DISEASE MODIFYING ANTIRHEUMATOID DRUGS IN RHEUMATOID ARTHRITIS.

1. DMARDS
IN
RHEUMATOID
ARTHRITIS
AYAN GHOSAL
PGT
DEPT OF PMR

2. EFFICACY OF DMARDS IN RA
• High Chances of remission.
•Control of Extra-articular disease To some extent.
•Prevention of Radiographic damage To some extent.
•Control of associated Co-morbidities Only to limited
extent.

3. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS
Synthetic
(sDMARDs)
Conventional
(csDMARDs)
Targeted
(tsDMARDs)

4. csDMARDs
•FIRST LINE:
Methotrexate(MTX)
Sulfasalazine (SSZ)
Hydroxichloroquine (HCQ)
Leflunomide (LEF)

5. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS:
2nd LINE
DMARDS
GOLD
•AURANOFIN
•NA
AUROTHIOMAL
ATE
IMMUNOSUPPRESS
ANTS
•AZATHRIOPIN
•LEFLUNOMIDE
•MMF
•CYCLOSPORINE
CHEMO. AGENTS
•CYCLOPHOSPHAMIDE
CHELATING
AGENT
•D
PENICILLAMINE

6. METHOTREXATE:
• DMARD OF CHOICE.
• In 50-60% of patients remission or low disese activity seen
with monotherapy.
• The initial DMARD for majority of patients.
• The main component of combination DMARDs.
• With Biologics, increase efficacy , reduce antibody
formation.
• Successful in treating RA associated conditions: Felty’s
syndrome, large granular lymphocyte syndrome, Adult onset
still disease, Cutaneous vasculitis of RA.

7. METHOTREXATE:
• MECHANISM OF ACTION:
oInhibition of ATIC→↑Adenosine BOTH intra and
extracellular. ADENOSINE HAS POTENT ANTI
INFLAMMATORY EFFECT.
oInhibition of TYMS→↓pyrimidine synthesis
oInhibition of DHFR→ ↓Transmethylation reactions,
ESSENTIAL FOR CELLULAR FUNCTIONING

8. SAFETY MONITORING:
Baseline < 3 month 3-6 months > 6 months
CBC, LFT, Cr, HBV,
HCV;
Vaccinate:
Influenza,
Pneumococcus,
HBV
Every 2-4 wk Every 8-12 wk Every 8-12 wk
• HALF LIFE: 6 Hours. Elimination by kidney.
• Active Form : MTX PG, Elimination half life 3.1 weeks.
• DOSE: 7.5 – 25mg/wk, escalated at 2.5mg/wk basis in 8wks
• Oral dose, when > 15 mg, split or give SC.
METHOTREXATE:

9. SIDE EFFECTS:
• Dyspepsia, Nausea, Anorexia: 20-70% in 1st Year.
• Mucocutaneous: 33%,Dose dependent, respond to folic
acid.
• Hepatotoxicity: AST/ALT elevation.
• Severe myelosuppression: 1-2%,Dose dependent,
respond to folic acid.
• Pulmonary : Interstitial pneumonitis, interstitial fibrosis,
noncardiogenic pulmonary oedema(rare), pleuritis and
effusion, pulmonary nodule.
• MTX Flu: after the weekly dose.
• Nodulosis: 8%
• Leucocytoclastic vasculitis.

10. SPECIAL CASE
• Fertility:
• F: no effect
• M: reversible sterility
• Stop 3 mo before conception
Pregnancy:
• Contra-indicated (X)
• Aminopterin syndrome.
• Abortifacient
Lactation
• Contraindicated
• Elderly
• Lower initial dose (5-7.5mg/wk) based on CrCl, NOT >2Omg/wk
• Pediatrics
• Based on wt.0.3-1 mg/kg/wk.

11. CONTRAINDICATION OF
METHOTREXATE
• Active infection,
• Symptomatic pulmonary disease,
• WBC <3000/mm3,
• Platelet <50,000/ml3,
• CrCl <30 ml/min,
• History of myelodysplasia or recent lymphoproliferative disorder,
• LFT >2 x Upper Limit of Normal,
• Acute or chronic HBV or HCV,
• Pregnancy, lactation

12. LEFLUNOMIDE:
• MECHANISM OF ACTION:
INHIBIT
Dihydroorotate
dehydrogenase
Reduced UMP
Reduced
lymphocyte
synthesis
Active
metabolite
teriflunomide
Inhibit tyrosine
kinases

13. LEFLUNOMIDE:
• HALF LIFE: 2 WEEKS. Elimination: Kidney 50% Gut 50%
• DOSE: 10-20 MG/DAY,100mg loading dose for 3 days.
• No dose adjustment in elderly.
• Pediatrics: Based on wt.,
SAFETY MONITORING:
Baseline < 3 month 3-6 months > 6 months
CBC, LFT, Cr, HBV,
HCV; vaccinate:
influenza,
Pneumococcus
HBV
Every 2-4 wk Every 8-12 wk Every 8-12 wk
<20kg, 20-40 kg >40kg
10mg other
day
10mg daily 20mg daily

14. LEFLUNOMIDE:
SIDE EFFECTS:
• Diarrhea: Most common.
• Hepatotoxicity: More common with MTX combination.
• Cardiovascular: HTN, Dyslipidemia
• Dermatological: Skin rash,2nd to 5th month, SJS or
TEN,Alopecia
• Pulmonary: ILD, 3 Month.
• Hematological: Rare, Pancytopenia,NOT
LYMPHOPROLIFERATIVE DISORDER.
• Weight Loss.

15. SPECIAL CASE:
• Fertility:
No much data, test level, may require washout.
• Pregnancy:
• Contra-indicated (X)
• Measure level in blood, when>0.02mg/L require active washout.
• Wait for three full menstrual cycle after washout.
• Lactation:
• Contraindicated

16. LEFLUNOMIDE:
CONTRAINDICATION:
• Active infection,
• WBC<3000/µl
• Platelet<50000/µl,
• History of myelodysplasia or recent lymphoproliferative
disorder,
• LFT >2 x ULN,
• Acute OR Chronic HBV/HCV.
• Pregnancy, Lactation.
• Severe renal impairment.
• Severe hypoproteinemia.
• Hypensensitivity.

17. HYDROXYCHLOROQUINE:
• Do not retard bone erosion in RA.
• Slowest acting DMARD.
• MECHANISM OF ACTION:
INCREASE
lysosomal pH
from 4 to 6
Chemotaxis
Phagocytosis
Superoxide
production
Inhibit
stimulation of
TOLL LIKE
RECEPTOR 9
(TLR)
family

18. HYDOXYCHLOROQUINE
• Half Life: 40-50 days.
• Elimination: Via urine unchanged.
• Dose: 200–400mg/day orally.
• 6.5mg/kg/day of ideal body wt to prevent ocular toxicity.
• Pediatrics: 3-5mg/kg/day
SAFETY MONITORING:
Baseline < 3
month
3-6
months
> 6 months OPHTHALMOLOGICAL
EXAMINATION
CBC, LFT, Cr ;
Vaccinate: influenza,
Complete
ophthalogical
examination within
1 yr.
none none none 2-5 YEARLY
SHOULD START <=5 YR

19. HYDOXYCHLOROQUINE
SIDE EFFECTS:
• Ocular toxicity : blurring of vision, accommodation or
conversion defect.
• Retinal toxicity: high dose, prolonged use, CKD stage
III, tamoxifen
• Dermatological: hyperpigmentation, photosensitivity,
alopecia, hair depigmentation.
• Neuromuscular: Headache,insomnia,irritability,Proximal
weakness with peripheral neuropathy and cardiac
myotoxicity ,normal CPK
• Metabolic: reduce blood glucose HbA1C.
• Cardiovascular: Rare; Conduction defect, Cardiomyopathy .
• GI: nausea,vomiting diarrhoea abdominal cramp.

20. SPECIAL CASE:
•FERTILITY:
•No effect.
•PREGNANCY:
•Relatively safe (C)
•LACTATION:
•Relatively safe.

21. CONTRAINDICATION
• H/O Vision changes attributed to 4-aminoquinolone
derivatives
• Hypersensitivity.
• Severe liver disease.

22. 5-ASA
Sulfapyridine
Sulfasalazine
SULFASALAZINE:

23. SULFASALAZINE:
MECHANISM OF ACTION
oInhibition of
arachidonic acid
cascade
Multiple cellular
effects
Inhibition of
ATIC→
↑Adenosine
Systemic effects
via MALT

24. • HALF LIFE: SSZ: 6-17HOURS, SULFAPYRIDINE: 8-21 HRS
• ELIMINATION: Extensively liver metabolization,excreted by urine(5-
ASA), feces(sulfapyridine)
• DOSE: START AT 500MG/DAY, INCRESED BY 500MG/ WEEK ,
• MAX DOSE: 2-3 G/DAY
• Concominant Folate administration.
SAFETY MONITORING:
SULFASALAZINE:
Baseline < 3 month 3-6 months > 6 months
CBC, LFT, Cr, ;
Vaccinate:influenza,
Pneumococcus
Every 2-4 wk Every 8-12 wk Every 8-12 wk

25. SIDE EFFECT:
• Gastrointestinal: Nausea, Upper abd. Discomfort, 8%,
with dizziness and headache,diarrhoea
• Dermatological: 5%, 3 Months;Mainly rash,
Photosensitivity.
• Hematologic: 3%, 3 months, avoid in G6PD deficiency.
• Hepatotoxicity: Transient liver enzyme elevation.
• Pulmonary: Rare, Revesible infiltrate, cough,
eosinophilia, fever, wt loss.
• Minor: irritability, anxiety, hypogammaglobulinemia,aseptic
meningitis.

26. SPECIAL CASE:
• FERTILITY:
• FEMALE: No effect
• Male: reversible seritity, improves in 2-3 months
• Pregnancy:
• category B,C; First choice in women wishing to be pregnant.
• Breast feeding:
• Relatively safe.(B, C)
• Lactation:
• Relatively safe.
• Elderly:
• Not required.
• Pediatrics:
• Based on wt. 10-12.5mg/kg/day wkly increase to 50mg/kg/day.
SULFASALAZINE:

27. SULFASALAZINE:
CONTRAINDICATION:
• Sulfa allergy, salicylate allergy.
• Plt <50,000/mL3,
• LFT >2 X ULN,
• Acute HBV/HCV,
• Some classes of chronic HBV/HCV.

28. COMBINATION DMARD THERAPY IN RA
• Superior efficacy without increased toxicity.
• Early suppression of bony progression.
• MTX is the ANCHOR DRUG.
• Initial or Step up both are superior to monotherapy
• Triple therapy(MTX,HCQ,SSZ) superior than MTXmonotherapy or
double combination(MTX+HCQ or MTX+SSZ)
• Triple therapy non inferior to MTX+etanercept.
• Initial combination and step up combination both are similarly
effective in sudjective and objective disese control at 1-2 years.
• INITIAL COMBINATION = MORE EARLY SUPPRESSION OF BONY PROG.

29. AZATHRIOPINE: (DOSE: 50-200MG/DAY)
SUBSTITUTE TO METHOTREXATE.
• Reduce antibody foration when used with biologics.(50%
vs 77%)
• Pregnancy, liver, pulmonary & renal diseases,MTX Flu.
• RA associated ILD.
• NEUTROPENIA IS MOST COMMON SIDE EFFECT.
CYCLOSPORINE: (DOSE: 2.5-5mg/kg/day)
• Showed efficacy with MTX.
• NOT used because of side effect: HTN and Raised Serum
Crt.
• May be used in RA patient with Hepatitis C.
USE OF SENOND LINE DMARDS IN RA

30. Tetracyclines:
• Minocycline(100mg BD) and doxycycline (20-100mg BD)
showed efficacy in combination with MTX.
• Minocycline showed potential in early RF positive
patients.
• Potential side effects: Vertigo,Light headedness, Lupus
like syndrome, cutaneous hyperpigmentation.
USE OF SENOND LINE DMARDS IN RA

31. NOVEL DRUG:TARGETED SYNTHETIC DMARDS:
TARGETED TO JANUS KINASE (JAK)
 Tofacitinib: Active RA with MTX, with or
without biologics.
• Pan-JAK inhibitor
• 5mg BD orally
• S/E: ↑risk of infection, ↑LFT, Dyslipidemia,
neutropenia, URTI, Nasopharyngitis, diarrhea
Safety precautions:
1. CBC & LFTmonthly for 3 month, then 3 monthly.
2. Screening for latent TB.
3. Lipid profile: 8-12 weekly
4. Vaccination.
Contraindication:
• Active infection
• Lymphocyte <500/miL
• Acute or chronic hepatitis.
 Baricitinib: JAK1/2 inhibitor, Phase III trial
 Fibotinib: JAK1 inhibitor, Phase III trial
 Decernotinib: JAK 1/3 inhibitor
 Peficitinib: JAK 1/3 inhibitor

32. ACR-EULAR 2019
UPDATE:

36. SPECIAL CASE:
• Pregnancy and RA:
• RA Tend to improve in pregnancy.
• Active RA during pregnancy result in LBW.
• Methotrexate and Leflunomide must be discontinued.
• 75% will show improvement and flare after delivery.
• Flare managed by: Prednisolone, HCQS, SSZ.
• HIV & RA:
• HCQ,SSZ, Corticosteroid
• HEP B & HEP C:
• Acute/Active & Receiving treatment: continue
• Not receiving treatment: In Hep C , avoid MTX, LEF, Cylosporine.
In Hep B, refer for antiviral management.

37. THANK
YOU