56

CASE 33-3, QUESTION 3: R.W. is initiated on hydroxychloroquine 400 mg orally daily. How long should

she be on the initial treatment dose?

Three to six months of the initial treatment dose of hydroxychloroquine is

recommended unless R.W. does not tolerate the side effects or does not benefit from

the medication. After R.W. has responded to the initial dose, then

hydroxychloroquine can be tapered to 200 mg daily for maintenance therapy.

CASE 33-3, QUESTION 4: How often should eye exams be performed for R.W.?

At high doses of hydroxychloroquine and over time, it may damage the retina of the

eye (retinal toxicity), causing vision problems. Eye exams should be performed at

baseline before initiating hydroxychloroquine and every 3 months based on the

manufacturer’s recommendation. If based on the AAO, an eye exam should be

performed at baseline and then every 5 years. If low doses of hydroxychloroquine are

used in the treatment of SLE, the risk of retinal toxicity is low. Long-term users of

high-dose hydroxychloroquine will need to monitor their eye health regularly to

prevent retinal toxicity.

CASE 33-3, QUESTION 5: What are the goals of SLE treatment?

Since there is no cure for SLE, the goals of treatment are to reset the patient’s

immune system to a state of remission, reduce the incidence of drug toxicity, and

prevent multi-organ damage.

Corticosteroids

Corticosteroid treatment is considered for patients with SLE who have not responded

to NSAIDs and hydroxychloroquine. Corticosteroids possess anti-inflammatory

effects and work by inhibiting T and B cell responses.

57 They provide immediate

relief for mild-to-moderate symptoms compared to immunosuppressant treatments.

Low-dose corticosteroid, such as prednisone, may be effective for mild-to-moderate

symptoms. For instance, low-dose oral prednisone (6–10 mg daily) over a duration

of 4 to 6 weeks is recommended for mild disease activity. Short-term use of tapered

courses of prednisone will help reduce acute flares with or without systemic

symptoms starting at adult doses of 1 mg/kg/day, up to 60 mg daily, and tapered over

8 weeks. Short-term treatment can minimize risks of developing side effects

associated with long-term corticosteroid use, such as weight gain, decreased bone

mineral density, muscle wasting, hypercholesterolemia, and hyperglycemia. More

severe adverse effects associated with long term use of high-dose corticosteroids

may include diabetes, osteoporosis, mood changes (e.g., anxiety, insomnia,

depression, and delirium), Cushing’s syndrome, and risks of cardiovascular events.

Topical corticosteroids are recommended for cutaneous SLE manifestations.

Adjunctive treatments with NSAIDs or celecoxib may be combined with prednisone

to reduce its dose and side effects, or allow it to be administered as an every other

day therapy. High-dose oral corticosteroids (e.g., prednisone 40–60 mg daily) or

intravenous corticosteroids (e.g., methylprednisolone 0.5–1.0 g daily) are considered

for more severe disease.

27

CASE 33-3, QUESTION 6: If R.W. is to be initiated on chronic, high-dose corticosteroid therapy for

management of her SLE symptoms, what should she be monitored for?

With the use of high-dose corticosteroids, it important to monitor for weight gain,

hyperglycemia, osteoporosis, glaucoma, cataracts, hypercholesterolemia, mood

changes, and premature atherosclerosis. Steroid medications can have serious longterm side effects, and the risk of the side effects increases with higher doses and

chronic therapy.

Disease-Modifying Antirheumatic Drugs (DMARDs)

Methotrexate (MTX, Rheumatrex, Trexall) is a folate antagonist that inhibits

dihydrofolate reductase, an essential enzyme for DNA synthesis. MTX is usually

considered for treatment of rheumatoid arthritis, in terms of arthritis and skin

manifestations. It is an effective alternative agent to hydroxychloroquine and

corticosteroids for SLE patients with arthritis, rash, or serositis.

53,58,59 When used

with or without corticosteroids, MTX is dosed between 7.5 mg and 15 mg weekly,

orally or subcutaneously, not to exceed 25 mg/week. Subcutaneous injection is

recommended for patients who experience drug-induced nausea. Side effects are

dose dependent and can range from mild to severe. Mild side effects include

gastrointestinal effects (e.g., nausea and vomiting) versus leukopenia or

thrombocytopenia which are more severe side effects. Hepatotoxicity could occur

from MTX use. Patients should receive baseline liver function tests and periodically

throughout therapy. They should also be screened for preexisting liver disease,

excessive alcohol use, or diabetes. Patients with liver disease (e.g., hepatitis B or C)

should avoid MTX because of liver toxicity risk. Similarly, MTX should be used

cautiously in patients with renal disease because of increased risk for renal toxicity.

Other adverse effects may include lung toxicities, such as cough, shortness of breath,

and pulmonary infiltrates.

53,58 MTX is teratogenic and contraindicated in pregnant

women (Pregnancy Category X). Men and women who take MTX should stop 1 to 3

months before trying to conceive. The 3-month period allows the complete

elimination of MTX from the body.

Leflunomide (Arava) is a pyrimidine synthesis inhibitor that inhibits the formation

of DNA in the cells of the body, particularly the immune cells that contribute to the

inflammation, swelling, stiffness, and joint pain. Leflunomide can be used as a

steroid-sparing treatment for SLE patients with photosensitive rashes and arthritis. It

is also used either as monotherapy or in combination with MTX. Treatment may be

initiated with or without a loading dose, depending on the patient’s risk for ARAVAassociated hepatotoxicity and ARAVA-associated myelosuppression.

60 Patients who

are at a low risk for ARAVA-associated hepatotoxicity and ARAVA-associated

myelosuppression, the oral loading dose is 100 mg daily for 3 days, followed by a

maintenance oral dose of 20 mg daily. Alternatively, an oral loading dose of 100 mg

once a week for 3 weeks, in addition to the maintenance dose have been used to

reduce the increased incidence of diarrhea. If diarrhea persists to be a bothersome

side effect, in spite of the use of antidiarrheal medication, then the dose can be

reduced to 10 mg daily. In contrast, patients who are at a high risk for ARAVAassociated hepatotoxicity (i.e., concomitant MTX use) or ARAVA-associated

myelosuppression (i.e., concomitant immunosuppressant use) should receive an oral

dose of 20 mg daily without a loading dose.

60 Similar to MTX screening, patients

initiated on leflunomide should receive baseline liver function tests and complete

blood count tests every 3 to 4 months. Furthermore, they should also be screened for

preexisting liver disease and excessive alcohol use. Leflunomide is teratogenic and

contraindicated in pregnant women (Pregnancy Category X). Women should use oral

contraceptives or other forms of effective birth control methods while taking the

drug. More importantly, they should continue to do so until 2 years after

discontinuation of leflunomide since its active metabolite, teriflunomide, remains in

the plasma. Cholestyramine (Questran) can be used to accelerate the elimination of

leflunomide and reduce the plasma levels of teriflunomide.

61

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Immunosuppressants

Azathioprine (Imuran, Azasan), a purine analog, inhibits DNA synthesis and blocks

cell proliferation.

58

It is used to treat non-renal SLE manifestations, such as

photosensitive rashes. Prior to starting azathioprine treatment, genotyping or

phenotyping of the thiopurine S-methyltransferase (TPMT) is strongly

recommended.

62 Caution is recommended for patients with reduced thiopurine

methyltransferase activity because they may be at increased risk of bone marrow

suppression.

57,63 Patients who are homozygous, or carry two nonfunctional TPMT

alleles will experience life-threatening myelosuppression when treated with

azathioprine because of high concentrations of thioguanine nucelotides. Bone marrow

suppression can occur in any patient, is dose-dependent, and is reversible by

reducing the dose of azathioprine.

64 Side effects include gastrointestinal (e.g., nausea,

vomiting, diarrhea, and stomach pain) and leukopenia. Anemia and thrombocytopenia

may result from high doses of azathioprine or from poor metabolizers of the drug.

Mycophenolate mofetil (MMF; CellCept) inhibits inosine monophosphate

dehydrogenase, an essential enzyme for DNA synthesis in lymphocytes. Its active

metabolite inhibits the proliferation of T and B cells.

57 Similar to methotrexate, MMF

treatment could be used to treat SLE patients with arthritis. It is also used for SLE

patients with renal symptoms. It has been demonstrated to be superior to azathioprine

as maintenance therapy of LN.

65 Patients with SLE and nephritis had a much better

response with a 6-month induction trial of mycophenolate versus azathioprine for

prolonging time to treatment failure, time to renal flare, and time to rescue therapy.

MMF is teratogenic (Pregnancy Category D) and should not be used in pregnant

women or who plan to become pregnant. It could cause birth defects and reduces the

effectiveness of oral contraceptives. Women who take this drug should wait at least 1

to 3 months after stopping the drug before trying to conceive. Common side effects

may include gastrointestinal (e.g., nausea, vomiting, and diarrhea), risk of infection,

and decreased white blood cell counts.

53

CASE 33-3, QUESTION 7: R.W.’s daughter has also been diagnosed with SLE. She is 28 years old and is

married. She and her husband want to start a family. R.W. heard about MMF as one of the treatment options

for SLE. She asks you if her daughter can benefit from taking MMF.

You explain that MMF is not an option because it is teratogenic and has been

associated with infertility even though it is classified as Pregnancy Category D.

Furthermore, MMF has been reported to cause risk of birth defects if taken during

pregnancy (i.e., cleft lip/palate or ear malformations). Women who take this drug

should wait at least 1 to 3 months after stopping the drug before trying to conceive.

Cytotoxic Drug

Cyclophosphamide (Cytoxan) is an alkylating agent. Its active metabolite,

aldophosphamide, interferes with DNA links and causes cell death.

52

It is the agent of

choice for treatment of LN, severe CNS, lung, or hematologic manifestations.

53,66

It is

teratogenic (Pregnancy Category D) and should not be used in pregnant women or

who plan to become pregnant. Cyclophosphamide has been reported to cause birth

defects, especially if taken during the first trimester. Birth defects may include

growth restriction, ear and facial abnormalities, hypoplastic limbs, and absence of

digits.

67 Cyclophosphamide has a serious adverse effect profile that includes

hemorrhagic cystitis, bacterial and viral (herpes zoster) infections, and infertility. Its

metabolite, acrolein, is toxic to the bladder. Hemorrhagic cystitis and bladder cancer

risks can be minimized by hydrating the patient (orally and intravenously), frequent

bladder emptying, and using mesna as a protectant prior to intravenous use.

53 Mesna

(sodium 2-mercaptoethane sulfonate) is a sulfhydryl donor which binds and

detoxifies acrolein.

68 Urinalysis testing and monitoring for hematuria should be

performed regularly. If patient develops hemorrhagic cystitis, cyclophosphamide

therapy should be discontinued. The risk of bladder cancer is increased after

receiving a total dose of 30 g.

58

Because immunosuppressants and cyclophosphamide can increase the prevalence

of secondary malignancies, such as cervical cancer in female patients with SLE, the

ACR recommends annual Pap exams as part of laboratory monitoring.

53,69

Infertility,

from ovarian failure in females or azoospermia in males, can occur in patients with

SLE and of childbearing age.

7 Gonadotropin-releasing hormone analogs may

preserve gonadal protection and can be considered for patients who are concerned

with infertility associated with cyclophosphamide.

CASE 33-3, QUESTION 8: R.W. asks you what other commonly used drugs for SLE treatment should her

daughter avoid taking if she wanted to become pregnant.

Other than MMF, her daughter should avoid taking leflunomide (Pregnancy

Category X), MTX, (Pregnancy Category X), and cyclophosphamide (Pregnancy

Category D) for treatment of her SLE if she plans to get pregnant. Women should use

oral contraceptives or other forms of effective birth control methods while taking

leflunomide. More importantly, they should continue to do so until 2 years after

discontinuation of leflunomide since its active metabolite, teriflunomide, remains in

the plasma. Cholestyramine (Questran) can be used to accelerate the elimination of

leflunomide and reduce the plasma levels of teriflunomide.

61 Men and women who

take MTX should stop 1 to 3 months before trying to conceive. The 3-month period

allows the complete elimination of MTX from the body. Cyclophosphamide has been

reported to cause birth defects, especially if taken during the first trimester. Birth

defects may include growth restriction, ear and facial abnormalities, hypoplastic

limbs, and absence of digits.

65

CASE 33-3, QUESTION 9: Over the next couple of months, R.W. continues to have mild-to-moderate flares

of her skin and joints because of SLE, despite hydroxychloroquine therapy. Her primary care physician is

considering cyclophosphamide for her. What common toxicity should R.W. be monitored for?

R.W. should be monitored for bladder toxicity. Acrolein, a compound of one of

cyclophosphamide’s active metabolite aldophosphamide, is toxic to the bladder

epithelium and could cause hemorrhagic cystitis.

70 Hemorrhagic cystitis is associated

with hematuria and occasional dysuria.

CASE 33-3, QUESTION 10: How is the risk for bladder toxicity reduced?

By administering mesna and plenty of fluids (orally and intravenously) the risk of

bladder toxicity is reduced. Mesna (sodium 2-mercaptoethane sulfonate) is a

sulfhydryl donor that binds and detoxifies acrolein. Pulsed or intermittent dosing of

cyclophosphamide can decrease the cumulative drug dose and reduce bladder

exposure to acrolein.

CASE 33-3, QUESTION 11: Considering her present symptoms, should R.W. be initiated on

cyclophosphamide?

Because her symptoms are still mild to moderate without signs of CNS, lung, or

renal complications, cyclophosphamide is not recommended. Cyclophosphamide is

primarily reserved for treatment of LN, severe CNS associated with SLE, lung, or

hematologic manifestations.

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Biologic Therapy

Belimumab (Benylsta) is the first biologic agent approved for adjunctive treatment of

SLE in patients with active, autoantibody-positive SLE. It is a human IgG1 lambda

monoclonal antibody that stimulates B-lymphocytes (BLyS). Belimumab is also

referred to as a B cell–activating factor (BAFF)-specific inhibitor. B cells have three

membrane receptors: B cell–maturation antigen, transmembrane activator and

calcium modulator and cyclophilin ligand interactor, and BAFF receptor.

18 BAFF is

involved in B cell survival, activation, and differentiation. It is elevated in patients

with B cell–mediated autoimmune diseases, such as SLE.

71 Belimumab is

hypothesized to decrease the amount of abnormal B cells.

Phase II clinical trials reported that belimumab combined with standard therapy

offered better response to patients with active SLE versus standard therapy alone.

71,72

Belimumab’s efficacy was further demonstrated in two phase III randomized,

placebo-controlled clinical trials (BLISS-52 and BLISS-76). A total of 1,684

patients were randomized to receive either belimumab or placebo in combination

with standard therapy.

73,74 The combination of belimumab and standard therapy was

found to be superior to placebo plus standard therapy. Furthermore, the combination

of belimumab and standard therapy was well tolerated, improved SLE Responder

Index response rates, and reduced disease activity and severe flares.

73,74 Belimumab

has not been studied in patients with severe active LN or severe active CNS lupus;

therefore, it cannot be recommended for use in patients with these symptoms. More

importantly, it is not recommended to be administered in combination with other

biologics or intravenous cyclophosphamide because it has not been studied in these

settings.

Possible side effects (≥5%) of belimumab may include diarrhea, nausea, fever,

insomnia, nasopharyngitis, pharyngitis, bronchitis, extremity pain, migraine, and

depression.

75,76 More common side effects reported from the belimumab study group

were serious infections, primarily upper respiratory tract infections.

75 Therefore,

patients being treated for chronic infections should not start belimumab therapy. If an

infection develops while receiving belimumab, temporary discontinuation of the drug

is recommended. From clinical trials, mortality (resulting from infection,

cardiovascular disease, and suicide) was increased in patients receiving belimumab

versus those on placebo therapy.

71–74 Hypersensitivity reactions, including infusion

reactions and anaphylaxis, may occur. Patients should be closely monitored for

potential side effects and reactions.

Belimumab is administered parenterally as an intravenous infusion over 1 hour

(Table 33-3). Premedication with an antihistamine for prophylaxis against infusionrelated reactions and hypersensitivity reactions is recommended as part of the

therapy. There are no dosage adjustments required for patients with hepatic and renal

impairment.

CASE 33-3, QUESTION 12: Over the next year, R.W. continues to have bothersome symptoms associated

with her SLE, despite hydroxychloroquine therapy. She resists the recommendation to use steroids because of

risks of weight gain, osteoporosis, and vision problems. She is excited to hear about a recently approved drug

for SLE, belimumab. R.W. asks you for the mechanism of action of belimumab.

Belimumab is a monoclonal antibody that inhibits the B cell–survival factor, Blymphocyte stimulator (BLyS). As a BLyS-specific inhibitor, belimumab blocks the

binding of BLyS to receptors on B cells, thus inhibiting the survival of B cells

including autoreactive B cells. It also reduces the differentiation of B cells into

immunoglobulin-producing plasma cells. Belimumab reduces disease activity and

possibly a number of severe flares and steroid use when administered in combination

with standard therapy. It is approved for treatment of patients with active,

autoantibody-positive lupus in combination with standard therapies (i.e.,

hydroxychloroquine, azathioprine, and MTX).

Table 33-3

Preparation and Administration Instructions of Belimumab

18,76

Reconstitution

Remove belimumab vial from refrigerator and allow it to stand for 10 to 15 minutes to reach room temperature.

Reconstitute belimumab powder with Sterile Water for Injection, USP, as follows, with reconstituted solution to

make a concentration of 80 mg/mL belimumab.

Reconstitute 120 mg vial with 1.5 mL sterile water.

Reconstitute 400 mg vial with 4.8 mL sterile water.

Direct the stream of sterile water to the side of the vial to minimize foaming.

Gently swirl the vial for 60 seconds. Allow vial to sit at room temperature during reconstitution, gently swirling

the vial every 5 minutes until powder is dissolved. Do not shake. It usually takes 10–15 minutes, but it may take

up to 30 minutes. Protect solution from light.

If a mechanical reconstitution device (swirler) is used to reconstitute belimumab, it should not exceed 500 rpm,

and the vialshould not be swirled for longer than 30 minutes.

Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow and without

particles. Small bubbles can occur and are acceptable.

Dilution Instructions

Belimumab should only be diluted with 0.9% sodium chloride injection, USP (normalsaline). Dextrose IV

solutions are incompatible with belimumab. Dilute the reconstituted product to 250 mL in normalsaline for IV

infusion. From a 250-mL infusion bag or bottle of normalsaline, withdraw and discard a volume equal to the

volume of the reconstituted solution of belimumab required for the patient’s dose. Then add the required volume

of reconstituted solution into the infusion bag or bottle. Discard any unused solution.

Inspect visually for any particular matter and discoloration before administration. Discard if present.

Use reconstituted solution immediately, otherwise it should be stored protected from sunlight and refrigerated at

2°C–8°C (36°F–46°F). Solutions of belimumab diluted in normalsaline may be stored at 2°C–8°C (36°F–46°F)

or room temperature. The time from reconstitution to completion of infusion should not exceed 8 hours.

No incompatibilities exist between belimumab and polyvinyl chloride or polyolefin bags.

Administration Instructions

Administer the diluted solution of belimumab by IV infusion only, over a period of 1 hour.

Belimumab should be administered by health care professionals prepared to manage anaphylaxis.

Do not infuse belimumab concomitantly in the same IV line with other agents.

IV, intravenous; USP, US Pharmacopoeia.

CASE 33-3, QUESTION 13: How is belimumab dosed and administered?

Belimumab is given at a recommended dose of 10 mg/kg that is administered

intravenously as an infusion over 1 hour, 2 weeks apart for the first three doses, and

4 weeks apart thereafter.

CASE 33-3, QUESTION 14: What are the necessary precautions taken prior to administration of

belimumab?

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