This document discusses the treatment of rheumatoid arthritis (RA) with non-steroidal anti-inflammatory drugs (NSAIDs). It provides several case studies examining the risks and appropriate use of NSAIDs like aspirin and ibuprofen in patients with conditions like asthma, heart failure, or pregnancy. It emphasizes monitoring patients for side effects of NSAIDs like tinnitus, gastrointestinal bleeding, renal impairment, and drug interactions affecting dental procedures or risk of myocardial infarction. The document recommends alternative analgesics or disease-modifying treatments like hydroxychloroquine or methotrexate based on individual patient factors and risks.

1. Week
3
Rheumatoid Arthritis
Part 2
Anas Bahnassi PhD CDM CDE

2. A case approach to treatment with NSAIDs
What is the role of NSAID when added to
DMARDs treatment?
The purpose of NSAID therapy, which has no
disease-modifying activity, is to provide rapid
pain relief and reduction of joint inflammation.
Aspirin currently seldom is the NSAID of choice
because of well-documented GI toxicity and
the availability of safer and more convenient
NSAIDs.

3. A case approach to treatment with NSAIDs
A patient with RA, had her aspirin dosage increased to 975 mg QID approximately
1 week ago. She now complains of, “… ringing in my ears all the time!” What is the
most probable cause of this symptom?
Aspirin-induced tinnitus (i.e., a ringing or high-pitched buzzing
sensation in the head) is noticeable to most patients with normal
hearing when serum levels are 10 to 30 mg/dL; however, in some
patients tinnitus might not be encountered until
serum levels exceed 25 mg/dL.Serum salicylate
concentrations usually are within the therapeutic
range when tinnitus is apparent. Tinnitus,
therefore, can be used to titrate patients to
therapeutic doses of aspirin; however, patients
with preexisting hearing loss might not experience
tinnitus despite potentially toxic concentrations.

4. A case approach to treatment with NSAIDs
What are appropriate alternatives for patients
who cannot tolerate therapeutic doses of aspirin?
Patients who complain of GI side effects commonly use
aspirin formulations that contain buffering agents.
Enteric-coated aspirin is associated with fewer GI
complaints than uncoated aspirin.
Sustained-release (SR) aspirin is intended to provide more
stable salicylate concentrations with less frequent
administration. The relative advantage of SR aspirin
compared with regular or enteric-coated aspirin remains
unclear.

5. A case approach to treatment with NSAIDs
Aspirin was ordered for the relief of pain in an asthmatic patient with
allergy to aspirin. Why might another NSAID, also be contraindicated
for this patient?
Aspirin intolerance, especially in association with
asthma, is cause for serious concern.
Challenge with aspirin in these patients can precipitate
an acute, life-threatening, bronchospastic reaction.
10% of asthmatics have a history of aspirin-induced
bronchospasm, more often women than men and
rarely in children.
A somewhat smaller number of patients with recurrent
rhinitis also experience this problem

6. A case approach to treatment with NSAIDs
A.C. is scheduled to have an impacted wisdom
tooth removed. She states that she is taking an
aspirinlike product for arthritis. Why would the
specific NSAID she is taking affect this dental
procedure?
Just like Salicylate, nonaspirin NSAIDs can prolong bleeding
times by inhibiting platelet aggregation, but these drugs bind
reversibly to COX resulting in reversible platelet inhibition.34
Therefore, nonaspirin NSAIDs should be discontinued about 5
half-lives before surgical procedures.

7. A case approach to treatment with NSAIDs
K.H., a 28-year-old pregnant woman with RA, is concerned about the
possible effects of NSAIDs on her baby. What are the risks to the fetus
with uninterrupted consumption of NSAIDs? What are maternal- and
lactation-related effects of these medications?
Fetal effects of NSAIDs include possible premature ductus arteriosus closure,
increased cutaneous and intracranial bleeding, transient renal impairment, and a
reduction in urine output.
High doses can inhibit uterine contraction, resulting in prolonged labor. NSAIDs also
can increase peripartum blood loss and anemia.
Aspirin and nonaspirin NSAIDs should be used sparingly at lowest effective
doses during in pregnancy and discontinued at least 6 to 8 weeks before
delivery to minimize adverse fetal and maternal effects.
Aspirin generally should be avoided for women who plan to nurse their baby
because salicylate serum concentrations in breastfed neonates raise concerns
about the potential for metabolic acidosis, bleeding, and Reye syndrome.
According to the American Academy of Pediatrics, the nonaspirin NSAIDs
generally are compatible with breastfeeding.

8. A case approach to treatment with NSAIDs
Naproxen 500 mg BID with meals has been prescribed, if the patient were to
develop dyspepsia during therapy, should she be given misoprostol for prophylaxis
against GI complications of NSAID therapy or would a COX-2 selective NSAID be
preferable? What is the correlation between dyspepsia and gastroduodenal
mucosal injury?
5% and 15% of patients with RA discontinue NSAID
therapy because of dyspepsia.
NSAID-induced gastroduodenal mucosal damage
primarily results from inhibition of COX-1 in the
mucosal lining.
Dyspepsia can be managed by ingesting the NSAID
with meals or a large glass of water
Routine concomitant antiulcer prophylactic therapy is
not warranted for all patients taking NSAIDs

9. A case approach to treatment with NSAIDs
A 68-year-old man with HF managed with furosemide 40 mg/day, digoxin 0.125 mg/day, metoprolol 50
mg BID, and lisinopril 40 mg/day, returns for a prescription refill of ibuprofen 600 mg TID, which he takes
for his RA. Over the past 2 weeks he noticed :  leg swelling + weight gain of several pounds + increasing
shortness of breath (SOB), and easy fatigability.
Why might these signs and symptoms be associated with ibuprofen?
Monitor NSAID therapy in patients with heart failure, liver disease with associated
ascites, compromised renal function, or when diuretics are administered concomitantly.
Renal function depends on prostaglandin E2 production to offset the vasoconstrictor
effects of high concentrations of angiotensin, vasopressin, and catecholamines.
Inhibition of COX in kidneys reduces prostaglandin conc. and unopposed
vasoconstriction  urine output declines, serum blood urea nitrogen and serum
creatinine levels rise, and fluid is retained.
This potential complication is associated with all of the currently marketed NSAIDs.
Ibuprofen is among several NSAIDS (e.g., celecoxib, high doses of diclofenac) that are
associated with an increased risk of MI.

10. A case approach to treatment with NSAIDs
How can you manage this patient’s DRP?
• Ibuprofen should be discontinued.
• NSAID therapy should not be restarted until renal function normalizes.
• Alternative therapy should be considered.
• Sulindac has less ADRs…. Less effective…
• Celecoxib also has renal side effects (edema, hypertension).
• NSAIDs need to be used at the minimal effective dose for the minimal
possible duration.
• High doses of ibuprofen and celecoxib should be avoided in patients
with high risk
of MI.
• Acetaminophen can be used as analgesic.
• Intra-articular injections of corticosteroids can be useful in inflamed
joints with limited number.

11. A case approach to treatment with NSAIDs
What other renal syndromes are associated with NSAID therapy?
• Nephrotic syndrome: can appear anytime.
• Hematuria, pyuria, and proteinuria without prior renal disease differentiates
nephrotic syndrome from other NSAID-induced renal problems.
• Urine is maximally concentrated (hyponatremia can be potentiated by
thiazide diuretics).
• Interstitial nephritis
• Abnormalities of water metabolism
• Hyperkalemia
• Local prostaglandin synthesis also can stimulate renin production within the
kidney. NSAID therapy can critically attenuate this regulatory mechanism in
some situations, resulting in reduced aldosterone-mediated potassium
excretion and hyperkalemia.

12. A case approach to treatment with NSAIDs
What instructions should be provided to a RA patient receiving a NSAID
prescription?
• NSAID provides pain relief but does not slow or stop the
progression of the disease.
• Moderate to high daily doses of NSAIDs are required for antiinflammatory activity, as opposed to analgesic and antipyretic
effects.
• Aspirin is sensitive to moisture.
• Recognize the signs and symptoms of GI bleeding.
• The patient should be instructed to contact their health care
provider immediately for further instructions if any of these
signs or symptoms occur.

13. A case approach to treatment with NSAIDs
When should routine renal or liver function be tested during NSAID
therapy?
• Patients at high risk for NSAID-induced renal disease
should have their serum creatinine checked weekly
for several weeks after initiation of therapy.
• NSAID-induced nephrotic syndrome and allergic
interstitial nephritis occur, on average, about 6.6
months and 15 days after NSAID initiation,
respectively.
• In most cases, liver function testing (LFT) is
unnecessary.

14. A case approach to treatment with NSAIDs
Treatment was initiated with HCQ. What dosages would be appropriate, and
when should clinical improvement be expected?
• Dosages for HCQ generally range from 2 to 6.5 mg/kg/day.
• If the patient responds well, the maintenance dose can be
reduced by 50% and the medication continued at a dose of
200 to 400 mg/day (155–310 mg of base).
• About two-thirds of patients who tolerate HCQ respond
favorably.
• Benefits usually are apparent within 2 to 4 months of therapy,
but can vary between 1 and 6 months.
• 37% of patients discontinued HCQ within a year and 54%
within 2 years primarily owing to lack of efficacy.

15. A case approach to treatment with NSAIDs
How great is the risk of retinopathy from antimalarials when used for the
treatment of RA? What monitoring parameters are appropriate?
• HCQ seems to be the least toxic of all DMARDs.
• Retinal damage and subsequent visual impairment, is rare.
• Risk of retinopathy seems to correlate with cumulative dose
(>800 g) and age (>70 years).
• Doses exceeding 6.0 to 6.5 mg/kg are associated with
increased risk of retinal damage.
• The retinopathy can be progressive even after discontinuation
of the drug.
• Baseline eye examination is not required in patients younger
than 40 with no family history of eye disease.

16. Why is MTX a good choice for this patient?
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Young age of onset
Multiple joint involvement
Extra-articular manifestations
Radiographic evidence of erosions
Elevated ESR, and positive RF with a high titer of 1:1,280
[positive RF is generally a titer ≤1:20 and titers correlate with
disease severity]).
• Prognosis poor, and a relatively potent DMARD should be
initiated to maximize the preservation of joint function.
MTX is currently the initial DMARD of choice:
• MTX has a rapid onset (usually 1–2 months before a “plateau”
of effectiveness)
• High efficacy rate, and the most predictable benefit of any
DMARD.

17. How should MTX be administered when it is used in
the treatment of RA?
7.5mg
Weekly
Pulse
Dosing
divided into 3
doses of 2.5
mg Q 12 h
1
2
3
4
Less hypotoxic
Max dose of 25mg/wk
15mg
Weekly
X12wks
Administer SC or IM
Longer period
Discontinue

18. What subjective and objective data should be evaluated for evidence
of MTX adverse effects in RA patients treated with MTX?
• Nausea and other GI distress, malaise, dizziness, mucositis, and mild
alopecia are commonly encountered adverse effects associated with lowdose MTX therapy.
• More serious, but less common, adverse effects include
myelosuppression, pneumonitis, and hepatic fibrosis and cirrhosis.
• CBC, LFTs, and a serum creatinine concentration should
be evaluated at baseline, monthly for the first 6
months of therapy, and then every 4 to 8 weeks during
MTX therapy.

19. When should folate (or folinic acid) be administered to reduce the risk of
MTX-related toxicity?
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Folate supplementation effectively prevented, or
managed, GI disturbances, mucositis (mouth or GI
ulcerations), and possibly hepatotoxicity and alopecia
attributable to MTX therapy.
A slightly higher dose of MTX might be needed in folate
users to produce clinical benefits similar to that achieved
by patients without folate supplementation, perhaps
because MTX is a folate antagonist.
Although either folic acid or folinic acid is effective, folic
acid 1 mg/day or 7 mg once a week is preferred over
folinic acid because of cost and ease of administration.

20. The patient is treated with MTX 7.5 mg and with folic acid 7 mg orally once a week.
Nine weeks later, she returns to the clinic with subjective and objective improvement in morning stiffness,
fatigability, and joint tenderness and swelling. However, she has noted increased SOB and dyspnea over
the past week. Why might these symptoms be related to MTX?
• Pneumonitis, a rare complication of MTX therapy, is characterized by a
nonproductive cough, malaise, and fever, progressing to severe dyspnea.
• Recognition of this unusual reaction is important to ensure that MTX is
discontinued before the pneumonitis progresses to respiratory failure.
• After discontinuation of MTX, pulmonary function improves.
• Corticosteroids can accelerate improvement in pulmonary symptoms
associated with pneumonitis.
• The patient's dyspnea and SOB might be related to MTX. If appropriate tests
rule out other causes for her pulmonary complaints, MTX-induced
pulmonary toxicity should be considered and MTX treatment discontinued.

21. What major MTX food and drug interactions need to be considered by patients and
providers?
• NSAIDs increase MTX serum concentrations and increase the risk of toxicity.
• MTX doses should be adjusted cautiously in patients taking NSAIDs
concurrently.
• Trimethoprim can increase the risk of MTX-induced bone marrow
suppression.
• The concurrent use of MTX and LEF has been associated with major liver
damage, including fatalities; as a result, this combination should be
avoided.
• Caffeine may interfere with the anti-inflammatory effects of MTX. Because
MTX is protein bound and renally excreted, other drugs (e.g., salicylates,
etretinate, probenecid, penicillin, ciprofloxacin) also might interact with
MTX

22. A 36-year-old woman, has severe, progressive RA and is not responding
sufficiently to MTX therapy. Would LEF be a reasonable consideration for her?
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LEF is as safe and effective as MTX or SSZ in and can be
combined with MTX therapy.
Diligent patient’s monitoring is crucial for hepatoxicity.
Active metabolites are responsible pharmacologic activity.
Metabolite’s half-life is approximately 2 weeks.
LEF should be initiated with a loading dose of 100 mg once
daily for 3 days to reduce time to steady state, followed by
20 mg once daily (10mg if not tolerated).
Diarrhea, rash, alopecia, and reversible liver enzyme
elevations.
LEF is not recommended in patients with preexisting liver
disease, including hepatitis B or C.
Baseline ALT followed by monthly ALT testing for several
months

23. The patient does not respond to LEF and the treatment discontinued, What
precautions must be taken when discontinuing LEF?
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LEF (pregnancy category X).
After discontinuation of therapy, p to 2 years may need to
elapse before plasma M1 metabolite levels of LEF are
undetectable.
Cholestyramine is recommended for all women who discontinue
LEF and who are hoping to become pregnant.
Cholestyramine 8 g TID is administered for 11 days (which need
not be consecutive).
Plasma levels of the metabolite should become nondetectable
(<0.02 mg/L) at the end of therapy.
The patients blood should be tested at least 14 days apart to
verify the absence of the metabolite.
If plasma M1 levels remain >0.02 mg/L, more cholestyramine
should be administered.
Cholestyramine or activated charcoal also can be used to
enhance elimination of LEF in patients who experience
hepatotoxicity or who overdose with this drug.

24. A patient with severe RA begins etanercept after both MTX and LEF therapy
failed. Why is etanercept a reasonable therapeutic option?
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Etanercept (Enbrel) can be used for moderate to severe
active RA, either alone or in combination with MTX.
It is a soluble TNF receptor that competitively binds two
TNF molecules, rendering both inactive.
Etanercept also is approved for use in juvenile RA and
psoriatic arthritis.
Dose is 25 mg subcutaneously twice weekly.
It may be self-injected by the patient after proper training.
It must be reconstituted using only the diluent supplied
Contents should be swirled, not shaken, to avoid excessive
foaming.
Injection sites (e.g., thigh, abdomen, upper arm) should be
rotated.
Clinical response usually appears within 1 to 2 weeks of
treatment, and nearly all patients respond within 3 months

25. After 3 weeks of etanercept therapy, the patient seems to respond well.
However, she dislikes the subcutaneous administration of
etanercept twice weekly and wants another medication that
can be administered on a much more convenient basis.
How do the other TNF-inhibitors differ from etanercept,
and is B.W. a candidate for one of these alternatives?
• Infliximab (Remicade), is a chimeric (mouse/human) IgG antibody
directed against TNF that is approved for the treatment of Crohn
disease and for the treatment of RA in patients who have not
responded adequately to MTX.
• The usual dose of infliximab is 3 mg/kg intravenously at 0, 2, and 6
weeks, then every 8 weeks thereafter
• Convenience of infrequent dosing is tempered by the need for
supervised intravenous administration.
• Infliximab should be given with MTX therapy to prevent the
formation of antibodies to infliximab.

26. After 3 weeks of etanercept therapy, the patient seems to respond well.
However, she dislikes the subcutaneous administration of
etanercept twice weekly and wants another medication that
can be administered on a much more convenient basis.
How do the other TNF-inhibitors differ from etanercept,
and is B.W. a candidate for one of these alternatives?
• Infliximab (Remicade), is a chimeric (mouse/human) IgG antibody
directed against TNF that is approved for the treatment of Crohn
disease and for the treatment of RA in patients who have not
responded adequately to MTX.
• The usual dose of infliximab is 3 mg/kg intravenously at 0, 2, and 6
weeks, then every 8 weeks thereafter
• Convenience of infrequent dosing is tempered by the need for
supervised intravenous administration.
• Infliximab should be given with MTX therapy to prevent the
formation of antibodies to infliximab.

27. After 3 weeks of etanercept therapy, the patient seems to respond well.
However, she dislikes the subcutaneous administration of
etanercept twice weekly and wants another medication that
can be administered on a much more convenient basis.
How do the other TNF-inhibitors differ from etanercept,
and is B.W. a candidate for one of these alternatives?
• Adalimumab (Humira), is a genetically engineered, fully
humanized IgG1 monoclonal antibody, as opposed to the chimeric
infliximab.
• It is self-administered subcutaneously by the patient as a 40-mg
injection every other week, whether as monotherapy or in
combination with traditional DMARDs (e.g., MTX).
• In radiographic data reflecting 1 or 2 years of treatment,
adalimumab slowed the progression of joint damage.
• Data are available supporting the efficacy and safety of
adalimumab for up to 7 years.

28. After 3 weeks of etanercept therapy, the patient seems to respond well.
However, she dislikes the subcutaneous administration of
etanercept twice weekly and wants another medication that
can be administered on a much more convenient basis.
How do the other TNF-inhibitors differ from etanercept,
and is B.W. a candidate for one of these alternatives?
• Although infliximab is ultimately administered every 2 months.
• it must be administered intravenously and in combination with
MTX (or possibly at a higher dose) to minimize HACA formation.
• Adalimumab’s ease of administration (self-injected subcutaneous
injection) and infrequent dosing interval compares favorably with
etanercept (twice weekly injections) and anakinra (daily
injections) but it is administered more frequently than infliximab
• All are priced similarly.
• Additional therapeutic benefit might be achieved from weekly
dosing of adalimumab, but the cost will be higher .

29. What are the Adverse Effects of Anti-Tumor Necrosis Factor Antibodies?
• Similar to etanercept.
• Treatment risks include: injection site pain, local reactions,
upper respiratory tract infections, nausea, flulike symptoms,
rash.
• Serious adverse effects include: serious infections, increased
incidence of lymphoma. are similar as well.
• As with all anti-TNF agents, a tuberculosis skin test result and
chest radiograph must be obtained before initiating treatment.
• Development of antibodies against infliximab occurs
frequently with monotherapy.
• Only 5% of patients may develop antibodies for adalimumab.
• Patients who switch from one anti-TNF agent to another owing
to loss of efficacy of the initial agent are able to attain a good
response from the second.

30. The patient would prefer to avoid anakinra [Kineret] because it requires daily
subcutaneous injection dosing. Apart from this inconvenience, what are its therapeutic
advantages over the anti-TNF agents?
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Anakinra the only available IL-1Ra identical in composition
to human IL-1Ra
Recommended dose is 100 mg daily by self-administered
subcutaneous injection
Improves signs and symptoms and radiographic evidence of
joint erosion in RA patients.
Combination with MTX seems to be more effective, still not
recommended due to increased incidence of serious
infections and leukopenia
It does not worsen of heart failure
Anakinra seems to offer no advantages and some real and
potential disadvantages when compared with the anti-TNF
agents.

31. Pharmacottherapy
Anas Bahnassi PhD CDM CDE
abahnassi@gmail.com
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