This document discusses rheumatoid arthritis and gout. It provides information on the pathogenesis, clinical presentation, diagnosis and management of these conditions. It lists various disease-modifying antirheumatic drugs and biological agents used to treat rheumatoid arthritis, along with their mechanisms of action, dosing and side effects. It also discusses the evaluation and treatment of acute and chronic gout, including use of colchicine, NSAIDs, allopurinol and febuxostat.

1. Rheumatoid arthritisRheumatoid arthritis
and goutand gout
.
Prof Dr Lokendra SharmaProf Dr Lokendra Sharma
Department of Pharmacology,
SMS Medical College
Jaipur

2. Early RA: First few months of symptoms

3. http://www.archrheumatol.net/atlas/case31.html
Rheumatoid Nodules

4. Rheumatoid Arthritis: Hands
5 Months of Disease 5 Years of Disease

5. Rheumatoid Arthritis: 10 Years Later

6. Rheumatoid Arthritis: Feet

7. Rheumatoid Arthritis:
A systemic autoimmune
disease
 unknown cause
Synovial tissues proliferate
erosions of bone.

9. RA Epidemiology:
2x4 time women
 child-bearing
age
‘Rare’ in men < 45
years
On the Terrace, 1878

10. DMARDs
Conventional
 Methotrexate
 Hydrochloroquine
 Sulfasalazine
 Leflunomide
 Gold
 Azathioprine
 Minocycline
 Cyclophasphamide –
severe RA
Biologicals
 Etanercept
 Infliximab
 Anakinra
 Adalimumab
 Abatacept
 Rituximab
Prosorba column-
severe RA,Psoriatic A

11. DMARDS Mechanism AE & Risk Approximate
time to
benefit
Month/weak
Dose Comments/
MCQ
Diet Glucosemene
& condrotin
Pain relief
Methotrexate Antimetobolite
DNA Synthsis
Cell division
Hepatoxicity,
Myelotoxioity
fibrosing
alveolitis
1-2M 5-
25mg/
wk
Ist line
Sulfasalazine Antimetabolite
& Antimalarial
Hepatoxicity,
myelotoxicity
Hypersensitivi
ty reactions
1-3M 2-
4g/day
Oligospermia,
Pro drug

12. DMARDS AE & Risk Appoxim
ate time
to benefit
Month/w
eak
Dose Comment/
MCQ
Antimalarial
(Hydrochloro
quine)
Interfere
with Antigen
processing
Retinopathy Macular
damage (HCQ)
2-6 M 200-400
mg/day
Leflunamide Blocks T- Cell
division
Hepatotoxicity,
Myelotoxicity,
Hypertension
4-12 wk 10-
20mg/day
Gold salt
(Parentral)
unknown Hypersensitivity,
Nephritis fibrosing
alveolitis
3-6M 50mg/mon
th
1m
Auranofin
(Oral Gold)
unknown Diarrhoea,
Hypersencentivity
reaction
4-6m 3mg twice
a day
Cyclosporin T-cell activity
intibitor
Nephrotoxicity,
Hypertension
6-12wk 150-
300mg/day
Severe
active RA
not
responde
MTX

13. DMARDS AE & Risk Appoximate
time to
benefit
Month/wea
k
Doge MCQ
Azathioprime Cytostatic Hapatotoxicity,
Myelotoxicle
Gastrointestinal
2-3m 50-
150mg/
day
Not1st
line,
active RA,
with SLA
Bucillamine Proteinuria,
Hepatotoxic,
Mylosupression
1-3m 100-
200mg/
day
Tacrolimus Renal insuff, HT,
Anemia, Impaired
glucose tolerance
6-12 wk 3mg/da
y
D-
Penicillamine
Unknown
alter T-cell
function
Myelosuph,
proteinurea,
Nephrotoxic
3-6m 250-
750mg/
day
Persistent
active
disease
Minocycline Hyperpigmintation,
dizziness,vaginal
yeast infection
1-3m 100mg
BD

14. Biological DMARDS
Anti – TNFx Dose Command Structure Use Anti
TNFx
SE
Etanercept
Infliximab
Adalimumab
Certolizumab
Golimumab
50mg/wk/sc
3mg/kg/8wk
40mg/2wk sc
200 mg/2wk
sc
50mg/4wk sc
Decoy (R) for
TNFx
RA & Crohns
dz antibody to
TNF given
with MTX
Human
fusion
protein
Mouse/hum
an MaB
Fully human
MaB
RA, JRA,
Psoritic
arthritis
ankylosing
spondelyti
s crohns
disease
Infection CHF
Neurological
Malignancy
Autoimmunity
Hematological
Hypersencitivity
Anti-B-cell
therapy
Rituximab
1000mg/repea
t after 2 wk
Premedication
Methylprednis
olone
Chlorphenara
mine
PCM

15. Biological DMARDSAnti – TNFx Dose Command Structure
Inhibitory of T-cell
activation abatacept
125mg sc/wk Favorable safety
profile
Anti-1L6
Tocilizumab
8mg/kg/4wk More effective
than anti TNF in
MTx intolerant
patients
Anti 1L-1 blocking
agent
Anakinra
IL-1 trap
100 mg /sc /daily
Phase I
Less effective Recombinant form of
human 1L-1 Ra

16. Extra-articular RA
• Subcutaneous nodules
• Pleural/Pericardial
Disease
• Sjogren’s Syndrome
• Felty’s Syndrome
• Vasculitis

17. Joint Distribution: RA Compared to OA
Rheumatoid Arthritis Osteoarthritis

18. Stevens-Johnson syndrome
target skin lesions
mucous membrane
erosions
epidermal necrosis
with skin
detachment

19. Redness and Swelling of Acute Gouty
Attack
http://medicine.ucsd.edu/clinicalimg/extremities-gout.jpg

20. Tophaceous Deposits of Urate
http://arthritis.about.com/od/goutdiag/

21. Gout - acute arthritis
acute synovitis,
ankle & first MTP
joints

22. Gout - acute bursitis
acute olecranon
bursitis

23. Gout - acute arthritis
acute synovitis,
ankle & first MTP
joints
Arthrocentesis

24. Chronic tophaceous gout
tophus = localized deposit of
monosodium urate crystals

25. Gout - tophus
Classic location of
tophi on helix of
ear

26. Gout - X-ray changes
DIP joint
destruction
phalangeal bone
cysts

27. Gout - X-ray changes
bony erosions

29. Drugs Used for Therapy of GoutDrugs Used for Therapy of Gout
N
N NH
N
OH
HO
O
N
N NH
N
OH
HO
OH
pKa 5.6

30. DMARDS Mechanism AE & Risk Use
Colchicine Interfere
with PMN
Gastrointestinal
Hamatological
(agran& apla)Muscle
weekness
High dose acute gout
with allopurinol and
probenacid
Low dose prevent
recurence
NSAID Inhibit PG
Probenacid Inhibit urate
excretion
Induce acute attach Decrese secretion of
anionic drugs
Allopurinol
100 &300mg
Inhibit
xanthine
oxidase
Rash ,abn liver
function,GIT
,marrow
supp,vasculitis,Toxic
epi nec
Chronic Gout
With chemotherapy
Recurrent renal Ca
oxalate stone
Febuxostat Oral
xanthine
oxidase
inhibitors
Minimal ADR
use in renal patient

31. Drugs Increasing Risk of Toxicity
Macrolide antibiotic
Azole antifungals
Calcium channel blockers
Amiodarone
Cyclosporin
Statins

33. Estimation of 24-hr Urinary
Uric Acid
Indications: Gout in
–men less than 25 years
–premenopausal women

34. Urate Lowering Therapy: Indications…
>3 attacks per year
2/yr if disabling, prolonged, interferes with ADL
Clinical or radiographic signs of chronic gouty joint disease
Gout with renal insufficiency
Urinary uric acid excretion >1100 mg/day (6.5 mmol)

35. Urate Lowering Therapy: Indications
Serum uric acid persistently >10.1
Tophi in soft tissues or subchondral bone
Recurrent urate urolithiasis
? Strong family history of gout

36. Goals of Therapy
Serum urate <6 mg/dL (<357 µmol/L)
<5 mg/dL (<297 µmol/L) in patients
with tophi
A fall of <0.6 mg/mo ensures
recurrence free achievement of
target

37. General Principles
Should not be initiated during an attack
Conventional interval: 4 wk
Exceptions:
Inter-critical interval <4 wk
Chronic tophaceous gout
Titrated against serum urate at 3 to 4 wks
Treatment should be
Continuous
Duration: indefinite

38. Choice of Drugs
Xanthine oxidase inhibitors:
allopurinol, febuxostat
Uricosuric drugs:
probenecid, sulfinpyrazone, benzbromarone
Uricase:
pegloticase (porcine), rasburicase (recombinant)

39. Allopurinol
Urate-lowering drug of general choice
Particularly suitable for overproducers
Started with 100 mg/day single dose
after meals with plenty of fluid
Doses >300 mg divided
Increased at 2 to 3 wks by 100 mg till target reached
Maximum: 900 mg/day
Monitoring parameters
CBC, serum uric acid, ALT, S Cr, at start of therapy

40. Allopurinol: Adverse Effects
Diarrhea, and drug fever
Rashes, rarely TEN and Steven Johnsons
Association: HLA- B*5801
Leukopenia or thrombocytopenia
Interstitial nephritis, vasculitis
Allopurinol hypersensitivity syndrome (AHS):
erythematous rash, fever, eosinophilia, hepatitis, and
acute renal failure
Rare but life-threatening, mortality 25%

41. Starting Dose and Titration of
Allopurinol on eGFR
eGFR Starting dose Titration
≥60 ml/min 100 mg/day 100 mg every 2-3 wk
30-59 ml/min 100 mg/day 50 mg every 2-3 wk
10-29 ml/min 50 mg/day 50 mg every 2-3 wk

42. Rational Treatment in Two Phases:Rational Treatment in Two Phases:
Phase I – control pain and inflammation:
NSAIDs (ibuprofen – may use indomethacin) or
colchicine
Phase II – decrease the serum urate (< 4.0 mg/dL)
> 800 mg in 24 hr urine suggests overproduction –
use allopurinol
< 500 mg in 24 hr urine suggests decreased renal
clearance – use probenecid

43. Febuxostat
investigational agent (NDA 12/2004)
oral xanthine oxidase inhibitor
chemically distinct from allopurinol
94% of patients reached urate < 6.0
mg/dl
minimal adverse events
can be used in patients with renal
disease

44. Febuxostat…
Indications:
Intolerance/allergy to allopurinol
Mild to moderate CKD
40 mg produces a reduction equivalent to
300 mg allopurinol
Started at 40 mg/day
Increased to 80 mg if target not reached after 2 wks
Maximum recommended dose 120 mg

45. Febuxostat
AEs:
liver function abnormalities
Nausea
arthralgia
rash
Monitoring: transaminases

46. Uricosuric Drugs
Indication: Intolerance to allopurinol
Requisite: 24-hr urinary uric acid <800 mg
Contra-indications:
Nephrolithiasis or uric acid nephropathy
Uric acid overproduction
Renal insufficiency
Extensive tophi

47. 1. Most common cause of Moebius syndrome is use of
which of the following drug in pregnancy?
a. Misoprostol
b. Thalidomide
c. Methotrexate
d. Dinoprostone
(a)

48. 2. Which of the following drugs
cause oligospermia?
a. Leflunomide
b. D-Penicillamine
c. Methotrexate
d. Sulfasalazine
(d)

49. 3.Allopurinol prevents conversion
of
a. Hypoxanthine to xanthine
b. Xanthine to hypoxanthine
c. Hypoxanthine to I.M.P.
d. Xanthine to uric acid
(a)

50. 4.Which of the following NSAIDs has
been approved for use in children?
a. Indomethacin
b. Ibuprofen
c. Ketorolac
d. Piroxicam
(b)

51. 5.Which of the following disease modifying
anti-rheumatoid drugs is a prodrug?
a. Etanercept
b. Nimesulide
c. Sulfasalazine
d. Colchicine
(c)

52. 6. All of the following drugs can produce
hyperuricemia EXCEPT
a. Ethambutol
b. Pyrazinamide
c. Sulfinpyrazone
d. Hydrochlorothiazide
©

53. 7. Drug of choice for acute gout is
a. Colchicine
b. Indomethacin
c. Allopurinol
d. Dexamethasone
(b)

54. 8. Most common dose limiting adverse
effect of colchicine is
a. Sedation
b. Kidney damage
c. Diarrhea
d. Muscle paralysis
©

55. 9. Which of the following drugs is useful in
chronic gout but is NOT a uricosuric agent?
a. Probenecid
b. Phenylbutazone
c. Sulfinpyrazone
d. Allopurinol
(d)

56. 10. Allopurinol is useful in all of
the following conditions EXCEPT
a. Cancer chemotherapy induced hyperuricemia
b. Hydrochlorothiazide induced hyperuricemia
c. Acute gouty arthritis
d. Kala –azar
©

57. 11. Rasburicase is a newer drug used in
gout. It act by
a. Decreasing urate synthesis
b. Increasing urate oxidation
c. Decreasing intestinal absorption of uric acid
d. Increasing renal excretion of uric acid
(b)

58. 12. A drug that is effective for rheumatoid
arthritis but is not appropriate for
osteoarthritis is
a. Acetaminophen
b. Infliximab
c. Keterolac
d. Rofecoxib
(b)

59. 13. Among NSAIDs aspirin is
unique because it
a. Irreversibly inhibits its target enzyme
b. Reduces the risk of colon cancer
c. Reduces fever
d. Selectively inhibits COX-2 enzyme
(a)

60. 14. Most specific drug for the
treatment of peptic ulcer caused due
to chronic use of NSAIDs is
a. Rabeprazole
b. Loxatidine
c. Misoprostol
d. Esomeprazole
©

61. 15. A drug X is useful in the treatment of
rheumatoid arthritis. It is available only in
parenteral formulation and its mechanism of
action is antagonism of tumor necrosis factor.
Which of the following can be X?
a. Cyclosporine
b. Penicillamine
c. Phenylbutazone
d. Etanercept
(d)

62. 16. Which of the following
increases uric acid excretion?
a. Allopurinol
b. Aspirin
c. Colchicine
d. Probenecid
(d)

63. 17. True about COX-2 are all EXCEPT
a. Furosemide
b. Sulfinpyrazone
c. Allopurinol
d. Piroxicam
(d)

64. 18. Allopurinol potentiates the
action of
a. Corticosteroids
b. Probenecid
c. 6-Mercaptopurine
d. Ampicillin
©

65. 19. Probenecid interacts with
a. Streptomycin
b. Ampicillin
c. Vancomycin
d. Erythromycin
(b)

66. 20. Drug useful for gout
a. Pyrazinamide
b. Rifampicin
c. Allopurinol
d. Naloxone
©

67. 21. Loading dose of leflunomide in
rheumatoid arthritis is
a. 20 mg
b. 10 mg
c. 100 mg
d. 400 mg
(c)

68. Thanks