Guidelines in the
Management of RA
Haya M. Al-Malaq
Lecturer, Clinical Pharmacy Dept.
Clinical Pharmacist Rheumatology
Haya_malak@yahoo.com
Introduction
• Rheumatoid arthritis (RA) is an
autoimmunedisorder of unknown
etiology characterized by symmetric,
erosive synovitis and, in some cases,
extraarticular involvement. Most
patients experience a chronic
fluctuating course of disease that,
despite therapy, may result in
progressive joint destruction,
deformity, disability, & even premature
death.
Epidemiology
• RA results in more than 9 million
physician visits and more than 250,000
hospitalizations per year. Disability
from RA causes major economic loss
and can have a profound impact on
families. RA affects 1% of the adult
population this is due to low diagnosis
(difficult to diagnose in early stages).
• Females more than male.
Pathophysiology
Pathophysiology
• The cause of RA is still unknown, it
could be infection & as the case of other
autoimmune diseases the immune
system (AB to organism) begins to
attack its self (molecules in the
synovium that looks like the offending
organism) Some infectious organisms
mentioned in this context have been
Mycoplasma, Erysipelothrix, parvovirus
B19 and rubella, EBV, human herpes
virus.
Pathophysiology
• Genetic predisposition is important, risk
factors include cigarette smoking, hormonal
factors (more in women).
• Once triggered, B lymphocytes produce
immunoglobins, & RF of the IgG & IgM
classes that are deposited in the tissue, this
subsequently leads to the activation of the
serum complement cascade & recruitment
of the phagocytic arm of the immune
response, which further exacerbates the
inflammation of the synovium, leading to
edema, vasodilation and infiltration by
activated T-cells
Pathophysiology
• Early and intermediate molecular
mediators of inflammation include
TNF-α, IL-1,6,8,15, transforming growth
factor beta, fibroblast growth factor and
platelet-derived growth factor.
• Synovial macrophages and dendritic
cells further function as antigen
presenting cells by expressing MHC
class II molecules, leading to an
established local immune reaction in
the tissue.
Pathophysiology
• The disease progresses in concert with
formation of granulation tissue at the
edges of the synovial lining (pannus)
with extensive angiogenesis and
production of enzymes that cause tissue
damage.
• Once the inflammatory reaction is
established, the synovium thickens, the
cartilage and the underlying bone
begins to disintegrate and evidence of
joint destruction accrues.
S&S
Synovitis
• Most commonly affected joints are, small
joints (including the hands, feet and cervical
spine), but larger joints (shoulders, knees
etc) can also be involved; the pattern of joint
involvement can differ from patient to
patient.
• Inflammation in the joints manifests itself as
a soft, "doughy" swelling, pain, tenderness
to palpation and movement, local warmth,
and functional impairment.
• Morning stiffness is often a prominent
feature and may last for more than an hour
Deformity
• The fingers are typically deviated
towards the little finger (ulnar
deviation) and can assume unnatural
shapes.
• Classical deformities are the
Boutonniere deformity
• swan neck deformity
• The thumb may develop a "ZThumb" deformity
Extra-articular
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general tiredness and lassitude,
low-grade fever,
elevated ESR, and anemia.
GI bleeding as a side effect of drugs used in treatment,
especially NSAIDs .
Extra-articular manifestations occur in about 15% of
patients
Hepatosplenomegaly which may occur with
concurrent leukopenia and is then referred to as Felty's
syndrome,.
lymphocytic infiltration affecting the salivary
&lacrimal glands (Sjögren's syndrome).
pericarditis, pleurisy, alveolitis, scleritis, and
subcutaneous nodules.
Management
1-Diagnosis
Diagnostic Criteria
The ACR has defined the following criteria (>4) for the
classification of RA:
• Morning stiffness of >1 hour most mornings for at
least 6 weeks.
• Arthritis and soft-tissue swelling of >3 of 14
joints/joint groups, present for at least 6 weeks
• Arthritis of hand joints, present for at least 6 weeks
• Symmetric arthritis, present for at least 6 weeks
• Subcutaneous nodules in specific places
• Rheumatoid factor at a level above the 95th percentile
• Radiological changes suggestive of joint erosion
Blood Test
• RF (patients can be seronegative RA),
not very specific test, 80% -ve in the 1st
yr.
• anti-citrullinated protein antibodies
(ACPA), more specific, can detect pt in
early stages or even before occurrence
of the disease.
• ESR, CRP, CBC, RF, liver enzyme,
ANA, Ferritin can reveal
hemochromatosis.
2-Document baseline disease
activity & damage
3-Prognosis
Prognosis
• Selection of the treatment regimen
requires a assessment of prognosis.
Poor prognosis is suggested by
earlier age at disease onset, high titer
of RF, elevated ESR, and swelling of
20 joints .
• Extraarticular manifestations of RA
may also indicate poor prognosis.
Prognosis
• Studies have shown that patients
with active, polyarticular, RFpositive RA have a 70% probability
of developing joint damage or
erosions within 2 years of the onset
of disease
Assessment of Disease Activity
4-Initial therapy
Goals of Management
• RA are to preventor control joint
damage by inducing complete
remission.
• Prevent loss of function.
• Decrease pain.
• Maximize the QOL.
Complete Remission Is Absence
of:
• 1) symptoms of active inflammatory
joint pain
• 2) morning stiffness
• 3) fatigue,
• 4) synovitis on joint examination
• 5) progression of radiographic
damage on sequential radiographs
• 6)elevation of ESR or CRP levels
Patient education
• It is a chronic disease.
• Risks of joint damage and loss of
• Reviewing the risks and benefits of
existing treatment modalities.
• Periods of rest, job modification, time
off from work, changes in
occupation, or termination of work
may be necessary
Patient education
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Surgery
Longitudinal treatment plan
Treatment options
Cost
Adverse effects
Expected time of response
Non-Pharmacological Tx
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Patient education.
Instruction in joint protection,
conservation of energy,
home program of joint range of motion
strengthening exercises
Regular participation in dynamic and
even aerobic conditioning exercise
programs
Pharmacological Therapy
General Guidelines
• NSAIDs, glucocorticoid joint
injection, and/or low-dose
prednisone may be considered for
control of symptoms.
• The majority of patients with newly
diagnosed RA should be started on
DMARD therapy within 3 months of
diagnosis.
General Guidelines
• DMARD control not cure so periodic
assessment is required for efficacy & SE
& therapy modification.
• If disease activity is confined to one or a
few joints, then local glucocorticoid
injection may help. For patients with
severe symptoms, systemic
glucocorticoids may need to be
initiated, or the dosage may need to be
increased, for a short period of time.
• Try to avoid narcotic addiction.
Common DMARD
General Guidelines
• Pharmacologic therapy for RA often
consists of combinations of NSAIDs,
DMARDs, and/or glucocorticoids.
NSAIDs
• These agents have analgesic and
antiinflammatory properties but do not
alter the course of the disease or
prevent joint destruction, so not used
alone.
• Choice of available agents is based on
considerations of efficacy, safety,
convenience, and cost.
• Selective vr non-selective, no difference,
cost.
Risk factors for NSADs SE
• advanced age.
• history of ulcer.
• concomitant use of corticosteroids or
anticoagulants
• higher dosage of NSAID
• use of multiple NSAIDs
• serious underlying disease
Approaches to reduce SE
• use of low-dose prednisone instead
of an NSAID,
• use of a nonacetylated salicylate,
• use of a highly selective COX-2
inhibitor,
• or use of a combination of an NSAID
and a gastroprotective agent as: H2
blocker, PPI, PG analogue
DMARDs
• hydroxychlor
oquine
(HCQ),
• sulfasalazine
(SSZ),
methotrexate
(MTX),
• leflunomide
• etanercept
• infliximab.
• azathioprine
(AZA)
• D-penicillamine
(D-Pen)
• gold salts
• minocycline
• cyclosporine.
Many factors influence the choice
of DMARD
• relative efficacy
• Convenience of administration,
• requirements of the monitoring
program,
• costs of the medication and monitoring
• time until expected benefit
• frequency
• seriousness of adverse reactions.
• Patient factors (compliance, diseases,
prognosis, pregnancy/lactation).
DMARDs
• HCQ or SSZ first,
• active disease or poor prognosis, MTX
or combination therapy.
• MTX alone or in combination should be
included in patient with no MTX.
• HCQ is indicated for milder disease, no
monitoring (ophtha exam).
• SSZ act more quickly, start gradually,
watch for leucopoenia.
DMARDs
• Most select MTX as initial therapy esp.
in severely active disease, CI: liver
disease, renal impairment, lung disease,
or alcohol abuse, monitor liver fx,
contraception is recommended.
• leflunomide as an alternative to MTX as
monotherapy, especially for patients
who cannot tolerate MTX, long t1/2,
can be combined e MTX for max effect.
DMARDs
• AZA is rarely used
• D-Pen is effective but its use is
limited, in part, by an inconvenient
dosing schedule.
DMARDs
• IM gold treatment is effective but injections
are required every week for 22 weeks before
less-frequent maintenance dosing is
initiated, oral gold need 6 m to be effective.
• Tetracyclines (minocycline), may be
effective, needs more research.
• Cyclosporine is beneficial as monotherapy
and has short-term efficacy similar to that of
D-Pen. The use of cyclosporine, however,
has been limited by its toxicity, HTN & renal
toxicity.
DMARDs
• Staphylococcal protein A immunoadsorption.
Extracorporeal
• immunoadsorption of plasma against a
• staphylococcal protein A column was reported
to be efficacious in a portion of patients with
severe refractory RA .
• Given the difficulty and cost of administering
weekly treatments for 12 weeks, the limited
duration of the response, and the high
frequency of side effects, this treatment should
be considered only for patients with refractory
RA in whom treatment with several DMARDs
has failed.
• Glucocorticoids. Low-dose oral
glucocorticoids (10 mg of prednisone
daily, or the equivalent) and local
injections of glucocorticoids are highly
effective for relieving symptoms in
patients with active RA.
• Discuss ADRs.
• 1,500 mg of elemental calcium/day
,400–800 IU of vitamin D/day.
• Hormone replacement therapy
• bisphosphonates
Biological Agents
• Anti–tumor necrosis factor (antiTNF-alpha)- biological agents
etanercept and infliximab are
beneficial in combination with MTX,
avoid in TB, watch for infx, high cost.
• Adalimumab: new agent
• IL-1 receptor antagonist: Anakinra,
modest effect.
Combination therapy
• Cyclosporine plus MTX
• MTX, HCQ, and SSZ
• Plus lo dose CS
Practice points
• glucocorticoids can offer immediate
short-term relief and can serve as
anadjunct to existing DMARD
therapy.
• the impact of glucocorticoids on
structural damage and their optimal
role in the management of RA
require further investigation.
Practice points
• MTX remains the standard of therapy
for both early and established RA ???
• MTX is effective as both
monotherapy and in combination
therapy
• a step-up approach has been
successful in improving clinical
response and slowing radiographic
progression
Practice points
• TNF-a inhibitors produce prompt
clinical response and can slow
radiographic progression
• infections, including opportunistic
infections, should be watched for
and, if found, treated aggressively in
patients receiving TNF-a inhibitors
Guidelines for monitoring
drug therapy in RA
• These guidelines are drawn from a
synthesis of expert opinion, a survey
of rheumatologists, published
guidelines, and, whenever possible,
data on toxicity.
• Toxicity may range from mild to
serious and from reversible to
irreversible.
• We define rare toxicities as those
which occur in <1% of patients using
the agent, uncommon in 1-10%, and
common in >10%.
Toxicities of drugs used in RA that
require monitoring include:
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Gastrointestinal (GI) bleeding.
Hypertension.
Hyperglycemia.
Macular damage.
Renal damage.
Hepatotoxicity.
Myelosuppression.
Reduction in the incidence, severity, &
unfavourable outcomes of these toxicities can be
attempted by
• 1) pretreatment assessment to identify
patients with risk factors for toxicity.
• 2) careful patient & physician education
about safe dosage & S&S of toxicity
• 3) appropriate monitoring with
physician follow up & periodic lab
studies.
NSAIDs Toxicities
• dyspepsia (common).
• gastric or small bowel bleeding or
ulceration (uncommon).
• renal insufficiency, confusion,
depression, rash, headache, and
hepatic toxicity (rare).
NSAIDs Toxicities
• reversibly inhibit platelet function
and prolong bleeding time.
• Patients with prior aspirin
hypersensitivity are also at risk for
developing bronchial spasms (rare).
• There appear to be few differences in
the frequency of serious toxicities
among the different NSAIDs
NSAIDs Toxicities
To avoid GI SE:
• Take drug with food.
• Misoprostol should be considered for
patients who require NSAID
treatment & are elderly or have a
history of PUD, GI bleeding, or CVD.
• Sucralfate, H2 blockers, & antacids to
reduce dyspipsea.
NSAIDs Toxicities
Renal complications:
• High-risk groups for renal toxicity
include
• the elderly, particularly those receiving
diuretics.
• patients with preexisting renal disease,
CHF, cirrhosis, atherosclerotic heart
disease, or any altered physiologic state
in which renal blood flow is being
maintained by compensatory
vasodilatation.
NSAIDs Toxicities
To prevent renal toxicity in patients who
are at risk:
• NSAIDs should be started in modest
doses & then carefully increased.
• Patients should be instructed to report
if signs of fluid retention evidenced by
weight gain or edema develop, if they
become ill & dehydrated, or if they are
to begin treatment with diuretics or
ACE).
NSAIDs Toxicities
Renal complications:
• monitor SrCr in high-risk patients
every wk for several wks after Tx is
started.
• The average time of drug exposure
has been 6.6 m for NSAID-induced
nephrotic syndrome and 15 days for
allergic interstitial nephritis.
NSAIDs Toxicities
Liver toxicity:
• may cause elevation of liver enzyme levels,
but severe hepatotoxicity is rare.
• There is no evidence that abnormal findings
on LFT in the absence of clinical symptoms
change the outcome or are associated with
serious hepatotoxicity
• Liver function should be monitored in
patients who are treated with diclofenac or
in those who have intrinsic liver disease or
in whom it is suspected. Table 1
DMARDs
Hydroxychloroquine (HCQ)
• The major toxicity of antimalarial
agents is retinal damage (rare), which
can lead to visual impairment.
• It has less toxicity to be monitored.
• Goal for monitoring is to detect early
reversible retinal toxicity.
Hydroxychloroquine (HCQ)
The major risk factor for retinal toxicity
appears to be the combination of:
• cumulative dose >800 gm.
• age >70 years (increased prevalence of
macular disease).
• HCQ dosage of >6.0-6.5 mg/kg/d, in
patients with abnormal hepatic or renal
function.
Hydroxychloroquine (HCQ)
• Patient should report any visual symptoms.
• Baseline evaluation < 40 is not required.
• After 6 month of therapy should do
evaluation then every 6-12 months.
• Patients with abnormal RF or those who
have received HCQ > 10 years require more
frequent ophthalmologic evaluation.
• Table 1.
Sulfasalazine (SSZ)
Hematologic toxicities of SSZ:
• leukopenia (1-3%)
• thrombocytopenia (rare).
• hemolysis in patients with (G6PD)
deficiency.
• agranulocytosis (rare).
• aplastic anemia (rare)
Sulfasalazine (SSZ)
• Leukopenia is most likely to occur in
the first 6 m of TX, may occur later.
• Early dosage reduction &/or
cessation may reverse leukopenia.
• Patients should be questioned about
allergies to sulfa drugs & cautioned
about oligospermia.
Sulfasalazine (SSZ)
• The main goal of monitoring is to
detect hematological toxicities.
• a baseline assessment of AST or ALT
in patients with known or suspected
liver disease.
• Table 1
Methotrexate (MTX)
• The most serious toxicities of MTX
include hepatic fibrosis (rare) &
cirrhosis (rare), pneumonitis
(uncommon), & myelosuppression.
Methotrexate (MTX)
• Independent risk factors for the
development of serious liver disease in
patients with RA include:
• age
• duration of therapy,
• obesity,
• diabetes,
• alcohol intake,
• prior history of hepatitis B or C
Methotrexate (MTX)
• Prevention of hepatic fibrosis and cirrhosis
includes:
• avoidance of MTX in patients with liver disease
risk factor.
• In patients with suspected liver disease, a
pretreatment liver biopsy should be obtained.
• Avoid alcohol consumption while taking MTX.
• Patients should report symptoms of jaundice or
dark urine.
• Liver biopsy is recommended for patients with
liver function abnormalities that persist during
treatment with, or following D/C of MTX.
Methotrexate (MTX)
• Risk factors for myelosuppression include
the use of antifolate agents such as
trimethoprim, the presence of folate
deficiency, and renal insufficiency.
• CBC & RF q4-8wks.
• Review of a radiograph obtained within 1
year prior to the initiation of MTX therapy is
recommended to determine if preexisting
lung disease is present and to provide a
baseline for future comparison
• Use fa supplementation.
• pregnancy should be avoided.
Gold compounds
• The major serious toxicitieshematologic, renal, and pulmonaryrare.
• monitoring should be considered if
protein excretion is >500 mg/24 hours.
• Oral less toxic than parental.
• Patients need to be educated about the
need for frequent monitoring & for
reporting of rash, mucositis, hematuria
or bleeding, or any new illness while
receiving gold.
D-penicillamine (DP)
• rash (common), stomatitis (common),
dysgeusia or metallic taste (common),
myelosuppression (especially
thrombocytopenia) (rare), & proteinuria
(rare).
• renal failure (rare) and induction of
autoimmune syndromes such as SLE.
• Slowly increasing the dosage of DP by 125250-mg increments every 3 months up to 750
mg/d to decrease thrombocytopenia.
• Patients taking DP should report any new
symptoms.
Azathioprine (AZA)
• capable of inducing myelosuppression at
dosages used to treat RA (1-2 mg/kg/day).
• The rationale for monitoring is to decrease
the incidence and severity of
myelosuppression.
• Risk factors include: concomitant
allopurinol or ACE inhibitors & RF.
• Prevention: reducing the dose to 1/4 with
concomitant allopurinol, avoiding ACEI, &
decreasing the dose in patients with renal
insufficiency.
Glucocorticoids
• increased appetite, weight gain, fluid
retention, acne, cushingoid facies,
HTN, diabetes, atherosclerosis,
glaucoma & cataract, osteoporosis, a
vascular necrosis, increased
susceptibility to infection, &
impaired wound healing.
Glucocorticoids
Patient's risk factors for steroid AE:
• family Hx of diabetes,
• established HTN or diabetes,
• preexisting cataract(s) or glaucoma,
• low BMD,
• Hx of osteoporotic fracture, or
significant osteoporosis risk factors
such as premature menopause.
Glucocorticoids
• Initial assessment may include measuring Wt & BP,
• serum glucose and cholesterol levels,
• in patients at high risk for osteoporosis, consideration
of BMD measurement & supplementation with
calcium & vit D.
• Baseline eye examination in patients over the age of 65
or with a family history of glaucoma.
• Table 1.
Antirheumatic agents and
teratogenicity, lactation, and
fertility
• The majority of RA patients are
females and some are at a
reproductive age.
• Decisions regarding the use of
medications in pregnancy require
consideration of the risks & benefits
to mother & fetus.