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Treatment of Major Rheumatic Diseases

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Title: Treatment of Major Rheumatic Diseases


1
Treatment of Major Rheumatic Diseases
  • Dr Tanya Potter
  • Consultant Rheumatologist

2
Aims
  • 1 To pass your exam
  • 2 Encourage safe prescribing (and you will
    remember that have an exam in this also)

3
  • Rheumatoid arthritis (RA) or osteoarthritis (OA)
    most common types seen in clinics ( exams)
  • Dramatically improved treatments in past 20 yrs

4
Osteoarthritis
  • most common
  • 75 people gt 70 radiographic OA F M 2.51

5
Osteoarthritis
  • Joint space narrowing
  • Osteophytes
  • Subchondral sclerosis
  • Bone cysts

6
Management
  • Pain relief is key
  • Seek improvement in joint mobility or walking
    time
  • e.g. how long it takes for pt to walk to end of
    corridor
  • Quality of life- can use functional measures to
    see how well person is doing. Use several simple
    questions
  • How well can one button clothes?
  • Can make own meals everyday?
  • Gives good reliable data

7
OA - Goals of Treatment
  • No cure
  • Meds can improve function by reducing pain
  • Can limit final impairment
  • Non-pharmacological and pharmacological
  • Non-pharmacological
  • Patient education (education leaflets/ websites)
  • Wt loss (10-15 lb weight loss can reduce pain
    100)
  • Every lb gained, X four across weight bearing
    joint
  • Muscle strengthening important -esp. quads muscle
  • PT OT important
  • Use devices for joint protection (canes, walkers
    etc)

8
Drugs
  • Mild to moderate
  • Paracetamol
  • Topical agents non steroidals, rubefacients
  • Moderate to severe
  • As above, plus
  • NSAIDs
  • combination analgesics (paracet opiods) /
    Opiods/ Tramadol

9
Paracetamol
  • Analgesic/ antipyretic
  • Unknown mechanism of action
  • combo with opiods? better response
  • when cant use NSAIDs (gu / du/ renal/ warfarin)
  • Doesnt alter platelet function (bleeding/
    surgery)
  • Safer for elderly
  • Caution with chronic liver dz (hepatotoxicity, gt
    2 gm)
  • Thrombocytopaenia, neutropaenia rare

10
Tramadol
  • Centrally acting analgesic
  • Use in addition to NSAID
  • Effects mu receptors Same potency as opiods
  • Can use as adjunctive therapy
  • Less opiod SE esp constipation/ nausea/ vomiting
  • Balance problems
  • smaller potential of abuse or dose acceleration,
    (pt needs more drug in shorter time period) c.f.
    opiods

11
Strong opiods
  • Use in pt with limited options
  • loss of function due to pain
  • renal or heart disease preventing operation
  • Select pt carefully
  • Use during period of disease flare, then decrease
    use
  • Limitations
  • Nausea, vomiting, constipation, urinary
    retention
  • Chronic use leads to physical dependence
  • Can use with anti-inflammatory
  • Lots of choice (short or long acting, patches)

12
NSAIDS
  • 25 million NSAID prescriptions/ yr in UK
  • Non selective
  • Aspirin
  • Ibuprofen
  • Naproxen
  • Indomethacin
  • Piroxicam
  • Selective cox 2 inhibiters
  • Celecoxib
  • Etoricoxib
  • Meloxicam
  • etodolac

13
NSAID risk
  • How many GI bleed admissions annually in the uk?
  • What percentage are likely to due to NSAIDs?
  • How many deaths annually?

14
Upper GI complications
  • 65,000 emergency upper GI admissions p.a. in UK
  • 12,000 of these admissions (including 2,230
    deaths) attributable to NSAID use
  • Further 330 attributable deaths occur in
    community
  • 2 of NSAID users admitted annually for GI
    emergencies

15
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16
GI event may be devoid of warning symptoms
Many patients asymptomatic prior to serious
NSAID-associated GI event (bleeding, perforation)
n 141
n 1,921
19
42
58
81
without symptoms
with symptoms
17
prostoglandins
18
NSAIDs Inhibit cox enzymes
Asthma
blocked
19
Action
  • Reduce prostaglandin production- less
    inflammatory mediators
  • Unopposed leukotrione action
  • Antipyretic effects partly due to a decrease in
    prostaglandin that is responsible for elevating
    the hypothalamic set point for temp control in
    fever

20
COX enzyme
  • Cyclo-oxygenase (COX) has two forms
  • COX-1 protects the stomach lining from harsh
    acids and digestive chemicals. It also helps
    maintain kidney function
  • COX-2 is produced when joints are inflamed or
    injured

21
Action
  • Different NSAIDs inhibit the enzyme by different
    mechanisms
  • Aspirin binds covalently with a serine residue
    of the enzyme (irreversible)
  • Ibuprofen/Piroxicam reversible competitive
    inhibitors of COX non selective
  • Paracetamol acts partly by reducing cytoplasmic
    peroxidase

22
Older nonselective NSAIDs (Ibuprofen, Naproxen)
  • Block both COX-1 and COX-2, GI upset, bleeding as
    well as decreasing inflammation
  • Advice patients to take them with food or a glass
    of milk and should avoid alcohol.
  • Pros
  • OTC version of these drugs are inexpensive
  • Low doses of aspirin taken over long term helps
    to prevent heart attacks, strokes and bowel
    cancer
  • Cons
  • GI upset ie nausea, ulcers
  • Kidney problems from overuse
  • Interacts with warfarin

23
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24
COX-2 inhibitors (Celecoxib, meloxicam,
etorocoxib)
  • Target only the COX-2 enzyme that stimulates the
    inflammatory response
  • Pros
  • less likely to cause GI upset compared to the
    older NSAIDs
  • longer lasting drug longer relief
  • do not thin the blood therefore can consider
    co-prescription with warfarin
  • Cons
  • More expensive compared to traditional NSAIDs
  • Results not as good as endoscopic drug studies
    suggest

25
Indications
  • Commonest use arthritis ie RA or OA and gout
  • Back pain, sciatica, sprains and strains and
    rheumatism
  • Dental pain
  • Post op pain
  • Period pain
  • Renal/ureteric colic
  • Fever
  • migraines

26
CAUTIONS
  • Elderly
  • Pregnancy- miscarriage, early closure of ductus
    arteriosus
  • Breast feeding
  • Coagulation defects
  • Renal, cardiac (heart failure/ hypertension/ IHD)
    or hepatic impairment

27
Contraindications
  • Severe heart failure
  • COX-2 IHD, stroke, PVD and moderate to severe
    heart failure
  • CSM advice previous or active peptic ulceration
  • hypersensitivity to aspirin or any NSAID which
    includes those in whom attacks of asthma,
    angioedema, urticaria or rhinitis have been
    precipitated.

28
SIDE EFFECTS
  • GI ND, dyspepsia bleeding and ulceration,
  • Hypersensitivity
  • Headaches, dizziness, nervousness, depression,
    drowsiness, insomnia, hearing disturbances
  • Photosensitivity
  • Fluid retention (heart failure), raise blood
    pressure
  • Hepatic damage, pancreatitis
  • Eye and lung changes (alveolitis)
  • Stevens-Johnson syndrome toxic epidermal
    necrolysis (rare)

29
GI
  • Similar anti inflammatory effects of selective
    and non selective NSAIDs
  • Non selective
  • 15-40 dyspepsia, nausea, abdo pain
  • 10 discontinue
  • Severe GI toxicity 4.5/100pt years
  • Selective Cox 2 inhibiters
  • Similar GI symptoms
  • lt 6 discontinue
  • Severe toxicity 2.1/100 pt years
  • NNT 42 to prevent 1 serious GI event

30
Cardiovascular toxicity
  • Increased cardiovascular risk of selective NSAIDs
    is a problem
  • unopposed pro-thrombotic effects of
    COX-1-mediated production of thromboxane A2
  • Also, coxibs effects on blood pressure and renal
    function could turn out to be more detrimental
    than those of conventional NSAIDs.

31
prostoglandins
32
CV risk
  • It is a real risk APPROVE study
  • Data obscured by clinical trials not recruiting
    normal pts
  • Data obscured by drug company manipulation of the
    results of clinical trials
  • Up to 42 higher risk of MI with selective
  • 0.6/yr vs 0.3/yr

33
All NSAID/ CVS
  • Rise in BP 3-5mm
  • Equate with an increase
  • CCF 10-20
  • CVA 20
  • Angina 12
  • Lowest risk of all with naproxen (aspirin like
    effects)

34
Naproxen
  • Pain and inflammation in rheumatic disorders
  • 0.5-1g / day in 1-3 divided doses
  • In high risk pts, give with PPI
  • Which one?

35
NSAIDs - past strategies
  • Enteric Coating
  • Pro-drugs hepatic metabolism
  • Gastro-protective agentsPPIs, misoprostol, H2
    blockade

36
OA- Adjunctive therapy
  • Intra articular steroids plus local anesthetic
    for joint inflammation
  • Decrease production of inflammatory mediators
  • Can last a 3-6 months use with physio
  • Probably can be done safely up to four times a
    year
  • not too frequently can effect the cartilage

37
Visco-supplementation
  • Crosslinked hyaluronic acid polymers
  • OA (knee)
  • Intra-articular injections X 3-5
  • Change viscosity in joint
  • Pain relief with improved mobility
  • Success rate is 50-70 for up to 4-6 months
  • no systemic SE

38
Visco-supplementation
  • OA, where physio, weight loss, simple analgesia
    /- NSAIDs insufficient
  • IA steroids not helpful /not lasting
  • Awaiting/ unfit for surgery

39
Capcaisin cream
  • 0.025 preparation (Zacin)
  • Depletes Substance P from nerve endings
  • Slow to act (1/12 to max effect)
  • More effective than topical NSAIDs
  • May reduce analgesic requirement

40
What are the alternatives?
  • Cod liver oil other fishy oils
  • Evening primrose oil
  • Borage or Starflower oil
  • Change in balance of cell membrane fatty acids

41
Alternatives?
  • Glucosamine 1.5 gram/day
  • substrate for glucosaminoglycans
  • Pain relief mobility
  • Possible 10-25 analgesic effect
  • -disease modifier ?
  • ? Nutrition for cartilage
  • ? Stimulate metabolism
  • Vitamin C
  • Framingham study results show reduced pain OA of
    knee hip
  • may improve integrity of cartilage

42
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43
Gout
  • Joint inflammation caused by uric acid crystal
    deposits in the joint space

44
Gout
  • Primary
  • Over production (10)
  • Under secretion (90)
  • Enzyme mutations
  • Predominantly secondary
  • Overproduction (mutations, heavy exercise,
    obesity)
  • Under excretion severe renal diseases, drugs,
    alcohol, HBP

45
  • 2-17 of population are hyperuricaemic
  • The higher the uric acid the higher the chance of
    gout
  • Self reported adult prevalence of 8/1000
  • 2-7M1F
  • Increase in blacks may reflect increased rates of
    hypertension

46
Figure 4 Simplified diagram of uric acid
production and excretion
2/3
1/3
2/3
1/3
Roddy E et al. (2007) The changing epidemiology
of gout Nat Clin Pract Rheumatol 3 443449
doi10.1038/ncprheum0556
47
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48
Epidemiology
  • Middle aged men
  • Dietary purine consumption
  • Alcohol
  • DrugsLow dose aspirin, diuretics
  • Inherited metabolic abnormalities

49
Clinical features
  • Gouty Tophi on pinnae
  • Olecranon bursitis
  • Gouty tophi on hands
  • Gouty nephropathy
  • stones
  • Large joint oligoarthritis
  • 1st metatarsophalangeal
  • joint arthritispodagra

50
erosions with a punched out appearance
51
Management
  • Prevent occurrence
  • Diagnose
  • Treat acute flare
  • Reduce risk of further flare
  • Reduce associated morbidity secondary to HBP,
    hypercholesterolaemia

52
Aspirate joint
  • Differential diagnosis monoarthritis?

53
Management of Acute Gout (1)
  • Goal is to rapidly resolve pain and inflammation
  • High doses of NSAID used
  • Naproxen. 500mg bd until the attack has passed
  • Indomethacin, diclofenac, etoricoxib also used

54
Management of Acute gout(2)
  • Alternative to NSAIDs
  • Colchicine
  • inhibits microtubule polymerization by binding to
    tubulin,
  • inhibition of neutrophil motility and so produces
    an anti-inflammatory response.

55
Treatment
  • Colchicine 500mg bd to tds
  • DO NOT USE BNF DOSE OF COLCHICINE
  • 2/3 will respond cf 1/3 placebo
  • peak plasma concentration 1-2 hrs and a half life
    of 4 hrs
  • Metabolised by the liver with possible
    enterohepatic circulation
  • 20 excreted unchanged in urine
  • Avoid IV
  • Good alternative for patients receiving
    anticoagulants/patients in heart failure (doesnt
    induce fluid retention) or those who cannot
    tolerate NSAIDs for any other reason

56
Side effects colchicine
  • GI
  • Haemorrhagic gastroenteritis
  • Myoneuropathy on prolonged course

57
Acute gout treatment cont.
  • NSAIDs- take early
  • Upper limit of usual therapeutic dose
  • Selective and non selective
  • Glucocorticoids
  • Intra-articular
  • Oral pred
  • IM pred

58
Management of Chronic Gout(1)
  • When is gout chronic?
  • Recurrence of acute attacks, presence of tophi,
    or signs of gouty arthritis may call for
    preventative treatment.
  • Urate lowering therapy has been shown to be cost
    effective in patients with 2/more acute attacks/
    year

59
Management of chronic gout
  • Decision to treat
  • Number of attacks
  • The uric acid level
  • Presence of reversible risk factors
  • Tophi
  • Renal impairment
  • Aim to reduce uric acid to below 0.36mmol/l or
    lower in the presence of tophi

60
Choice of drug
  • Decrease uric acid production by inhibiting
    xanthine oxidase
  • Not used in a history of hypersensitivity
  • Promote renal excretion of urate uricosurics
  • Not useful if decreased GFR or history of renal
    colic

61
Management of Chronic GoutAllopurinol
  • Allopurinol 1st line therapy for Chronic Gout
  • Xanthine Oxidase inhibitor
  • ?Uric acid formation
  • Not to be started in the acute phase
  • Start 2-3 weeks following acute phase.
  • Initiation of allopurinol treatment may trigger
    acute attack?start with NSAID or colchicine
    continue for 1 month after hyperuricaemia is
    corrected

62
Management of chronic goutAllopurinol Dose
  • Initial 100mg OD ( Preferably after food)
  • Then adjusted accordingly to plasma/urinary uric
    acid levels
  • Mild 100-200mg daily
  • Moderately severe 300-600mg daily
  • Severe 700-900mg daily

Dosesgt 300mg should be given in divided doses
63
Management of Chronic GoutAllopurinol ctd
  • Caution
  • Hepatic impairment
  • Renal Impairment
  • Pregnancy
  • Breast Feeding
  • Contraindications
  • Acute gout!
  • Side effects ( extensive list in BNF)
  • Rashes Withdraw therapy(if mild re start but
    withdraw immediately if reccurs)
  • Neuropathy
  • Blood disorders
  • Renal impairment
  • Hepatoxicity

64
Uricosurics
  • High dose aspirin (note low dose retains urate)
  • Sulfinpyrazone
  • Probenecid
  • Benzbromarone
  • Use colchicine prophylaxis
  • Slowly increase dose
  • Alkaline diuresis with water loading and oral
    bicarb

65
Management of Chronic gout (5)Sulfinpyrazone
  • A uricosuric drug increases the excretion of
    uric acid
  • Used instead of allopurinol, or in conjunction.
  • Dose 100-200mg daily, increasing over2-3 weeks to
    600mg(rarely 800mg) daily, until serum uric acid
    levels normal.
  • Cautions
  • Hepatic impairment
  • Renal impairment
  • Pregnancy
  • Contraindications
  • in patients with a history of hypersensitivity to
    aspirin or any other NSAIDwhich includes those
    in whom attacks of asthma, angioedema, urticaria
    or rhinitis have been precipitated by aspirin or
    any other NSAIDs)
  • coagulation defects
  • Hx of MI/Stroke or PAD
  • moderate or severe heart failure
  • active pepticulceration

66
Also address
  • Obesity
  • Triglycerides
  • Alcohol
  • Hypertension
  • Thiazide therapy- consider alternative

67
Questions?
68
RA ( Psoriatic Arthritis)
  • 600,000 people in UK
  • many unable to work
  • 42 registered disabled within 3 years
  • 80 moderate to severe disability in 20 years

69
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70
Management
  • MDT
  • Physiotherapy OT very important
  • must see early or lose mobility quickly
  • Range of motion, exercise how to protect joints
  • NSAIDs
  • consider low-dose corticosteriods (suppress
    symptoms while DMARDSs have time to work)

71
  • 5-10 very aggressive disease
  • 60 moderate
  • severe disability, co-morbidity, reduced life
    expectancy, despite conventional therapy
  • Large burden on hospital social services,
    carers
  • Successful reduction disease progression may reap
    long term cost savings
  • e.g. Reduction in need for joint replacement

72
DMARDS What are they?
  • Disease -modifying antirheumatic drugs, (used in
    other chronic inflammatory diseases as well)
  • DMARDs influence the disease process, unlike
    NSAIDs which just alleviate symptoms
  • varying and sometimes poorly understood
    mechanisms of action
  • e.g. methotrexate, sulfasalazine, gold compounds,
    penicillamine, chloroquine and biologic agents-
    which target the action of TNF alpha

73
Current Treatment
  • Early Aggressive
  • Sulphasalazine, Methotrexate, Cyclosporin,
    Leflunomide, (IM Gold)
  • Single or combination Rx

74
RA/ PsA
  • Others (D-penicillamine, azathioprine,
    hydroxychloroquine)
  • More aggressive (cyclophosphamide, mycophenolate)
  • Any/ all may be ineffective /or toxic

75
Methotrexate
  • dihydrofolate reductase inhibitor/ folate
    antagonist purine antagonist
  • dihydrofolate reductase reduces folate to FH4,
    the latter being an essential co-factor in DNA
    synthesis)
  • uses RA (1st line DMARD), psoriasis (if severe/
    resistant to topical treatments), cancer, Crohns
    disease

76
  • CI severe blood disorders, active infections,
    immunodeficiency, kidney or liver failure,
    pregnancy (females and males must avoid
    conception for at least 3/12 after stopping
    treatment), breast-feeding
  • cautions effusions (especially ascites and
    pleural effusions as these act as storage for
    the drug thereby increasing its toxicity), UC,
    peptic ulcer, decreased immunity and prophyria

77
  • Se mucositis/ GI upset, myelosuppression, skin
    reactions. Rarely pulmonary fibrosis/
    pneumonitis, hepatotoxicity, neurotoxicity,
    seizures, renal failure (due to precipitation of
    the drug in the renal tubules)
  • interactions NSAIDs (caution), trimethoprim,
    co-trimoxazole. These increase toxicity levels

78
  • dose methotrexate is usually given orally but
    can be given im or subcut (intrathecally- only in
    oncology)
  • 7.5mg once WEEKLY
  • max 25mg/week.

79
  • Pre-tx assessment
  • FBC, UE's, creatinine, LFT's, CXR.
  • Monitoring
  • FBC fortnightly- until 6/52 after last dose
    increase, and provided it is stable monthly
    thereafter.
  • LFT's fortnightly
  • UE's 6-12 monthly (more frequently if there is
    any reason to suspect deteriorating renal
    function).

80
  • Action to be taken (i.e. discuss with
    rheumatologist) if
  • WBC lt4.0x109/l, neutrophilslt2.0x109
  • Plateletslt150x109 /l
  • gt2-fold rise in AST, ALT (from upper limit of
    reference range)
  • Unexplained fall in albumin
  • Rash or oral ulceration
  • New or increasing dyspnoea or cough
  • MCVgt105fl (investigate and if B12 or folate low
    start appropriate supplementation)
  • Significant deterioration in renal function
  • Abnormal bruising or sore throat

81
  • note that in addition to absolute values for
    haematological indices a rapid fall or a
    consistent downward trend in any value should
    prompt caution and extra vigilance.

82
Sulphasalazine (EN)
  • 1st or 2nd choice in UK mild to moderate
  • not teratogenic or strong immunosupressant
  • Up to three months to take effect
  • GI SE, elevated LFTs, bone marrow depression
  • Monitoring bloods 3 monthly
  • first introduced for antibiotic action in colon,
    for inflammatory bowel disease.
  • mode of action unclear - ?anti-inflammatory,
    immunomodulatory and/or antibacterial

83
Corticosteriods
  • start early to tide over or adjunct e.g. to MTX
  • Prednisolone
  • Modest dose (7.5-10 mg/day) decrease
  • Long term dose should not exceed 10 mg/day
  • Treat acute flares IA IM or IV
  • SE
  • Wt gain, Cushings, bruising, osteoporosis,
    infection risk
  • Discontinuation may be difficult

84
Gold therapy
  • Establishedgt 50 yrs as effective treatment
  • weekly painful injection for 6/52 then 2-4 /52
  • freq lab monitoring BM suppression nephritis
  • Decreases phagocytosis monocyte activation
  • Inhibits lymphocyte responses
  • SE
  • 35 discontinue
  • rash stomatitis
  • proteinuria
  • glomerulonephritis

85
Hydroxcloroquine (Plaquinal)
  • Least toxic, no blood tests
  • 6 month response mild RA/ skin or joint lupus
  • decreases antigen processing by macrophages
    dendritic cells
  • ocular toxicity (rare- high cumulative dose)
  • retinal deposits
  • (useful in SLE)

86
Cyclosporin A
  • Nephrotoxicity espec with NSAIDs
  • causes hypertension
  • usually in combination
  • Azathiaprine
  • moderate efficacy, three months to reach efficacy
  • purine antagonist, interferes with nucleotide
    synthesis
  • SEs liver toxicity, bone marrow toxicity,
    monitoring 3/12
  • Cyclosporin azothiaprine used in 2-5 of pts

87
Leflunomide
  • pyrimidine antagonist
  • comparable efficacy to SZP
  • probably comparable toxicity
  • may be tolerated/ effective where other drugs
    not suitable
  • after methotrexate, before CyA

88
Mycophenolate Mofetil
  • Reversible inhibitor inosine monophosphate
    dehydrogenase
  • inhibition lymphocyte proliferation/ antibody
    formation/ adhesion molecule expression
  • Improved safety cf. other immunosupressants
  • SLE nephritisrefractory to cyclophosphamide
  • Scleroderma.
  • (RA)

89
Biological therapy Anti-TNFs
  • anticytokine therapy
  • specifically target TNF-alpha, which is an
    important mediator of rheumatoid inflammation
  • uses RA, psoriatic arthritis and ankylosing
    spondylitis
  • current guidelines (developed by the British
    Society for Rheumatology in 2003) restrict their
    use in the UK to patients who fail two or more
    conventional second-line agents

90
Pre-administration
  • Disease Activity Score (DAS) of joint count on
    two occasions (one month apart) before treatment
  • Pre-tx bloods (FBC, UE, LFT, ANA and DNA
    binding), check for TB, do not administer live
    vaccines, check cardiac function and
    demyelinating diseases (b/c these are all
    side-effects of medication)
  • for subcutaneous self-administration assess
    patients ability to self-administer include
    training plan

91
Adalimumab, Infliximab Etanercept
  • monoclonal antibody against TNF-alpha or fusion
    protein against soluble TNF alpha
  • MOA/ a TNF receptor joined to the Fc domain of a
    human IgG molecule (basically acts to mop up TNF
    molecules taking them out of circulation).
  • CI/ pregnancy, breastfeeding, severe infections.
  • Severe infections- TB, septicaemia

92
Biological therapy B-cell depletion, e.g.
Rituximab
  • a monoclonal antibody against CD20 which causes
    lysis of B-cells
  • uses/ lymphoma chemotherapy, RA.
  • used with methotrexate in patients who have had
    an inadequate response to the anti-TNFs.
  • MOA/ binds to CD20 molecule on the B-cell.

93
References
  • www.rheumatology.org.uk
  • BNF
  • various pharmacology books and websites..

94
Psoriatic arthritis
  • 10 with psoriasis get psoriatic arthritis.
  • Often asymmetrical inflammatory arthropathy
  • NSAIDs Sulphasalazine in early stages, but
    neither affects the psoriasis.
  • Methotrexate, CyA anti-TNF drugs treat both the
    arthritis the psoriasis

95
Ankylosing spondylitis
  • DMARDS dismal in treating axial disease
  • NSAIDs for pain stiffness
  • Exercise physio
  • Sulphasalazine, Methotrexate particularly
    useful with peripheral disease
  • Anti-TNF drugs for axial disease

96
Questions?
97
OSTEOPOROSIS
  • Common, preventable, potentially disabling
  • Worth treating to prevent further , improve
    quality of life
  • Primary Care

98
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99
Socioeconomic Costs Osteoporotic Fractures
  • 200,000 osteoporotic fractures each year cost
    NHS an estimated 1.5 billion
  • 1 in 2 women experience a fracture by the age
    70.
  • 1 in 12 men at risk of fracturing due to
    osteoporosis at some time in their life.

D1202
100
Age Related Changes in Bone Mass1
Bone Mass
1. Compston JE. Clinical Endocrinology 1990 33
653-682.
D1202
101
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102
  • Osteopaenia T score lt-1-lt2.5
  • Osteoporosis T score lt-2.5
  • T score means comparing the pts density to a 25
    year old female.

103
Identifying those at risk
  • Predisposing factors-
  • alcohol, smoking
  • liver or renal disease
  • malabsorption, poor Ca intake
  • Low BMI
  • thyroid disease, DM, Cushings, hyperparathyroidism
  • immobility, inflammatory disease, RA
  • hypogonadism in men

104
Identifying those at risk
  • drugs
  • Current or planned long term oral corticosteroid
    use (gt7.5mg prednisolone / day for gt 3/12
  • Anticonvulsants
  • heparin

105
Management 1. Patient Education
  • Lifestyle Changes
    Diet
    Weight
    bearing exercise
    Habits smoking excess alcohol
  • Falls Prevention
    home assessment
    hip
    protectors

106
NICE guidance 1
  • Primary prevention
  • Complex
  • gt70 with a risk factor for fracture or an
    indicator for fracture and t score lt-2.5

107
NICE 2
  • Secondary prevention ie at least 1 fracture Ca
    vit D
  • gt75yrs bisphosphonate
  • 65-74 DEXAlt and if lt2.5 then bisphos
  • lt65 treat if T score lt -3, or -2.5 plus a risk
    factor

108
NICE 3
  • Prevention of steroid induced OP
  • Lifestyle advice
  • Ca vit d
  • lt65 yrs DEXA, bisphosphonate if osteopaenic
  • gt65 bisphosphonate

109
Osteoporosis Pharmacology
Bisphosphonates
Calcitonin
Osteoporosis
Vitamin D
Raloxifene Teriparatide
Calcium salts
110
Calcium
  • Indications Osteoporosis, ?Ca2, ? PO4
  • Contraindications Conditions associated with
    ?Ca2
  • Side effects GI disturbances, arrhythmias,
    bradycardia
  • Interactions effects potentiated by thiazides
    and decreased by corticosteroids. Decreases
    absorption of tetracyclines and biosphosphonates.
  • In osteoporosis, calcium intake double
    recommended amount reduces rate of bone loss.
  • Dose 400-800mg/ day
  • Adcal D3 forte, calcichew D3 Forte

111
Vit D
  • Examples ergocalciferol, calciferol, cacitriol
  • Mechanism of action stimulates absorption of
    calcium and phosphate from intestine and
    decreases renal excretion of calcium
  • Indications Osteoporosis, CRF, osteomalacia,
    hypoparathyroidism
  • Side effects Vascular calcification,
    nephrocalcinosis, soft-tissue calcification

112
Bisphosphonates Pharmacology
  • Alendronate and residronate orally, pamidronate,
    ibandronate and zoledronate IV
  • Mechanism of action inhibit osteoclastic
    activity. Specifically reduce the resorption and
    formation of hydroxyapatite crystals.
  • Indications postmenopausal osteoporosis, pagets
    disease of bone, malignancy-associated
    hypercalcaemia
  • Adverse effects bone pain, osteomalacia
    (etidronate), oesophagitis, nausea, diarrhea
  • 70mg alendronate once a week with ca and vit d

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Raloxifene (Evista)
  • Selective oestrogen receptor modulator (SERM)
    treatment / for prevention of postmenopausal
    osteoporosis
  • Demonstrates oestrogen agonist activity on bone
    partially on cholesterol metabolism, but
    oestrogen antagonism in uterine and breast
    tissues.
  • ? Benefits in stroke and breast cancer reduction

114
Strontium ranelate (Protelos)
  • granules for oral suspension
  • treatment of postmenopausal osteoporosis
  • As good as bisphosponates well tolerated (even
    in very elderly)
  • Increases bone formation decr bone resorption
  • Absorption affected by food milk/derivatives.
  • Suspension should ideally be given at bedtime, at
    least two hours after any food drink
  • cost per month comparable with branded
    bisphosphonates raloxifene.

115
Calcitonin
  • Synthesised and secreted by parafoliicular C
    cells of thyroid gland
  • Mechanism of action decreases osteoclastic bone
    resorption and calcium and phosphate resorption
    from kidney.
  • Indications osteoporosis, pagets disease of
    bone, malignancy-associated hypercalcaemia
  • Adverse effects allergic reaction (flushing,
    redness or tingling of face), nausea, increased
    urinary frequency
  • Dose for postmenopausal osteoporosis 200 units
    (1 spray) intranasally

116
teriparatide rDNA (Foresteo)
  • Synthetic parathyroid hormone 5X greater BMD in
    lumbar spine than alendronate after 6/12
  • BUT daily injections with 20mg Forteo for 18/12
  • Teriparatide 20mcg daily - 1 prefilled pen
    271.88
  • Raloxifene 60mg daily
    21.74
  • Fosamax once weekly 70mg 23.12
  • stimulates new bone formation

117
Teriperatide cont
  • animal studies increased incidence osteosarcoma
  • Can use for secondary prevention if gt65 and
    bisphosphates not helpful and T score lt-4

118
Denosumab
  • Fully human monoclonab antibody to RANK ligand
  • RANK is expressed by pre-osteoclasts, and induces
    their conversion into mature osteoclasts
  • There for inhibits clasts, reducing bone
    resorption
  • Sub cut every 6 months
  • Cost similar to branded bisphosphonates

119
So
  • Plenty of hope with new treatments
  • BUT
  • Also plenty of
  • a) COST
  • b) scope for causing harm

120
  • Questions?
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