Drugs for Arthritis

The Case
A 61 year old woman with new onset
inflammatory, large and small joint,
somewhat asymmetric polyarthritis
What is the diagnosis?
What is the treatment?
Arthritis
Arthritis is derived from the Greek words
arthron meaning joint and itis meaning
inflammation.
There are more than 100 types of arthritis.
Some types of arthritis are caused from
inflamation.
Some types are caused from viruses,
bacteria, injury, or sodium urate crystals.
Osteoarthritis
Syndrome of joint pain + loss of join form & function
caused by a progressive loss of articular cartilage
accompanied by attempted repair of articular cartilage,
remodeling and sclerosis of subchondral bone
(formation of subchondral bone cysts & osteophytes)

Joint degeneration Structural Changes :
articular cartilage fibrillation & erosion
Subchondral bone thickening
Osteophytes





Normal jointcartilage
Osteoarthritis
Osteoarthritis: Symptoms & Causes
Symptoms
Swelling, stiffness,
and pain.
Joints ache after
physical activity.
Stiffness or pain in
the neck or lower
back which can
result in numbness
of the legs or arms.
Causes
Trauma to joints such
as repetitive
movements over a
long time.
Acute injury can lead
to osteoarthritis years
later.
Age.
Metabolic disorders
that can cause
cartilage deterioration.


Common places osteoarthritis :
Lower back
knees
hips
neck
thumbs
ends of fingers
Diagnosis
No single test can diagnose osteoarthritis.
The doctor will review the medical history, ask the
patient to describe symptoms, conduct a physical
exam, check reflexes, and check the patients ability
to bend and walk.
X-rays may show cartilage or bone damage.
Fluid from the joint may be extracted to check for
pieces of bone or cartilage.
(Event of morning Stiffness)
, stiffness and swelling
Management of OA
1. Patient education (avoid physical stress ,avoid injury)
2. Physiotherapy (physical therapy and rehabilitation):
muscle strengthening, joint stability & mobility exercise
Prevent debilitation as aging progresses
Appropriate exercise and conditioning
3. Occupational Therapy :
Assistive devices for ambulation (canes, walkers)
Patellar taping (for knee OA), appropriate footwear and
bracing
Assistive devices for activities of daily living
4. Dietary consideration : - Maintain optimal weight
- Nutritional supplementation
5. Early and adequate drugs treatment
6. Surgery



OBESITY
Risk of OA with obesity
BMI > 30 4 fold greater risk of OA
Weight reduction lowers risk of OA
5 Kg weight loss 56% reduction in risk of knee
OA if BMI > 25
TREATMENT OF OA
Confirm diagnosis exclude tendonitis or
bursitis adjacent to joint
Initial treatment
Muscle strengthening exercises and
reconditioning walking program
Appropriate footwear
Weight loss
Local heat/cold and topical agents
Paracetamol

OA: Management Summary (contd)
Second-line approach
NSAIDs if paracetamol fails
Intra-articular agents
Opioids

Third-line -SURGERY
Arthroscopy
Osteotomy
Total joint replacement
American College of Rheumatology
American College of
Rheumatology Subcommittee on
Osteoarthritis Guidelines.
Recommendations for the medical
management of osteoarthritis of
the hip and knee: 2000 update.
Arthritis and Rheum
2000;43(9):1905-15.
Drugs Therapy for OA
Symptomatic (Fast Effect)
Per oral :
Analgesic
Simple Analgesic : Paracetamol (acetaminophen)
Combination Analgesic : - Paracetamol + Codeine
- Paracetamol + Ibuprofen
NSAID :Conventional : Aspirin, Sodium Diclofenac, Ketoprofen
Cox 2 selective inhibitor : Celecoxib, Etoricoxib, Valdecoxib, Parecoxib
Rofecoxib, Lumiracoxib (Withdrawal from market)
- Opioid Analgesic
Intra-articular injection
Corticosteroid : triamcinolone hexacetonide, dexamethasone,
methylprednisolone

Symptomatic (Slow Effect)
= SYSADOA (Symptomatic slow acting Drugs for OA)
Per Oral : Glucosamine, Chondroitin, Diacerein
Intra-articular : Hyaluronic Acid

Structure/Disease Modifying Osteoarthitis Drugs (S/DMOAD)
Glucosamine
Chondroitin
Diacerein
Hyaluronic Acid



Drugs Therapy for OA
EULAR RECOMMENDATIONS 2004

Evidence based medicine
Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155
(Ayurveda, Siddha, Unani)
Opioids
Is there a role for opioid analgesia in
osteoarhtritis?
Is there a role for chronic therapy
with opioid analgesics?





Yesall the guidelines and UpToDate recommend considering
narcotic analgesia for acute exacerbations unresponsive to
conventional therapy. Tramadol is specifically identified by the
ACR as well as UpToDate as the initial agent of choice.
Yessome patients may require chronic therapy with opioids.
ACR guidelines support opioid therapy when other treatments
have failed or are not appropriate. American Pain Society
guidelines for nonmalignant pain should be followed.
Making Sense of Oral Medications
Recommendations
Continuous versus As Needed
Preferable on a periodic basis in patients
with non-inflammatory OA; continuous only
if this regimen is inadequate.
Medications normally take 2 to 4 weeks to
assess; if inadequate, the dose should be
increased.
If not effective after 2 to 4 weeks, then another
agent should be tried.
If there is a history of GI disease, a selective
COX2 inhibitor or a nonselective agent with
anti-ulcer prophylaxis may be used.
Opioids may be used for severe breakthrough
pain, patients who have failed other therapies,
and where surgery is not an option.
Steroid Injections -How they Might Work
Mechanism of action is
unknown, however:
Inhibit accumulation of
inflammatory cell lines
Reduction of prostaglandin
synthesis
Inhibit leukocyte secretion
from synovial cells
Decrease interleukin secretion
by the synovium
Increase viscosity of synovial
fluid
Steroid Injections (intraarticular)
Systemic corticosteroid therapy
has no place in the treatment of
osteoarthritis.
Generally employed no more
than 3 to 4 times per year
secondary to risks of direct
articular cartilage damage;
however, some argue the steroid
may prevent the biochemical
degradation.
Variable duration of activity
modification after injection.
Not clear who will benefit from a
steroid injection; some authors
recommend the patient with an
effusion or acute synovitis.
Who Deserves an Injection?
AAOS (American Acad of Orthopaedic Surgeons)
Inflamed knees respond best to injections.
Localized knee pain felt only with weight-
bearing is less likely to respond.
ACR (American College of Rheumatology)
Intraarticular glucocorticoid injections are of
value in the treatment of acute knee pain in
patients with, and may be particularly
beneficial in patients who have signs of local
inflammation with a joint effusion.
EULAR (European League Against Rheumatism)
Intra-articular injection of long acting steroid
is indicated for acute exacerbation of knee
pain, especially if accompanied by effusion
Chondroitin sulfate (CS) belongs to the group of
glycosaminoglycans, important constituents of cartilage
extracellular matrix.







Chondroitin sulfate is a symptomatic slow acting drug for osteoarthritis
(SYSADOA) in Europe, where it has been approved as a drug for more
than ten years in several countries.

OX
CH OX
2
O
O
HO
O
COOR
O
NHCOCH 3
R: Na, H
OH
n
X: SO
3
R
,
H
Chondroitin sulfate

Hardingham T. Osteoarthritis Cart (1998) 6, (Supplement A), 3-5.
Lequesne M. G. Rev Rhum (Eng/Ed) 1994; 61: 69-73.

STIMULATES:
proteoglycans
HA
EFFECT:
-anti-inflammatory
activity
-Membrane
stabilising action

INHIBITS:
cartilage degradative enz. (collagenase
,elastase, proteoglycanase, fosfolipase
A2, N-acetylglucosaminidase, etc.)
cartilage damaging substances (free
radicals)
apoptosis
NO
Stromelysin (MMP-3)
NF-kB


CHONDROITIN SULFATE ACTION MECHANISMS


(3) Ronca F et.al. Osteoarthritis Cart (1998) 6, (Supplement A), 14-21. (4) Blanco FJ. et. al. Rev. Esp.
Reumatol 2001; 28, 1: 12-17.

9 randomized, controlled, clinical trials have been conducted in Europe
with Condrosan / Condrosulf (CS), comparing its effect against
placebo (PBO) and sodium diclofenac (SD) (150 mg) in 1163
patients with knee and hand osteoarthritis (OA)

The results from these clinical trials conclude that CS is as effective as
SD and around 50% more effective than PBO (p < 0.05) in the
reduction of OA symptoms. Besides, its efficacy lasts for at least 3
months after treatment suppression (carry-over effect).
CLINICAL EVIDENCE
Morreale, et al. J. Rheumatol. 1996, 23: 1385-1391. Kissling R. et al. Osteoarthritis Cart 1997, 5 (Supplement A), 9: 70. Bucsi
L, et.al. Osteoarthritis Cart 1998, 6 (supplement A):31-36. Pavelka K, et al. Litera Rheumatologica 1998, 24:21-30. Uebelhart
D, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46. Uebelhart D, et al. Osteoarthritis Cart 2004, 12:269-276. Michel B,
et al.. Osteoarthritis Cart 2001, 9 (supplement B), LA2. (12) Verbruggen G, et al. Osteoarthritis Cart (1998) 6, (Supplement
A), 37-38. Vebruggen G. et al. Clinical Rheumatology 2002, 21: 231-241. Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.
du Souich P, Vergs J. Clin. Pharm. Ther. 2001; 70: 5-9.

CS may act as a structure disease
modifying OA drug (S/DMOAD), it
may slow down disease progression.
3 clinical trials in knee OA have evidenced a
stabilization of joint space width with CS
treatment as opposed to a narrowing of joint
space with PBO.

2 clinical trials in hand OA concluded that
disease progression was lower in CS-
treated patients and less patients from this
group developed erosive OA.

S/DMOAD
The tolerance of Chondroitin Sulfate is very well
documented; equivalent to PBO and much higher
than that of SD.

It is not metabolized by enzymes from cytochrome P450.
It can not present drug interactions at this level.

Pharmacosurveillance data from Europe, where no
serious adverse events have been reported for
more than 10 years, support the safety of the product.
SAFETY PROFILE
Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.
Clinical efficacy on symptom reduction and improvement
of functional capacity

Persistent clinical effect after treatment suppression
(evidenced for at least 3 months)

Greater safety than conventional therapy (analgesics,
NSAIDs). It does not cause drug interactions.

Chondroitin Sulfate Advantages
Glucosamine
Glucosamine sulfate (+ chondroitin
sulfate) are particularly popular
treatments for osteoarthritis.
Several early studies demonstrated
that glucosamine was superior to
placebo and comparable to NSAIDs
for knee OA. (manufacturer
supported)
Other studies measuring changes in
joint space narrowing suggested a
chondroprotective effect against
articular cartilage loss.
STIMULATES:
proteoglycans
EFFECT:
-anti-inflammatory
activity
-Membrane stabilising
activity

INHIBITS:
cartilage degradative enz.(collagenase
, aggrecanase, fosfolipase A2, etc.)
Stromelysin (MMP-3), MMP-2, MMP-9
free radicals
PGE2
IL-1
NF-kB


GLUCOSAMINE SULFATE ACTION MECHANISMS


Studies of radiolabeled glucoasmine do demonstrate uptake in the joint
articular cartilage.
Thought to stimulate chondrocytes to make proteoglycans.
Real mechanism of action is largely unknown.
Glucosamine
Cochrane Review 2005:
WOMAC outcomes of pain, stiffness and function did not show
a superiority of glucosamine over placebo. Glucosamine was as
safe as placebo

NIH multi-centered trial:
Glucosamine and chondroitin alone or in combination did not
reduce pain effectively in the overall group of patients
Exploratory analyses suggest that the combination of glucosamine
and chondroitin may be effective in the subgroup of patients with
moderate-to-severe knee pain
European trials that showed a benefit with glucosamine used as
glucosamine sulfate; most of the American trialsincluding
GAITused glucosamine hydrochloride



Clegg DO et al. (2006), N Engl J Med 354(8):795-808
Glucosamine
Using Glucosamine:
Safe, however, questions exist
as to adverse effects, purity
and efficacy.
Not recommended in patients
with seafood allergy;
chondroitin may have
anticoagulant effect.
No studies demonstrating
consistent benefit of adding
chondroitin.
Trial of 1500 mg/d for 6 to 8
weeks


Hyaluronic Acid
Synovial fluid is an ultrafiltrate of
plasma modified by the addition
of hyaluronic acid (HA), which is
produced by the synovium.
In osteoarthritis, the HA is
decreased and compromised.
Exogenous supplementation of
intraarticular HA is thought to
support changes in the character
of synovial fluid.
STIMULATES:
Hyaluronic acid
Glucosaminoglicans
Tissue inhibitor of
metalloproteinases
(TIMPs)
EFFECT:
-anti-inflammatory activity
-Improve synovial fluid
viscosity

INHIBITS:
Apoptosis
Stromelysin (MMP-3)
free radicals
PGE2
NO
Leucocyte proliferation, migration
and phagocytosis
- Counteract some IL-1 effect


HYALURONIC ACID ACTION MECHANISMS


Hyalgan
Whats the Evidence?
Cochrane Review 2005
Viscosupplementation is an
effective treatment for OA of the
knee with beneficial effects: on
pain, function and patient global
assessment; and at different post
injection periods but especially at
the 5 to 13 week post injection
period.
Questions?
Is HA superior to corticosteroid
injections or saline injections?
Do HA injections result in lower
utilization of NSAIDs?
Hyalgan
Using Hyalgan:
Indications: indicated for the
treatment of osteoarthritis not
responsive to non-pharmacologic
measures and to simple analgesics.
Requires sterile technique, remove
joint effusion if present prior to
injection.
Three to five weekly injections
recommended.
Is it safe?
No concern of inhibition of
prostaglandins.
Post-injection synovitis is described,
and can last up to three weeks.
Rheumatoid Arthritis
Rheumatoid arthritis is caused from
inflammation.
The primary site of inflammation is the
synovial membrane.
Inflamed synovial tissue may fill the joint
cavity and invade articular cartilage and bone.
The inflamed synovial tissue may cause
erosion of bone and cartilage.
Rheumatoid Arthritis Continued
Eventually irreversible damage may occur such
as total destruction of the joint with fusion of
adjacent bony surfaces.
In milder forms joints may withstand
inflammation for months or years before
irreversible damage occurs.
For all types of arthritis early detection and
treatment produce the most favorable results.
Rheumatoid Arthritis: Symptoms & Causes
Symptoms
Stiffness, pain,
redness, warmth, &
swelling over the joint.
Loss of appetite, fever,
& lack of energy.
Rheumatoid nodules,
psoriasis of the skin &
nail bed, dry eye
syndrome, & scleritis.

Causes
Rheumatoid arthritis is
an autoimmune
disease.
For unknown reasons
the immune system
attacks the individuals
own cells inside the
joint.
Rheumatoid Arthritis
Treatment
goal of treatment
reduce inflammation and pain,
preservation of function, and
prevention of deformity.
Rheumatoid Arthritis
Treatment
Nonpharmacologic treatment
Education and emotional factors
Physical and occupational therapies
Systemic and articular rest
Exercise
Heat and cold
Assistive devices like splints, canes, raised toilet
seat and/or crutches or walker
Weight loss

Rheumatoid Arthritis
Treatment
Nonsteroidal Anti-inflammatory agents like
aspirin: usually given in a dose of 1 gram three
to four times per day. If patients develop
tinnitus, a common side effect, the dose
should be reduced by .6-.9 grams every 3 days
until the patient improves. Enteric coated
aspirin and nonacetylated forms of aspirin like
salsalate may be associated with less GI
distress. GI irritation may also be reduced by
taking the aspirin with meals or antacids.

Rheumatoid Arthritis
Treatment
Other NSAIDs: Ibuprofen, naproxen, sulindac
and other NSAIDs may also be effective
though they are associated with a number of
side effects including
GI irritation and peptic ulcers (misoprostol can
reduce the incidence of peptic ulcers associated with
NSAIDs)
Kidney damage
Liver damage

Rheumatoid Arthritis
Treatment (Disease Modifying Agents
(DMARDs)
Methotrexate: considered by many to be the
drug of choice for RA. It produces a beneficial
effect in 2-6 weeks and is given once weekly.
The usual dose is 7.5-15 mg once a week. The
most common side effect is gastric irritation
and stomatitis. Other side effects are
hepatotoxicity, pancytopenia and interstitial
pneumonitis.

Rheumatoid Arthritis
Treatment
Antimalarials such as hydroxychloroquine
sulfate is effective in 25-50% of patients and in
most cases after 3-6 months of therapy. It is
reserved for mild disease.
Gold salts are used, especially in cases where
patients are not responding to Methotrexate or
in case of erosive disease.
Corticosteroids produce immediate and
dramatic anti-inflammatory benefit but are
limited by their many side effects

Rheumatoid Arthritis
Treatment
Sulfasalazine is a good second line agent for
rheumatoid arthritis with an efficacy similar to
gold and penicillamine. Side effects include
neutropenia and thrombocytopenia.
Azathioprine is an antimetabolite which is
reserved for use in case of severe cases.
Penicillamine
Rheumatoid Arthritis
Prognosis
Patients can follow two divergent courses: 50-
75% experience remission in 2 years (these
patients are negative for rheumatoid factor and
have good functional status even during
disease activity). Conservative therapy is
advised for this group. Patients who have
severe disease have a worse prognosis, and
on an average die 10-15 years earlier than
people without RA. Since most of the joint
damage occurs in the first two years, these
patients should be started on a disease
modifying agent early.
Rheumatoid Arthritis
Juvenile chronic arthritis is similar to
rheumatoid arthritis but is seen in
children. Synovitis persisting for 6 weeks
is essential to making this diagnosis. Four
forms are recognized:
polyarticular form resembles adult RA
oligoarticular form affects young girls during
peak ages of 2-4
systemic onset disease or Stills disease is
characterized by fever and rash
a juvenile form of ankylosing spondilitis
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