Rheumatoid arthritis Part 2

Rheumatoid Arthritis Part 2

Anas Bahnassi PhD CDM CDE

3 Week

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.


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.


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.


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


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.


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.


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


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.


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.


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.


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 anti-inflammatory 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.


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.


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.


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.

Why is MTX a good choice for this patient?

• 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.

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

Less hypotoxic

15mg Weekly X12wks

Max dose of 25mg/wk 1 Administer SC or IM 2

Longer period 3 Discontinue 4

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 low-dose 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.

When should folate (or folinic acid) be administered to reduce the risk of MTX-related toxicity?

• 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.

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.

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

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?

• 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

The patient does not respond to LEF and the treatment discontinued, What precautions must be taken when discontinuing LEF?

• 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.

A patient with severe RA begins etanercept after both MTX and LEF therapy failed. Why is etanercept a reasonable therapeutic option?

• 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

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.


• 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.


• 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.


• 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 .

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.

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?

• 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.

Pharmacottherapy Anas Bahnassi PhD CDM CDE

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Health & Medicine

Rheumatoid arthritis Part 2