Pain & Analgesia: Disease Modifying Anti Rheumatic Drugs (DMARDS) Flashcards
What are the important disease affecting the joints?
- OA= degenerative, ‘wear and tear’, very common, experienced by most elderly people
- Crystal arthropathies= uric acid deposition (gout), calcium pyrophosphate deposition (pseudogout)
- Inflammatory joint diseases= immunologically-led pathology, inflammation central feature
What are the inflammatory joint diseases?
-RA Connective tissue disease: -Systemic lupus erythematosus -Systemic sclerosis -Mixed connective tissue disease Seronegative spondylarthropathies- axial skeleton -Psoriatic arthritis (men> women) -Ankylosing spondylitis -Enteropathic arthritis (IBD) -Reactive arthritis (infections) -Behcet's disease
What is the pathophysiology of inflammatory joint diseases?
- Immune system mistakenly attacks the tissue that lines and cushions the joints (synovium)
- Joint becomes stiff, swollen and painful
- Cartilage wears away- release of destructive enzymes
- RA= pannus (thickened synovium), white cells
Describe RA
- Chronic inflammatory disease= 1-3% population, women 2-3 x men
- Joints primarily involved early= synovial joints simultaneously (polyarthritis), small joints of hands and feet (symmetrical), painful, swollen and stiff and deformed joints
- Systemic (extra-articular) manifestations later= heart, small vessels, lungs, kidneys, eyes, spleen
- Younger onset than OA= 25-50, disability more severe, systemic
How does RA present?
-Joint stiffness (morning and after rest)
=Joint pain (difficulties with daily activities)
-Flare-ups and remissions
-Joint structure damages= weak ligaments, tendons and muscles around hands decrease grip and manual dexterity
-Disuse atrophy (wasting of muscles)
What is the aetiology of RA?
- Unknown
- Probably multifactorial= inappropriate immune-mediated inflammatory response
- Genetic predisposition (HLA-DR4 increase risk by 5x)
- Environmental factors may trigger immune response= infectious (parvovirus), diet
What are the stages of RA?
- Inciting agent
- Immune system activation
- Immune complexes deposition (synovium)
- Complement activation
- Inflammatory response= T cells, B cells, macrophages, cytokines, antibodies, complement
- Joint destruction
Describe the pathogenesis of RA
- Inflammation and oedema of synovium (T cells)
- Synovial hypertrophy and proliferation increases fluid
- Pannus formation (granulation tissue)
- Destruction of cartilage and bone by pannus= pro-inflammatory cytokines (TNFa, IL-1, interferon x), metalloproteases (collagenases)
- Muscles wasting
- Joint deformity and ankylosis (fuse bony ends)
What are the clinical features of RA?
- Onset insidious in 70% (may be abrupt)
- Often begins with ache and morning stiffness (>30 mins)
- Early symptoms may be the thought ‘age-related’
- Most commonly presented: polyarticular and symmetrical
- Typically small joint of feet and hands
- Tenderness in all joints affected, swelling of joints
- Early afternoon fatigue and malaise also occur
- Deviation of fingers/ Z deformity of thumb/ weakening of muscles/ subluxation of joints
What are the extra-articular manifestations of RA?
-General= weight loss; malaise and fever, lymphadenopathy
-Skin= ‘rheumatoid’ nodules
-Eye= keratoconjuctitis, scleritis, episcleritis
-Respiratory= pleurisy, pleural effusions, interstitial fibrosis, rheumatoid nodules, bronchiolitis
-Cardiac= pericarditis, myocarditis, endocarditis, valvular heart disease
-GI= adverse effects from drugs
-Renal= amyloidosis, drug induced nephropathy, renal tubular acidosis
-Neurological= entrapment syndrome (carpal tunnel), peripheral neuropathy from vasculitis- sensory and motor, mononeuritis multiplex
-Haematological= anaemia, leucopoenia, lymphoma, thrombocytosis
More likely in RF factor/ HLA-DR4 positive
What are the x-ray investigations used to diagnose RA?
- Soft tissue swelling and widening of joint space (early)
- Osteoporosis and uniform narrowing of joint space (later)
- Bone erosions and cysts (due to pannus destruction)
- High-resolution ultrasound and MRI
What laboratory tests are used to aid diagnosis?
- ESR raised (90%)
- Anaemia (normochromic normocytic)
- Synovial fluid (cloudy, sterile, decreased viscosity, increased white cells)
- Rheumatoid factor (75%) decreased prognosis
- Other autoantibodies
- Anti-citrullinated protein antibodies (ACPAs)
What are the goals for pharmacological management of RA?
- Relieve symptoms early
- Put disease into remission early
- Prevent joint-damage long-term
Describe early stage RA management
- Analgesic drugs (paracetamol, codeine)
- Non-steroidal anti-inflammatory drugs= ibuprofen, diclofenac, COX-2 selective drugs (celecoxib)
Describe RA treatment management after diagnosis
- DMARDs= disease-modifying anti-rheumatic drugs, more powerful but adverse effects
- Corticosteroids/ immunosuppressants= intra-articular injections, occasionally systemic oral treatment
- Biological therapies if failure to respond to DMARDs
Why do we use DMARDs?
- Reduce underlying disease activity
- Reduce pain and disability
- Achieve remission
- Reduce inflammatory destruction of joints
- Prevent progression
What are the initial choices of DMARD?
-Methotrexate
-Sulfasalazine
Plus corticosteroid
-Immunosuppressant drugs= LEFLUNOMIDE, azathioprine, ciclosporin, cyclophosphamide
-Older DMARDs= HYDROXYCHLOROQUINE, penicillamine, gold salts
What happens to DMARD choice when disease becomes refractory/ aggressive/ systemic?
-Cytokine modulators =infliximab (TNFa inhibitors) =etanercept (TNFa i) =adalimumab (TNFa i) -Other new biologics =abatacept (T cells) =rituximab (B cells) =anakinra (IL-1) =toclizumab (IL-6)
What are the general points about DMARDs?
- Not analgesics
- Target immune-mediated inflammatory activity
- No immediate therapeutic effect (2-6 months for full response)
- Response should allow NSAID dose to be reduced
- No objective benefit= discontinue= try another
- Retard erosive damage as judged radiologically
What is mechanism of action of methotrexate?
- Dihydrofolate reductase inhibitor
- Enzyme important in regenerating folic acid
- Generation in thymidine bases in DNA
- Inhibit chances of rapidly dividing cells can replicate contributing to further damage
Describe methotrexate
-Immunosuppressant= blocks DNA synthesis in proliferating cells by binding with and blocking the action of folic acid reductase
-Indications= RA, psoriasis, Crohn’s disease, malignancy
-By mouth once weekly with food (can also be given by injection)
-Usually prescribed with folic acid
-GI upset (sickness, diarrhoea, mouth ulcers), hair loss, skin rashes, blood cell formation disruption, teratogenic, infections, liver, pulmonary toxicity
-Contra-indications= pregnancy, immunosuppression, liver disease
Bone marrow disruption
What are the dangers of immunosuppressant drugs?
-Viruses (herpes zoster)
-Fungi (candida)
-Tuberculosis
-Malignancy
Cellular immune system > humoral
What is the structure of sulfasalazine?
- Combination of sulphonamide (antibiotic) and 5-ASA (amino salicylic acid)
- Joined by azo bond, cleaved in the colon
Describe sulfasalazine
-Aminosalicylate= combination of 5-ASA and sulfapryridine
-Anti-inflammatory, systemic immunosuppressant activity
-Indication= active RA, IBD (UC, Crohn’s)
-By mouth as enteric-coated tablets (initially 500 mg to 2-3 g daily)
-Rashes, GI upset, decreased WBCs (neutrophils) and platelets (monitor FBC), reversible azoospermia, anaphylaxis, photosensitivity, decreased folate
Bone marrow disruption
