Rheumatology 3 - Rheumatoid arthritis Flashcards Preview

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Flashcards in Rheumatology 3 - Rheumatoid arthritis Deck (46):
1

What is the pathogenesis of RA?

Environmental factors (smoking, gut biome, periodontis), epigenetic modification and susceptibility genes lead to altered post-transcriptional reguation - leading to self protein citrullination.

This leads to loss of tolerance - ACPA, RF

Transitions to arthritis with synovitis, structural damage and exacerbation of coexisting conditions.

2

What are features found in RA on joints?

Pannus formation
Synovitis
Bone erosion
Cartilage degradation with joint space narrowing

3

What are genetic risk factors for RA?

DRB1
STAT4
PADI
PTPN22

4

What are environmental risk factors for RA?

Smoking
Periodontitis
Gut dysbiosis
Anti-CCP (enolase)

5

What are inflammatory mediators involved in RA?

TNF, IL1, IL6 (macrophages)
IL-2, IFN (lymphocytes)
IL-12, IL-15, IL-18 (drive towards Th1 lymphocytes)
IL-17 (Th17 lymphocytes)

6

What are other mediators implicated in joint destruction?

PG, COX (inflammation, swelling)
RANKL (bone damage)
MMP, Aggrecanase (cartilage loss)

7

What cell types are most involved in RA pathogenesis?

Macrophage
T-cell
Synovial fibroblast
B-cells
PMN (in fluid mainly)

Driven by IL-1, TNF, IL-6

8

What is a feature of Treg cells in RA?

Fox P3 +ve
Fox P3 inhibits differentiation to Th1, Th2, Th17

9

What cytokines drive t-cell expansion in RA?

IFN, IL-2
IL-12, IL-15, IL-18, IL-17

10

What cytokines drive leucocyte trafficking in RA?

IL-1, TNF, IL-8, MCP, MIP

11

What cytokines drive local inflammation and damage in RA?

IL-1, IL6, TNF

12

What is the cause of bone erosion in RA?

Mediated by Osteoclasts
Macrophages are potential OCs
Inflammatory milieu drives osteoclast activity
CKs TNF, IL-1, IL-6 are important

13

What is meant by cytokine disequilibrium in RA?

INcreased TNF and IL-1, vs soluble TNF receptor, IL-10 and IL-1 receptor antagonist

14

What proporotion of RA patients are seronegative?

1/3

15

How is a Dx of RA made?

Small joints
symmetrical
6 weeks duration
Arm stiffness for 1 hour
RhF or anti-CCP
Nodules
Erosions

16

What is the feature of small joint involvement in RA?

DIP joints are spared, with fixed deformity and erosion/destruction

17

How are small joints differently involved in SLE?

DIP joints are spared, but deformity is passively correctible and there is minimal destruction

18

How is small joint involvement different in gout vs RA?

gout has involvement of the DIPJ, with tophi and large, marginal punched out lesions

19

How is small joint involvement different in psoriatic arthritis vs RA?

Nail changes are common, DIP joints are NOT spared and there is erosion and new bone formation with pencil in cup appearance

20

How is small joint involvement different in OA?

DIP joints are not spared, there are heberden's nodes and there are osteophytes, and juxta-articular sclerosis

21

What is rheumatoid factor?

autoantibody (usually IgM) - against Fc of IgG
+ve RF and arthritis is not specific for RA

RF is associated with Rheumatoid nodules, vasculitis and worse prognosis

22

What are 3 causes of high titre RF and Sn for each?

RA - 70-90%
Sjogren's - 75-95%
Cryoglobulinaemia - 40-100%

23

What are significant causes of false +ve rheumatoid factor?

Hep B or C
Bacterial endocarditis
TB
Syphilis
Viral infection
Sarcoidosis
IPF
PBC
Malignancy

24

What is anti-CCP?

highly specific for RA (90%)
highly predictive of RA in asymptomatic and undifferentiated patients
Sn = 70%
Marker of severe erosive disease
Not for marker of severe disease

25

What is the effect of smoking on CCP?

increases anti-CCP

26

What are genetic factors predisposing to RA?

HLADR4
PTPN22
STAT4
PADI

27

What are environmental triggers for RA?

EBC, CMV, Parvovirus, Barmah Forest, RR fever, foreign or auto antigen exposure

28

What is the most potent environmental factor?

SMOKING

29

What is an AE of MTX plus leflunomide?

Pneumonitis, peripheral neuropathy, transaminitis

30

Why is MTX the gold standard of therapy?

Effective in 75% of patients
Flare with drug discontinuation
Improved mortality
MTX lung rare in practice - monitor LFT/UEC/Creat/FBC
Folinic acid rescue if sepsis and leucopenia

31

What are features of leflunomide?

Inhibits pyrimidine biosynthesis
Can be combined with SZP/HCQ or MTX
Pancytopenia/transaminitis/pneumonitis
Cholestyramine rescue if sepsis and leucopenia
Diarrhoea in 20% (most common AE)

32

What immunological pathway blockade works in RA?

TNF-a
IL-1
Il-6
costim
B-cell depletion
JAK kinase blockade
IL-12/23 blockade

CD4 T-cell depletion does not work

33

What cell types does TNFa promote?

synoviocytes, chondrocytes and osteoclasts

34

Which TNFi is not cytolytic?

etanercept

35

What are key points of TNF blockade?

rapid onset - 1-2 weeks (60% of patients respond)
no difference in efficacy between agents
acceptable toxicity (Infection, TB risk, demyelination, lymphoma)
? induction of remission - BEST study w infliximab

36

What are issues with TNF blockade?

TB
Congestive heart failure - NYHA Class III or above
De-myelinating disease (? optic neuritis/demyelinating conditions)
Lymphoma
Lupus like syndrome or ANA/dsDNA
Cancer in the last 5 years

37

What are pathologies that respond to TNF blockade?

Infections (bacterial) - staph/strep/pneumococcus
Zoster!
Chronic HSV (ophthalmic)
Melanoma

38

What is the relationship between TNF blockade and malignancy?

SIR around 1.0 with Lymphoma
No definite increase in risk of solid tumours
Increased skin cancer (melanoma and non-melanoma)
No TNFi if cancer in last 5 years

39

What is the management of latent/active TB prior to TNFi commencement?

Latent - Quant gold+ve
- isoniazid for 4-6 weeks pre therapy, continue for 9 months (high rate abnormal LFTs with isoniazid)
Active TB
- pulm or non-pulmonary
- treat with std chemo
- should have at least 2 months of therapy before commenting TNFi

40

What is the effect of IL-6 in RA?

activation of autoreactive T-cells
Increase in RF
Hyper-gammaglobulinaemia
Leukocytosis
Anaemia
Thrombocytosis
Activation of osteoclasts
Induction of MMPs
Increase in acute phase proteins
Hypoalbuminaemia
Amyloidosis
Induction of VEGF

41

What are precautions in IL-6R blockade

tocilizumab = Anti-IL6R
Increased LFTs 11% esp with MTX
Increased total and HDL cholesterol but decreased CRP - lower CV risk

42

What is the role of b-cell depletion in RF?

reduced rheumatoid factor by B-cells leads to reduced complement fixation and inflammation.
RITUXIMAB is anti-CD20, measure CD19 to check levels

43

What is the role of abatacept in RA?

blocks costimulation of T-cells by binding to B7, interrupting CD28-b7 interaction
CTLA-4 blockade significant improves S+Sx and QoL in addition to MTX

44

What is the role of tofacitinib in RA?

oral JAK3/1 inhibition, reduces signs and symptoms of RA as monotherapy - suppreses STAT1 dependent genes

45

What patients with RA require aggressive treatment of OP?

CRP/ESR high at baseline/in spite of therapy
high swollen joint count
persistent inflammatory symmetrical arthrtitis (PISA)
RhF/anti-CCP high
erosions

46

What patients should be selected for aggressive bDMARD therapy?

Failed non biologic dmard
Cant tolerate non-biologic dmard
Persistently elevated ESR/CRP
Persistently elevated joint count