AN APPROACH TO A PATIENT WITH

RHEUMATOID ARTHRITIS

DR.MD.NUR-E-AZAMHMO,MU-5,DMCH

CASE SCENARIO• Mrs. Salma,42 yrs,non diabetic,normotensive,non asthmatic hailing from

gabtoli,dhaka with complanits of epigastic pain and vomiting foe last 3 days.no history of fever.passage of bloody stool or vomiting,previous yellow coloration of skin and sclera.pain in the epigastric region ,aggravated by taking meal,not relieved by anything,no radiation associated with vomiting.she also gives history pain over multiple small and large joints of both upper and lower limb for last 8 years.dignosed as a case of Rheumatoid arthritis. for this she used to take same medication for last 8 yrs.like deltason and rheumacap sr.mtx ,folison etc.now she also complaints of burning sensation of distal upper and lower limbs for last 2 yrs.puffiness of face for last 6 months.low back pain for same duration.she gives no history of trauma,no alteration of bowel bladder.on exam,her face is pufffy,abdominal obesity present,BP 160/80.pulse 82b/min.rr;18/min.Heart:S1 S2 normal.lungs:fine crepts in RLZ.abdomen is distended,stria present mostly vertical.no lynphadenopathy present. rheumatological xm revealed,there is wasting of both thaner and hypothenar muscle,dorsal guttering and ulner deviation present.there is swelling of 1st 2nd &3rd metacarpophalyngeal &PIP joints of both hands.wrist joint also swollen & tenderness present.

Mrs.SALMA,42yrs,B-41,W-801,MU-5

• abd exam revealed duodenal point tenderness +ve, no organomegaly,no shifting dullness.neurological xm revealed sensation impaired below ankle and below wrist joint.all jerks are normal.no bony deformities of spine,no local tenderness.respiratory systen reveals there is late inspiratory fine crackles in Rt lower zone.other system reveals all normal.our provisional diagnosis is NSAIDs induced peptic ulcer disease with iatrogenic cushing syndrome with Rheumatoid arthritis with HTN with electrolyte imbalance.inv revealed.Hb 10gm/dl.WBC 7000/cmm.s. creatinine 1.8.s. electrolyte Na 128 K 3.2 .cl 82.co2 18.upper GI endoscopy shows there is ulceration over 1st part of duodenam antral erosion and mucosal edema.USG of WA shows,bilateral renal echogenicity is increased.early parenchymal disease.serum cortisol level at 8 am 60nmol/L.at 4 pm 45 nmol/L.RBS 9.5 mmol/L.X ray L/S spine shows osteoporotic changes.Xray chest shows there is fibrotic bands in Rt lower zone..ECG ..antero lateral ischaemia.our final diagnosis is RA with NSAIDs induced PUD with Hypo kalaemia and hyponataemia with Iatrogenic Cushing syndrome with CKD with HTN with IGT with IHD with RLZ fibrosis with osteoporosis

• h/o presenting complaints - Onset - progression - distribution of disease - stiffness - aggravating or relieving factor - diurnal variation - other systemic feature - functional disability

• General systematic medical history.• Past medical and surgical history.• Family history.• Drug history.

The Rheumatologic History

A. ONSET- acute- < 6 wks eg.infectious arthritis crystal arthropathy reactive arthritis.

Chronic - >6 wks eg. Non inflamatory arthritis (OA) Inflammatory arthritis(RA) Fibromyalgia.

B. EVOLUTION – chronic eg.OA intermittent eg. Crystal / lymes arthritis

migratory arthritis eg.Rheumaticfever, Gonococcal, viral arthritis

Chronology of complaints

C. Extent of articular involvement - Monoarticular (one joint involved)

- Oligo or pauciarticular (< = 4 joint) - Polyarticular (> 4 joints)

D. Distribution of joint involvement -symmetrical- upper and lower limb eg. RA, SLE

-Asymmetrical-eg. psoriatic arthritis, spondyloarthropathy, gout -Involvement of axial skeletal-eg AS, OA, RA(only cervical spine)

• Constitutional symptoms• Skin rashes• Mucous membrane lesions• Ocular• Nails• Raynauds• Serositis

Extra articular signs & symptoms

CAUSES OF MONOARTHRITIS

• Common• • Septic arthritis• • Gout• • Pseudogout• • Reactive arthritis• • Trauma• • Haemarthrosis• • Seronegative

spondyloarthritis• Psoriatic arthritis

• Ankylosing spondylitis

• Enteropathic arthritis

• Less common• • Erythema

nodosum• • Rheumatoid

arthritis• • Juvenile

idiopathic

• arthritis• • Pigmented

villonodular• synovitis• • Foreign body

reaction• • Other infection• Gonococcal• Tuberculosis• • Leukaemia*• • Osteomyelitis*

CAUSES OF POLYARTHRITISCharacteristicsCommon1) Rheumatoid

arthritis Symmetrical, small and large joints,

upper and lower limbs

Viral arthritis Symmetrical, small joints; may be

associated with rash and prodromal

illness; self-limitingOsteoarthritis

Symmetrical, targets PIP, DIP and first

CMC joints in hands, knees, hips, back

and neck; associated with Heberden’s

and Bouchard’s nodes

Psoriatic arthritis Asymmetrical, targets PIP and DIP joints

of hands and feet (sausage appearance

on examination), nail pitting, large joints

also affectedAnkylosingspondylitis andenteropathic

arthritisTends to affect large

joints, lower more

than upper limbs, possible history of

inflammatory back pain

SLE Symmetrical, typically affecting small

joints, clinical evidence of synovitis

Unusual

Less common

Juvenile idiopathicarthritisSymmetrical, small

and large joints,upper and lower

limbsChronic gout Affects

distal more than proximal joints,

history of acute attacks

Chronic sarcoidosis(p. 709)Symmetrical, small

and large jointsPolymyalgiarheumaticaSymmetrical, small

and large joints

RareSystemic sclerosis

and polymyositisSmall and large

jointsHypertrophicosteoarthropathySmall joints,

clubbingHaemochromatosisSmall and large

jointsAcromegaly Mainly

large joints and spine

(CMC = carpometacarpal; DIP = distal interphalangeal; PIP = proximal

interphalangeal)

Acute Polyarthritis

• Infection• Gonococcal• Meningococcal• Lyme disease• Rheumatic fever• Bacterial

endocarditis• Viral (rubella,

parvovirus, Hep. B)

• Inflammatory• RA• JRA• SLE• Reactive arthritis• Psoriatic arthritis• Polyarticular gout• Sarcoid arthritis

• Swelling• Posture of joint• Deformity• Warmth• Redness• Tenderness• Limitation of joint movement• Crepitus• Stability• Function

Rheumatic disease signs

Evaluation of a patient with arthritis in rheumatology opd

• Articular or non articular• Inflammatory or non inflammatory• Acute or chronic• Monoarticular or polyarticular• Extra articular signs

• Rheumatological history and clinical examination • Inflammatory /non-inflammatory arthritis• Mono/ Oligo arthritis• Polyarthritis• Soft tissue rheumatism• Lab investigations• Synovial fluid analysis• Imaging

Outline

Inflammatory Vs.Mechanical

Feature Inflammatory Mechanical

Morning stiffnessFatigueActivityRestSystemicCorticosteroid

>1 h

Profound ImprovesWorsensYesYes

< 30 min

MinimalWorsensImprovesNoNo

Inflammatory Vs. Noninflammatory

Feature Inflammatory Noninflammatory

Pain (when?)SwellingErythemaWarmthAM stiffnessSystemic featuresî ESR, CRPSynovial fluid WBCExamples

Yes (AM)Soft tissue SometimesSometimesProminent SometimesFrequentWBC >2000Septic, RA, SLE, Gout

Yes (PM)BonyAbsentAbsentMinor (< 30 ‘)AbsentUncommonWBC < 2000OA, AVN

ARTICULAR VS NONARTICULAR PAIN

ARTICULAR

- Deep or diffuse pain.- Painful or limited range of movemnt -

both active and passive - Swelling of joint- Crepitation.- Joint instability.- Locking of joint.- Deformity.

NONARTICLAR

- localised pain- Point or local tenderness - Painful active movements but

not on passive - Physical findings are remote from

joint capsule.- swelling,crepitation,joint

instability, deformity are rare.

RHEUMATOID ARTHRITIS• RA is the most common persistant inflammatory arthritis.M:F

ratio=1:3.• Most common age group 30-50 yrs.• Genetic epigenetic and Environmental factor are implicated in

pathogenesis of RA.• HLA-DR4,IL-1,6,15,17,TNF,TH17,B cell ,T cell,Synovial fibroblast cell are

involved in pathogenesis.• Infiltration of synovial membrane withlymphocyte,plasma

cell,dendritic cell .macrophage->lymphoid follicle form within synovial membrane->release of IL-1,6,15,17,TNF->act on fibroblast->release of cytoline chemokine MMA->activation of osteoclast and chondrocyte->formation of inflammatory granulation tissue named pannus->destruction of cartilage and bone->deformity of joint

COX-2 = cyclo-oxygenase type 2; PGE2 = prostaglandin-E2; NO = nitric oxide

-COX-2-PGE2

-NO-Adhesion molecules

-Chemokines-Collagenases

-IL-6

Proinflammatory effects of IL-1

Proinflammatory effects of TNF--

-TNF---Osteoclast activation

-Angiogenic factors

-IL-1 -cell death

IL-1 and TNF-- Have a Number of Overlapping Proinflammatory Effects

PATHOLOGICAL CHANGE IN RA

• JOINT DISTRIBUTION (0-5)• 1 large joint• 0• 2-10 large joints • 1• 1-3 small joints (large joints not counted)• 2• 4-10 small joints (large joints not counted)• 3• >10 joints (at least one small joint)• 5• SEROLOGY (0-3)• Negative RF AND negative ACPA• 0• Low positive RF OR low positive ACPA• 2• High positive RF OR high positive ACPA• 3• SYMPTOM DURATION (0-1)• <6 weeks• 0• ≥6 weeks• 1• ACUTE PHASE REACTANTS (0-1)• Normal CRP AND normal ESR• 0• Abnormal CRP OR abnormal ESR• 1

≥6 = definite RA

2010 ACR/EULARClassification Criteria for RA

What if the score is <6?

Patient might fulfill the criteria…

Prospectively over time (cumulatively)

Retrospectively if data on all four domains have been adequately recorded in the past

• These criteria describe either spontaneous remission or a state of drug-induced disease suppression.

Stage 1:Early1.No distructive change on x-ray2.Evedance of ostioporosis may be present

Stage 2: Moderate 1.Osteoporosis with or without slight subchondral bone distruction,slight

cartilage distruction may be present2. No joint deformity, limitation of joint mobility present3. Adjacent muscle atrophy.4. Extra articular soft tissue lession such as nodule and tenosinusitis may be

present

ACR Classification Criteria for Determining Progression of Rheumatoid Arthritis

Stage 3: SEVERE1. Cartilage and bone distruction in addition to osteoporosis2. Joint deformity3. Extensive muscle atrophy4. Extra articular soft tissue lesion

Stage 4: Terminal 5. Fibrous bony ankylosis6. Stage 3 criteria

Ref:steinberocker o ,et.al:JAMA:140:659,1949

Early RA

SCLERITIS IN RA

RHEUMATOID NODULE

HAND IN RA

X RAY OF RA

RA PRESENTATION

• Z - deformity • Subcutaneous nodules

CHANGES IN SPINE IN RA

Serial X-rays of a knee in RA

DEFORMITIES IN RA• Swan neck deformity

SCLEROMALACIA IN RA

ADVANCED RA.

Rheymatoid nodule

INVOLVEMENT OF JOINTS IN RA• Commonly affected joints• MCP 90-95%• PIP 65-90%• Temporomandibular 20-30%• MTP 50-90%• Ankle 50-80%• Knee 60-80%• Hip 40-50%• Shoulder 50-60%• Cervical spine 40-50%• Elbow 40-50%• Wrist 80-90%

History and physical examination

Is it articularTrauma/fractureSoft tissue rheumatism

no

> 6 weeks

yes

Chronic yes

Acute Infectious arthritrisCrystal induced

Reactive arthritis

No

Signs of inflammation

DIP, CMC1,Hip ,Knee

jointosteoarthritis

yes

OsteonecrosisCharcots joint

no

yesChronic inflammatory

arthritis

Joints involved

1-3

Psoriatic Pauci JA symmetrical

>3

Psoriatic Reactive

no

yesPCP,MCP/

MTP

yes

Rheumatoid

no

SLE/Scleroderma

no

TERMINOLOGY

• Malignant RA: severe and progressive RA with severe extra articular manifestatio,systemic feature and vasculitis.

• Palindromic RA: recurrent acute episode of monoarthritis lasting 24 to 48 hours.knee and finger joints most commonly affected.

• Caplan,s syndrome: Rheumatoid lung nodue with Pneumoconiosis.

• Felty,s syndrome: RA with splenomegaly with neutropenia.

EXTRA ARTICULAR MENIFESTATION OF RA• Fever• • Weight loss• • Fatigue• • Susceptibility to infection• Musculoskeletal• • Muscle-wasting• • Tenosynovitis• • Bursitis• • Osteoporosis• Haematological• • Anaemia• • Thrombocytosis• • Eosinophilia• Lymphatic• • Felty’s syndrome• (see Box 25.56)• • Splenomegaly• Nodules• • Sinuses • Fistulae

• Ocular• • Episcleritis• • Scleritis• • Scleromalacia• • Keratoconjunctivitis sicca• Vasculitis• • Digital arteritis• • Ulcers• • Pyoderma gangrenosum• • Mononeuritis multiplex• • Visceral arteritis• Cardiac• • Pericarditis• • Myocarditis• • Endocarditis• • Conduction defects• • Coronary vasculitis• • Granulomatous aortitis• Pulmonary

• • Nodules• • Pleural effusions• • Fibrosing alveolitis• • Bronchiolitis• • Caplan’s syndrome• Neurological• • Cervical cord compression• • Compression neuropathies• • Peripheral neuropathy• • Mononeuritis multiplex• Amyloidosis (p. 86)

SEROLOGY• Rheumatoid factor• Rheumatoid factor (RF) is an antibody directed against• the Fc fragment of human immunoglobulin. In routine• clinical practice, IgM rheumatoid factor is usually measured,• although different methodologies allow measurement

• Anti-citrullinated peptide antibodies• Anti-citrullinated peptide antibodies (ACPA) recognise• peptides in which the amino acid arginine has been converted• to citrulline by peptidylarginine deiminase, an• enzyme abundant in inflamed synovium and in a variety• of mucosal structures. ACPA have similar sensitivity to• RF for RA (70%) but much higher specificity (> 95%),• and are increasingly being used in preference to RF in• the diagnosis of RA.f IgG and IgA RFs too.

Anti-CCP Antibody Test in RA • Antibodies to Cyclic Citrullinated Peptides (anti-CCP) Similar

sensitivity for RA (70%)• Specificity for RA (>95%) better than RA Factor• In early polyarthritis anti-CCP are useful for Dx• Anti-CCP are associated with more severe disease• They spell a poor prognosis and rapid progression• They may be positive in asymptomatic patients yearsbefore the

onset of symptoms73• Anti-CCP :IgG against synovial membrane peptides damaged via

inflammation• Sensitivity (65%) & Specificity (95%)• Both diagnostic & prognostic value• Predictive of Erosive Disease Disease severity Radiologic

progression Poor functional outcomes

• TEST• SENSITIVITY• SPECIFICITY• ANTI CCP• 41%• 98%• RF• 62%• 84%• ANTI CCP+ RA• 33%• 99.6%

SEROLGY IN RA:ANTI-CCP AND RA FACTOR

Conditions associated with apositive rheumatoid factor

• Frequency (%)• Rheumatoid arthritis with nodules and• extra-articular manifestations• 100• Rheumatoid arthritis (overall) 70• Sjögren’s syndrome 90• Mixed essential cryoglobulinaemia 90• Primary biliary cirrhosis 50• Infective endocarditis 40• Systemic lupus erythematosus 30• Tuberculosis 15• Age > 65 yrs 20• Normal healthy people can be positive for rheumatoid factor.

CONDITIONS ASSOCIATED WITH POSITIVE ANA WITH FREUENCY

• Condition Approximate frequency• Diseases where ANA is useful in diagnosis• Systemic lupus erythematosus 100%• Systemic sclerosis 60–80%• Sjögren’s syndrome 40–70%• Dermatomyositis or polymyositis 30–80%• Mixed connective tissue disease 100%• Autoimmune hepatitis 100%• Diseases where ANA is not useful in diagnosis• Rheumatoid arthritis 30–50%• Autoimmune thyroid disease 30–50%• Malignancy Varies widely• Infectious diseases Varies widely• N.B. 5% of healthy individuals have an ANA titre > 1:80.

Investigations and monitoring ofrheumatoid arthritis

• To establish diagnosis• • Clinical criteria• • ESR and CRP• • Ultrasound or MRI• • Rheumatoid factor and• anti-citrullinated peptide• antibodies• To monitor disease activity and

drug efficacy• • Pain (visual analogue scale)• • Early morning stiffness• (minutes)• • Joint tenderness

• • Joint swelling• • DAS28 score• • ESR and CRP• • Ultrasound• To monitor disease damage• • X-rays • Functional assessment• To monitor drug safety• • Urinalysis• • Full blood count• • Urea, creatinine and liver• function tests

F ra c tu reT u m o ur

M e ta bo lic bo n e d ise a se

N o rm a l

X -ra y(M R I/C T p rn )

C lo tt in g s tu d iesP la te le ts

B le e d in g t im e

C o a gu lo pa thyP seu d og o ut

T u m o urT ra u m a

B lo o dy

In tra -a rt icu la r #

B o n e m a rro w +

C rys ta ls :M S U:g o u t

C P P D :P se u do g o ut

+ G ra m /C u lt:In fe c tio us a rth rit is

F B C , R F, A N F H L A B 27

- C u ltu reS p A , R A , S LE

S a rco id e tc

> 2 0 00 W B C> 7 5 % P M N L

O AIn te rn a l de ran g e m e nt

S o ft t is su e in ju ryV ira l in fe c tion

< 2 0 0 0 W B C< 7 5 % P M N L

Jo in t a sp ira tion

E ffu s ionS ig n s o f in f la m m a tion

B u rs it isT e n d in it is

F ib ro m a y lg ia

P o in t te n d ern e ssT rig g e r p o in ts

S ig n ifica n t tra u m aF o ca l b o ne p a in

H is to ry an d e xam in a tion

A rth ra lg ia 1 o r m o re jo in ts

• Control disease activity• Alleviate pain• Maintain function for essential daily activities• Maximize quality of life• Slow progression/rate of joint damage• Prevent deformity

Goals of Therapy

The New Treatment Paradigm

MANAGEMENT OF R.A.• Medications are divided into three main classes 1.NSAIDs• 2.corticosteroids• 3.DMARDs• 4.BIOLOGICS• 5.Surgery• Medical Management – Drug Classes• NSAIDs – Cox-1 & Cox-2 inhibitor• Glucocorticoids – Prednisolone,• MPIAS – Intra articular steroids• DMARDs – MTX, SSZ, HCQ, CQ• Immunosuppressive Rx.– AZT, Leflunomide, CSCytotoxic agents

– CyclophosphamideBiologics – TNF-antibodies, IL-1 R antagonist

• Old drugs – Gold salts, D-Penicillamine

Nonsteroidal anti inflammatory drugs

•Examples of NSAIDs include:Aspirin IndomethacinIbuprofenNaproxenPiroxicamNabumetoneDiclofenacAll NSAIDs should be taken with meals to prevent stomach upset.

NSAIDS in RA

• NSAIDs COX 1& COX2 • Selective COX 2 Inhibitors• Improved GI tolerability• Reduced effects on RBF• No effect on platelets Called as COXIBs• May have adverse effecton heart• Celecoxib Etoricoxib Meloxicam Constituent

pathway Renal and GI homeostasis Inducible pathway Inflammation

NSAIDs COX 1

• NSAID Class of Drugs Non Selective

• Ibuprofen• Ketoprofen• Diclofenac• Aceclofenac• Piroxicam• Lornaxicam• Naproxen

• Indomethacin• NSAIDs used as

analgesics • Ketorolac• Aspirin (NSAID)• Selective COX-2• Celecoxib, Etoricoxib • MeloxicamAnalgesics

Tramadol Paracetamol

Pros and Cons of NSAID Therapy• PROS• Effective control ofinflammation and pain• Effective reduction inswelling• Improves mobility,flexibility, range of motion• Improve quality of life• Relatively low-cost• CONS• Does not affect diseaseprogression• GI toxicity common• Renal complications(eg. Irreversible renalinsufficiency,

papillarynecrosis)• Hepatic dysfunction CNS toxicity

Glucocorticoids (GCs)

• GCs is added at low to moderately high doses to Synthetic or Biologic DMARDs whether monotherapy or in combination.

• Morning 8-10am low dose <10mg/d gives a rapid relief of symptoms because it behaves as:

• Anti cytokines (Anti IL-1,IL-2, Anti TNF ) • Anti COX NSAID effect • Anti LOX So they have actions equivalent to Anticytokines

DMARDs, NSAIDs As well as inhibit lymphocyte proliferation & antigen presentation.

• Glucocorticoids (GCs) (cont.) GCs has a disease modifying effect without harmful side effects especially if used with Ca & Vit D in a dose <10mg (7.5mg/d) But more rapid improvement may be achieved by addition of GCs at a higher dose in cases of visceral involvement, e.g. pericarditis, pleurisy, fever, vasculitis)for a short term Ask for bone mineral density (BMD) DEXA scan during follow up.

• Glucocorticoids (GCs) (cont.) GCs minipulse therapy: During exacerbation of the disease GCs are used in a dose of 200-250mg IM or IV for 3 successive days, then go back to maintenance low dose This minipulse is equivalent to 1000mg/d pulse therapy in SLE No prolonged suppression of hypothalamic pituitary adrenal axis (HPA); so it has no adverse effect like that of long term use of GCs.

Pros and Cons of Corticosteroid Therapy

• PROS Anti-inflammatory andimmunosuppressive effects• Can be used to bridgegap between initiationof DMARD

therapy andonset of action• Intra-articular steroid (IAS)injections can be used

forindividual joint flares• CONSDoes not conclusivelyaffect disease progression• Tapering anddiscontinuation of useoften unsuccessful• Low doses result in skinthinning, ecchymoses,

andCushingoid appearance• Significant cause of steroid-induced osteopenia

Newer "second- line“ drugs or "biologic" medications

Leflunomide Etanercept Infliximab Annakira Adalimumab Rituximab Abatacept Golimumab Certolizumab Tocilizumab

Immunosuppressive Medicines

Are powerful medications that suppress the body's immune system. A number of immunosuppressive drugs are used to treat rheumatoid arthritis. They include Methotrexate Azathioprine Cyclophosphamide Chlorambucil and Cyclosporine

Combination DMARD therapy

MTX + SSZ + OH-ChloroquineMTX + CSA MTX + EtanerceptMTX + RemicadeMTX + AdalimumabMTX + Leflunomideexcellent safety & improved efficacy over MTX alone

DRUG ,M/A,DOSE,SIFE EFFECT,MONITIRING,FREUENCY• Methotrexate Inhibits DNA• synthesis and• cell division• 5–25 mg/wk GI upset,

stomatitis, rash,• alopecia, hepatotoxicity, acute• pneumonitis• FBC, LFTs Initially monthly,• then every 3 mths• Sulfasalazine Unknown 2–4

g/day Nausea, GI upset, rash,• hepatitis, neutropenia,• pancytopenia (rare)• FBC, LFTs Monthly for 3 mths,• then 3-monthly• Hydroxychloroquine Unknown

200–400 mg/day Rash, nausea, diarrhoea,

• headache, corneal• deposits, retinopathy• (rare)• Visual

• acuity,• fundoscopy• 12-monthly• Leflunomide Blocks T-cell• division• 10–20 mg/day Nausea, GI

upset, rash,• alopecia, hepatitis,• hypertension• FBC, LFTs,• BP• 2–4-weekly• D-Penicillamine Unknown 250–

750 mg/day Rash, stomatitis, metallic

• taste, proteinuria,• thrombocytopenia• FBC, urine• (for protein)• Initially 1–2-weekly;• 4–6-weekly for

• maintenance• Gold Unknown 50 mg/mth by

IM• injection• Rash, stomatitis, alopecia,• proteinuria, thrombocytopenia,• myelosuppression• FBC, urine• (protein)• Each injection• Ciclosporin Blocks T-cell• activation• 150–300 mg/day Nausea, GI

upset, renal• impairment, hypertension• FBC, LFTs,• U&E, BP• 2–4-weekly• (BP = blood pressure; FBC = full

blood count; LFT = liver function tests; U&E = urea and electrolytes)

DMARDsNAME DOSE SIDE EFFECTS MONITORING ONSET OF ACTION

1) Hydroxycloroquine: 200mg twice daily Skin pigmentation Fundoscopy& 2-4 months quine x 3 months, then , retinopahy perimetry yearly once daily ,nausea, psychosis, myopathy

2) Methotrexate :7.5-25 mg once a GI upset, Blood counts,LFT 1-2 months week orally,s/c or hepatotoxicity, 6-8 weekly,Chest i/m Bone marrow x-ray annually, suppression, urea/creatinine 3 pulmonary monthly; fibrosis Liver biopsy

• 3)Sulphasalazine - 2gm daily p.o Rash, Blood counts 1-2 months myelosuppression, ,LFT 6-8 weekly may reduce sperm count

• 4)Leflunomide: Loading 100 mg Nausea,diarrhoea, LFT 6-8 weekly 1-2 months daily x 3 days, alopecia, then 10-20 mg hepatotoxicity daily p.o

When to start DMARDs?

DMARDs are indicated in all patients with RA who continue to have active disease even after 3 months of NSAIDS use.

The period of 3 months is arbitary & has been chosen since a small percentage of patients may go in spontaneous remission.

The vast majority , however , need DMARDs and many rheumatologists start DMARDs from Day 1.

How to select DMARDs?

There are no strict guidelines about which DMARDs to start first in an individual.

Methotrexate has rapid onset of action than other DMARD.

Taking in account patient tolerance, cost considerations and ease of once weekly oral administration METHOTREXATE is the DMARD of choice, most widely prescribed in the world.

Should DMARDs be used singly or in combination?

• Since single DMARD therapy (in conjunction with NSAIDS) is often only modestly effective , combination therapy has an inherent appeal.

• DMARD combination is specially effective if they include methotrexate as an anchor drug.

• Combination of methotrexate with leflunamide are synergestic since there mode of action is different.

Limitations of conventional DMARDs

• 1) The onset of action takes several months.• 2) The remission induced in many cases is partial.• 3) There may be substantial toxicity which

requires careful monitoring.• 4) DMARDs have a tendency to lose effectiveness

with time-(slip out). These drawbacks have made researchers look for

alternative treatment strategies for RA- The Biologic Response Modifiers.

Methotrexate monotherapy

• In cases of DMARDs naïve patients Methotrexate should be initiated as first line mono-therapy {with/without Glucocorticoids} at the maximally tolerated dose (7.5-25mg & rarely 30mg/week). (7.5- 20 PO & switch to SC or IM if the dose >20mg/week).

• MTX is the most effective, safe (ease of administration, low cost and of long term therapy (515ys). It is first line agent & the anchor drug for combination therapy with other DMARDs & Biologic agents. Do not forget to add 1mg folic acid/day to guard against GIT, hematologic or pulmonary side effects.

Methotrexate Adverse Events

• • GI - Mucositis, diarrhea, abdominal pain• Hematologic - Cytopenias, macrocytosis• Hepatic- Transaminitis, fibrosis, and cirrhosis• Pulmonary - Hypersensitivitypneumonitis, pulmonary fibrosis• Infections• Neoplasia - reversible lymphoproliferativedisorder, lymphoma, and leukemia• Accelerated nodulosis and vascultitis• Reproductive – abortifacient and teratogen– Must use birth control and d/c drug 2-6 months beforeplanned pregnancy

BIOLOGICS IN RA

• Cytokines such as TNF-α ,IL-1,IL-10 etc. are key mediators of immune function in RA and have been major targets of therapeutic manipulations in RA. Of the various cytokines,TNF-α has attaracted maximum attention.Various biologicals approved in RA are:-

• 1) Anti TNF agents : Infliximab Etanercept Adalimumab• 2) IL-1 receptor antagonist : Anakinra• 3) IL-6 receptor antagonist : Tocilizumab• 4) Anti CD20 antibody : Rituximab• 5) T cell costimulatory inhibitor : Abatacept

Biological DMARDs characteristics

• Provides rapid relief of signs & symptoms of RA • Onset of action within days or weeks. • Slowing or halting the progression of joint

erosion. • Leads to remission in 2/3 of cases of RA; the

remaining 1/3 shift to another biologic after 3-6 month.

• Anti TNF are contraindicated during pregnancy and lactation.

Agent Usual dose/route Side effects Contraindications

• Infliximab 3 mg/kg i.v infusion at Infusion reactions, Active(Anti-TNF) wks 0,2 and 6 followed increased risk of infections,uncontrolled by maintainence dosing infection, reactivation DM,surgery(with hold for 2 every 8 wks of TB ,etc wks post op) Has to be combined with MTX.

• Etanercept 25 mg s/c twice a wk Injection site Active . reaction,URTI ,(Anti-TNF) May be given with MTX infections,uncontrolled or as monotherapy. reactivation of DM,surgery(with hold for 2 TB,development of wks post op) ANA,exacerbation of demyelenating disease.

• Adalimumab 40 mg s/c every 2 Same as that of Active infections(Anti-TNF) wks(fornightly) infliximab May be given with MTX or as monotherapy

• Anakinra 100 mg s/c once Injection site Active infections (Anti-IL-1) daily pain,infections, May be given with neutropenia MTX or as monotherapy.Abatacept . mg/ kg body wt. 10 Infections, infusion Active infection(CTLA-4-IgG1 At 0, 2 , 4 wks & reactions TBFusion protien) then 4wkly Concomittant with otherCo-stimulation anti-TNF-αinhibitor

• Rituximab 1000 mg iv at Infusion reactions Same as above(Anti CD20) 0, 2, 24 wks InfectionsTocilizumab 4-8 mg/kg Infections, infusion Active infections( Anti IL-6) 8 mg/kg iv monthly reactions,dyslipidemia

Biologic DMARDs: Precautions & Contraindications:

• Increase risk of bacterial infection: (septic arthritis, osteomyelitis, pyelonephritis, pneumonia, cellulitis)

• Screening for active or latent TB with +ve purified protein derivative (PPD) test.

• Indurated area <5mm is +ve in patients who are immunocompromised

• Also ask for X-Ray chest, history of TB treatment• CHF: in spite of increased TNF in heart failure. • Optic neuritis, demyelinating diseases. • Significant coronary artery disease

• Not contraindicated in solid tumors if there is no recurrence in the past 5 years, however it should be avoided in lymphomas.

• COPD • Viral infection HCV, HBV, HIV (reactivation of viral

infection) • Temporarily suspended in patients undergoing

surgery (one week before & one week after surgery).

• Avoid vaccination with live attenuated vaccine (German measles, oral Polio, Rabies and Herpes Zoster)

• Influenza vaccine & pneumococcal vaccine if required should be given 2-4 weeks prior to administration of biologic therapy.

How long should Rx to be continued?

• Once remission is achieved , maintenance dose for long period is recommended.

• Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is discontinued in most instances.

• DMARDs are discontinued by patients because of toxicity or secondary failure(common after 1-2 yrs) and such patients might have to shift over different DMARDs over 5-10 yrs.

• Disease flare may require escalation of DMARD dose with short course of steroids.

• Methotrexate + Synthetic DMARDs • Patients present with inspite continue active to disease

of MTX monotherapy, addition of another conventional DMARD is combined with MTX

• treatment according to disease activity • (i) MTX + HCQ. (ii) MTX + SSZ. (iii) MTX + Leflunomide.• Most experts no longer use loading dose if combined

with MTX because of increased liver toxicity while HCQ minimize hepatic toxicity of MTX & lower LDL & T.G

• (iv) MTX + one or two or 3 DMARDs ± short term GCs. combination of these drugs with different modes of action allows the use of lower (individual) drug doses thus minimizing toxicity without reducing efficacy. MTX in a step up combination therapy.

COMBINATION THERAPY

• According to disease activity• MTX + one or two or 3 DMARDs ± short term GCs. combination

of these drugs with different modes of action allows the use of lower (individual) drug doses thus minimizing toxicity without reducing efficacy.

• Methotrexate + Biologics If the treatment target is not achieved (remission/low disease

activity) with MTX + two or more synthetic DMARDs ± short term GCs after 3-6 month

Or in cases of High Disease Activity (HDA) and poor prognostic factors; addition of biologic therapy should be considered from the start

TREATMENT PROTOCOL

• If biological DMARDs + MTX is considered start with 1st generation anti TNFα (i)Etanercept (Totally humanized)

• (ii)Adalimumab (Totally humanized) 40 mg SC/2 weeks. mg SC/week

iii)Infliximab (REMICADE): Chimeric monoclonal Ab (mouse 25% & human 75%) 3mg/kg slow IV infusion (2hrs) 0,2 W, 6 W 2 month.

MTX is included in all combination therapy

• Combination between MTX + biologic therapy provides great benefit in improving signs & symptoms of RA

• preventing radiographic destruction & improving physical functions in comparison to MTX or biologic monotherapy.

• No combination of two biologic therapy because of high rate of adverse effects & lack of any additive effect

Indication of 2nd G BIOLOGICAL Agents

• If the treatment target is not achieved (remission/low disease activity) with MTX + 1st generation anti TNF , go to 2nd generation Biological drugs.

• (i)Abatacept (selective co-stimulation modulator). Dose according to body weight (10mg/kg)

• (ii)Rituximab(anti CD 20)• (iii)Tocilizumab (IL-6 inhibitor) 8mg/kg/month

It has been proven to work with or without methotrexate

Immunosuppresive therapyAgent

• Usual dose/route Side effects• Azathioprine: 50-150 mg orally GI side effects ,

myelosuppression, infection, • Cyclosporin: A 3-5 mg/kg/day . Nephrotoxic ,

hypertension , hyperkalemia• Cyclophosphamide: 50 -150 mg orally

Myelosuppression , gonadal toxicity ,hemorrhagic cystitis , bladder cancer

Refractory severe RA• In cases of refractory severe RA with

contraindications to all biologic & synthetic DMARDs :

• Try Azathioprine Cyclosporine A ( keep an eye on BP & renal profile) Or Cyclophosphamide (which is used in exceptional situations).

• A number of DMARDs has been excluded such as: D-Penicillamine, Minocycline, Auranofen because of its insufficient effect.

• Gold being effective drug, but limited availability & newer therapies resulted in less wide spread of the drug.

How to monitor Rx Response in RA?

• Disease activity is assesed by several parameters• duration of morning stiffness,• tender joint count,• swollen joint count• observer global assessment,• patient global assessment• visual analogue scale for pain,health assessment

questionnaire,• ESR,• NSAID pill count,• DAS score etc

CALCULATION of DAS28 SCORE• Count the number of tender joints• • Count the number of swollen joints• • Measure the ESR• • Ask the patient to rate global activity of arthritis during the• past week from 0 (no symptoms) to 100 (very severe)• • Enter data into an online calculator1 or work out using a• formula2

• DAS28 = 0.56 × square root (tender joints) + 0.28 × square• root (swollen joints) + 0.70 × loge(ESR) + 0.014 (global activity• score)

RA - When is it in remission?• Morning stiffness <15 minutes• No joint pain• No fatigue• No joint tenderness/pain on motion• No soft tissue swelling• ESR <30mm/hr (female) <20mm/hr (male)

REMISSION

Rx in REMISSION

• If a patient with long standing (sustained) remission for 12 month

• Tapper GCs at 1st. • Start to tapper biologic DMARDs (expand

interval between the doses or reduce the dose).

• But continue synthetic DMARDs in low dose because stoppage of synthetic DMARDs may lead to flare.

• Older onset• Female• Greater number of joints• Uncontrolled polyarthritis• Structural damage/deformity• Functional disability• Extra-articular features• Psychosocial problems• Rheumatoid factor• (HLA-DR4/DR1 ‘shared epitope’)

POOR PROGNOSIS

Comorbidities in RA Patient• Osteoporosis due to disease itself or GCs so add Ca &

Vit D & ask for DEXA as follow up.• Cardiovascular disease: RA is a CV risk factor it is 60%

higher just a year after diagnosis of RA. • It is the FIRST cause of death in RA. • Intensive treatment by MTX & anti TNF Biologic

therapy reduce CV events by 70% (low dose aspirin, check for cholesterol level, HTN, DM, obesity, smoking or other risk factors).

• Infection: is the SECOND most common cause of death.

• COPD: RA patients are two times more likely to have COPD.

Drugs & Pregnancy IN RA

NSAIDS: safe until week 34 (patent ductus)OH-chloroquine: safe, cleft palateSulfasalzine: continue if on it; Methotexate: teratogen, ok in small doses; stop 3 months before conceptionCyclophosphamide:Teratogen,Safe > 2nd trimesterBiologic agents: unknown; stop 3 months before conceptionSteroids: non-fluorinated do NOT cross placenta

Transitional Care Unit

Surgical Approaches

• Synovectomy is ordinarily not recommended for patients with rheumatoid arthritis, primarily because relief is only transient.

• However, synovectomy of the wrist is recommended if intense synovitis is persistent despite medical treatment over 6 to 12 months.

• Total joint arthroplasties , particularly of the knee, hip, wrist, and elbow, are highly successful.

• Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome), arthroscopic procedures, and, occasionally, removal of a symptomatic rheumatoid nodule.

Total Knee Replacement

Total Hip Replacement

Arthroscopy

• Support injured joints and weak muscles• Improve joint mobility and stability• Help to alleviate pain, swelling and muscle spasm• May prevent further damage and deformity

Braces/casts/splints

Synovectomy•Increases function of the joint•Decreases pain and inflammation•Beneficial as an early treatment option•Not a cure!

Arthrodesis•Fusion of bones in a joint•Bones are held together by plates, screws, pins, wires, or rods•New bone begins to grow •Limited joint motion•Pain reduction

SOME PHOTOS OF CLINICAL INTEREST

Nail Pitting - Psoriasis

Keratoderma Blenorrhagicum

SLE – Interarticular Rash Hands

• Adult Still’s Disease and JRA Rash

Disseminated Gonococcemia – Pustules

Gouty Arthritis

Rheumatic Fever – Subcutaneous Nodes

• Erythema Marginatum – Rheumatic Fever

Alopecia - SLE

Photosensitivity

Butterfly Rash – SLE

Psoriasis

Dactylitis “Sausage Toes” – Psoriasis

Acute Polyarthritis - Psoriatic

Reactive Arthritis – Palate Erosions

Keratoderma Blenorrhagica – Reactive Arthritis

Enthesitis in Reactive Arthritis

Gouty Arthritis

Acute Monoarthritis

JUVENILE ARTHRITIS

INFECTIOUS ARTHRITIS

GOUT

SLE

RA

osteoarthritis

osteoarthritis

osteoarthritis

BOUTOUNNARE NODULE IN OA

THANK YOU ALLEID MUBAROK

HAPPY DURGA PUJA