Professor Syed Atiqul HaqChairman, Department of Rheumatology

Bangabandhu Sheikh Mujib Medical University

Major HeadingBackground

Patient education

Disease activity assessment

Drugs

Follow up and monitoring

Pregnancy & lactation

Practice Points

Conclusions

Role of an Internist in RA

Diagnosis

Treatment

Referral

Follow up

Predictors of Poor Prognosis

• Functional limitation

• Extra-articular disease e.g. nodules, vasculitis,

Felty’s syndrome

• RF or anti-CCP positive at high titer

• Bony erosion by radiograph (? deformities)

Goals of Management

Relief of Pain

Suppression of active & progressive disease

Conservation & restoration of function in affected joints

Tools of Management

Doctor-patient relation

Patient education

Vaccination

Drugs

Rest & physical measures

Referral

Information to be ProvidedNatural course and outcomes

Therapeutic options

Vaccination

Lifestyle modifications

Reassurance with facts

Need for long-term adherence & follow up

Disease activity measures

Natural Course & Prognosis• Prolonged course

– Intermittent exacerbations & remissions

• Progressive joint damage

• Disability:

– 40% partially disabled in 3 years

– 80% moderate-severely disabled in 20 years

• 25% requires large joint replacements

• Spontaneous remissions: rarely lasting

“When you cannot measure it,

when you cannot express it in numbers,

you have scarcely,

in your thoughts,

advanced to the stage of science,

whatever the matter may be”

-- Lord Kelvin (1824-1907)

Visual Analog Scale

DAS28(4) = 0.56*sqrt(t28) + 0.28*sqrt(sw28) + 0.70*Ln(ESR) + 0.014*GH

Disease Activity Assessment

CDAI

• Tender joint count (0-28)+ swollen joint

count (0-28)+Patient global score (0-10)+

(Physician’s global score (0-10)= 0-76

Classification of Severity

DAS 28 CDAI

Remission <2.6 <2.8

Low 2.6-3.2 2.8-10

Moderate 3.2-5.1 10-22

Severe >5.1 >22

Groups of Drugs• Pain-killers: NSAIDs, analgesics, steroids

• DMARDs

• Steroids

• Antidotes:

– Folic acid, anti-ulcer drugs, calcium, vitamin D

• Drugs for common co-morbidities:

– anti-depressants

NSAIDs• Development of full effect takes 2-4 weeks

• Optimum dose, interval and duration needed for response

• Continuous use during initial months offers greater relief &

safety compared to use on need basis

• Avoid multiple NSAIDs in combination

• If inadequate response in 2-4 wk, with a single NSAID:

– Switch over to another

– Add paracetamol/tramadol/prednisolone

NSAIDs: Vascular Events

• Most NSAIDs increase vascular events:

– Highest: diclofenac, indomethacin,

meloxicam

– Naproxen neither increases nor decreases

– Ibuprofen reduces efficacy of aspirin

Choice of NSAIDs• Non-selective COX inhibitors

– Naproxen has greatest cardiovascular safety– Indomethacin is the most effective NSAID for at least some patients

– Other NSAIDs are also effective

– Diclofenac cheapest in BD

– PPI in patients at risk for g.i. bleeding

• Selective COX-2 inhibitors are as effective as conventional

– Commonly used: etoricoxib, meloxicam, aceclofenac

– cardiovascular effects limit use to those at risk for g.i. bleeding

Routes of Steroid Administration

Oral

Intra-articular

Indications for Oral Prednisolone• Severe extra-articular manifestations, e.g., vasculitis,

neuropathy, DPLD

• Bridge therapy: early 3-6 months of DMARDs

– Severe pain and gross functional decline

– Bread-winners of family

– Elderly bed-bound patients

– Risk factors for toxicity or contra-indications to NSAIDs

– Early (<6 months), severe disease with predictors of poor prognosis

Intra-articular Steroids

• Indications:

– Severe inflammation in residual 1-3 joints after resolution

in all others

– Severely affected 1-3 joints interfering with ADL, e.g.,

knees

• 72 hrs rest recommended after administration

• Drugs: triamcinolone hexacetonide or acetonide

Effects

• Slowly suppresses inflammation

– Reduces pain and need for NSAIDs

• Prevents progression of joint damage

– eventually prevents deformities

DMARDs

• cDMARDs

– csDMARDs

– ctDMARDs

• bDMARDS

– boDMARDs

– bsDMARDs

cDMARDs

csDMARDs• Methotrexate

• Sulphasalazine

• Leflunomide

• Hydroxychloroquine

• Gold salts

• Tacrolimus

• Ciclosporin

• Bucillamine

ctDMARDs

• Tofacitinib

bDMARDs

• Anti-TNF: infliximab, etanercept,

adalumimab

• Anti-IL6: Tocilizumab

• Anti-B cell (CD20): Rituximab

MTX: Dosing Protocols

1. Start 7.5 to 10 mg/wk

– ↑ at 4 wk intervals by 2.5-5 mg/wk. Maximum 25 mg

– eGFR 30 to 59 ml/min: start with 5 mg, increase at 6 to 8 wk intervals. Max. 20 mg/wk

– Weight >90 kg: start with 10 mg/wk

– Suitable for pts with established RA, staying far from facilities

Contraindications• Age >70 years

• Significant renal disease (eGFR <30)

• Hepatic disorders

• Cytopenias

• Pregnancy, desired pregnancy, lactation

• Active infections, including tuberculosis

• Malignancies

• DPLD

• Uncontrolled cardio-respiratory failure

• Major psychiatric disorders, dementia

Sulfasalazine

• Dose : 500mg/d in 1st wk then↑500mg/d wkly until 2-3 gm/d

• Safe in pregnancy and lactation

• Avoided in patients with HO allergy to Sulfa drugs

Leflunomide (LEF)

• Mono & combination therapy

• Pts who cannot tolerate or do not respond

adequately to MTX

• Dose - 20 mg/d

• Contra-indications similar to MTX

• Least toxic & least effective as monotherapy

• Combined particularly with MTX

• Dose 4-6.5 mg/kg/day (200–400 mg/d)

• Baseline eye exam before/within a yr

• Monitoring (1 yr) for retinopathy by Amsler

grid→abnormality→Ophthalmologist

Hydroxychloroquine (HCQ)

Common AEs of DMARDS

MTX – anorexia, nausea, stomatitis, dizziness, hair loss,

hepatotoxicity, cytopenias, pneumonitis

SSZ - skin reaction, LFT abnormality, headache, GI

upset, reversible oligospermia & infertility

LEF -GI upset, HTN, weight loss, LFT abnormalities

HCQ- corneal deposits, retinopathy, GI upset, skin

changes

Monitoring Intervals

• Till substantial improvement and consequent

reinforcement of DMARDs: 4-6 weeks

• After substantial improvement: 8-12 weeks

– May be progressively increased to 6 months when

the disease condition and drugs are stable

Monitoring Tools -- Clinical

• Response to treatment: DAS28,

CDAI, VAS

• Adverse effects

Monitoring Tools -- Laboratory

• Parameters of efficacy

– ESR, CRP

• Parameters of toxicity

– CBC

– ALT, serum albumin

– Serum creatinine

– Selective: depending on clinically apparent AEs

Guidelines For Dose TitrationParameter Don’t increase Reduce Stop

Remission/LDA Achieved Sustained 1 yr

Clinical AEs Mild Moderate Severe

ALT >1.5-2 ULN >2-3 ULN >3 ULN

S. Creatinine (MTX)

>1.4-1.6 >1.6-2 >2

Hb% <8 g/dl <7 g/dl <6 g/dl

WBC count <4,500 <4,000 <3,000

Platelet count <1,50,000 <1,00,000 <80,000

“Some fell by laudanum and some by steel,

And death in ambush lay in every pill”

-- Sir Samuel Garth (1661 -- 1719)

Pregnancy Concerns…• Some patients enjoy partial remission

• MTX & leflu teratogenic. Stopped before conception

– MTX: 3 months

– Leflunomide: 18 months

• Sulphasalazine safe: continued up to term

• HCQ borderline

• Common pain-killers are safe up to 6 months

– Premature closure of ductus during last 3 months

• LDGC safer than others

Tr. Before & During Pregnancy

• Sulphasalazine (full dose) + some NSAID (up to 6

months)

• In dire cases: SSZ+ HCQ+ LDGC+ some NSAID (up

to 6 months)

• LDGC may replace NSAIDs during last trimester

Safe Drugs During Lactation

SSZ

HCQ

NSAIDs

LDGC

• Be sure of Dx

• Mild-moderate-severe

• Predictors of poor prognosis

• Contra-indications to MTX

• Predictors of NSAID GI toxicity

• Rask factors for osteoporosis

• Vaccination status

Vaccination

• Pneumococcal 23-valent

• Influenza

• Hepatitis B

Baseline Lab Evaluation

CBC

Serum creatinine

Hepatic transaminases

Serum albumin

CXR

HBsAg

Extended Baselines

Anti-HCV

Fasting blood glucose

Lipid profile

Pregnancy test

HIV

Abdominal USG

Minimal Baseline: Resource Constraint

CBC

S. ALT

S. Creatinine

Pain Relief: Titration of Therapy

Titrate against Efficacy & Toxicity

Introduce NSAID

wait 2 to 4 wks

No response-switch to one with higher efficacy, or add

analgesic

wait 2 to 4 wks

If no response add 5 to 10 mg Pred

• Mild disease:

– HCQ/SSZ/CQ+ NSAIDs

– SSZ in women with childbearing potential

• Moderate disease:

– MTX/SSZ+NSAID low dose prednisolne

• Severe disease, particularly early:

– MTX+SSZ+HCQ+ 2.5 to 7.5 mg Pred+NSAID

• Introduce first DMARD (MTX or SSZ)

• Build up the dose

– till toxicity supervenes

– highest recommended dose reached

– Target achieved

Treatment Targets

• Remission (DAS28 <2.6, CDAI <2.8)

• LDA (DAS28 <2.6-3.2, CDAI <2.8-10)

Quantitation of Response

• Partial response: decrease of DAS28 by >1.2

• Achievement of target: remission or LDA

3 Timelines

• 3 months: partially responded (DAS28 decreased

by > 1.2) or failed

• 6 months: Target (LDA or remission) achieved or

not

• Any time: unacceptable (intolerable or serious)

adverse events

Strategies After Failure of Initial Therapy

• Triple therapy: MTX+SSZ+HCQ

• MTX+Leflu

• MTX+biologics

• MTX+calcineurin inhibitors

• Leflu+cyclosporin

Titration of Therapy -- for Disease ControlTitrate against Efficacy & Toxicity

• If no response in 3 months, substitute with another

DMARD, or combination therapy

• If target not achieved in 6 mo, combination therapy

• If no further response after 9 months or target not achieved

after a 2nd block of 6 months:

– HDA/PPP: MTX+biologics

– MDA or resource constraint: a different combination

Taper off the NSAID (switch to ad lib)

If no relapse, slowly taper off prednisolone, if given

If no relapse, very slowly reduce the dose of DMARD

to the lowest recommended dose

Maintain for years

When To Refer to Rheumatologist?• When the disease is not controlled with effective DMARD

combinations

• When conventional DMARDs are not tolerated

• Severe extra-articular manifestations, e.g., vasculitis, SSS

• Pain is not controlled with maximum tolerated combinations of pain-killers

• When you don’t feel satisfied with improvement in functional capacity & QoL

• Early aggressive disease

RA could not dampen her spirit

• "I think when you are involved with RA, you are

involved with loss and maybe sometimes despair,

but art is a good balance for that. It’s life-giving,

it gives you an opportunity to play, and it can be

meditative.“

• May be true to every profession if you work with

passion