Pacor ML et al. Safety of rofecoxib in subjects with a history of adverse cutaneous reactions to aspirin and/or

non- steroidal anti-inflammatory drugs. Clin Exp Allergy. 2002; 32:397.

Quiralte J et al. Safety of selective cyclooxygenase-2 inhibitor rofecoxib in patients with NSAID-induced

cutaneous reactions. Ann Allergy Asthma Immunol. 2002;89:63.

Szczeklik A et al. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy. 2001;31:219.

Woessner KM et al. The safety of celecoxib in patients with aspirin-sensitive asthma. Arthritis Rheum.

2002;46:2201.

Hoover T et al. Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology

and risk factors. Clin Exp Allergy. 2010;40:50.

Bas M et al. A randomized trial of icatibant in ACE-inhibitor–induced angioedema. N EnglJ Med. 2015;372:418.

Sica DA, Black HR. Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin

receptor blocker therapy. Congest Heart Fail. 2002;8:334.

Kyrmizakis DE et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Arch

Otolaryngol Head Neck Surg. 2004;130:1416.

Pylypchuk GB. ACE inhibitor-versus angiotensin II blocker-induced cough and angioedema. Ann Pharmacother.

1998;32:1060.

Brockow K. Immediate and delayed reactions to radiocontrast media: is there an allergic mechanism? Immunol

Allergy Clin North Am. 2009;29:453.

Laser EC. Pseudoallergic drug reactions. Radiographic contrast media. Immunol Allergy Clin North Am.

1991;11:645.

Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S126.

Greenberger PA et al. Two pretreatment regimens for high- risk patients receiving radiographic contrast media.

J Allergy Clin Immunol. 1984;74(4 Pt 1):540.

Schabelman E, Witting M. The relationship of radiocontrast, iodine, and seafood allergies: a medical myth

exposed. J Emerg Med. 2010;39:701.

Fishbane S et al. The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis. 1996;28:529.

Chertow GM et al. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant.

2006;21:378.

MacDougall IC et al. A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency

anemia in patients with CKD. Clin J Am Soc Nephrol. 2014;9:705.

Baile GR. Comparison of rates of reported adverse events associated with IV iron products in the United States.

Am J Health Syst Pharm. 2012;69:310.

FERAHEME Ferumoxytol Injection [package insert]. Waltham, MA: AMAG Pharmaceuticals Inc; 2015.

http://www.feraheme.com/pdfs/Feraheme_Full_Prescribing_Information_2015.pdf. Accessed June 1,

2015.

Onken JE et al. Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the

REPAIR-IDA trial. Nephrol Dial Transplant. 2014;29(4):833–842.

Onken JE et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of

intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion. 2014;54(2):306–315.

INJECTAFER Ferric Carboxymaltose Injection [package insert]. Shirley, NY: American Regenet, INC; 2013.

http://www.injectafer.com/pdf/Prescribing_Information.pdf. Accessed June 1, 2015.

Bregman DB et al. Experience with intravenous ferric carboxymaltose in patients with iron deficiency anemia.

Ther Adv Hematol. 2014;5(2):48–60.

Wedner HJ. Drug allergy prevention and treatment. Immunol Allergy Clin North Am. 1991;11:679.

Castells M. Rapid desensitization for hypersensitivity reactions to medications. ImmunolAllergy Clin North Am.

2009;29:585.

Solensky R. Drug desensitization. Immunol Allergy Clin North Am. 2004; 24:425.

Stark BJ et al. Acute and chronic desensitization of penicillin- allergic patients using oral penicillin. J Allergy Clin

Immunol. 1987;79:523.

Earl HS, Sullivan TJ. Acute desensitization of a patient with cystic fibrosis allergic to both beta-lactam and

aminoglycoside antibiotics. J Allergy Clin Immunol. 1987;79:477.

p. 699

Systemic lupus erythematosus (SLE) affects multiple organ systems with

diagnoses based on clinical findings and objective criteria from the

American College of Rheumatology (ACR) and Systemic Lupus

Collaborating Clinics (SLICC) guidelines.

Case 33-1 (Questions 1–4),

Case 33-2 (Question 1),

Table 33-2, Figure 33-1

Management of SLE is complex and involves many specialists, including

cardiologists and rheumatologists.

Case 33-2 (Question 2)

SLE treatment includes NSAIDs, corticosteroids, antimalarials, and

immunosuppressants. The goals of SLE treatment should be considered

when devising a treatment plan.

Case 33-2 (Question 3),

Case 33-3 (Questions 1–3,

5–6),

Table 33-4

Pregnancy considerations should be applied when selecting drug

treatments for female patients with SLE.

Case 33-3 (Questions 7–8)

Hydroxychloroquine and cyclophosphamide could cause bothersome side

effects. Monitoring parameters and management of hydroxychloroquine

and cyclophosphamide side effects should be considered for SLE

patients.

Case 33-3 (Questions 4,

9–11),

Table 33-4

Belimumab is the first FDA-approved biologic treatment for SLE. The

appropriate use and monitoring parameters should be considered to

optimize its efficacy.

Case 33-3 (Questions

12–17),

Table 33-3, Table 33-4

There are several drug–drug interactions pertaining to the treatments for

SLE. Concomitant use of hydroxychloroquine and antacids could have a

potential adverse effect.

Case 33-4 (Questions 1, 2),

Table 33-5

Pharmacists can play an important role in the education of SLE,

management of side effects, and monitoring of drug–drug interactions.

Case 33-3 (Questions 2, 3,

5-9, 13), Case 33-4

(Questions 2–3),

Table 33-4, Table 33-5,

Table 33-6

GENERAL PRINCIPLES

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, inflammatory disease

that affects multiple organ systems and primarily the connective tissue. Its

presentation and disease progression are unpredictable and highly variable. This

multi-organ disease is characterized by inflammation, autoantibody production, the

deposition of complement-fixing immune complexes, and a clinical pattern

alternating between disease flares and periods of remission.

1

In essence, the immune

system attacks the body’s own cells and tissue, resulting in a continuous inflammatory

response and tissue and/or organ damage over time. While SLE can eventually affect

any organ such as the lungs, nervous system, and cardiovascular, it mainly affects the

skin, joints, and kidneys.

2 The 10-year survival rate is approximately 70% for

patients with SLE.

3

EPIDEMIOLOGY

SLE is more common among women than men (9:1) and generally occurs during

childbearing age, with a peak age of onset between 15 and 45 years.

4,5

It is estimated

that more than 16,000 new cases of SLE are reported annually in the U.S. with an

average prevalence of 1.5 million Americans. Approximately 5 million people are

afflicted with SLE globally.

6 Progression of SLE is usually slow. It typically begins

as a benign disease without signs or symptoms (preclinical phase) to disease with

mild-to-moderate symptoms with exacerbations or flares, resulting in the

involvement of additional organs and sustained damage (clinical phase). Over time

the disease will progress, continually relapsing and remitting until eventually

reaching severe potentially fatal disease (comorbidities phase).

7

Isolated skin and

musculoskeletal involvement are

p. 700

p. 701

associated with a milder course of disease and a higher survival rate over patients

with renal and CNS involvement, which indicate more severe and progressive

disease conditions.

PATHOPHYSIOLOGY

The specific cause of SLE is unknown. Many genetic, ethnic, environmental, and

hormonal factors are identified as potential causative risk factors. As part of the

genetic component involved in the development of SLE, there is no clear Mendelian

pattern of inheritance. Siblings of patients with SLE have a risk disease of

approximately 2%.

8

Identical twins have approximately 10-fold higher risk of SLE

than dizygotic twins.

4 First degree relatives of patients with SLE have a 20-fold

increased risk of developing SLE when compared to the healthy population.

9,10 The

genetic risk for the disease is more likely associated with multiple genes than the

deficiency of a single gene. Interestingly, genome-wide association studies have

identified risk alleles shared between SLE and other autoimmune disorders such as

rheumatoid arthritis, Graves’ disease, multiple sclerosis, type 1 diabetes, and

psoriasis.

11 SLE is more likely to develop in women of color, at a rate of 2 to 3 times

higher than the rate for Caucasian women.

6 Furthermore, the symptoms are found to

be more severe in African-American, Asian, Native American, and Hispanic

women.

4,12 However, individuals of all ages, genders, and ancestral backgrounds are

susceptible to having the disease.

The association of environmental factors to SLE remains unclear. Some of the

exposure-related factors that have been implicated for causing SLE include smoking

and ultraviolet radiation.

13 The proposed hypothesis behind cigarette smoke is that it

is associated with the indirect generation of anti-double stranded-DNA (antidsDNA) and related to immunoregulatory effects of tobacco exposure. Thus, in

genetically predisposed individuals with a smoking-related decreased ability to clear

apoptotic cells, the excess levels of intracellular antigens may lead to the production

of autoantibodies such as anti-dsDNA.

14

UV Radiation

Exposure to sunlight may cause the occurrence of SLE and could exacerbate

preexisting symptoms. Ultraviolet radiation has been implicated in cutaneous

manifestations of SLE, such as macular, papular or bullous lesions, and erythema.

15

Systemic disease is rarely induced by ultraviolet radiation. Possible mechanisms that

may link the pathogenesis of ultraviolet radiation and SLE include circulating

antibodies to the Ro/Sjogren’s syndrome type A (anti-Ro/SSA) and anti-La Sjogren’s

syndrome type B (anti-La/SSB) antigen particles that result in an autoimmune

response.

2,15 Nevertheless, both anti-Ro/SSA and anti-La/SSB are more commonly

associated with Sjogren’s syndrome than with SLE.

Viral Infection

It has been considered for many years that viruses, particularly the herpes families

and the Epstein–Barr virus (EBV) may trigger SLE via polyclonal immune activation,

resulting in an activation of the autoimmune system.

16 EBV may reside in and interact

with B cells, promoting interferon alpha production and contributing to the

inflammatory process.

Female Hormones

The increased prevalence in the female gender proposes that hormones such as

estrogen or progesterone may play a role in aggravating the disease. Both estrogen

and progesterone levels are increased during pregnancy and at conception. These

hormones can lead to an increase in mature, high-affinity autoreactive B cells,

resulting in an autoimmune reaction.

17 Evidence that SLE worsens during pregnancy

ironically does not contribute to this theory as levels of estrogen and progesterone

are lower in second- and third-trimester pregnant patients with SLE compared to

healthy pregnant patients.

17

Interestingly, hormone replacement therapy is linked to

worsening SLE symptoms in postmenopausal women.

18 The X chromosome may also

independently contribute to the incidence of SLE, where the combination of two X

chromosomes increases the severity of SLE over an XY combination.

19 The gene

CD40 is located on the X chromosome and has been known to contribute to the

pathogenesis of the disease.

13

Immunologic Abnormalities

SLE is a disease of an overall dysregulated, aberrant immune function, indicated by a

large number of autoantibodies involved. Abnormalities of the immune system

include immune complexes, T lymphocytes, cytokines, and antibodies.

13 Antigen

receptor-mediated activation is changed in T and B cells for patients with SLE. B

cells play a pivotal role in the disease. They produce autoantibodies, which amplify

inflammation and mediate tissue damage. The autoantibodies are immunoglobulin G

(IgG)-mediated, and T lymphocytes help stimulate B cells to produce antibodies.

Moreover, B cells process and present antigen and autoantigen to T cells and

contribute to disease manifestation.

20 The innate immune system (i.e., toll receptors,

plasmacytoid dendritic cells, and interferon alpha) and adaptive immune network

also contribute to the production of autoreactive B cells and autoantibodies.

21

Similarly, cellular debris from apoptosis further stimulate activation of the immune

system. The decreased clearance of cellular debris may be related to lowcomplement levels, such as C1q, C2, and C4, which normally function to help

phagocytes and macrophages eliminate apoptotic material and self-reactive B cells.

As a result, deposits of immune complexes can lead to organ damage, systemic

inflammation, and pain.

5,13

CLASSIFICATION CRITERIA

In 1971, the Diagnostic and Therapeutic Criteria Committee of the American College

of Rheumatology (ACR) developed a disease classification criteria system. As there

1.

2.

3.

4.

5.

is no single test to diagnose SLE, the classification criteria have been used for the

diagnosis of SLE. The original classification was revised in 1982 and again in 1997

to include more organs than just cutaneous involvement (Table 33-1).

22

In 2012, the

Systemic Lupus Collaborating Clinics (SLICC) revised and validated the ACR SLE

classification criteria in order to improve its clinical relevance and incorporate

updated information about immunology in SLE (Table 33-2).

23 Either classification

system, ACR 1997 or SLICC 2012, can be used.

CLINICAL PRESENTATION

The clinical features of the disease are diverse and vary among patients. Signs and

symptoms may be subtle early in the course of the disease; and the spectrum of mild

to severe symptoms may fluctuate, with periods of remission, throughout the disease

process.

24 Clinical patterns of the disease can be categorized as constitutional,

musculoskeletal, and mucocutaneous.

Constitutional symptoms usually include fatigue, general malaise, fever, and

weight loss. These may occur in the early stages of the disease. Fatigue is the most

common complaint and can be a debilitating symptom early on.

25,26 Musculoskeletal

symptoms include arthritis, arthralgia, and myalgia. Early in the course of the disease

the symptoms may be confused with rheumatoid arthritis, especially with intermittent

symmetric arthritic and joint pain. Arthritis associated with SLE is non-erosive and

does not damage the joint even though it affects the joints of the hands, wrist, knees,

and feet. Myopathy may also be present during periods of active disease, or

secondary to treatment of hydroxychloroquine and corticosteroids.

27

p. 701

p. 702

Table 33-1

American College of Rheumatology Revised Criteria for Classification of

Systemic Lupus Erythematosus, 1982 with 1997 Updates

22,46

Criterion Definition

Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the

nasolabial folds

Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular

plugging; atrophic scarring may occur in older lesions

Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or

physician observation

Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician

Arthritis, non-erosive Involving two or more peripheral joints, characterized by tenderness, swelling,

6.

7.

8.

9.

10.

11.

or effusion

Serositis Pleuritis—convincing history of pleuritic pain or rubbing heard by a physician

or evidence of pleural effusion

Or

Pericarditis—documented by electrocardiogram (ECG) or rub or evidence of

pericardial effusion

Renal disorder Persistent proteinuria >0.5 g/day or >3+ if quantitation not performed

Or

Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed

Neurologic disorder Seizures—in the absence of offending drugs or known metabolic

derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)

Or

Psychosis—in the absence of offending drugs or known metabolic

derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)

Hematologic disorder Hemolytic anemia—with reticulocytosis

Or

Leukopenia—<4,000/mm

3 on ≥2 occasions

Or

Lyphopenia—<1,500/mm

3 on ≥2 occasions

Or

Thrombocytopenia—<100,000/mm

3

in the absence of offending drugs

Immunologic disorder Anti-DNA: antibody to native DNA in abnormal titer

Or

Anti-Sm: presence of antibody to Sm nuclear antigen

Or

Positive finding of antiphospholipid antibodies on

an abnormalserum level of IgG or IgM anticardiolipin antibodies,

a positive test result for lupus anticoagulant using a standard method,

Or

a false-positive test result for at least 6 months confirmed by Treponema

pallidum immobilization or fluorescent treponemal antibody absorption test

Positive antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an

equivalent assay at any point in time and in the absence of drugs associated

with drug-induced lupus syndrome

Anti-DNA, anti-deoxyribonucleic acid; Anti-Sm, anti-Smith antibodies; IgG and IgM, immunoglobulins G and M.

Mucocutaneous manifestations occur frequently in patients with SLE. The malar or

butterfly rash across the face is one of the classic cutaneous signs; however, it may

not be present in all patients with SLE. It is an erythematous skin rash distributing

over the cheeks and the bridge of the nose but spares the nasolabial folds. It can

persist for weeks and resolves without scarring. The malar rash should be

differentiated from flushing, glucocorticoid-induced dermal atrophy, rosacea,

seborrheic, atopic, and contact dermatitis.

2 Other cutaneous signs may include

alopecia, discoid lesions, photosensitivity reactions, periungual erythema, nail fold

infarcts, and splinter hemorrhages.

28,29

In comparison, mucosal symptoms can include

vasculitis and painful, recurrent ulcers in the mouth, nose, and genital cavity.

27

Raynaud’s phenomenon may also occur in patients with SLE. It is described as a

vasospastic disorder of the extremities, commonly affecting the hands and is

1.

2.

characterized by color changes as a result of decreased temperature or intense

stress.

18

It can also lead to avascular bone necrosis, which is a major cause of

disability in SLE patients.