Rheumatoid Arthritis Flashcards
1
Q
What is RA?
A
An autoimmune condition leading to inappropriate immune system activity causing synovial and connective tissue inflammation
2
Q
What are the consequences of inflammation seen in RA? (4)
A
- Loss of cartilage
- Formation of scar tissue
- Ligament laxity
- Tendon contractures
3
Q
What are the 3 key symptoms present in RA that would help you distinguish it from OA?
A
- Affected joints are symmetrical
- Duration of morning stiffness >1 hour (gets better throughout the day)
- Presence of systemic symptoms, especially during flares
4
Q
Joint damage occurs early in the course of RA. Damage is ____________, and __________ ____ follows
A
irreversible; functional loss
5
Q
Looking at an RA hand, for example, what are 4 things you’d see that stand out (especially in intermediate to late stages)?
A
- Thumb curving outward (tendon contracture)
- Ulnar drift (fingers curving towards outer side of hand)
- Valley forming between tendons due to muscular atrophy
- Rheumatoid nodules
6
Q
How are blood vessels affected in RA? (5)
Only treatment is?
A
- Rheumatoid vasculitis
- Occurs with severe, long-standing RA
- Leads to substantial morbidity
- Can affect any blood vessel
- Symptoms experienced depend on affected vessels
- Only treatment: Aggressive treatment of RA itself
7
Q
How are lungs affected in RA? (5)
A
- Pleuritis
- Pleural effusion
- Fibrosis
- Pulmonary nodules
- Drugs used to treat RA may also impact lung function
8
Q
How are the eyes affected in RA? (4)
A
- Episcleritis
- Scleritis
- Uveritis and iritis
- Painful, visual acuity loss
9
Q
How is the heart affected in RA? (3)
A
- Pericarditis
- Myocarditis
- Increase risk of CAD, HF, and Afib
10
Q
How are the muscles affected in RA? (3)
A
- Generalized weakness and pain
- From synovial inflammation, myositis, vasculitis
- Steroid-induced
11
Q
How are bones affected in RA? (2)
A
- Osteopenia common
- Local bone loss around affected joints
12
Q
How is skin affected in RA? (3)
A
- Rheumatoid nodules
- Ulcers
- Steroid-induced changes
13
Q
What are 3 lab test findings that could be indicative of RA?
A
- Rheumatoid factor (in 60-70% of patients though)
- Elevated ESR and CRP
- Anti-cyclic citrullinated peptide antibody (anti-CCP)
14
Q
The biggest goal in RA treatment is achieving remission or low disease activity. What 5 criteria define that?
A
- A patient assessment of global disease activity (PtGA) ≤2
- Tender/swollen joint count ≤1
- A measure of function based on the Health Assessment Questionnaire (HAQ)
- CRP score ≤1
- A physician global assessment ≤2
15
Q
What are the 4 general principles of RA management?
A
- Early recognition and diagnosis
- Early use of DMARDs
- Within 3 months - Concept of “tight control”
- Responsible NSAID and glucocorticoid use
16
Q
The most important non-pharm therapy for RA is?
A
Patient education
17
Q
What are the 3 classes of RA maintenance medications?
A
- Traditional DMARDS (tDMARDS)
- Biologic DMARDs
- Synthetic DMARDs - not used much atm
18
Q
What are the 2 classes of RA flare management medications?
A
- Corticosteroids
- NSAIDs/Analgesia
19
Q
What are the 4 general characterstics shared between the tDMARDs?
A
- Slow onset of action
- Controls symptoms
- May delay or stop progression of disease
- Requires regular monitoring
20
Q
What are the 4 tDMARDs we discussed?
A
- METHOTREXATE - most important
- Hydroxycholoroquine
- Sulfasalazine
- Leflunomide
21
Q
What is the MOA of hydroxychloroquine?
A
Inhibits neutrophils and chemotaxis; impairs complement system
22
Q
What is the MOA of sulfasalazine? (2)
A
- Prodrug metabolized into 5-ASA and sulfapyridine
- Modulates mediators of inflammatory response; may inhibit TNF
23
Q
What is the MOA of methotrexate?
A
Anti-folate –> less DNA synthesis, repair, cellular replication and immune response
24
Q
What is the MOA of leflunomide? (2)
A
- Inhibits pyrimidine synthesis, leading to anti-inflammatory effects
- Modulates many signaling pathways
25
How long is the onset for the tDMARDs?
HCQ
SSZ
MTX
LEF
HCQ = 2-6 months
SSZ = 2-3 months
MTX = 1-2 months
LEF = 1-3 months
26
What is the dosing of methotrexate?
7.5 to 25 mg po weekly.
Have titrate to target, but 25 mg is the goal. Can go down to 15 mg if poor tolerance. No going higher.
27
True or False? Methotrexate can be used in dialysis pts
True - halve the dose
28
The most well tolerated tDMARD is?
Hydroxycholoroquine (less potent though)
29
Leflunomide's most prominent side effect is?
Nausea/diarrhea
30
What are the common side effects of methotrexate (6 - know the top 3)?
1. Nausea/vomiting*
2. Fatigue*
3. Stomatitis*
4. Photosensitivity
5. Hair loss
6. Skin itch/burnin/rash
31
What are 4 ways to manage MTX side effects?
1. Folic acid 1-5mg/day
2. Split dosing on same day
3. Subcut form reduces GI side effects
4. Adding PPI for 3 days around MTX dose to reduce GI side effects
32
What is the important serious side effect seen with hydroxychloroquine use?
Ocular toxicity (metabolites deposit in eye over time which can lead to vision loss).
33
What are the serious side effects seen with MTX use? (5)
1. Hepatotoxicity
2. Hematologic abnormalities
3. Pulmonary toxicity
4. Reversible sterility in men
5. Infection increase
34
True or False? DMARDs are immunosuppressant
True
35
One CI for hydroxychloroquine is?
Pre-existing retinopathy
36
What is a precaution for using methotrexate?
Caution in lung dysfunction
37
What are 3 CIs for using methotrexate?
1. Severe hepatic impairment
2. Current hematologic abnormalities
3. Pregnancy/breastfeeding
38
What are 5 DIs seen with methotrexate? (Only need to know 2 most important)
1. NSAIDs*
2. Trimethoprim*
3. PPIs
4. Loop diuretics
5. Live vaccines
39
Discuss NSAID DI with MTX. Why is it flagged? Should it be?
1. NSAIDs decrease clearance of MTX, which increases toxicity potential.
2. However, at <15mg/week - likely no risk. At 15-25mg/week - very low risk.
3. It is only a real risk if using high cancer doses (500-2000mg), otherwise, it isn't contraindicated in normal use
40
What is the MTX trimethoprim DI?
Pancytopenia
41
How is efficacy of tDMARDs monitored? (3)
1. Disease activity (ESR, CRP) every 1-3 months initially
2. Radiographs every 6-12 months
3. Patient assessment
42
What should be monitored safety-wise when on MTX? (3)
1. CBCs and LFTs
2. Creatinine
3. Chest x-ray (baseline)
43
Of the tDMARDs, should know the order of efficacy
HCQ
SSZ
MTX
LEF
MTX = LEF > SSZ > HCQ
44
What is the place in therapy for hydroxycholoroquine? (3)
1. Useful for early, mild RA
2. Best tolerated of the DMARDs
3. Combined with other DMARDs (monotherapy generally rare)
45
What is the place in therapy for sulfasalazine? (3)
1. Use if other options not tolerated
2. Most effective the earlier used
3. Combined with other DMARDs (monotherapy generally rare)
46
What is the place in therapy for MTX? (3)
1. Highly effective in mod-severe disease
2. Significantly improves efficacy when combined with biologics
3. Standard therapy - "backbone" (1st line)
47
What is the place in therapy for leflunomide? (2)
1. Replacement for MTX if not tolerated
2. May be added in low doses to MTX
48
Central to the inflammatory process of RA are _________, ___________ and ___________ within the synovium, which produce cytokines:
1. ___-_
2. ____________
monocytes, macrophages; fibroblasts
1. TNF-a
2. Interleukins
49
What are the 4 main classes of biologic DMARDs?
1. TNF-a inhibitors
2. Interleukin - 1 or 6 inhibitors
3. T-cell co-stimulation inhibitors
4. B-cell depletors
50
Common side effects for all biologics are? (4)
1. Nausea
2. Headache
3. Diarrhea
4. Malaise
51
Concerns for all biologics includes injection site reactions. Should know what these reactions are and how to pre-treat.
1. SC --> minor redness, itching, swelling, pain
2. IV --> headache and nausea, hives, fever, chills fatigue
3. Hypersensitivity
4. Anaphylaxis uncommon
5. Often pre-treat: acet + antihistamine + steroid ~90 mins prior
52
Concerns for all biologics includes infection rate increase. What are some common and serious infections that can occur? When is risk highest?
Common: sinusitis, pharyngitis
Serious: TB, Hep B/C
Risk highest early in therapy
53
Concerns for all biologics includes infection rate increase. How might we mitigate infection risk? (3)
1. Screening prior to therapy
2. Vaccinations up to date
3. Never use 2 biologics in combination
54
If infection occurs while on biologic DMARD, what do we do?
Temporary ds/c of biologic
55
Concerns for all biologics includes neutropenia. What's the issue here? Ds/c therapy or no?
1. Increases severity of infections
2. Not a reason to ds/c therapy, but monitoring is important
56
Concerns for all biologics includes antibody development. What is happening here?
1. Clearance of drug increased by body's defenses
2. Usually occurs within 2-6 months of starting therapy
57
Concerns for all biologics includes malignant disease. Overall there is no cancer risk increases except for: (2)
1. Skin cancer
2. Lymphomas
58
Biologics should be avoided in those with active malignancies. But what about people with previous skin cancer or lymphoma?
1. Preferentially avoid if previous skin cancer
2. Use rituximab in those with previous lymphoma
59
Of the biologic DMARDs, which ones don't get antibody development?
Which ones, might get it, but lower chance?
1. Does not occur with IL-6 inhibitors
2. T-cell inhibitor and B-cell depletors: possible effect, but less than TNF-inhibitors
60
High TNF in RA patients leads to ____ _______
bone erosion
61
What are the TNF-alpha inhibitor drugs?
(ACE Got Incinerated)
1. Adalimumab
2. Certolizumab
3. Etanercept
4. Golimumab
5. Infliximab
62
Onset of TNF-a inhibitors is?
Within weeks
63
What is ACR50?
How many patients achieve at least a 50% reduction in symptoms
64
What is the ACR50 of TNF-a inhibitors?
40%
Goes up in combination with MTX
65
_________ and _________ are the 2 TNF-a inhibitors that are ONLY indicated in combination with MTX
Infliximab; Golimumab
66
What is the dosing form and frequency of adalimumab? (TNF-a)
Subcut Q2 weeks
(May dose weekly if monotherapy)
67
What is the dosing form and frequency of certolizumab? (TNF-a)
This has an initial, maintenance, and optional dosing scheme.
Subcut
1. Initial = Q2 weeks for 3 doses
2. Maintenance = every other week
3. Optional monthly dose
68
What is the dosing form and frequency of etanercept? (TNF-a)
Subcut once weekly or divided dose twice weekly
69
What is the dosing frequency of IV golimumab (TNF-a)?
Starts with dosing at 0, 4, and 8 weeks, then Q8 weeks
70
What is the dosing frequency of SQ golimumab (TNF-a)?
Once monthly
71
What is the dosing form and frequency of infliximab? (TNF-a)?
Starts with 0, 2, and 6 weeks, then Q8 weeks
72
TNF-a inhibitors and pregnancy. Yay or nay?
Yay. All of them seem to be fine for the most part.
Certolizumab is preferred option if not already on one. If on one, keep them on it, no need to switch
73
What are the 2 CIs of TNF-a inhibitors?
1. Active severe infection
2. Moderate to severe HF
74
What are the 2 DIs in TNF-a inhibitors?
1. Live vaccines
2. Additive immunosuppression with other drugs
75
What are 5 potential AEs of TNF-a inhibitors?
1. Liver enzyme elevations
- Concern if ALT ≥5x ULN
2. Heart failure
- Evidence not conclusive
3. Cutaneous (skin)
4. Autoimmune disorder
5. Seizure risk
- Avoid in pts with seizure disorder
76
What is the MOA of IL-1 and 6 inhibitors?
Antagonize the receptors leading to reduction in cytokine activity, which leads to decreased immune response which leads to less or no cartilage damage.
77
The IL-1 inhibitor is? (Anakin+Shinrabanshoman)
Anakinra
78
The IL-6 inhibitors are? (2)
(Tien Shinhan)
1. Tocilizumab
2. Sarilumab
79
How long is onset for the IL-1/6 inhibitors?
Weeks, but peaks at 5-6 months
80
What are the CIs for the IL-1/6 inhibitors?
1. Anakinra - none
2. Tocilizumab - active infections
3. Sarilumab - none
81
Is Anakinra more or less efficacious than other biologic agents?
Less - only 40% achieving ACR20 (vs. ACR50 for other medications)
82
What is the efficacy of Tocilzumab and Sarilumab?
~40% achieve ACR50 - comparable to TNF-a inhibitors
83
All of the IL-1/6 inhibitors are __ injections
SC
(Tocilizumab has IV option)
84
How often is anakinra injected?
How about in ESRD?
Once daily
ESRD: dose every other day
85
How often is IV tocilizumab dosed?
Every 4 weeks
86
How often is SC tocilizumab dosed in the following:
<100kg pt
>100kg pt
<100: every other week
>100: weekly
87
How often is sarilumab dosed?
Every 2 weeks
88
The fun thing about IL-1/6 inibitors is that if CrCL >30 mL/min then dosage adjustment is necessary. True or False?
False - no adjustment needed
89
What are the only AEs seen with Anakinra?
Injection site reactions and infections.
- Maybe headache and nausea
90
What are the AEs of tocilizumab and sarilumab? (5)
1. GI perforation (unique + rituximab)
- Rare
- Caution if at risk of GI issues
2. Dyslipidemia (unique): Increase TC/TG and decrease HDL
3. Antibody development not linked to decreased effect (unique)*
4. HTN
5. Other concerns similar to TNF-a inhibitors
91
What are 3 DIs seen with IL-1/6 inhibitors?
1. Decrease IL-1/6 activity = increased CYP activity
2. Additive immunosuppression
3. Live vaccines
92
What is the Tocilizumab specific DI?
Simvastatin increased 4-10x
93
When might T-cell co-stimulation inhibitors be used in therapy? (3)
1. Used if inadequate response to DMARDs or TNF inhibitors
2. Monotherapy or combination with tDMARDs (MTX)
3. 3rd line
94
What is the only T-cell co-stimulation inhibitor medication?
Abatacept
95
What is the dosing frequency of abatacept? (3 steps to using it)
1. Optional IV loading dose
2. Then administer SQ 24h later
3. Maintenance = SQ once weekly
96
What are the 2 unique adverse effects of abatacept? (2nd one is unique in the sense that there is zero adverse effect here)
1. COPD exacerbations
2. No impact on liver function
97
Abatacept and blood glucose. What's going on here? (2)
1. Blood glucose may slightly increase as an adverse effect. Pretty small, but if pre-diabetic, this could push them over the edge.
2. Blood glucose might need to be monitored while using abatacept in this type of patient
98
What is the MOA of the B-cell depletor?
1. B-cell cell depletors bind to B-cells to cause lysis
99
What is the B-cell depletor medication?
Rituximab
100
Rituximab has only been studied in combination with? (2)
MTX AND failure on a TNF-a inhibitor
101
What is the onset of rituximab?
May be delayed up to 6 months
102
The only class of biologic DMARDs that seems to not halt radiographic progression of RA is?
B-cell depletor (Rituximab)
103
Explain the dosing and administration of Rituximab (B-cell depletor). Fairly unique compared to the other bDMARDs (5)
1. 2 dose course: 1g IV given two weeks apart
2. MUST pretreat with methylprednisolone, acet, and diphenhydramine
3. Re-treat when needed (~6 months)
4. Some require two courses for efficacy
5. Withhold HTN meds morning of infusion
104
What are the AEs of rituximab? (5 - know the 2 most important)
1. Serious infection rate is non-existent initially; then increases on repeat courses*
2. HTN
3. GI perforation
4. Blood glucose increase
5. Mucocutaneous reactions (SJS, TEN)*
105
What are the top 3 concern for all biologics? Remember the RxFiles chart with the 3 red concerns. (top 2 being the MOST important)
1. Infections
2. Injection/infusion reaction
3. ?Malignancy
106
Of the 4 biologic classes which one has no risk of liver injury?
T-cell inhibitors
107
Of the 4 biologic classes which one has HF risk?
TNF-a inhibitors
108
Of the 4 biologic classes which one cannot be used in COPD?
T-cell inhibitors
109
Of the 4 biologic classes which two can cause GI perforation?
IL-6 inhibitors and B-cell depletor
110
Of the 4 biologic classes which one should not be used in seizure?
TNF-a inhibitors
111
Of the 4 biologic classes which two can cause blood glucose increase?
T-cell inhibitor (most important) and B-cell depletor
112
Of the 4 biologic classes which one has greatest risk in metabolic disorder (HTN and increased lipids)?
IL-6 inhibitors
113
Biologic DMARDs are usually considered once other options have been tried.
Of the 4 classes, should know which is 1st line through 4th line.
1st line = TNF-a inhibitors
2nd line = IL-6 (sometimes IL-1) inhbitors
3rd line = T-cell inhibitor
4th line = B-cell depletor
114
The 5th/last line treatment option for RA maintenance is?
Janus Kinase Inhibitor
115
The 3 Janus Kinase Inhibitor medications are? (BUT)
1. Baricitinib
2. Upadacitinib
3. Tofacitinib
116
What is the dose formulation of JAK inhibitors?
Oral, which is totally a benefit.
117
What is one adverse effect that is avoided by JAK inhibitors which most of the biologics have to worry about?
No concern about antibody development
118
Although JAK inhibitors seem to have fairly similar efficacy to biologics, why are they last line? (5)
Really bad adverse effects such as:
1. CV risk
2. Malignancy
3. GI perforation
4. Bradycardia
5. Dyslipidemia
119
What is the major DI seen with JAK inhibitors? (enzyme related more so)
Tofactinib/upadacitinib are major 3A4 substrates
120
What does the efficacy data show for corticosteroids in RA treatment? (4)
1. Reduces joint tenderness more than placebo and NSAIDs
2. Reduces pain more than NSAIDs
3. Improved QoL measures
4. Small radiographic progression decrease
121
The most important benefit of corticosteroids in RA treatment is?
Subjective symptomatic improvement
122
What are the 3 treatment modalities of corticosteroids in RA treatment?
1. Short-term use
2. Chronic use
3. Pulse therapy
123
The most common treatment modality for corticosteroids in RA treatment is short-term. What sort of doses are we seeing here? What other properties (2)?
1. Doses of 10-15 mg prednisone equivalent per day
2. Taper and ds/c as symptoms improve
3. Limited safety issues if dose/duration kept low
124
What sort of doses are seen in chronic corticosteroid use for RA? What are 2 things to keep in mind for this kind of treatment?
1. Doses of 5-10 mg prednisone equivalent per day indefinitely
2. Long-term steroid safety issues become apparent
3. Increases need for monitoring and adjunctive therapy
125
What is the dosing and dosing regimen of corticosteroid pulse therapy for RA treatment?
Methylprednisolone 1000mg IV for 3 consecutive days once monthly for 6-8 months
Last resort option in RA
126
What are the issues of pulse therapy of corticosteroids? (4)
1. CV collapse
2. Hypokalemia
3. Heart attack
4. Severe infection
127
How long until onset of corticosteroids?
Within days
128
What needs to be monitored when using corticosteroids? (5)
1. Cataracts
2. Dyslipidemia
3. Hyperglycemia
4. Osteoporosis
5. Weight gain
129
What are 4 potential issues seen with corticosteroid intra-articular injections?
1. Tendon rupture
2. Acute synovitis
3. Localized skin hypopigmentation
4. Septic arthritis
130
What is the guideline approach to using corticosteroids in RA? (5)
1. Consider for flares or as "bridging"
2. Aim for a max dose of 10mg/day
3. Never use as monotherapy
4. Find minimum dose/duration
5. Consider avoiding in those more at risk of steroid side effects
131
This slide is all you need to know about NSAID use in RA.
Dose (1)
Length? (2)
Cautions? (2)
1. Provide high dose NSAIDs at initial diagnosis
2. Use for at least 2 weeks for maximum benefit
3. Should not need to use chronically
4. Cautiously combined with other treatments
5. Consider providing GI protection
132
Acetaminophen and opioids for RA analgesia. Yay or nay?
1. Acet sometimes added - efficacy pretty poor, but if helping, go ahead
2. Avoid opioids
- Limited evidence in RA
133
This is just a summary slide of combination therapy of RA. No question associated, just read it.
1. NSAIDs + Glucocorticoids can be added to any regimen
2. MTX can be added to all biologics
3. LEF + biologics similar to MTX + biologics
4. tDMARD double therapy - any two of MTX, SSZ, HCQ or LEF
5. tDMARD triple therapy - MTX + SSZ + HCQ
6. ACR50 of single, double or triple combo tDMARDs: 29%, 40% and 55%
7. Biologic + two tDMARDs – unclear benefit/harm; “reasonable” in guidelines
8. Recommend AGAINST multiple biologics
9. ACR50 of MTX vs. MTX + biologic: 20% vs. 58%
134
Summary. What are the 4 ways we can manage RA flares?
1. Intraarticular glucocorticoid if few joints
2. Initiate/increase glucocorticoid
3. Consider increasing DMARD dose
4. Add new DMARD if frequent flares
135
The Canadian RA guidelines kinda suck. What are 3 general principles to know?
1. “Treatment should aim to achieve remission and, when not feasible, minimal disease activity.”
2. “Patients receiving treatment should be counselled regarding potential harms and appropriate monitoring.”
3. “Patients with rheumatoid arthritis should receive preventative care and screening tailored to individual risk factors.”
- E.g. Vaccination, osteoporosis prevention, physical activity, cardiovascular risk screening, smoking
136
What do the ACR guidelines say to use for first-line initial therapy approach for low disease activity?
Conditional recommendation, in order of preference for initial therapy: HCQ>SSZ>MTX>LEF
- Monotherapy preferred
137
What do the ACR guidelines say to use for first-line initial therapy approach for moderate-to-high disease activity? (4)
1. Methotrexate strongly recommended over HCQ or SSZ
2. Methotrexate conditionally recommended over leflunomide
3. Methotrexate monotherapy recommended over double or triple traditional DMARDs therapy
4. Methotrexate monotherapy conditionally recommended over combo with biologic
138
What do the ACR guidelines say regarding corticosteroids?
Avoid systematically prescribing them during initiation of a DMARD, but can consider in some cases
139
What do the ACR guidelines say regarding the administration of MTX? (3)
1. Oral preferred over SQ
- Consider SQ if target dose of oral is not adequate (low quality evidence)
2. Achieve a target dose of at least 15mg within 4-6 weeks
3. To improve tolerability, split dosing of MTX and increase folic acid dose
140
What do the ACR guidelines suggest when MTX monotherapy fails to achieve goal of therapy?
How about when a biologic fails?
1. Preferentially add a biologic DMARD instead of SSZ/HCQ
2. Preferentially switch to a biologic of a different class, rather than the same class
141
What do the ACR guidelines say regarding tapering or discontinuing DMARDs?
Conditionally recommend remaining on all DMARDs at current doses
- Only consider taper if pt will remain on therapeutic dose of at least 1 DMARD, AND has been in remission for at least 6 months
142
What do the ACR guidelines say regarding comorbidities? (2)
1. Pulmonary disease: still consider MTX over other DMARDs
2. HF: Avoid TNF biologics if class III or IV
143
When should RA therapy be escalated? (4)
1. Failure to achieve remission or acceptable disease activity after 3-6 months at optimal doses
2. Inability to taper steroids
3. Recurrent flares
4. Disease progression on x-ray
144
What should be done in RA patients in pregnancy pre-conception? (2)
1. Must ds/c unsafe meds
- MTX - male and female - stop for 3 months prior to conception
- LEF - male and female - take cholestyramine , measure levels until <0.02mg/mL, then wait an additional 3 months
2. Achieve remission on safe options:
- HCQ and SSZ good options
- All biologic agents, except, rituximab, have favorable safety profiles
- Certolizumab has the most robust data; compatible with all trimesters
145
What can be used for RA treatment peri-pregnancy? (3)
1. Corticosteroids may be used sparingly
2. Ensure folic acid 5mg/d if previous MTX use
3. Cautious use of NSAIDs
146
What agents are okay to use for RA during lactation? (4)
1. NSAID use (ibu preferred) acceptable
2. Low dose prednisone (<20mg/d) compatible
3. HCQ and SSZ safe to continue
4. TNF-inhibitors, IL-6 inhibitors safe
147
What agents should not be used for RA during lactation? (2)
1. MTX
2. LEF
