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Treatment of Major Rheumatic Diseases. Dr Tanya Potter Consultant Rheumatologist. Aims. 1 To pass your exam 2 Encourage safe prescribing (and you will remember that have an exam in this also). Rheumatoid arthritis (RA) or osteoarthritis (OA) most common types seen in clinics (& exams)

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Treatment of major rheumatic diseases

Treatment of Major Rheumatic Diseases

Dr Tanya Potter

Consultant Rheumatologist


Aims

  • 1 To pass your exam

  • 2 Encourage safe prescribing (and you will remember that have an exam in this also)



Osteoarthritis
Osteoarthritis types seen in clinics (& exams)

  • most common

  • 75% people > 70 radiographic OA F: M 2.5:1


Osteoarthritis1
Osteoarthritis types seen in clinics (& exams)

  • Joint space narrowing

  • Osteophytes

  • Subchondral sclerosis

  • Bone cysts


Management
Management types seen in clinics (& exams)

  • 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


Oa goals of treatment
OA - types seen in clinics (& exams)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…)


Drugs
Drugs types seen in clinics (& exams)

  • Mild to moderate

    • Paracetamol;

    • Topical agents: non steroidals, rubefacients

  • Moderate to severe

    • As above, plus

    • NSAIDs

    • combination analgesics (paracet +opiods) / Opiods/ Tramadol


Paracetamol
Paracetamol types seen in clinics (& exams)

  • Analgesic/ antipyretic

  • Unknown mechanism of action

  • combo with opiods better response

    when can’t use NSAIDs (gu / du/ renal/ warfarin)

  • Doesn’t alter platelet function (bleeding/ surgery)

  • Safer for elderly

  • Caution with chronic liver dz (hepatotoxicity, > 2 gm)

  • Thrombocytopaenia, neutropaenia rare


Tramadol
Tramadol types seen in clinics (& exams)

  • 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


Strong opiods
Strong opiods types seen in clinics (& exams)

  • 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)


Nsaids
NSAIDS types seen in clinics (& exams)

  • 25 million NSAID prescriptions/ yr in UK

  • Non selective

    • Aspirin

    • Ibuprofen

    • Naproxen

    • Indomethacin

    • Piroxicam

  • Selective cox 2 inhibiters

    • Celecoxib

    • Etoricoxib

    • Meloxicam

    • etodolac


Nsaid risk
NSAID risk types seen in clinics (& exams)

  • How many GI bleed admissions annually in the uk?

  • What percentage are likely to due to NSAIDs?

  • How many deaths annually?


Upper GI complications types seen in clinics (& exams)

  • 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


GI event may be devoid of warning symptoms types seen in clinics (& exams)

Many patients asymptomatic prior to serious NSAID-associated GI event (bleeding, perforation)

n = 141

n = 1,921

19%

58%

42%

81%

without symptoms

with symptoms


prostoglandins types seen in clinics (& exams)


NSAIDs: types seen in clinics (& exams)

Inhibit cox enzymes

Asthma

blocked


Action
Action types seen in clinics (& exams)

  • 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


Cox enzyme
COX enzyme types seen in clinics (& exams)

  • 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


Action1
Action types seen in clinics (& exams)

  • Different NSAID’s 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


Older nonselective nsaid s ibuprofen naproxen
Older nonselective NSAID’s types seen in clinics (& exams) (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


Cox 2 inhibitors celecoxib meloxicam etorocoxib
COX-2 inhibitors types seen in clinics (& exams)(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 NSAID’s

    • longer lasting drug – longer relief

    • do not thin the blood therefore can consider co-prescription with warfarin

  • Cons:

    • More expensive compared to traditional NSAID’s

    • Results not as good as endoscopic drug studies suggest


Indications
Indications types seen in clinics (& exams)

  • 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


Cautions
CAUTIONS types seen in clinics (& exams)

  • Elderly

  • Pregnancy- miscarriage, early closure of ductus arteriosus

  • Breast feeding

  • Coagulation defects

  • Renal, cardiac (heart failure/ hypertension/ IHD) or hepatic impairment


Contraindications
Contraindications types seen in clinics (& exams)

  • 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.


Side effects
SIDE EFFECTS types seen in clinics (& exams)

  • GI – N&D, 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)


GI types seen in clinics (& exams)

  • 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

    • < 6% discontinue

    • Severe toxicity 2.1/100 pt years

      NNT 42 to prevent 1 serious GI event


Cardiovascular toxicity
Cardiovascular toxicity types seen in clinics (& exams)

  • 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.


prostoglandins types seen in clinics (& exams)


Cv risk
CV risk types seen in clinics (& exams)

  • 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


All nsaid cvs
All NSAID/ CVS types seen in clinics (& exams)

  • 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)


Naproxen
Naproxen types seen in clinics (& exams)

  • Pain and inflammation in rheumatic disorders

  • 0.5-1g / day in 1-3 divided doses

  • In high risk pts, give with PPI

  • Which one?


Nsaids past strategies
NSAIDs - past strategies types seen in clinics (& exams)

  • Enteric Coating

  • Pro-drugs; hepatic metabolism

  • Gastro-protective agents:PPIs, misoprostol, H2 blockade


Oa adjunctive therapy
OA- Adjunctive therapy types seen in clinics (& exams)

  • 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


Visco supplementation
Visco-supplementation types seen in clinics (& exams)

  • 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


Visco supplementation1
Visco-supplementation types seen in clinics (& exams)

  • OA, where physio, weight loss, simple analgesia +/- NSAIDs insufficient

  • & IA steroids not helpful /not lasting

  • Awaiting/ unfit for surgery


Capcaisin cream
Capcaisin cream types seen in clinics (& exams)

  • 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


What are the alternatives
What are the alternatives? types seen in clinics (& exams)

  • Cod liver oil & other fishy oils

  • Evening primrose oil

  • Borage or Starflower oil

  • Change in balance of cell membrane fatty acids


Alternatives
Alternatives? types seen in clinics (& exams)

  • 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


Gout types seen in clinics (& exams)

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


Gout types seen in clinics (& exams)

  • Primary

    • Over production (10%)

    • Under secretion (90%)

    • Enzyme mutations

  • Predominantly secondary

    • Overproduction (mutations, heavy exercise, obesity)

    • Under excretion severe renal diseases, drugs, alcohol, HBP


  • 2-17% of population are hyperuricaemic types seen in clinics (& exams)

  • The higher the uric acid the higher the chance of gout

  • Self reported adult prevalence of 8/1000

  • 2-7M:1F

  • Increase in blacks may reflect increased rates of hypertension


Figure 4 types seen in clinics (& exams)Simplified diagram of uric acid production and excretion

1/3

2/3

2/3

1/3

Roddy E et al. (2007) The changing epidemiology of gout

Nat Clin Pract Rheumatol3: 443–449 doi:10.1038/ncprheum0556


Epidemiology
Epidemiology types seen in clinics (& exams)

  • Middle aged men

  • Dietary purine consumption

  • Alcohol

  • Drugs:Low dose aspirin, diuretics

  • Inherited metabolic abnormalities


Clinical features
Clinical features types seen in clinics (& exams)

  • Gouty Tophi on pinnae

  • Olecranon bursitis

  • Gouty tophi on hands

  • Gouty nephropathy&

    stones

  • Large joint oligoarthritis

  • 1st metatarsophalangeal

    joint arthritis‘podagra’


erosions with a punched out appearance types seen in clinics (& exams)


Management1
Management types seen in clinics (& exams)

  • Prevent occurrence

  • Diagnose

  • Treat acute flare

  • Reduce risk of further flare

  • Reduce associated morbidity secondary to HBP, hypercholesterolaemia


Aspirate joint
Aspirate joint types seen in clinics (& exams)

  • Differential diagnosis monoarthritis?


Management of acute gout 1
Management of Acute Gout (1) types seen in clinics (& exams)

  • Goal is to rapidly resolve pain and inflammation

  • High doses of NSAID used:

    Naproxen. 500mg bd until theattack has passed

    Indomethacin, diclofenac, etoricoxib also used


Management of acute gout 2
Management of Acute gout(2) types seen in clinics (& exams)

Alternative to NSAIDs

Colchicine

inhibits microtubule polymerization by binding to tubulin,

inhibition of neutrophil motility and so produces an anti-inflammatory response.


Treatment
Treatment types seen in clinics (& exams)

  • 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 (doesn’t induce fluid retention) or those who cannot tolerate NSAIDs for any other reason


Side effects colchicine
Side effects colchicine types seen in clinics (& exams)

  • GI

  • Haemorrhagic gastroenteritis

  • Myoneuropathy on prolonged course


Acute gout treatment cont
Acute gout treatment cont. types seen in clinics (& exams)

  • NSAIDs- take early

    • Upper limit of usual therapeutic dose

    • Selective and non selective

  • Glucocorticoids

    • Intra-articular

    • Oral pred

    • IM pred


Management of chronic gout 1
Management of Chronic Gout(1) types seen in clinics (& exams)

  • 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


Management of chronic gout
Management of chronic gout types seen in clinics (& exams)

  • 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


Choice of drug
Choice of drug types seen in clinics (& exams)

  • 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


Management of chronic gout allopurinol
Management of Chronic Gout types seen in clinics (& exams)Allopurinol

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


Management of chronic gout allopurinol dose
Management of chronic gout types seen in clinics (& exams)Allopurinol 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

Doses> 300mg should be given in divided doses


Management of chronic gout allopurinol ctd
Management of Chronic Gout types seen in clinics (& exams)Allopurinol 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


Uricosurics
Uricosurics types seen in clinics (& exams)

  • 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


Management of chronic gout 5 sulfinpyrazone
Management of Chronic gout (5)Sulfinpyrazone types seen in clinics (& exams)

  • 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 NSAID—which 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


Also address
Also address… types seen in clinics (& exams)

  • Obesity

  • Triglycerides

  • Alcohol

  • Hypertension

  • Thiazide therapy- consider alternative


Questions
Questions? types seen in clinics (& exams)


Ra psoriatic arthritis
RA (& Psoriatic Arthritis) types seen in clinics (& exams)

  • 600,000 people in UK

  • many unable to work

  • 42% registered disabled within 3 years

  • 80% moderate to severe disability in 20 years


Management2
Management types seen in clinics (& exams)

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)


5-10% very aggressive disease types seen in clinics (& exams)

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


Dmards what are they
DMARDS: What are they? types seen in clinics (& exams)

  • 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


Current treatment
Current Treatment types seen in clinics (& exams)

  • Early & Aggressive

  • Sulphasalazine, Methotrexate, Cyclosporin, Leflunomide, (IM Gold)

  • Single or combination Rx


  • Ra psa
    RA/ PsA types seen in clinics (& exams)

    • Others (D-penicillamine, azathioprine, hydroxychloroquine)

    • More aggressive (cyclophosphamide, mycophenolate)

    • Any/ all may be ineffective + /or toxic


    Methotrexate
    Methotrexate types seen in clinics (& exams)

    • 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, Crohn’s disease


    • CI: types seen in clinics (& exams) 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


    • Se: types seen in clinics (& exams) 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


    • dose: types seen in clinics (& exams) methotrexate is usually given orally but can be given im or subcut (intrathecally- only in oncology)

    • 7.5mg onceWEEKLY

    • max 25mg/week.


    Pre-tx assessment: types seen in clinics (& exams)

    • FBC, U&E'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

    • U&E's 6-12 monthly (more frequently if there is any reason to suspect deteriorating renal function).


    • Action to be taken (i.e. discuss with rheumatologist) if: types seen in clinics (& exams)

    • WBC <4.0x10^9/l, neutrophils<2.0x10^9

    • Platelets<150x10^9 /l

    • >2-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

    • MCV>105fl (investigate and if B12 or folate low start appropriate supplementation)

    • Significant deterioration in renal function

    • Abnormal bruising or sore throat



    Sulphasalazine en
    Sulphasalazine (EN) indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Corticosteriods
    Corticosteriods indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Gold therapy
    Gold therapy indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Established> 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


    Cyclosporin a
    Cyclosporin A indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Leflunomide
    Leflunomide indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • pyrimidine antagonist

    • comparable efficacy to SZP

    • probably comparable toxicity

    • may be tolerated/ effective where other drugs not suitable

    • after methotrexate, before CyA


    Mycophenolate mofetil
    Mycophenolate Mofetil indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Reversible inhibitor inosine monophosphate dehydrogenase

    • inhibition lymphocyte proliferation/ antibody formation/ adhesion molecule expression

    • Improved safety cf. other immunosupressants

    • SLE nephritis;refractory to cyclophosphamide

    • Scleroderma.

    • (RA)


    Biological therapy anti tnfs
    Biological therapy: indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.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


    Pre administration
    Pre-administration indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Disease Activity Score (DAS) of joint count on two occasions (one month apart) before treatment

    • Pre-tx: bloods (FBC, U&E, 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 patient’s ability to self-administer; include training plan


    Adalimumab infliximab etanercept
    Adalimumab, Infliximab & Etanercept indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Biological therapy b cell depletion e g rituximab
    Biological therapy: B-cell depletion, e.g. Rituximab indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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.


    References
    References indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • www.rheumatology.org.uk

    • BNF

    • various pharmacology books and websites..


    Psoriatic arthritis
    Psoriatic arthritis indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Ankylosing spondylitis
    Ankylosing spondylitis indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Questions1
    Questions? indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.


    Osteoporosis
    OSTEOPOROSIS indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    Common, preventable, potentially disabling

    Worth treating to prevent further #, & improve quality of life

    Primary Care


    Socioeconomic Costs Osteoporotic Fractures indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Attainment of Peak indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    Bone Mass

    Consolidation

    Age Related Bone Loss

    Menopause

    Men

    Fracture

    threshold

    Women

    0 10 20 30 40 50 60

    Age (years)

    Age Related Changes in Bone Mass1

    Bone

    Mass

    1. Compston JE. Clinical Endocrinology 1990; 33: 653-682.

    D1202


    • Osteopaenia: T score <-1-<2.5 indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Osteoporosis ; T score <-2.5

    • T score means comparing the pts density to a 25 year old female.


    Identifying those at risk
    Identifying those at risk indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Identifying those at risk1
    Identifying those at risk indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • drugs

      • Current or planned long term oral corticosteroid use (>7.5mg prednisolone / day for > 3/12

      • Anticonvulsants

      • heparin


    Management 1 patient education
    Management 1. Patient Education indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Lifestyle Changes: Diet Weight bearing exercise Habits: smoking & excess alcohol

    • Falls Prevention home assessment hip protectors


    Nice guidance 1
    NICE guidance 1 indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Primary prevention

    • Complex

    • >70 with a risk factor for fracture or an indicator for fracture and t score <-2.5


    Nice 2
    NICE 2 indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Secondary prevention ie at least 1 fracture Ca + vit D

    • >75yrs bisphosphonate

    • 65-74 DEXA< and if <2.5 then bisphos

    • <65 treat if T score < -3, or -2.5 plus a risk factor


    Nice 3
    NICE 3 indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • Prevention of steroid induced OP:

    • Lifestyle advice

    • Ca & vit d

    • <65 yrs DEXA, bisphosphonate if osteopaenic

    • >65 bisphosphonate


    Osteoporosis pharmacology
    Osteoporosis indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.Pharmacology

    Bisphosphonates

    Calcitonin

    Osteoporosis

    Raloxifene & Teriparatide

    Vitamin D

    Calcium salts


    Calcium
    Calcium indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Vit d
    Vit D indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Bisphosphonates pharmacology
    Bisphosphonates indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.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, paget’s 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


    Raloxifene evista
    Raloxifene (Evista) indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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


    Strontium ranelate protelos
    Strontium ranelate (Protelos) indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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.


    Calcitonin
    Calcitonin indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

    • 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, paget’s 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


    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

    teriparatide rDNA (Foresteo)


    Teriperatide cont
    Teriperatide cont spine than alendronate after 6/12

    • animal studies increased incidence osteosarcoma

    • Can use for secondary prevention if >65 and bisphosphates not helpful and T score <-4


    Denosumab
    Denosumab spine than alendronate after 6/12

    • 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


    So spine than alendronate after 6/12

    • Plenty of hope with new treatments

    • BUT

    • Also plenty of

    • a) COST &

    • b) scope for causing harm



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