Rheumatology 3 - Rheumatoid arthritis Flashcards
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.
What are features found in RA on joints?
Pannus formation
Synovitis
Bone erosion
Cartilage degradation with joint space narrowing
What are genetic risk factors for RA?
DRB1
STAT4
PADI
PTPN22
What are environmental risk factors for RA?
Smoking
Periodontitis
Gut dysbiosis
Anti-CCP (enolase)
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)
What are other mediators implicated in joint destruction?
PG, COX (inflammation, swelling)
RANKL (bone damage)
MMP, Aggrecanase (cartilage loss)
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
What is a feature of Treg cells in RA?
Fox P3 +ve
Fox P3 inhibits differentiation to Th1, Th2, Th17
What cytokines drive t-cell expansion in RA?
IFN, IL-2
IL-12, IL-15, IL-18, IL-17
What cytokines drive leucocyte trafficking in RA?
IL-1, TNF, IL-8, MCP, MIP
What cytokines drive local inflammation and damage in RA?
IL-1, IL6, TNF
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
What is meant by cytokine disequilibrium in RA?
INcreased TNF and IL-1, vs soluble TNF receptor, IL-10 and IL-1 receptor antagonist
What proporotion of RA patients are seronegative?
1/3
How is a Dx of RA made?
Small joints symmetrical 6 weeks duration Arm stiffness for 1 hour RhF or anti-CCP Nodules Erosions
What is the feature of small joint involvement in RA?
DIP joints are spared, with fixed deformity and erosion/destruction
How are small joints differently involved in SLE?
DIP joints are spared, but deformity is passively correctible and there is minimal destruction
How is small joint involvement different in gout vs RA?
gout has involvement of the DIPJ, with tophi and large, marginal punched out lesions
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
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
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
What are 3 causes of high titre RF and Sn for each?
RA - 70-90%
Sjogren’s - 75-95%
Cryoglobulinaemia - 40-100%
What are significant causes of false +ve rheumatoid factor?
Hep B or C Bacterial endocarditis TB Syphilis Viral infection Sarcoidosis IPF PBC Malignancy
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
What is the effect of smoking on CCP?
increases anti-CCP
What are genetic factors predisposing to RA?
HLADR4
PTPN22
STAT4
PADI
What are environmental triggers for RA?
EBC, CMV, Parvovirus, Barmah Forest, RR fever, foreign or auto antigen exposure
What is the most potent environmental factor?
SMOKING
What is an AE of MTX plus leflunomide?
Pneumonitis, peripheral neuropathy, transaminitis
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
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)
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
What cell types does TNFa promote?
synoviocytes, chondrocytes and osteoclasts
Which TNFi is not cytolytic?
etanercept
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
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
What are pathologies that respond to TNF blockade?
Infections (bacterial) - staph/strep/pneumococcus
Zoster!
Chronic HSV (ophthalmic)
Melanoma
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
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
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
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
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
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
What is the role of tofacitinib in RA?
oral JAK3/1 inhibition, reduces signs and symptoms of RA as monotherapy - suppreses STAT1 dependent genes
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
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
