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A broad spectrum of drugs

for rheumatic diseases

• Analgesic drugs (acetaminophen, opioids)
• NSAIDs (analgesic and anti-inflammatory)
• Glucocorticoids (anti-inflammatory effect )
• DMARDs also referred to slow-acting
antirheumatic drugs (SAARDs).
• Biologic Agents
• Analgesic/ antipyretic
• Unknown mechanism of action combo with
opiods better response when cannot use NSAID
• Doesn’t alter platelet function (bleeding/ surgery)
• Safer for elderly
• 1g qds max
• Caution with chronic liver (hepatotoxicity, > 2 gm)
• Thrombocytopaenia, neutropenia rare
• Centrally acting analgesic
• Use in addition to NSAID
• Effects in receptors; Same potency as opiods
• Can use as adjunctive therapy
• Less opiod SE : constipation/ nausea/ vomiting
• Balance problems
• smaller potential of abuse or dose acceleration,
(needs more drug in shorter time period) c.f. opiods
• Use in patient with limited options
• loss of function due to pain
• renal or heart disease preventing operation
• Select patients carefully
• Use during period of disease flare, then decrease use
• Nausea, vomiting, constipation,urinary retention
• Chronic use leads to physical dependence
• Can use with anti-inflammatory
• Lots of choice (short or long acting, patches)
Nonsteroidal anti-infllammatory drugs
• Act by inhibiting the syntesis of prostaglandins
and thromboxanes, a group of lipid mediators
formed from arachidonic acid
• acute arthritis,chronic arthritis, ankylosing
spondylitis and other inflammatory diseases
degenerative diseases of joint and spine, and
acute pain syndromes
NSAIDs - mechanism of action
Common used NSAIDs
• Acetyl salisilic acid (>3 g/d)
• Arylpropionic acid (ibuprofen,naproxen)
• Arylacetic acid (diclofenac,indometacin)
• Thiazinecarboxamides
• Selective COX-2 inhiibitors (coxibs)
– Gastrointestinal tolerance
– Cardiovascular, nephrotoxity (side effect)
actions mechanisms
• The main anti-inflammatory effect is achieved by
controlling the rate of synthesis of mRNA and proteins
• Increased of lipocortin synthesis and subsequent
inhibition of phospholipase A2
• Reduced production of cytokines their activation,
proliferation, differentation and migration
• Reduced of inflammatory enzymes (collagenases,
elastase and plasminogen activator)
• Alteration in T and B cell function (IL-1, IL-2, lL-4, IL-5,
IL-6 dan TNF alfa )
actions mechanisms
• Reduction of Fc and C3 receptor expression
• Changes in white cell traffic (in 4-6 hours and
return to normal by 24 hours) due to large
intravenous doses. Increased neutrophils,
lymphocytes, eosinophlis, monocytes
• Stabilization of neutrophil lysosomal
• Reduced NO synthesis in macrophages
Glucocorticoids - complications
hypertension, sodium and water retension-oedema,
hypokalemic alkalosis
diabetes mellitus, hyperosmolar non-ketotic coma,
hyperlipidemia, induction of obesity
growth failure, secondary amenorrhoea, supression HPA axis
impaired wound healing, subcutaneus tissue atrophy
superimposition of a variety of bacterial,fungal, viral and parastic
Glucocorticoids –
dosages and indications
• RA patients
7.5 – 10 mg/daily of prednisone or
metylprednisolone oral (low doses)
20-40 mg of metylprednisolone intra-articular
• SLE, PAN (vasculitis) and PM/DM patients (high
1-2 mg/per kg/daily oral or pulses therapy
(500-1000 mg of metylprednisolone
intravenous for 3-5 consecutive days)
DMARDS: What are they?
• Disease -modifying antirheumatic drugs
• DMARDs influence the disease process, unlike
NSAIDs which just alleviate symptoms
• varying and sometimes poorly understood
mechanisms of action
• e.g. methotrexate, sulfasalazine, gold
compounds, penicillamine, chloroquine and
cyclosporine, azathioprene, mycofenolate
Onset of action of disease
-modyfing drugs
• After 1-3 months
– Leflunomide: RA
– Metothrexate: RA, SLE
– Cyclosporin: RA, SLE, DM/PM
– Cyclophosphamide: RA, SLE, DM/PM, PSS,
PAN (vasculitis)
– Sulfasalazin: RA,AS
– Azathioprine: RA, SLE, DM/PM, PSS
Onset of action disease
-modyfing drugs

After 4 to > 6 months

• – Chloroquine: RA, SLE
• – Hydroxychloroquine: RA, SLE, SS
• – Auorothioglucose: RA
• – Auranofin: RA
• – D-penicillamine: RA, PSS
• dihydrofolate reductase inhibitor/ folate antagonist –
purine antagonist
• dihydrofolate reductase reduces folate to FH4, the latter
being an essential co-factor in DNA synthesis)
• RA (1st line DMARD), psoriasis (if severe/ resistant to
topical treatments), cancer, Crohn’s disease
orally but can be given im or subcut Usually 10mg
• max 25mg/week.
severe blood disorders, active infections,
immunodeficiency, kidney or liver failure, pregnancy
(females and males must avoid conception for at least
3/12 after stopping treatment), breast-feeding

effusions (especially ascites and pleural effusions as
these act as ‘storage’ for the drug thereby increasing its
toxicity), UC, peptic ulcer, decreased immunity and
• Sulfapyrine
• not teratogenic or strong immunosupressant
• Up to three months to take effect GI upset, elevated LFTs,
bone marrow depression
• Monitoring bloods 3 monthly
• first introduced for antibiotic action in colon, for inflammatory
bowel disease.
• mode of action unclear , anti-inflammatory,
immunomodulatory and/or antibacterial
Cyclosporine & Azathioprene
• Cyclosporine
• Nephrotoxicity espec with NSAIDs
• causes hypertension
• usually in combination

• Azathioprine
• moderate efficacy, three months to reach efficacy
• purine antagonist, & interferes with nucleotide
• SE: liver toxicity, bone marrow toxicity, monitoring 3/12
• Cyclosporin & azothiaprine used in 2-5% of pts
• pyrimidine antagonist
• comparable efficacy to SZP
• probably comparable toxicity
• may be tolerated/ effective where other
drugs not suitable after methotrexate, before
Mycophenolate Mofetil
• Reversible inhibitor inosine monophosphate
• inhibition lymphocyte proliferation/ antibody
formation/ adhesion molecule expression
• Improved safety other immunosupressants
SLE nephritis;refractory to cyclophosphamide
• Scleroderma.
• RA
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.
Biologic Agents
Action : Several Days
• Biologicals – anticytokine therapy:
• Anti TNF alfa inh, Anti IL-6, Anti IL-17, anti IL-23,
• Anti TNF alfa
infliximab, etanercept, adalimumab,Anakinra
• indicated in the treatment of:
rheumatoid arthritis (RA), psoriatic arthritis
(PA), ankylosing spondylitis (AS), juvenil
idiopathic arthritis (JIA)
• 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.
• Various biologicals approved in RA are:-
1) Anti TNF agents : Infliximab Etanercept Golimumab
2) IL-1 receptor antagonist : Anakinra
3) IL-6 receptor antagonist : Tocilizumab
4) Anti CD20 antibody : Rituximab
5) T cell costimulatory inhibitor : Abatacept
Anti TNF alfa
• anticytokine therapy
• specifically target TNF-alpha, which is an
important mediator of rheumatoid inflammation
• current guidelines (developed by the British
Society for Rheumatology in 2003) restrict their
use who fail two or more conventional second-
line agents
• ACR 2015 : single/monotherapy or combination
in severe disease
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 infection, reactivation DM,surgery(with hold for 2
dosing 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)
of demyelenating

Golimumab Once month, subcutan Same as that of Active infections

(Anti-TNF) May be given with infliximab
MTX or as
Etanercept: Adverse Events
 Serious infections and sepsis
 CNS demyelinating disorders
 Use with caution or avoid use in patients with
transverse myelitis, optic neuritis, multiple sclerosis
 Pancytopenia
 Use with caution in patients with history of
hematologic abnormalities
 Autoantibody formation
 Heart failure
Biological therapy: B-cell depletion
• a monoclonal antibody against CD20 which
causes lysis of B-cells
• uses/ lymphoma chemotherapy, RA, severe
• used with methotrexate in patients who have
had an inadequate response to the anti-TNFs.
• MOA/ binds to CD20 molecule on the B-cell.
Intravenous Ig
• First Study by Kitasato and Von Behring (1900)
• Based on Immunoglobulin production by B cells
• Used in various inflammatory disorders
• Treat for Kawasaki disease, Dermatomyositis,
Polydermatomyositis, ITP
• SLE, other inflammatory disesase , grey
• Limited RCT for SLE case, various improvement
Intravenous Ig
• Most Report and case study :IV Ig well tolerated
• Adverse of reaction : Flu like symptom
• Anaphylaxis reaction common in Nephropathy Ig
• Dose : Low dose 0,5 g/kg until 2 g/kg 2-5 days
• Be careful for renal impairment , inciden ARF
• Indication : GBS, Kawasaki Disease, ITP, CIDP
(FDA approved )