HLA DR4, Dw16, DR10, DR9, DR3 associated with rheumatoid arthritis.
HLADR5, DR7, DR2 may protect against rheumatoid arthritis ( Frequency less).
. May be manifestation of response to infection by mycoplasma, EBV, CMV, Parvovirus & rubella virus.
.Cigarette smoking – triggering factor.
Hyperplasia & hypertrophy of synovial cells.
Infiltration with mononuclear cells, macrophages.
Production of IL-1, IL-6 TNF alpha, PGE2, Leukotriene B4.
TNF alpha : proliferation of inflammatory cells
IL-1 : cartilage proteoglycan resorption, bone erosion,destructive aspect of RA
IL-6 : mediates IL-1 & TNF alpha actions
stimulates B cells
Diagnosis of rheumatoid arthritis Morning stiffness 1h Three or more joints involved Arthritis of hand joints Symmetric arthritis Rheumatoid nodules ( over bony prominence , extensor surfaces) Rheumatoid factor (positive < 5% normal subjects) Radiographic changes (must show erosion/decalcification) Present for 6wk Any 4 of the following must be present to allow diagnosis of RA ( Patients with 2 or more clinical diagnoses are not excluded )
RA- joint involvement
Interstitial lung disease
Rheumatoid Factor . : +ve In about 80% of cases
- Also present in about 5% of normal individuals
- when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of RA.
ESR. The higher the ESR the greater the inflammation., help determine how active the condition is.
C-Reactive Protein . High levels of C-reactive protein (CRP) are also indicators of active inflammation..
Anti-CCP Antibody Test . The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop.
Tests for Anemia . normocytic normochromic
X-Rays, Dexa Scans . Ultrasound. Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA.
Magnetic Resonance Imaging . Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI may be able detect bone erosions in the hands of RA patients where x-rays cannot.
Above lab findings plus clinical features are important to make the diagnosis
Disease Activity Score of 28 joints (DAS28). It is widely used as an indicator of RA disease activity and response to treatment The joints included in DAS28 are PIP , MCP joints, wrists , elbows , shoulders and knees
When looking at these joints, both the number of joints with tenderness upon touching ( TEN28 ) and swelling ( SW28 ) are counted.
In addition, the ESR is measured.
Score less than 3.2 means pt is inactive
3.2-5.1 means moderately active patient
more than 5.1 means pt is active
Goals of therapy Alleviate pain Preservation of function Control disease activity Maximize quality of life Slow progression/rate of joint damage
Splinting: prevents unwanted joint movement
Exercise: directed to maintain muscle strength & joint mobility
.Some studies suggest that omega-3 fatty acids may reduce rheumatoid arthritis inflammation.
Some Herbal remedies also found to be useful
First line drugs in mild/early cases
Afford symptomatic relief in pain , swelling , morning stiffness
Do not arrest disease process
Non selective Cox inhibitors :
Naproxen - 500 mg bd.
Piroxicam -20 mg qid
Nabumetone 1000mg od
Aceclofenac , Etodolac upto 1000 mg/day
Indomethacin reserve dg when other NSAIDs don’t provide relief
Aspirin is rarely used now
Adverse effects :G I bleeding, ulcers, hepatoxicity, rash.
Selective cox-2 inhibitors :
Etoricoxib 90 mg od has highest selectivity ratio for inhibition of cox 2. & has superior efficacy compared with 500 mg naproxen bd over 12 weeks
Rafecoxib valdecoxib are obsolete now because of their cardiotoxicity
Nitritoid rxns- sweating, flushing & headache, sp. with gold thiomalate
Rarely used now because of Questnable efficacy and high Toxicity
A copper chelating agents
Gold like action in RA
Dose: Start with 125-250 mg OD, then 250 mg BD
ADRs : Same as gold
Other: loss of taste, SLE & Myasthenia gravis
Rarely used because of toxicity
OTHER drugs approved are Chlorambucil, Cyclophosphamide , Cyclosporine, Azathioprine
Biologic therapies, or biologics
Newer drugs that reduce RA inflammation in a more highly targeted manner than the DMARDs. These are used when there is inadequate response with the DMARDS
Biologics are made through biotechnology and target very specific proteins or cells that are involved in the inflammatory process.
Biologics have also been shown to help reduce the progression of joint damage in RA.
The currently available biologic therapies for RA must either be injected under the skin [etanercept, adalimumab, anakinra] or infused [infliximab, abatacept, and rituxumab]).
TNF α inhibitors
MOA: it is recombinant fusion protein consisting of two soluble TNF p75 receptor moieties linked to Fc portion of human IgG1, it binds TNF α molecule
It decreases rate of formation of new erosion
DOSE: 25 mg twice weekly given s.c.
- Opportunistic infections, Activation of latent TB
MOA: it is fully human IgG1 anti TNF monoclonal antibody complexes with soluble TNF α and prevents its interaction with cell surface receptors causing down regulation of macrophages and Tcell function
DOSE: 40 mg given every 2 weely given s.c.
Respiratory infection is a common a/e
Comb with MTX to improve response
MOA: it is chimeral IgG1 monoclonal antibody that binds with TNF α
DOSE: 3-10 mg/kg as an i.v. infusion every 8 weekly
Comb with MTX improves response and decreases rate of formtion of new erosions more than MTX alone
A/E: URTI, nausea, headache, sinusitis, rash, activation of latent TB
C/I: multiple sclerosis as demyelinating syndromes have been reported
TNf- blocking agents More effective in combination with methotrexate Drug Primary action ROA Usual dose Half life Infliximab Chimeric anti TNF- Ab I/V inj. 3 mg/kg at 0,2,6 wks, then 8 wkly. Gradual ↑ to 10 mg/kg if incomplete response 9 days Etanercept Soluble TNF fusion protein, Binds TNF- α & β S/C inj. 25 mg twice/wk or 50 mg once/wk 4 days Adalimumab Human anti- TNF- α Ab S/C inj. 40 mg every 2 nd wk 2 wks
Anakinra - It is recombinant human IL-1 receptor antagonist.
Used in cases who have failed on others drugs.
A/e local reaction on s/c inj. & chest infection
Do not use in combination with TNF-alpha antagonists
IL-1R antagonists: ANAKINRA
IL-6 BLOCKING AGENT : TOCILIZUMAB
IL-6 activation leads to systemic inflammatory manifestations and abnormal lab findings in patients with RA.
Tocilizumab is a Humanized anti IL-6 monoclonal Ab that specifically inhibits the action of 1L-6
It is reserved for Resistant RA
It is recombinant fusion protein.
MOA: inhibits activation of T cell
DOSE: depends on body wt it is given as i.v inj.
<60 kg: 500mg
60-100 kg: 750 mg
Used when there is inadequate response to DMARDS
Risk of infections
Unfortunately not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents.
B CELL DEPLETION THERAPY
Targeting B-lymphocytes in these patients has opened a new therapeutic window
Chimeric monoclonal Ab, targets CD20 B cells
Used in resistant RA . Benefit in treatment of RA refractory to antiTNF agents
Combination therapy with methotrexate
Dose: 2 IV infusions 2 wks apart
ADRs: Mild infusion reactions (infrequent)
BIOLOGICS : FUNCTION AT A GLANCE
Adverse Effects of Biologics
Infusion related : dyspnoea , chest pain , rash, hypotension
FUTURE PROSPECTIVES compound MOA Development phase USA EU TNF inhibitors CDP-870 Anti-TNF Ab fragment III III Pegsunercept Pegylated soluble TNF R type 1 II ISIS-104838 TNF- antisense inhibitors II AGIX4207 TNF inhibitor (oral) II II IL based therapies Atlizumab Humanized anti-IL6 R monoclonal Ab II I HuMAX-IL-15/AMG-714 Anti-IL-15 monoclonal Ab II II ABT-874/J-695 Anti-IL-12 monoclonal Ab II II
FUTURE PROSPECTIVES Compound MOA Development phase USA EU Cell adhesion molecule inhibitors Natalizumab Humanized monoclonal Ab II II Co-stimulation inhs CTLA4-Ig CD27/B7 pathway inhibitor III Alefacept CD2 antagonist II
FUTURE PROSPECTIVES Immunoadsorption Apheresis – new technique used in pts who are not responding to drug therepy Compound MOA Development phase USA EU Other therapies CCI-779/ Temsirolimus Cell cycle inhibitor II Belimumab Ab against B cell stimulator protein II AT-001/dnaJp1 Heat shock derived protein II
FDA Adds Boxed Warning To Leflunomide For Severe Liver Injury
July 13, 2010 — The rheumatoid arthritis drug leflunomide has received a boxed warning about the risk for severe liver injury.
The FDA identified 49 cases of severe liver injury associated with the drug, including 14 cases of fatal liver failure.
Rheumatoid arthritis is a common autoimmune disease that can lead to serious functional limitations, joint destruction, extra-articular disease, poor quality of life, and premature death
Early recognition of arthritis and speedy referral to a rheumatologist are essential
Treatment should start early and aggressively to prevent functional limitations and structural damage
Innovations in treatment and monitoring have resulted in patients achieving early and sustained clinical and radiographic remission
Methotrexate is the first line drug, but in high risk patients early combination of methotrexate with prednisone or a tumour necrosis factor inhibitor improves outcomes