Antihistamine premedication is recommended as a prophylaxis to prevent infusion

reactions and hypersensitivity reactions. Patients should be monitored before and

after drug administration. Belimumab should be used with caution in patients with

chronic infections. Infections were the most common adverse events associated with

belimumab in BLISS-52 and BLISS-76 clinical trials. Upper respiratory tract

infections were the most common type, occurring in more than 5% of belimumab

patients.

CASE 33-3, QUESTION 15: When is belimumab not recommended for use in patients with SLE?

Belimumab is not recommended in patients with severe active lupus nephritis, or

in those with severe active CNS lupus as its efficacy has not been evaluated in these

types of patients. Furthermore, depression and suicidality have been reported in

clinical trials; therefore, it is not recommended for patients with uncontrolled

psychiatric disorders. Belimumab is not recommended in combination with other

biologics or IV cyclophosphamide as it has not been studied with these drugs.

CASE 33-3, QUESTION 16: Are there drug–drug interactions between belimumab and other combination

treatments for SLE?

There are no clinically significant drug–drug interactions identified with

belimumab in the clinical trials. It was administered concomitantly with

corticosteroids, antimalarial drugs, statins, NSAIDs, angiotensin-converting enzyme

inhibitors, and immunomodulatory and immunosuppressive agents.

CASE 33-3, QUESTION 17: Can R.W. receive immunizations while receiving belimumab treatment?

Live vaccines should not be administered within 30 days before treatment starts or

during treatment. Belimumab may interfere with R.W.’s response to immunizations.

Table 33-4 summarizes the current medications used for treating SLE.

53,57,69,75,76

There are drug interactions with the medications used for treating SLE symptoms.

Table 33-5 summarizes the possible significant drug–drug interactions.

77,78

Non-pharmacologic Therapy

Both the ACR and EULAR recommend non-pharmacologic treatments as part of the

management of SLE.

22,79 Sunscreens with a sun protective factor of 15 or greater

should be used daily. There are patients who are sensitive to UVA light and may

require broader-spectrum sunscreens. Patients are advised to apply sunscreen each

morning and prior to sun exposure. Wearing protective clothing and/or sun avoidance

for patients with SLE is encouraged. Sunbathing and the use of sunbeds in tanning

parlors are discouraged. In addition, patients with SLE should be educated about

lifestyle modifications, such as smoking cessation, weight control, and regular

exercise to reduce comorbidities of atherosclerosis, hypertension, and diabetes.

7

Psychosocial support is also an important aspect of management as the disease and

several of the medications may cause depression and anxiety. The medications’ side

effects can also affect a patient’s adherence to treatment and medical office visits.

DRUG-INDUCED LUPUS ERYTHEMATOSUS

Drugs can cause subacute cutaneous lupus erythematosus or drug-induced lupus (DIL)

(<1%) by inducing autoantibodies.

4 For as many patients that develop these

antibodies, a surprisingly low number of them do not develop signs of an

autoantibody-associated condition.

2 Over 38 drugs have been implicated with

causing the disease (Table 33-6).

42,80–82 However, most DIL cases have been

associated with the following medications: hydralazine, procainamide, and

quinidine.

The symptoms of DIL may present as arthralgia or myalgias, fatigue, and the

presence of anti-histone antibodies. The symptoms are similar to those of SLE;

however, they are generally not as severe. Typically, the symptoms are self-limiting

and resolve after discontinuing the offending drug. NSAIDs may be used to help

speed up the healing process. Corticosteroids may also be used if more severe

symptoms of DIL are present. The development of DIL occurs over long-term and

from chronic use of medications that have high risk for causing lupus.

The mechanism by which these drugs exert their effect is not well understood.

However, it may be attributed to a patient’s genetic predisposition as a slow

acetylator, which decreases the metabolism of some drugs such as procainamide and

hydralazine. Gene expression is regulated by DNA methylation and histone

modifications.

81,82 Procainamide and, particularly, hydralazine are hypothesized to

inhibit DNA methylation, which alters gene expression in T lymphocytes.

Subsequently, this process induces an over-expression of lymphocyte functionassociated antigen 1 (LFA-1 antigen), thus resulting in autoreactivity.

28,80

INVESTIGATIONAL AGENTS

Aside from the current therapies used for the treatment and management of SLE

symptoms, rituximab and abatacept are currently being studied in patients with SLE.

Both medications target T and B cells and have already been approved for the

treatment of rheumatoid arthritis along with other indications. More recently,

investigational biologic agents are being developed and are undergoing Phase I, II,

and III clinical trials. These newer biologic agents specifically target different

phases of the pathogenesis of SLE, have different mechanisms of action, and possess

milder adverse effect profiles. The investigational drug classes include immune cell–

targeted therapies, anti-cytokine therapy, therapies targeting costimulatory signaling

pathways, and neutralizing monoclonal antibody against interferon alpha.

57

TREATMENT APPROACHES

The primary goal of treatment for SLE is to control acute flares, and maintenance

strategies are used to suppress symptoms and to prevent further organ damage.

NSAIDs, hydroxychloroquine, and low-dose corticosteroids are considered

maintenance therapy to control mild-to-moderate symptoms of arthritis, dermatitis,

and constitutional symptoms. High-dose systemic corticosteroids, DMARDs,

immunosuppressants, and belimumab are used for patients with more serious active

disease, including those with more life-threatening forms such as LN.

66 Certain

DMARDs and immunosuppressants (i.e., leflunomide, MTX, cyclophosphamide, and

MMF) should be used with extreme caution in women of childbearing age and in

those who are planning to get pregnant because of teratogenic effects.

7 MMF is the

preferred maintenance therapy for LN in patients who can tolerate the medication,

who are not pregnant, and who respond to it. It can reduce the effectiveness of oral

contraceptives and, thus, additional or alternative non-hormonal methods of birth

control should be considered. Currently, only hydroxychloroquine and belimumab are

FDA-approved for the treatment of SLE. Immunosuppressants and DMARDs (i.e.,

azathioprine, cyclophosphamide, leflunomide, MTX, and MMF) have been used offlabel for managing SLE symptoms for years. Prophylaxis with aspirin or long-term

anticoagulation should be considered for patients with antiphospholipid antibodies

and who are at an increased risk of thrombosis.

18 Patients with mild disease require

frequent medical evaluations every 3 to 6 months. On the contrary, patients with

inactive disease may benefit from being monitored every 6 to 12 months.

p. 711

p. 712

Table 33-4

Medications Used for the Treatment of Systemic Lupus

Erythematosus

53,57,69,75,76

Medication

FDAApproved

for SLE Dose

Side

Effects/Toxicities Monitoring Parameters

Azathioprine No; offlabel

1–3 mg/kg/day Bone marrow

suppression, liver

toxicity, elevated

lymphocytes

Clinical:symptoms of infection.

Laboratory: CBC and platelet

count every 1–2 weeks with

initiation and dosage changes,

then every 1–3 months; monitor

LFTs and Scr; Pap test at

regular intervals.

Belimumab Yes IV: 10 mg/kg every

2 weeks for the

first 3 doses and

then administer

monthly

Serious infusion and

anaphylactic

reactions;

depression with

suicidal ideation

Clinical:symptoms of allergic

reaction, including hypotension,

angioedema, rash, urticarial,

pruritus, and difficulty breathing.

Symptoms of common infusion

reactions, including headache,

nausea and skin reactions.

Symptoms of infection, including

fever, nausea, diarrhea; chest

pain or shortness of breath.

Laboratory: CBC monthly.

Corticosteroids No; offlabel

Prednisone (or

equivalent) 0.125–1

mg/kg/day

Elevated blood

pressure, glucose

and cholesterol

levels; low

potassium or

reduced potassium

levels; reduced bone

density; cataracts;

weight gain;

infections; and fluid

retention

Clinical:symptoms of high blood

sugar, edema, shortness of

breath, high blood pressure,

visual changes, bone pain. CNS

symptoms of depression, suicidal

ideation, insomnia, or other mood

changes can occur at higher

doses (e.g., prednisone >60 mg).

Laboratory: glucose every 3–6

months, cholesterol annually, BP

at each visit, bone density.

Cyclophosphamide No; offlabel

IV: 0.5–1 g/m

2

monthly;

Oral: 1–2

mg/kg/day

Bone marrow

suppression,

malignancy,

immunosuppression,

hemorrhagic cystitis,

secondary infertility

Clinical:symptoms of infection

and presence of blood in urine.

Laboratory: CBC and urinalysis

monthly, urine cytology and Pap

test annually for life.

Hydroxychloroquine Yes 200–400 mg twice

daily

Ophthalmic damage Clinical: visual changes.

Laboratory: funduscopic and

visual field exam, frequency

determined by risk.

Leflunomide No; Offlabel

Loading dose: 100

mg daily × 3 days,

followed by 20 mg

daily;

Or

100 mg weekly × 3

weeks, then 20 mg

daily

ARAVAassociated

hepatotoxicity or

ARAVAassociated

myelosuppression:

20 mg daily without

a loading dose

Diarrhea, nausea,

rash, liver toxicity,

myelosuppression

Clinical: frequency and severity

of diarrhea.

Laboratory: LFTs, CBC

Methotrexate No; offlabel

Oral: 5–15 mg as a

single weekly dose,

Bone marrow

suppression, lung

Clinical:symptoms of infection,

shortness of breath, nausea,

or can be given as

3 divided

doses/week given

every 12 hours

(i.e., 2.5 mg × 3

doses with 12 hours

apart)

and liver toxicity,

infection

vomiting.

Laboratory: initial chest x-ray,

CBC and platelet count monthly,

LFTs, albumin, Scr every 4–8

weeks.

Mycophenolate

mofetil

No; offlabel

1,000–3,000 mg

daily

Bone marrow

suppression, liver

toxicity and infection

Clinical:symptoms of infection.

Laboratory: CBC and platelet

count every 1–2 weeks with

initiation and changes in dosage

(then every 1–3 months), monitor

LFTs and Scr, monitor changes

in BP.

NSAIDs No; offlabel

a

Product dependent Gastrointestinal

bleeding, liver and

kidney toxicity,

elevated blood

pressure

Clinical: dark/black stool, upset

stomach, nausea, vomiting,

abdominal pain, edema.

Laboratory: CBC, LFTs and Scr

annually; BP at each visit.

aAspirin is approved for treatment of SLE.

NSAIDs, nonsteroidal anti-inflammatory drugs; BP, blood pressure; CBC, complete blood count; IV, intravenous;

LFTs, liver function tests; SCr, serum creatinine.

p. 712

p. 713

Table 33-5

Summary of Drug Interactions with Medications for Systemic Lupus

Erythematosus

77,78

Medication Possible Interaction with Concomitant Drugs

Azathioprine Allopurinol, cyclosporine, etanercept, infliximab, leflunomide, sirolimus,

tacrolimus

Belimumab Drug interactions have not been formally studied

Corticosteroids Cimetidine, cisapride, clarithromycin, dihydroergotamine, ergotamine,

erythromycin, itraconazole, ketoconazole, lovastatin, mifepristone, quinidine,

rifabutin, rifampin, simvastatin, sirolimus, St. John’s wort, terfenadine,

tofacitinib

Cyclophosphamide Carbamazepine, etanercept, tofacitinib

Hydroxychloroquine Antacids, azathioprine, cyclosporine, digoxin, etanercept, infliximab,

leflunomide, mycophenolate, sirolimus, tacrolimus

Leflunomide Azathioprine, cyclosporine, etanercept, infliximab, methotrexate,

mycophenolate, sirolimus, tacrolimus

Methotrexate Celecoxib, diclofenac, etodolac, ketorolac, leflunomide, meloxicam, probenecid,

sulfamethoxazole, trimethoprim

Mycophenolate mofetil Ampicillin, antacids, cholestyramine, colestipol, etanercept, ethinylestradiol,

infliximab, leflunomide, nafcillin, quinidine, sirolimus, tacrolimus

NSAIDs ACE inhibitors, angiotensin receptor blockers, beta blockers, diuretics, other

antihypertensives, lithium

ROLE FOR PHARMACISTS

SLE disease is very complex and the symptoms are variable. Successful and

effective management of SLE requires the involvement of a multidisciplinary

healthcare team comprised of many specialists (e.g., rheumatology, cardiology,

nephrology, dermatology, psychology, and ophthalmology) and pharmacists.

Pharmacists have an important role in caring for patients with SLE, especially with

education, management of their medications, and the monitoring of drug–drug or

drug–herbal interactions. As part of the healthcare team, pharmacists can provide

drug education and counseling to patients with respect to proper administration of the

medications, common side effects, management of the side effects, and reinforcement

of adherence to their medications and office visits. Education and counseling of the

teratogenic effects of certain DMARDs and immunosuppressants should be offered,

as well as the information that the disease should remain inactive for at least 6

months prior to attempting to conceive.

53 More importantly, pharmacists can provide

education to help patients with SLE maintain a healthy lifestyle and better quality of

life (e.g., regular weight-bearing exercise, sufficient dietary vitamin intake, smoking

cessation, and limited alcohol intake to a minimum of two drinks daily).

83,84

CASE 33-4

QUESTION 1: S.P., a 35-year-old Asian woman with a 10-year history of SLE, sees you for follow-up

management of her medications. She currently takes hydroxychloroquine 200 mg PO daily as part of her

maintenance regimen. S.P. reports experiencing some heartburn and bloating symptoms over the past several

days and purchased an over-the-counter antacid, Tums. Tums helped to alleviate her gastrointestinal symptoms;

however, she notices feeling more fatigued lately. What is the potential drug interaction between

hydroxychloroquine and Tums?

Antacids that contain calcium carbonate, magnesium, or aluminum (i.e., Tums,

Maalox) can interfere with the absorption of hydroxychloroquine and reduce its

effectiveness when taken at the same time.

CASE 33-4, QUESTION 2: As her pharmacist, provide advice to S.P. regarding the appropriate

administration of hydroxychloroquine and Tums?

Table 33-6

Medications that may Cause Systemic Lupus Erythematosus (DIL)

81–/>83

Drug Class Very Low Risk

Low-to-Moderate

Risk High Risk

Antiarrhythmics Disopyramide, propafenone Quinidine Procainamide

Antimicrobials/antibiotics Nitrofurantoin Isoniazid, minocycline Anticonvulsants Phenytoin, primidone, ethosuximide Carbamazepine

Antihypertensives Enalapril, clonidine, atenolol,

labetolol, pindolol, minoxidil,

prazosin, chlorthalidone,

hydrochlorothiazide

Captopril, methyldopa,

acebutolol

Hydralazine

Anti-inflammatories Phenylbutazone Sulfasalazine, Dpenicillamine

Antipsychotics Perphenazine, phenelzine,

chlorprothixene, lithium

Chlorpromazine

Anti-thyroids Propylthiouracil

Miscellaneous Lovastatin, levodopa, alphainterferon, timolol eye drops

p. 713

p. 714

S.P. should be advised to separate the administration of hydroxychloroquine and

Tums by at least 4 hours to reduce the risk of a drug interaction. There has been no

clinically significant drug–drug interactions reported for concomitant use of

hydroxychloroquine and histamine (H2

) receptor antagonists.

CASE 33-4, QUESTION 3: What other counseling points could you offer to S.P. about her health?

S.P. should be advised to incorporate a heart-healthy exercise regimen (lowimpact aerobic exercise, such as walking, swimming, or Pilates) and diet (lowsodium, low-fat, and low-carbohydrate) to reduce modifiable cardiovascular risk

factors and on approaches to maintain adequate rest. Counseling should also be

provided regarding the use of sunscreen, vitamin D supplementation and adequate

calcium intake, smoking cessation, maintenance of schedule immunizations, and

prompt management of infections.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal

Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the

management of adult and pediatric lupus nephritis. Ann Rheum Dis. 2012;71:1771–1782. (39)

Bertsias G, Cervera R, Boumpas DT. Systemic lupus erythematosus: pathogenesis and clinical features. EULAR

Textbook on Rheumatic Diseases. 20th ed. Zürich, Switzerland: Eular Fpp. Indd. 2012;476–505. (2)

Krikorian S. Systemic lupus erythematosus. In: Helms RA et al, eds. Textbook of Therapeutics: Drug and Disease

Management. 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2006:1767–1787. (27)

Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating

Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677–2686. (23)

Tsokos GC. Systemic lupus erythematosus. N EnglJ Med. 2011;365: 2110–2121. (13)

Key Websites

American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology Revised

Criteria for Classification of Systemic Lupus Erythematosus. Available at

http://tinyurl.com/1997SLEcriteria. Accessed July 20, 2015.