Learning Outcomes

What Is Rheumatoid Arthritis?

❖ RA, is a form of inflammatory arthritis and an autoimmune disorder.

❖ Most common cause of chronic inflammatory joint disease

❖ The immune system - is designed to protect our health by attacking

foreign cells such as viruses and bacteria. Instead attacks the body’s own
tissue, specially the synovium, a thin membrane that lines the joints. As a
result of the attack, fluid builds up in the joints, causing pain in the
joints and inflammation that ‘s systematic -meaning it can occur
throughout the body
What Is Rheumatoid Arthritis?
Rheumatoid Arthritis
❖ Persistent joint inflammation can lead to the development of bone erosions,cartilage and
tendon degradation, and joint deformity.
❖ In about 40% of patients,inflammation also occurs at other sites (eg skin, eyes, lungs,
heart, kidneys, blood vessels, salivary glands, central and peripheral nervous
systems,and bone marrow).

❖ The pathophysiology of rheumatoid arthritis involves various cytokines, effector cells

and signalling pathways; tumour necrosis factor (TNF), interleukin-6 (IL-6)and
interleukin-1(IL1) appear to be the key cytokine mediators of the disease process.

❖ Rheumatoid arthritis has the potential to cause disability and death

Rheumatoid Arthritis

❖ Immune complexes composed of lgM activate complement and release

cytokines (mainly TNFa and IL-I) which are chemotactic for neutrophils.
❖ These inflammatory cells secrete lysosomal enzymes which damage
cartilage and erode bone, while PGs produced in the process cause
vasodilatation and pain.
❖ RAis a chronic progressive, crippling disorder with a waxing and waning
course. Multiple small joints of hands and feet are preferentially
affected;deformities are produced as the disease progresses.
Rheumatoid Arthritis - Epidemiology

❖ Affects 1-3% of the population world wide

❖ Incidence about 2-4 per 10,000 per year
❖ Representing 5-10%of all arthritis
❖ With a peak prevalence b/wages of 30-50 years
❖ Women are affected 3 or 4 times more commonly than men
❖ Incidence increases with age* • ~5%prevalence in women over age 55
Rheumatoid Arthritis - Causes

❖ Genetic susceptibility
❖ An immunological rxn: possible involve a foreign antigen preferentially
focus sed on synovial tissue.
❖ An inflammatory rxn in joints & tendon sheaths
❖ Appearance of rheumatoid factors in the blood & synovium
❖ Perpetuation of the inflammatory process
❖ Articular cartilage destruction
Rheumatoid Arthritis - Signs and Symptoms

Signs and Symptoms

❖ Joints may feel warm to the touch and decrease range of motion as well
as inflammation.
❖ Swelling and pain in the areas around the affected joints.
❖ Stiffness
❖ Malaises (feeling ill).
❖ Muscle aches
❖ Loss of appetite which can lead to weight loss
❖ Pain
Rheumatoid Arthritis - Pathogenesis –aetiology
❖ Exact aetiology still largely remain unknown

❖ Strong genetic association

- 25%of population carry at least one of the ‘risk’ genes.
- particularly HLA-DR4 (DW4,DW14,DW15).

❖ RA is a genetic associated disease

- not everyone with genetic composition will develop RA
- only about 10%genetic carrier actually develop RA

❖ Initiation/triggering factors
- e.g. infection,chemical,drugs,hormone,environment factors
Rheumatoid Arthritis - Clinical Presentation
Disease Onset

• Most onset at 20-50 years of age

•Symptoms Usually Develop Slowly Over Weeks Or months

Disease Patterns

• One-off presentation– i.e. remission after initial symptoms

•Intermittent symptoms/ flare up

•Persistence And Progression Symptoms

Common Affected Joints

• Wrists, shoulders, knees, and ankles joints

• Hands And Fingers – mostly on PIP and MCP joints

• Often Symmetrical
Rheumatoid Arthritis - Clinical Presentation -
Specific features
❖ Characteristic symptoms

•Early (and/or mild) symptoms

• Pain, effusion, inflammatory and distortion

• Joint stiffness after prolonged period of inactivity

• E.g. Morning stiffness, may occur for >1 hour

❖ Progressive symptoms of aggressive’ features

• Joint effusion and distortion in addition of initial symptoms

• Extra-articular features*

• Musculoskeletal system, skin connective tissue, multiorgan involvement

• Lung,heart, vascular and kidney involvement indicate severe disease manifestation

• Usually include features of systemic rheumatic disease

Rheumatoid Arthritis- Pathophysiology
Rheumatoid Arthritis- Pathophysiology
Rheumatoid Arthritis- Diagnosis
❖ Family history of inflammatory arthritis
❖ Early morning stiffness lasting longer than 1 hour
❖ Swelling in five or more joints
❖ Symmetry of the areas affected
❖ Physical examination: measuring heart rate, blood oxygen level, BP
❖ Symptoms present for longer than 6 weeks.
❖ bony erosions evident on X-rays of the wrists, hands or feet (uncommon
in early disease).
❖ raised inflammatory markers, such as CRP or ESR,in the absence of
infection presence of rheumatoid nodules
Rheumatoid Arthritis- Diagnosis
Management of Rheumatoid Arthritis

❖ No treatment cures for RA

❖ Goal of management

→ Remission of symptoms

→ Return of full function

→ Effective management of RA requires a multidisciplinary approach.

Management of Rheumatoid Arthritis

Non-Pharmacology Treatment

❖ Physiotherapy
❖ Occupational therapy
Management of Rheumatoid Arthritis
Pharmacological Management

❖ Non-steroid anti-inflammatory drugs (NSAIDs) & Coxibs

❖ Corticosteroids
❖ Disease-modifying anti-rheumatic drugs (DMARDs)
Management of RA - NSAIDs

NSAIDs

❖ Effective in relieving the joint pain and stiffness

❖ First line therapy
- Analgesic effect develop much earlier than anti-inflammatory effect
- Limited efficacy in suppressing disease progress - should be used in
conjunction with CS and/or DMARDs.
❖ Higher dose often required for RA
Management of RA - CORTICOSTEROIDS

Corticosteroids

❖ Suppress disease activity

❖ Potent anti-inflammatory agents
- Effective in almost all cases of RA
- Rapid onset of action when compared to other DMARDs
❖ Often use as 1st line therapy to induce remission +/- symptom relief - use
as chronic maintenance therapy is limited by adverse effects
Management of RA - CORTICOSTEROIDS

Corticosteroids

❖ Options: Oral VS Parenteral

→ no different in efficacy at equivalent dose

→ differences in adverse effects

→ parenteral administration often required for high dose

❖ Example: Dexamethasone (Decadron), Methylprednisolone (Depo-

Medrol, Medrol), Prednisolone, Prednisone, Triamcinolone (Aristospan)
Management of RA - DMARDs

DMARDs

❖ Act mainly through inhibition of inflammatory cytokines.

❖ Immunosuppressive and immunomodulatory agents

❖ DMARDs come in two types:

1. Non-biological DMARDs or conventional synthetic DMARDs [csDMARDs]
2. Biological DMARDs [bDMARDs]
Management of RA - DMARDs

DMARDs come in two types:

1. Non-biological DMARDs or conventional synthetic DMARDs [csDMARDs]

→ methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine.

1. Biological DMARDs [bDMARDs]

→ infliximab, adalimumab, etanercept, rituximab, abatacept, rituximab,

tocilizumab, tofacitinib
Management of RA - Drug Monograph
Methotrexate (MTX) Counselling
❖ Important considerations ❖ Take once a week/same time of the day
- Once a week regime
❖ Toxicity may occur: inform your GP
- Potential risk of to induce pneumonitis and
pulmonary fibrosis (methotrexate lung) ❖ Avoid excessive sun exposure. Use
sunscreen and protective clothing.
❖ Benefits may take 1-2 months to appear
❖ GI adverse effects +/- bone marrow
suppression

• Folic acid supplement to reduce risk

• 0.5-1 mg daily or 5-10 mg per week (not

on the day of MTX dosing)
Management of RA - Drug Monograph
MOA
Hydroxychloroquine

❖ Antimalarial found to induce remission in ❖ found to reduce monocyte IL-I,

upto 50%pts of RA consequently inhibiting B lymphocytes.
❖ Take 3-6 months –relatively low toxicity
Efficacy

•Inferior toMTX

• Limited effectiveness in prevent

joint deformation

❖ Place In Therapy

• Not usually used as sole DMARDs,but

maybe used as adjuvant to MTX
Management of RA - Drug Monograph
MOA
Sulfasalazine
❖ Not fully understood
❖ Efficacy ❖ Sulfasalazine works by reducing
- Mild-moderate efficacy in RA, limited inflammation. It is broken down in the
by ADRs • Often use with combination intestines into two components:
sulfapyridine and 5-aminosalicylic acid. The
with MTX +/- hydroxychloroquine
5-aminosalicylic acid part helps to reduce
❖ Place in therapy inflammation in the colon.
- No longer 1st line option, most likely use ❖ Suppress generation of superoxide radicals
as adjuvant to MTX or bDMARDs • Can and cytokine.
be the treatment of choice for patient
❖ Efficacy of sulfasalazine in RAis modest
with IBD comorbidity
❖ • Adverse effects -maybeunpleasant.
❖ - Neutropenia/thrombocytopenia & Hep B
Management of RA - Drug Monograph
MOA
Cyclophosphamide
❖ Not fully understood
❖ Not a common choice for RA unless ❖ Sulfasalazine works by reducing
other treatments failed inflammation. It is broken down in the
❖ Often use as pulse therapy intestines into two components:
sulfapyridine and 5-aminosalicylic acid. The
❖ Potentially serious side effects limit its
5-aminosalicylic acid part helps to reduce
use inflammation in the colon.
❖ Suppress generation of superoxide radicals
and cytokine.

❖ Efficacy of sulfasalazine in RAis modest

❖ • Adverse effects -maybeunpleasant.
❖ - Neutropenia/thrombocytopenia & Hep B
Treatment Pharmacological options
NSAIDS

❖ First line therapy

– Analgesic effect develop muchearlier than anti-inflammatory effect

– Limited efficacy in suppressing disease progress

- Should be use in conjunction with CS and/or DMARDs

❖ Higher dose often required for RA

❖ Others: Fish oil (omega-3)

- Should be use in combination with DMARD

- Limited & inconsistent data support its systemic benefit

- very high dose may be required

Treatment Pharmacological options

Corticosteroids
 Potent anti-inflammatory agents

Effective in almost all cases of RA

-Has rapid onset of action when compared to other DMARDs

 Often use as 1st line therapy to induce remission +/- symptom relief

- Use as chronic maintenance therapy is limited by adverse effects

Treatment
Corticosteroids
 Options
 Oral vs parenteral*
- nodifferent in efficacyat equivalentdose
- differencesin adverseeffects
- parenteraladministrationoften requiredfor highdose
 Dosetitration per treatmentoutcome(therapeutic and
adverse)
-Maintenancetherapyusualdosearound5-10mgor oral
prednisolone
-Adverseeffects are bothdose-dependent& durationdependent
- esp. osteoporosis,cushionsyndrome
Disease Modifying Antirheumatic drugs
(DMARDs): conventional synthetic DMARDs
(csDMARDs or non-biological drugs)
Methotrexate (MTX)
 Antineoplasticat highdose,immunosuppressive at lowdose(5-20
mg/wk)
• Highefficacy
• Effective against mosttreatment aims for RA
• E.g.achieveandmaintainremission,reduceorpreventprogressivejoint
damage,
maintainjoint function,reducefrequencyandseverity of acuteexacerbation
 Place in therapy
• 1st lineDMARDfor RAunlesscontraindicated
• Onset of action: 4-6 weeks
• Canbe combinedwith other DMARDs,esp. bDMARDs
 Pharmacological: DMARDs- csDMARDs

Methotrexate(MTX)
• Important considerations
• Usualyontheonceweeklyregime
• Potentialriskof inducepneumonitisandpulmonaryfibrosis(“methotrexatelung”)
• Analergic-type of hypersensitivity reaction
• Geneticandenvironmentalpredisposition
• Doseandduration dependent
• GI adverseeffects+/- bonemarrowsuppression
• Folicacid supplement toreducerisk
• 0.5-1 mgdaily or 5-10 mgperweek(not onthedayof MTXdosing)*
• Otheradverseeffects(refertoAMHor eTG)
MTX –counselling
• Dosingoncea weekonthesamedayeachweek;it mustnotbetakenevery
day.
• Informmedicalpractitionerif experiencescough,difficulty breathingor signs
of infection.
• Useof somemedicationswith methotrexatemayleadto toxicity; tel your
doctorandpharmacistthat youaretakingthisdrug.
• Avoidexcessiveorprolongedsunexposure,wearprotective clothinganduse
sunscreen.
• it maytake1–2 monthsbeforebenefit is see
Treatment
Pharmacological-DMARDs -csDMARDs
Hydroxychloroquine
 Antimalarial foundto induceremissionin upto 50%pts of RA
 Take 3-6months–relativelylowtoxicity
 Efficacy
• Inferior to MTX
• Limited effectiveness in prevent joint deformation
 Placein therapy
• Notusualy usedassole DMARDs,but maybeuseasadjuvant to MTX
Hydroxychloroquine
• MOA:
- foundto reducemonocyteIL- I, consequentlyinhibiting B
lymphocytes.
Treatment
Pharmacological-csDMARDs
Sulfasalazine
 Efficacy
• Mild-moderate efficacyin RA,limited byADRs
• Oftenusewithcombinationwith MTX+/- hydroxychloroquine(triple
therapy)
 Placeintherapy
• Nolonger1st line option,mostlikely useasadjuvantto MTXor
bDMARDs
• Canbethetreatmentof choicefor patientwith IBDcomorbidity
Sulfasalazine

 Acompoundof sul fapyridine and5-amino salicylic acid (5ASA);

> exerts antinflammatory activity in the bowelandis useful in ulcerative colitis.
> suppresses thedisease
 Mechanismof actionis not known
- Sulfapyridine split off in the colon bybacterial action & absorbedsystemicaly appears to
bethe activemoiety(contrastulcerativecolitis,in which5-ASAactinglocaly in thecolonis theactive
component).
- Suppressgenerationof superoxideradicals andcytokine
 Efficacy of sulfasalazine in RAis modest
• Adverseeffects-maybeunpleasant.
- Neutropenia/thrombocytopcnia,Hep B
Treatment
Pharmacological-csDMARDs
Cyclophosphamide
• Nota commonchoicefor RAunlessothertreatmentsfailed
• Oftenuseaspulsetherapy
• Potentialyserioussideeffectslimit its use
Leflunomide
• Secondaryoptionsfor RAin currentpracticesincetheavailabilityof bDMARDs
• Efficacy
• Compatibleto MTX(canalsouseasonceweeklyregime)• OthercsDMARDs •
Leflunomide

• Immunomodulatorinhibits proliferation of stimulatedlymphocytesin patients

with activeRA.
• Arthritic symptomsare suppressedandradiological progressionof diseaseis
retarded.
Treatment
Pharmacological-csDMARDs
Azathioprine, cyclosporin,tacrolimus, mycophenolate,gold,etc.
 Nolongerconsideras frontline optionsfor RAsince thedevelopmentof
bDMARDs
• Onlybeconsider whenthestandardtherapy failed, intolerable, or unable to prevent
significant diseaseprogression
Treatment
pharmacological-biological DMARDs
 Several recombinant proteins/monoclonal antibodies that bind to and inhibit
cytokines, especialy TNFα or I L-1 have been produced and found to afford
substantialbenefitin autoimmunediseaseslikeRA
 TNFα Inhibitor
 Cytokine TNFα – a keyrolein theinflammatorycascadeof RAby activating
membraneboundreceptors (TFR1andTFR,)onthesurfaceofT-cels,
macrophages
 TNFinhibitors mainlysuppressmacrophageandT-cel function;
 inflammatorychangesin thejoint regressandnewerosionsareslowed.
 QuickerresponsethancsDMARDs
Treatment
pharmacological-biological DMARDs
bDMARDs • Lymphocyte modifier

 Anti-cytokines • T-cels
• CD80/86:abatacept
• Anti- TNF
• Infliximab, adalimumab,
• B-cels
certolizumab, golimumab,etanercept • CD20:rituximab
• Activatorsinhibitor: belimumab
• Anti-IL
• IL-1: anakinra
• IL-6: tocilizumab, sarilumab*,
sirukumab*
• Januskinase(JAK)inhibitor
• Tofacitinib, baracitinib*
Treatment options
Pharmacological – DMARDs –
bDMARDs
 Treatment options
Pharmacological – DMARDs – bDMARDs
Anti-TNFα  Efficacy
• Studiesshowcompatibleor
 Agentscurrentlyavailable superiorto MTXandsuperiorto
• Monoclonal antibodiesthat bind otherscDMARD*
TNF • Esp. superiorin reducing
• Adalimumab(human), joint deformation measuredbyradio-
certolizumab (humanised) imaging,andhigherrate of repair*
• Infliximab (part • Efficacyalsodemonstratedin
human/mouse),golimumab (human) otherRheumatic
• Indicatedto beusein diseases
combinationof • Benefitforpatientswithother
MTXfor RA comorbidity
• SolubleTNFreceptor  Placeintherapy
• Etanercept(human) • 1st lineDMARD–
monotherapyor in
combinationwithcsDNARD(esp.
MTX)
 Treatment options
Pharmacological – DMARDs – bDMARDs
Anti-TNFα(cont.)
 Dosingandadministration
• IVinfusionfor infliximab
• s/cinjectionfor others(injectfrequencyrangebetweenevery1-4
weeks)
 Important considerations
• Increaserisk of all infections
• Pre-treatmentcourseof anti-TB therapy(e.g. Isoniazidfor 3 months) is recommendedfor mycobacteria+ve
• Themostseriousbeingreactivationof tuberculosis(TB)
(skinpricktest) patients

• Opportunistic infections (e.g. suchaslisteriosis) arealso morecommonin patients usingTNFinhibitors

• Malignancies
• Possibleincreasedrisk of lymphomaandothermalignancies
• Adverseoutcomevs. co-morbidity risk factor?*
• Increasedincidence of multiple sclerosis?*
• Aggravatepre-existingcongestiveheart failure
Etanercept-TNFαInhibitor
• Arecombinantfusionproteinof TNF-receptorwith Feportionof humanlgG1
• Administeredbys.c. injection50mgweekly
• It bindstoandpreventsTNFαfromactivatingTNFreceptorsonthe
membraneof T-cels/macrophages
• Dose:25--50mgs.c. onceor twiceweekly
lnfliximab
• Monoclonalantibodywhichbindsandneutralize TNFα;
• 3- 5 mg/kgis infusedi.v. every4-8 weeks.
Adalimumab:
 Recombinanthumanmonoclonalanti-TNFantibodyis administereds.c.40
mgevery2 weeks
Treatment options Pharmacological –
DMARDs – bDMARDs
Lymphocyte modifier
Rituximab: monoclonalantibodydepletesD-lymphocytes
 Efficacy
• Clinical datastil limited, but mostdemonstratedsimilar efficacyto anti-TNF
• Rituximab + MTXeffective in reducingsymptomsin patient whofailed to achieve
remission fromanti-TNF
 Placein therapy
• 2ndor 3rdline optionsof bDMARDs
• Currently only recommendedfor RAtreatment failure fromcsDMARDor bDMARD
 Important considerations
• Vaccination prior to initiation of therapy
Treatment options Pharmacological –
DMARDs – bDMARDs
Interferonbeta-1aandbeta-1b
 Naturaly occurringproteinsandglycoproteins
• Producedin response to viral infection
• Relatedto cytokines
 Efficacy
• Clinical evidence is less conclusive thananti-TNF
• Comparable or inferior toanti-TNF
 Recommendation
• TreatmentfailurefromMTXor anti-TNF
• Alternative therapy or asadd-on therapy
• Alternativeto anti-TNFfor patientnottolerating other1stlineagent
 Treatment
options: Non-
drug options
 Tailored exercise
• Newapproach?
• Includingmobilityexerciseandstrength/ enduranceexercise
• PTor OTthenadjustexerciseintensity basedonindividual’s strength, pain,
andflexibility
• Earlydataindicatesomemoderatebenefitin function,andquality of life
• Maywortha trial if without interferingwith pharmacotherapies
Life style management
of RA
 Regular aerobic exerciseimproves
ophysical function
ohelpsmaintainideal bodyweight
opsychologicalandcardiovascular health
o Low-impactlandexercise(egstationarycycling,walking)
o low-to moderate-intensitywater-basedexerciseis preferredfor patientswith painfuljoints or high
disease
activity.
o Strengthening(anaerobic)exerciseis also recommendedto preventmusclewasting.
o Weightbearingexerciseimproves bonehealth.
Life style management :
Mediterranean-style diet
 Characterisedby a highconsumption of
fruit, vegetables, cereals andlegumes, a
little redmeatbut morefish, oliveoil asthe
mainsourceoffat, & a moderate intakeof
wine
 Most universally accepteddietary
intervention
 Benefit of weight controlandreducing
cardiovascular risk.
Life style management: Smoking
Cessation
• Smokinglinkedto development of RA
• Poorprognosis& poorresponseto therapy
• ↑Risk of cardiovasculardiseasein pt groupalreadyat increasedrisk
References
• eTG
• AMH 2018
• KD Tripathi, Essentials of Medical Pharmacology,8th Edition,Jaypee
brothers medical publishers,New Delhi,June 2018
• https://emedicine.medscape.com/article/331715-treatment#d13