25 milliunits/mL; immediately prior to initiation and 8 to 10 days later in patients who may become pregnant, followed by repeat tests during therapy);

monitor skin (for lesions suspicious of skin cancer)

monitor for signs of lymphoma

monitor for signs of pure red cell aplasia or autoimmune hemolytic anemia

Question 69

Efgartigimod: mechanism of action, indications, dosage

Answer 69

Η εφγαρτιγιμόδη άλφα είναι ένα θραύσμα ανθρώπινου αντισώματος IgG1 που έχει σχεδιαστεί για αυξημένη συγγένεια με τον νεογνικό υποδοχέα Fc (FcRn).
Η εφγαρτιγιμόδη άλφα συνδέεται στον FcRn, με αποτέλεσμα τη μείωση των επιπέδων της κυκλοφορούσας IgG, συμπεριλαμβανομένων των παθογονικών αυτοαντισωμάτων IgG.
Η εφγαρτιγιμόδη άλφα δεν επηρεάζει τα επίπεδα άλλων ανοσοσφαιρινών (IgA, IgD, IgE ή IgM) ή εκείνα της λευκωματίνης.

• It may be considered early in the course of disease instead of glucocorticoids in diabetic patients or others where glucocorticoids may provide unacceptable risks or have intolerable side effects.
• It may also be used as a bridge therapy to slower-acting agents (eg, azathioprine or mycophenolate) or as
• chronic periodic maintenance therapy

IV: 10 mg/kg (maximum dose: 1,200 mg) once weekly for 4 weeks.

Question 70

Efgartigimod: adverse effects, contraindications

Answer 70

AEs
Decreased neutrophils, decreased white blood cell count, lymphocytopenia, headache, nasopharyngitis, and upper respiratory infection

CIs
None

Question 71

Ravulizumab: mechanism of action, indications, dosage

Answer 71

Ravulizumab is a humanized monoclonal antibody that specifically binds with the terminal complement protein C5, preventing disruption of neuromuscular transmission, presumably by inhibiting membrane attack complex-mediated destruction of the postsynaptic membrane.

• It may be considered early in the course of disease instead of glucocorticoids
• as a bridge therapy to slower-acting agents or as
• chronic periodic maintenance therapy

Weight 60 kg to <100 kg:

Loading dose: IV: 2,700 mg as a single dose.

Maintenance dose: IV: 3,300 mg once every 8 weeks starting 2 weeks after the loading dose.

Question 72

Ravulizumab: adverse effects, contraindications

Answer 72

AEs
Gastrointestinal: Diarrhea
Nervous system: Headache
Respiratory: Upper respiratory tract infection

CIs
Unresolved Neisseria meningitidis infection; patients not currently vaccinated against N. meningitidis, unless the risks of delaying ravulizumab treatment outweigh the risks of developing a meningococcal infection

Question 73

Rozanolixizumab: mechanism of action, indications, dosage, side effects

Answer 73

Rozanolixizumab is a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.

• It may be considered early in the course of disease instead of glucocorticoids
• as a bridge therapy to slower-acting agents or as
• chronic periodic maintenance therapy

SUBQ: Dose according to body weight once weekly for 6 weeks.
≥50 to <100 kg –> 560 mg

headache, infections, and diarrhea

Question 74

Zilucoplan mechanism of action and dosage

Answer 74

Zilucoplan binds to the complement protein C5 and inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

Question 75

Eculizumab: dosage and adverse effects

Answer 75

IV: Induction: 900 mg once weekly for 4 doses; Maintenance: 1.2 g at week 5, then 1.2 g every 2 weeks thereafter.

Eculizumab increases the risk of life-threatening Neisserial infections, including N. meningitidis

Question 76

Cyclosporine: indications and limiting side effects

Answer 76

In rare patients with contraindications to both drugs (eg, active liver disease for azathioprine and lymphopenia for either azathioprine or mycophenolate), cyclosporine or tacrolimus may be used as an initial oral glucocorticoid-sparing agent

Hypertension and nephrotoxicity

Question 77

Tacrolimus: indications and limiting side effects

Answer 77

In rare patients with contraindications to both drugs (eg, active liver disease for azathioprine and lymphopenia for either azathioprine or mycophenolate), cyclosporine or tacrolimus may be used as an initial oral glucocorticoid-sparing agent

Nephrotoxicity, hypertension, neurotoxicity, infections, malignancies

Question 78

Myasthenia gravis: Bridge therapy for patients intolerant to glucocorticoids

Answer 78

For patients with MG in whom it is especially desirable to avoid glucocorticoids (such as those with poorly controlled diabetes) or for those who are not successfully weaned to lower doses of prednisone, we often use immunotherapeutic agents with a quicker onset of effect until the more slowly acting immunotherapy takes effect

*Intravenous immune globulin (IVIG)
*Plasmapheresis
*Efgartigimod
*Ravulizumab
*Rozanolixizumab
* Zilucoplan

Question 79

Refractory MG: definition and management

Answer 79

● Disease that is unchanged or worse after glucocorticoids and at least one other immunotherapeutic agent, used in adequate dose and duration, with persistent symptoms or side effects that limit function
● Need for ongoing rescue therapy with intravenous immune globulin (IVIG) or plasma exchange, or frequent myasthenic crises, while on immunotherapy
● Intolerable adverse reactions or the presence of comorbid illnesses that preclude use of conventional immunotherapies

1) Eculizumab may be an effective therapy and has been approved by the US FDA and EMA for this use in refractory acetylcholine receptor (AChR) antibody-positive patients

2) Chronic, or maintenance, IVIG or plasma exchange (at regular intervals) can be used successfully in patients with refractory generalized MG of any serologic status.

3) Alternative agents include rituximab or cyclophosphamide

(Rituximab is particularly efficacious in muscle-specific tyrosine kinase (MuSK)-positive MG and should be considered early in the course of the disease)

Question 80

Myasthenic crisis management

Answer 80

https://www.uptodate.com/contents/image?imageKey=NEURO%2F82137&topicKey=NEURO%2F5125&search=myasthenia%20gravis&rank=12~150&source=see_link

Question 81

Rapid therapies for MG

Answer 81

https://www.uptodate.com/contents/image?imageKey=NEURO%2F68178&topicKey=NEURO%2F5125&search=myasthenia%20gravis&rank=12~150&source=see_link

A 2016 international consensus statement by the Myasthenia Gravis Foundation of America concluded that although clinical trials suggest equivalence, expert consensus suggests that plasma exchange is more effective and works more quickly in the treatment of impending or manifest myasthenic crisis