day 2 - drugs for bones and joints

Question 1

difference between COX1 and 2

Answer 1

Cox 1 is constitutive (activity is increased as part of inflammatory response also 2-4 fold). Cox 2 is inducible by inflammatory stimuli in many cells including macrophages, syniviocytes, chondrocytes, fibroblasts and endothelial cells.

Question 2

Analgesia in RA

Answer 2

Paracetamol
Paracetamol-opioid combinations
Non steroidal anti-inflammatory drugs
Do not change natural history of disease, used for symptom control only

Question 3

Disease Modifying Agents - RA

Answer 3

DMARDs (disease modifying anti-rheumatic drugs)

Immune modulators - restore ‘normal’ immune environment within synovium

Alter disease activity, outcome and progression, and provide symptom relief

Slow onset of action: weeks-to-months

Comparisons of efficacy based on functional indices reduction in joint swelling and lab markers e.g. ESR/CRP

All require regular monitoring for adverse effects

Should be started soon after diagnosis, or can have worse outcomes

Question 4

DMARDs- RA

Answer 4

Methotrexate
Sulfasalazine
Gold salts
Azathioprine
D-Peniciallamine
Hydroxychloroquine
Ciclosporin
Lefluonamide
Biological agents

Question 5

Methotrexate moa and dose

Answer 5

Competitive inhibition of dihydrofolate reductase. Also has other anti-inflammatory and cytokine modulating effects

Used in RA, psoriatic arthritis, and as a steroid sparing agent in other AI conditions

Low dose used in RA and other AI disease (high doses in haematological malignancies)

Dose:
Weekly dose (7.5 mg-20mg- per week).
Often taken in conjunction with folic acid (5mg, other 6days/week)

Coverts dietary folic acid to tetrahydrofolate – required for DNA and protein synthesis. Thus impairs cellular replication.
Cytokine modulation less understood

Question 6

Methotrexate- adverse effects

Answer 6

Usually well tolerated. BUT requires monitoring

SE related to inhibition of cellular replication
Mouth ulcers / nausea – Rx with folic acid
Bone marrow suppression inc. neutropaenia

Others:
Acute cutaneous reactions, hepatitis, pneumonitis (temporary discontinuation)
Chronic use can rarely lead to interstitial pneumonitis and hepatic cirrhosis
Renally excreted so care with CRF or agents that impair GFR

Teratogenic (3 month washout)

Question 7

Hydroxychloroquine moa and toxicity

Answer 7

Accumulates in cells – appears to block TLR signalling, phagocytic functions, and DC activation however exact mode of action poorly understood

Efficacy unclear but commonly used in SLE and RA

Toxicity based on cumulative dose
Eye: corneal (reversible) and macular retinopathy. Need baseline eye exam (peripheral and colour vision) and monitoring. Note – G6PD lysis
Common: GI upset

Question 8

Sulphasalazine moa and tox

Answer 8

Aminosalicylate (in common with mesalazine)

= 5-ASA linked to sulfapyridine.

Poorly absorbed, orally cleaved to 2 active components by colonic bacteria
5-ASA – anti-inflammatory/immunosuppressive effects
Sulfapyridine – (purported) anti-folate activity

SE:
Common: GI upset, headache
Rare: haematological dyscraisias, renal impairment, oligospermia, hypersensitivity reactions

Question 9

use of biologicals in RA

Answer 9

Natural substances, chemically altered used as therapeutic agents

Used in patients who have 
Active disease (DAS28 >5.1) on 2 occasions, 1 month apart
Not responded to at least 2 DMARDs (including methotrexate) after 6months, 2 months at standard dose

Target chronic inflammatory pathway

Aim
Improvement in DAS28 >1.2points at 6months

Question 10

Biological Agents- RA

Answer 10

Anti TNF
Infliximab, chimeric antibody of part mouse (variable region) part human antibody (Fc region) . Inhibits TNF by binding in the joint cavity, infusion with methotrexate once a week

Etanercept, recombinant human TNF fusion protein, competitively inhibits TNF binding to cell surface receptor, subcut injection twice a week

Adalimumab, recombinant human monoclonal antibody, subcut injection

Others: Golimumab, Tocilizumab, Abatacept, Certolizumab

Question 11

Rituximab

Answer 11

Monoclonal antibody to CD20
Depletes B cells
Used to treat moderate to severe RA patients who have failed anti TNF therapy
Given max 6-monthly
No long term data

Question 12

Osteoarthritis treatment goals

Answer 12

Age or injury related cartilage damage

Leads to joint damage

Presents with pain and swelling

Cellular mechanisms of disease poorly understood- therapeutic goals are reduction of pain and symptom control

Question 13

Osteoarthritis- Treatment

Answer 13

Simple analgesia (paracetamol, NSAIDS)
Physiotherapy
Exercise
Patient education 
Avoid weight gain
Bone protection 
-Bisphosphonates
		-Calcium supplementation +/- VD3
Joint injection
Joint replacement

Question 14

what is Gout

Answer 14

precipitation of monosodium urate crystals in tissues, imbalance between production and secretion of uric acid.
Hyperuricaemia associated with obesity, diabetes, hypertension, CAD, renal insufficiency, and increased triglycerides.

Question 15

uric acid excretion

Answer 15

UA: filtered at glomerulus. In hyperuricaemia large loads filtered, UA
re-absorption increases to avoid dumping of poorly soluble urate
into urinary tract (secretion impaired).

Uricosuric agents (probenicid, sulfinpyrazone and high dose aspirin)
block re-sorption of filtered and secreted UA in the renal tubules.

Thiazide diuretics and low dose aspirin reduce renal clearance of
uric acid-90%) may precipitate gout.

Question 16

Gout- acute treatment

Answer 16

AIM: relieve pain and inflammation.

NSAIDs e.g. high dose indomethacin

NOT allopuinol or probenicid acutely as cause mobilisation of uric acid stores as serum levels fall & will prolong acute attack.

Colchine: inhibits leukocyte micro-tubular formation and migration

must be given early until good pain relief or G.I side effects (nausea, vomiting , diarrhoea, abdo pain) t1/2=30hrs clearance reduced in renal impairment.

Steroids may be useful.

Question 17

Gout- Chronic treatment

Answer 17

Aim: control symptoms and prevent renal damage. Long –term hypouricaemic agents for those with recurrent attacks (>2/yr)

Allopurinol: Competitively binds xanthine oxidase which converts adenine & guanine (purines) to UA. Reduces precipitation in joints and kidneys.

Reduce dose in renal and hepatic failure.

S.E. headaches, dyspepsia, diarrhoea. Gout flare!

Rarely fever, renal failure, allopurinol hypersensitivity (Stevens-Johnson Syndrome and TEN). Note interaction with mercaptopurine and azathioprine

Other uses: prevention of tumour lysis syndrome

Question 18

Osteoporosis- treatment aims

Answer 18

Prevent further bone loss
Improve bone mineral density
Reduce fracture risk

Question 19

Osteoporosis- treatment

Answer 19

Calcium/ vitamin D
Bisphosphanates- inhibit bone resorbtion (osteoclasts):
- Alendronate, etidronate
Reduce vertebral and non vertebral fractures
Daily/ weekly tablets
Can cause :
oesphageal ulceration and hypophosphataemia (commonly)
Osteonecrosis of the jaw, atypical femoral fracture (rarely)

Denosumab (anti-RANKL)
SERM’s (selective estrogen receptor modulators e.g. raloxifene)
Strontium
Recombinant PTH (teriparatide)

NOTE - HRT is no longer used as increased risk of coronary events and breast cancer

Question 20

Ankylosing spondylitits

Answer 20

Ankylosing spondylitis (AS), a form of spondyloarthritis (SpA), is a chronic inflammatory disease of the axial skeleton manifested by back pain and progressive stiffness of the spine; it can also involve the hips, shoulders, and peripheral joints. Extraarticular manifestations, including uveitis, may also be seen in patients with AS and other forms of SpA. AS typically develops in young adults, with a peak age of onset between 20 and 30 years.

The name “ankylosing spondylitis” is derived from the Greek root “ankylosis,” meaning stiffening of a joint, and “spondylos,” which refers to a vertebra. “Ankylosing spondylitis” thus refers to the inflammatory disorder associated with fibrous or bony bridging of joints in the spine, including the bridging of intervertebral discs.

Question 21

Psoriatic arthropathy

Answer 21

INTRODUCTION — Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis [1]. It was initially considered a variant of rheumatoid arthritis, but subsequently emerged as a distinct clinical entity [2]. Historically, seronegativity for rheumatoid factor (RF) had been a requirement for the diagnosis; however, over 10 percent of patients with uncomplicated psoriasis and up to 15 percent of the normal population have RF present in their serum. As a result, the term “usually seronegative” arthritis is most suitable for PsA [3,4].

Patients with psoriatic arthritis (PsA) present with pain and stiffness in the affected joints. Morning stiffness lasting more than 30 minutes occurs in one-half of patients. The stiffness is accentuated with prolonged immobility and is alleviated by physical activity. A history of psoriasis is present in about 70 percent of patients presenting with arthritis.