Rheumatoid arthritis Flashcards
Genetics in RA
HLA-DR1,DR4, shared epitope in 3rd hypervariable region
Negative charge more important
Enviornmental risk factors
Smoking increases risk by 20-40 fold
Autoantigens in RA
Type II collagen, cartilage gp39, IgG, citrullinated peptides
Anti-modified protein antibodies in RA
ACPA(anti-CCP), Anti-Car P, Anti- MMA, Anti-hinge
Citrullination in RA
Induction of peptidyl arginine deaminase (PAD) -converts
arginine to citrulline
Regulatory gene in RA
PTPN22 -missense single-nucleotide polymorphism associated with RA and SLE
HLA DR-1,DR-4, smoking and PTP 22 associated with anti-CCP
Predominant cells in RA synovium
Lymphocytes. Neutrophils absent in synovium, but present in synovial fluid
T cells>50% -CD4 memory
TH1 and TH17, Low TH1 and TRegs
Role of IL-15 in RA
Abundant in synovium, some role in increasing TNF
IL-1 in RA
Increased in erosive disease
GM-CSF activates HLA-DR, current target
Metabolomics
Serum and urine metabolites can distinguish RA and OA
Decreased branched chain aa and increased lactate
Can predict response to TNF
RF in RA
Positive in 70% of RA
More in patients with nodules
Poor screening test
Predicts severe disease
Anti-CCP ab in RA
Sensitivity 60-80%, specificity >90%
Better predictor of severity than RF
Marker of erosive disease
Extra articular features of RA
Nodules, capillaritis, lung fibrosis,LNE,Splenomegaly(Felty)
Vasculitis, scleritis
Constrictive pericarditis
Methotrexate in RA
Anchor drug, reduces CV mortality
CI -Mild seronegative disease, hepatic/renal impairment, significant lung disease
S/c MTx very effective
Mx of MTx pneumonitis
Discontinue, supportive Mx, steroids
Methotrexate and lymphoma
Lymphoma increased in RA, presence of EBV
Periop Mx with MTx
Does not need to be ceased perioperatively
Leflunomide MOA in RA
Inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a role in the de novo synthesis of uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA.
Leflunomide side effects
Diarrhoea, hair loss,Pancytopenia -rare
Pneumonitis,Peripheral neuropathy
CI -Pregnancy and breast feeding, liver/haem abnormality
Long half life - cholestyramine washout
Biologics in RA
Etanercept - TNF alpha inhibitor
Abatacept - fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of CTLA-4. Binds to the CD80 and CD86 molecule and prevents interaction with CD28-> no T cell activation. More effect with anti-CCP positive. Lowest infection risk
Infliximab - TNF alpha inhibition by binding to soluble and transmembrane forms
Adalimumab -human monoclonal antibody against TNF-alpha
Rituximab- chimeric monoclonal antibody against the protein CD20
Golimumab- human monoclonal ab against TNF- alpha
Certolizumab - PEGylated Fab fragment of a humanized TNF inhibitor monoclonal antibody
Tocilizumab -humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Only biologic superior to Mtx and adalimumab as monotherapy
TNF inhibitors in RA
Reduce joint damage independent of clinical response
Radiologic changes - causes delay in changes
Works better in combination with Mtx
Only 40% go into remission
Less resistance to TNF inhibitors
Less frequency of monitoring , DNA ab in upto 40%
Cannot be used with h\o malignancy within last 5 yrs
Greatest risk with TNF inhibitor
TB
Screen ,if Mantoux positive >5mm-treat for latent TB ,commence treatment prior to starting TNF inhibitor
Highest risk of demyelination in TNF inhibitors
Etanercept -highest risk
S/E with tocilizumab
Infections, infusion reaction
Bowel perforation -CI with h\o diverticulitis
LFT derangement,lipid elevation, neutropenia
Rituximab in RA
Used in combination with Mtx Works better in seropositive RA Effective in rheumatoid lung disease Use in patients with malignancy, infection Do not use in Hep B , even if treated
MOA of Tofacitinib
JAK inhibitor- JAK3 and or JAK1
Monotherapy or combination with Mtx-more effective
S/E -Transaminitis, Increase Cr, neutropenia, increased lipid
High risk of herpes zoster, GI perforation
Not used in pregnancy, secreted in milk
MOA of Baricitinib
JAK 1 and JAK 2 inhibitor -More potent
More effective in combination with Mtx
Increased risk of DVT
Biologics in pregnancy
Infliximab, etanercept, adalimumab, certolizumab (avoid in 3rd trimester)
Most important diagnostic and prognostic marker in RA
Anti CCP
May predict development of RA
Marker of erosive disease
Conditions with high RF level
RA, Sjogrens, Cryoglobulinemia
Main epitope for Anti CCP
Filaggrin
Poor prognostic markers in RA
High titre RF,presence of anti-CCP; high CRP;smoking, baseline erosions on Xray, homozygosity for HLA-DRB01*04
Strongest factor for poor prog - erosions on XRay
Marker most predictive for death from CVD in RA
CRP
Agent least likely to slow radiological progression in RA
HCQ
Genes associated with risk of developing RA
DR4,STAT4, PTPN22,PADI
Indicators of activity in RA
High CRP, ESR,number of swollen joints
Most common ocular manifestation of RA
Keratoconjunctivitis sicca
Others -episcleritis, scleritis,corneal ulceration ,keratitis
