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Int J Clin Pharm (2014) 36:684692

DOI 10.1007/s11096-014-9966-1


Optimizing pharmacotherapy of systemic lupus erythematosus:

the pharmacist role
Maryam Al Hussaini Emad I. Hammouda
Ahmed E. Hammouda

Received: 22 October 2013 / Accepted: 27 May 2014 / Published online: 2 July 2014
 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014

Abstract Background Systemic lupus erythematosus

(SLE) is a systemic autoimmune disease that can affect any
part of the body. The management of the disease includes
nonpharmacotherapy and pharmacotherapy. Aim of the
review To provide an up-to-date review of the etiology,
epidemiology, clinical features, diagnostic findings, and
treatment options for SLE. Methods Data source: A PubMed search of English language journals using a combination of wordselderly, SLE, late onset SLE, etiology,
screening, diagnosis, or treatment to identify original
studies, guidelines, and reviews on SLE, SLE, late onset
SLE published between 2000 and present. Overall, original
studies, clinical reviews, references, and guidelines were
obtained and evaluated on their clinical relevance. The
literature included guidelines and considerations for the
etiology, diagnosis, screening, and management of SLE,
late onset SLE. Results SLE is a chronic autoimmune
disorder, the exact etiology of which is unknown. SLE
predominately affects younger women; however, it is
reported to occur in up to 20 % of patients 50 years or
older. In patients with SLE, nearly every system in the

M. Al Hussaini (&)
Department of Pharmaceutical Sciences,
College of Health Sciences, Public Authority for Applied
Education and Training (PAAET), Kuwait, Kuwait
E. I. Hammouda
Pharmacy Department, Tawam Hospital in Affiliation with John
Hopkins Medicine, Al Ain, United Arab Emirates
A. E. Hammouda
Faculty of Pharmacy, German University of Cairo, Cairo, Egypt


body is affected with varying degrees of severity ranging

from subclinical to fatal. The hallmark feature of SLE is
the production of autoantibodies directed primarily against
nuclear antigens, but also against cytoplasmic components
of cells. Conclusion The diagnosis of SLE is based on
criteria set by the American College of Rheumatology.
Management is individualized and depends on presenting
symptoms and reducing the likelihood of permanent damage to organs and tissues.
Keywords Elderly  Geriatrics  Late onset systemic
lupus erythematosus  Systemic lupus erythematosus 
Alanine transaminase
American College of Rheumatology
Angiotensin converting enzyme
Anti-deoxyribonucleic acid
Anti-doublestranded deoxyribonucleic
Anti-La/SS-B Anti-La Sjorgren syndrome type B
Anti-Ro/SS-B Anti-Ro/Sjorgren syndrome type B
Antinuclear antibodies
Anti ribonucleoprotein
Anti-Smith antibodies
Aspartate transaminase
Complete blood count
European league against rheumatism
Non-steroidal anti-inflammatory drugs
Systemic lupus erythematosus

Int J Clin Pharm (2014) 36:684692


Impact on Practice

Table 1 Factors associated with the development or exacerbation of


Sun exposure

Systemic lupus erythematosus (SLE) is a chronic

autoimmune disorder, the exact etiology of which is
unknown. SLE predominately affects younger women;
however, it is reported to occur in up to 20 % of
patients 50 years or older.
The hallmark feature of SLE is the production of
autoantibodies directed primarily against nuclear antigens, but also against cytoplasmic components of cells.
According to literature, hydroxychloroquine, an antimalarial drug, is frequently used as a first line treatment
option for patients with mild SLE.

Systemic lupus erythematosus (SLE) or lupus is a chronic,
progressive, autoimmune disorder that affects multiple
organ systems, with a broad range of clinical and laboratory manifestations [13]. The term lupus means wolf in
Latin and is named as such due to facial lesions found in
the disease process that are reminiscent of a wolfs bite [4].

Aim of the review

This review will provide up-to date information regarding
the etiology, environmental and genetic influences, clinical
features, diagnostic findings, and treatment options for
SLE. In addition it will update pharmacists knowledge
about pharmacotherapy of SLE. This can help in minimizing adverse drug reactions and prevent possible drug/
drug interactions during treatment.

Data source
A PubMed search of English language using a combination
of words: elderly, systemic lupus erythematosus, late onset
systemic lupus erythematosus, etiology, screening, diagnosis, or treatment to identify original studies, guidelines,
and reviews on systemic lupus erythematosus, SLE, late
onset systemic lupus erythematosus published between
2000 and present.

Genetic influence


Female hormones

Virus exposure
(e.g. EpsteinBarr virus)



Occupational exposure (silica,

mercury, etc.)

Source: Refs. [1, 2, 58]

Data synthesis
The literature included guidelines and considerations for
the etiology, diagnosis, screening, and management of
systemic lupus erythematosus, late onset systemic lupus

While the etiology is unknown, there are several factors
associated with the development of SLE (Table 1) [1, 2, 5
8]. Unexplainably, SLE patients do not clear apoptotic cells
appropriately [2, 9]. These cells release auto-antigens that
may help drive the defective immune process [9]. The
complex interaction between environment and immunologic factors in genetically susceptible individuals leads to
continued deregulation of the innate and adaptive immune
pathways [1, 7, 1012]. Autoantibodies often form long
before clinical manifestations result in chronic, widespread
tissue and organ damage [2, 6, 13, 14]. Patients with SLE
experience acute exacerbations and remissions resulting in
protean clinical and serologic manifestations [15, 16].
Systemic lupus erythematosus may develop as a result of
exposure to medications. It is estimated that 10 % of
patients diagnosed with SLE may have drug induced lupus,
and over 38 drugs (Table 2) have been implicated in the
disease development [7, 15, 1720]. However, most cases
have been associated with these three:


Study selection and data extraction


Overall, original studies, clinical reviews, references, and

guidelines were obtained and evaluated on their clinical

Lupus is most often initially diagnosed in young women of

reproductive age but does affect those 50 years of age or
older [16, 17, 21]. Early diagnosis and treatment are



Int J Clin Pharm (2014) 36:684692

Table 2 Medications that may contribute to the development of SLE

Drug class

Very low

Low to moderate

High risk


Disopyramide, propafenone





Isoniazid, minocycline


Phenytoin, trimethadione, primidone, ethosuximide



Enalapril, clonidine, atenolol, labetalol, pindolol, minoxidil,

prazosin, chlorthalidone, hydrochlorothiazide

Captopril, methyldopa,



Sulfasalazine, D-penicillamine


Perphenazine, phenelzine, chlorprothixene, lithium




Lovastatin, levodopa, aminoglutethimide, alpha-interferon,
timolol eye drops

Source: Refs [1820]

important. The average time to reach a diagnosis is 2 years

[7]. However, in the late onset population, the average time
to establish the diagnosis is often as long as 5 years [22].
Improvements in diagnostic techniques as well as more
intensive treatment methods have enhanced survival rates
dramatically in recent years [23]. The survival rate has
improved from a 4 years survival rate of 50 % in the
1950s to the present day 20 year survival rate of approximately 80 %. [2426]. The prevalence of SLE in the
United States population is 14.668/100,000 [7]. About
1020 % of patients will be diagnosed with late onset SLE
(first diagnosed age 50 years or older) and will often have
more mild manifestations of the disease that may result in a
delayed diagnosis [17, 22, 27]. The female predominance
may not be as significant in the late-onset populations [22].
Systemic lupus erythematosus is two to four times more
common among African Americans and other non-white
populations [16, 21].
Clinical manifestations
Lupus often follows a characteristic pattern of relapse and
remissions and typically develops over an extended period
of time [3, 5, 28]. It takes careful observation to make the
diagnosis. The clinical presentation of SLE may be comprised of both systemic symptoms as well as specific signs
of organ-system dysfunction [3, 28]. The incidence of
clinical findings of early and late-onset.
SLE may vary (Table 3) [17, 27, 29]. Common presenting findings of patients with SLE are fatigue, malaise,
fever, anorexia, and weight loss. They may also present
with an infection [5, 28]. Patients may present with a
number of dermatologic findings, including discoid and
malar lesions, photosensitivity, alopecia, periungual erythema, nail fold infarcts, and splinter hemorrhages [3, 5,
28]. Thirty-five percent of patients with SLE will have
some form of glomerulonephritis or nephrotic syndrome


symptoms and signs on clinical examination, predicting a

worse outcome [30]. Patients with renal complications
often must have a renal biopsy to fully understand the
extent of disease severity [7]. Myalgias and muscle
weakness are common. Up to 90 % of patients with SLE
present with symmetrical joint pain, that is typically a
migratory polyarthropathy, distinguished from rheumatoid
arthritis by its lack of joint destruction [3, 5, 28]. The
pathophysiology behind osteoporosis and the occurrence of
fractures in SLE is multifactorial. It involves both disease
and non-disease related factors, including complications of
the treatment itself [31]. The most common cardiac findings are pericarditis and pericardial effusion [3, 5, 28, 32].
Valvular abnormalities are frequent in patients with SLE,
especially the mitral valve. Screening with transthoracic
echocardiography may be indicated in patients with SLE;
especially for those with identified risk factors such as
corticosteroid use [32]. Systemic lupus erythematosus is
also associated with an increased risk of coronary disease
due to atherosclerosis [33]. The mechanism for neuronal
damage is consistent with the autoimmune nature of SLE,
that is immune anti-neuronal antibodies attack the neurons
causing damage and the neurologic symptoms as described
[5]. Cognitive dysfunction is a common neuropsychiatric
manifestation of SLE as it is found in up to 80 % of
patients to a variable extent [34]. Higher rates of anxiety
and depression are found in patients with SLE. Depression
occurs more commonly with changes in appearance, and
limitations due to complications or medication side effects
[35]. Health care providers should be alert for these
The clinical heterogeneity of SLE resulted in the development of classification criteria in 1982 by the American
College of Rheumatology [36]. These were revised in

Int J Clin Pharm (2014) 36:684692

Table 3 Clinical findings of early and late-onset SLE
Early onset SLE
(age \ 50 years)

Late onset SLE (age C 50 years)

Table 4 American College of Rheumatology criteria for diagnosis of
1. Malar rash: butterfly shaped rash over the nose and cheeks; can
be flat or raised

Physical findings

2. Discoid rash: a rash that appears as red, raised, disk-shaped


Malar rash

Pulmonary manifestations





3. Photosensitivity: unusual reaction to sun or light that causes a

rash to appear


Sjogrens syndrome

4. Oral ulcers: sores, usually painless, appearing in the mouth or


Purpura/cutaneous vasculitis
Raynauds phenomenon

5. Non-erosive arthritis: joint pain and swelling of two or more



6. Serositis: pleuritis (inflammation around the lungs) or

pericarditis (inflammation around the heart)

Fever and lymphadenopathy

7. Renal disorder: persistent protein ([0.5 g/day) or any cellular

casts in the urine

Nephritis/Nephrotic syndrome
Hematologic derangements
Serological findings
Increased frequency of antiRNP antibodies and antismantibodies
Low CH50

Increased frequency of RF and

ANA positivity
Increased frequency of the antinuclear autoantibodies, anti-Ro/
SSA and anti-La/SSB positivity

Anti-RNP antibodies anti-ribonucleoprotein, Anti-Sm antibodies antiSmith antibodies, CH50 50 % hemolytic complement, RF rheumatoid
factor, ANA antinuclear antibodies, Anti-La/SSB anti-La/Sjogren
syndrome type B, Anti-Ro/SSB anti-Ro/Sjogren syndrome type B

8. Neurological disorder: seizures or psychosis in the absence of

offending drugs or known metabolic conditions
9. Hematologic disorder: hemolytic anemia, leukopenia,
lymphopenia, or thrombocytopenia
10. Immunologic disorder: anti-DNA, anti-Smith antibodies, or
positive antiphospholipid antibodies on testing
11. Positive antinuclear antibody at any point in time in the
absence of medications/drugs
Four of 11 criteria are needed for the formal diagnosis of SLE
Source: Resources [12, 37, 38]

Source: Refs. [17, 27, 29]


Management is individualized, depends on symptoms, and

is directed at reducing the likelihood of permanent damage
to organs and tissues. Treatment strategies in late onset
SLE do not differ widely from those seen in younger
patients [17]. The disease course in late onset SLE is
usually mild requiring less use of cytotoxic/immune suppressive drugs and high dose corticosteroids for disease
control [17, 29]. Guidelines were developed in 1999 by the
American College of Rheumatology and in 2008 by the
European league against rheumatism (EULAR) task force
(Table 5) [43, 44]. The major challenge in treating SLE is
to inhibit clinically active disease without causing long
term consequences [17]. This is especially true in the older
patient. They are more likely to be affected by multiple
disease states and taking several medications; thus,
increasing the likelihood of drug interactions and adverse
drug reactions. In addition, the pharmacokinetics and
pharmacodynamics of drugs are often altered in the older
patient. The safety profiles and monitoring recommendations for medications used in SLE are provided (Table 6)
[14, 40, 43, 4549].



There is no cure for SLE, so early diagnosis and treatment

to control dysfunction and complications are important.

Both the ACR and EULAR recommend non-pharmacologic treatment in the management of SLE. Patients should

1997. This resulted in the establishment of 11 equally

weighted criteria (Table 4), with four needing to be present
for the formal diagnosis of SLE [12, 37, 38]. A subspecialist in rheumatology or nephrology may diagnose a
patient with only three criteria, if at least one is serologic
and one is clinical [7]. A patient can be described as having
latent or incomplete lupus with as few as one criterion
with additional common symptoms, such as fatigue, fever,
alopecia or Raynauds phenomenon [7, 39, 41].
Upon initial suspicion of lupus, the most important
laboratory screening measure is the blood test for antinuclear antibodies (ANA) [7, 38]. However, since ANA is
found in conditions other than SLE, more specific tests are
needed to help confirm the diagnosis, such as anti-doublestranded DNA (anti-dsDNA), anti-Smith (anti-Sm) and
antiphospholipid antibodies [37, 42]. The anti-dsDNA and
anti-Sm serological tests are considered definitive for lupus



Int J Clin Pharm (2014) 36:684692

Table 5 Treatment recommendations overview of SLE

American College of
Rheumatology Committee

European league against rheumatism

task force

Mild SLE

SLE without major manifestations

Nonsteroidal antiinflammatory drugs




Oral glucocorticoids (low


Nonsteroidal anti-inflammatory
drugs (used judiciously)

Serious, life threatening, or

organ threatening SLE

Non-responsive patients or unable to

reduce steroid dose

High dose glucocorticoids

cytotoxic agents
cyclophosphamide, and

Immunosuppressive agents
(azathioprine, mycophenolate, and

Lupus nephritis

Table 6 Summary of adverse effects and recommended monitoring

for medications used in the treatment of SLE

Adverse effects



bleeding, hepatic
toxicity, renal

CBC, creatinine,
AST, ALT, blood
pressure, monitor
for bleeding


cataracts, fluid
retention, glaucoma,

Blood pressure,
potassium, bone
mineral density


Retinal and macular


Fundoscopic and
visual fields, visual


GI side effects,

CBC, differential
and platelet count,


hemorrhagic cystitis,
severe infections,
nausea, vomiting,
reversible hair loss

CBC, differential
and platelet count,


hepatic toxicity,
pulmonary infiltrates
or fibrosis, stomatitis

CBC, hepatitis B
and C serology in
high risk patients,
AST, albumin,
creatinine, chest


Anemia, leukopenia,
infections, diarrhea,

CBC, differential
and platelet count



CBC, differential
and platelet count

Glucocorticoid in combination with

immunosuppressive agents
(cyclophosphamide and
Source: Refs. [43, 44]

be counseled on lifestyle modifications, such as smoking

cessation, weight control, and increasing exercise to limit
co-morbidities of atherosclerosis, hypertension, and diabetes [43, 44]. Patients should minimize sun exposure by
wearing appropriate clothing, applying topical sunscreens,
and avoiding tanning beds. Screening for bone loss should
be instituted and treatment commenced as needed [31].
Patient education and psychosocial support are an important aspect of management. Information about SLE and
specific problems of living with the disease should be
combined with medical therapy to help alleviate depression
and anxiety [50]. Unfortunately, challenges remain in
increasing a patients quality of life [2, 35]. Clinicians
should be alert to changes in psychosocial functioning and
treated and/or referred for appropriate counseling as

ALT alanine transaminase, AST aspartate transaminase, CBC complete

blood count

Nonsteroidal anti-inflammatory drugs

Source: Resources [14, 40, 43, 4549]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve arthralgia, inflammation, serositis,
and fever in patients with SLE. They can be used with or
without low doses of steroids or antimalarial agents [40,
44, 45]. NSAIDs inhibit the production of cyclooxygenase1 (COX-1) and cyclooxygenase-2 (COX-2) [51]. The
inhibition of COX-1decreases the production of

prostaglandins that protect the lining of the gastrointestinal

tract. The inhibition of COX-2 mediates the production of
prostaglandins which moderates inflammation and pain.
Therefore, NSAIDs that are selective COX-2 inhibitors,
such as celecoxib, have reduced the occurrence of adverse
gastrointestinal bleeding [51]. In a study of 50 SLE patients
with predominance of musculoskeletal complaints and less


Int J Clin Pharm (2014) 36:684692

severe organ involvement, celecoxib was found to be

effective and safe [52]. Regardless of their cyclooxygenase
selectivity, NSAIDs may cause renal impairment, fluid
retention, and interstitial nephritis [45]. Lupus nephritis is a
risk factor for NSAID induced acute renal failure [53].
Therefore, NSAIDs should be used for the shortest effective period of time especially in patients with renal
involvement, hypertension, or heart disease [44, 54].
Hydroxychloroquine, an antimalarial drug, is frequently
used as a first line treatment option for patients with mild
SLE. It is effective in preventing the occurrence of new
mild SLE manifestations [14]. A systematic review found
antimalarials reduced lupus activity by more than 50 % in
pregnant and non-pregnant patients and a [50 %
improvement in mortality [49].
Hydroxychloroquine also has been shown to have a
beneficial effect on dyslipidemia [55]. Hydroxychloroquine
inhibits toll like receptors which causes a down regulation
of interferon-a and decreases the antigen processing for
auto-antigen presentation [56]. The safety profile for
hydroxychloroquine is good. The ACR recommends
patients undergo a baseline eye examination before treatment and every 612 months thereafter [43]. It may be
used during pregnancy [44].
Systemic glucocorticoids are usually unnecessary in mild
SLE, but the lowest effective doses can be used if the
patient has cutaneous and musculoskeletal symptoms not
responding to other therapies [43]. Systemic glucocorticoids are used alone or in combination with other immunosuppressive agents for patients with significant organ
involvement or refractory symptoms. Due to the long term
adverse effects of glucocorticoid treatment, the shortest
effective duration should be used [40, 45]. Patients
requiring long term glucocorticoid therapy should be
monitored for the complications of hypertension, diabetes,
myopathy, psychosis, and cataracts.
Methotrexate (MTX), an antifolate, may be preferred in the
management of resistant arthritis and cutaneous SLE [14].
Methotrexate provides a significant advantage in patients
with moderately active lupus by allowing lower steroid
doses, and slightly decreasing lupus disease activity [57].
In a recent prospective open label study, low dose MTX
appears to be as effective as chloroquine, an antimalarial,


in patients with articular and cutaneous manifestations of

SLE [58].
Cyclophosphamide, an alkylating agent, is the standard of
care for lupus nephritis and is usually used in conjunction
with corticosteroids [40, 59]. It is also used with corticosteroids in patients with severe neuropsychiatric involvement [14, 60].
Mycophenolate, exerts its immunosuppressive effect by
inhibiting B- and T cell proliferation, causing suppression
of antibody production [45]. In a systemic review and
meta-analysis, mycophenolate in combination with corticosteroids was shown to be as effective as cyclophosphamide in the treatment of lupus nephritis and had less risk of
leukopenia [61].
Maintenance therapy, often with azathioprine or mycophenolate, is required for remission and prevention of
relapse after the initial control of lupus nephritis. In a
36-month, randomized, double-blind, double-dummy, trial
comparing oral mycophenolate mofetil and oral azathioprine, mycophenolate mofetil was superior to azathioprine
in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a
response to induction [62].
Azathioprine inhibits DNA synthesis and prevents lymphocyte proliferation in the immune system [14, 40, 45]. It
is used as a steroid-sparing agent in moderate to severe
lupus, and it is used in the maintenance phase of lupus
nephritis [14, 45].
Belimumab, a human monoclonal antibody, blocks the
biologic activity of B lymphocyte stimulator. This
decreases the antibody levels in the body which may help
reduce the autoimmune activity of SLE [40]. Belimumab
was approved by the FDA in 2011 for use in adults [7]. In
two phase III trials, BLISS-52 and BLISS-76, belimumab
showed noteworthy improvements in patients with SLE
after 52 weeks, but the advances were not statistically
maintained at week 76 [14]. Belimumab demonstrated a
steroid-sparing effect in these trials as well as a decreased
rate of disease flares [63]. To be included in the trial,
patients had to meet the ACR criteria for SLE, and they had
to have active disease. Patients also had to demonstrate a



Int J Clin Pharm (2014) 36:684692

Table 7 Summary of drug interactions used in the treatment of SLE


Possible drug interaction


Lithium, diuretics, beta blockers, ACEI,

angiotensin receptor blockers


No significant drug interactions reported


No significant drug interactions reported


Allopurinol, febuxostat, mesalamine, ACEI,



No significant drug interactions reported


Cholestyramine, antacids, and phosphate

binders should not be administered at the
same time


Drug interactions have not been formally


Source: Resources [4648, 65, 66]

positive ANA and be on a stable regimen of prednisone,

NSAIDs, antimalarials, or immunosuppressive drugs for
30 days prior to the start of the trial. Exclusion criteria
included severe active lupus nephritis, CNS lupus, and
pregnancy. Exclusion criteria also included prior therapy
within the last 3 months of IV cyclophosphamide, IV
immunoglobulin, IV prednisone, or drugs that target
B-lymphocytes [63]. The safety profile for belimumab is
good. Safety data from the BLISS trials demonstrated an
adverse effect profile and infection rate similar to that of
placebo [7]. Patients on belimumab should not receive live
vaccines 30 days before, or during treatment due to a
decreased ability to mount an immune response [47]. The
use of belimumab was not studied in older patients;
therefore, no efficacy data is available for this age group
[17, 64].
Pharmacists role

Review the patients medications for drug induced

lupus or for possible drug interactions (Table 7) [46
48, 65, 66].
Monitor for adverse reactions and therapeutic response.
Ensure the patient is current on inactivated influenza
and pneumococcal vaccines [43].
Monitor vitamin D levels and bone mineral density.
The majority of patients with SLE have insufficient
levels of vitamin D. This may be due in part to less sun
exposure, and medications used for the treatment of
SLE. Patients should be screened for insufficient
vitamin D and bone mineral density [67, 68]. Patients
on long-term glucocorticoids should receive sufficient
daily calcium and vitamin D and/or a bisphosphonate to
minimize the degree of bone loss [69].


Review patients history to determine increased risk of

NSAID-induced ulcers. The addition of a proton pump
inhibitor may be indicated.
Ensure that the patient is receiving daily supplemental
folic acid to reduce side effects related to the gastrointestinal system [70].
Confirm and make recommendations to ensure medications are administered correctly with regard to meals
and in relation to other medications.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder, the exact etiology of which is unknown.
SLE predominately affects younger women; however, it is
reported to occur in up to 20 % of patients 50 years or
older. In patients with SLE, nearly every system in the
body is affected with varying degrees of severity ranging
from subclinical to fatal.
The hallmark feature of SLE is the production of autoantibodies directed primarily against nuclear antigens, but
also against cytoplasmic components of cells. The diagnosis of SLE is based on criteria set by the American
College of Rheumatology. Management is individualized
and depends on presenting symptoms and reducing the
likelihood of permanent damage to organs and tissues.
Conflicts of interest All authors stated that there is no conflict of
interest in this study.

1. Agmon-Levin N, Blank M, Paz Z, Shoenfeld Y. Molecular
2. DCruz D, Khamashta M, Hughes G. Systemic lupus erythematosus. Lancet. 2007;369:58796.
3. Porth C, Matfin G. Pathophysiology: concepts of altered health
states. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott
Williams & Wilkins; 2009.
4. Boltzer JW. Systemic lupus erythematosus. I. Historical aspects.
MD State Med J. 1983;32:43941.
5. Schur PH, Gladman DD. Overview of the clinical manifestations
of systemic lupus erythematosus in adults. In: Basow DS, editor.
Uptodate. MA: Waltham; 2012.
6. Alarcon-Riquelme ME. The genetics of systemic lupus erythematosus. J Autoimmun. 2005;25:468.
7. Bernknopf A, Rowley K, Bailey T. A review of systemic lupus
erythematosus and current treatment options. Formulary.
8. Soldevilla H, Briones S, Navarra S. Systemic lupus erythematosus following HPV immunization or infection. Lupus.
9. Bilj M, Reefman E, Horst G, Limburg PC, Kallenberg CG.
Reduced uptake of apoptotic cells by macrophages in systemic

Int J Clin Pharm (2014) 36:684692
















lupus erythematosus: correlates with decreased serum levels of

complement. Ann Rheum Dis. 2006;65:5763.
Dorner T, Jacobi A, Lee J, Lipsky PE. Abnormalities of B cell
subsets in patients with systemic lupus erythematosus. J Immunol
Methods. 2011;363:18797.
Jonsen A, Bengtsson A, Nived O, Truedsson L, Sturfelt G. Gene
environment interactions in the aetiology of systemic lupus erythematosus. Autoimmunity. 2007;40:6137.
Tsokos G. Mechanisms of disease systemic lupus erythematosus.
N Engl J Med. 2011;365:211021.
Sebastiani GD, Galeazzei M. Infectiongenetics relationship in
systemic lupus erythematosus. Lupus. 2009;18:116975.
Yildirim-Toruner C, Diamond B. Current and novel therapeutics
in treatment of SLE. J Allergy Clin Immunol. 2011;127:30314.
Zandmann-Goddard G, Solomon M, Rosman Z, Peeva E, Shonfeld Y. Environment and lupus related diseases. Lupus.
Slawsky K, Fernandes A, Fusfeld L, Manzi S, Goss TF. A
structured literature review of the direct costs of adult systemic
lupus erythematosus in the US. Arthritis Care Res. 2011;63:
Arnaud L, Mathian A, Boddaert J, Amoura Z. Late-onset systemic lupus erythematosus. Drugs Aging. 2012;3:1819.
Vedove CD, Del Giglio M, Schena D, Gerolomoni G. Druginduced lupus erythematosus. Arch Dermatol Res. 2009;301:
Vasoo S. Drug induced lupus: an update. Lupus. 2006;15:75761.
Marzano A, Vezzoli P, Crosti C. Drug-induced lupus: an update
on its dermatologic aspects. Lupus. 2009;18:93540.
Pons-Estel GJ, Alarcon GS, Cooper G. Understanding the epidemiology and progression of systemic lupus erythematosus.
Semin Arthritis Rheum. 2010;39:257. doi:10.1016/j.semarthrit.
Font J, Pallares L, Cervera R, Lopez-Soto A, Navarro M, Bosch
X, Ingelmo M. Systemic lupus erythematosus in the elderly:
clinical and immunological characteristics. Ann Rheum Dis.
Doria A, Iaccarino L, Ghirardello A. Long-term prognosis and
causes of death in systemic lupus erythematosus. Am J Med.
Merrill M, Shulman LE. Determination of prognosis in chronic
disease illustrated by systemic lupus erythematosus. J Chronic
Dis. 1955;1:1232.
Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality
studies in systemic lupus erythematosus. Results from a single
centre. II. Predictor variables for mortality. J Rheumatol. 1995;
Urowitz MB, Gladman DD, Tom BD, Ibanez D, Farewell VT.
Changing patterns in mortality and disease outcomes for patients
Lazaro D. Elderly-onset systemic lupus erythematosus prevalence, clinical course and treatment. Drugs Aging. 2007;24:
McPhee SJ, Papadakis MA. Current medical diagnosis and
treatment. 48th ed. NewYork: McGraw-Hill; 2009.
Lalani S, Pope J, de Leon F, Peschken C. Clinical features and
prognosis of late-onset systemic lupus erythematosus: results
from the 1000 faces of lupus study. J Rheumatol. 2010;37:3844.
Gordon C, Jayne D, Pusey C, Adu D, Amoura Z, Aringer M, et al.
European consensus statement on the terminology used in the
management of lupus glomerulonephritis. Lupus. 2009;18:
Bultink I. Osteoporosis and fractures in systemic lupus erythematosus. Arthritis Care Res. 2012;64:28.

32. Bourre-Tessier J, Huynh T, Clarke A, Bernatsky S, Joseph L,
Belisle P, et al. Features associated with cardiac abnormalities in
systemic lupus erythematosus. Lupus. 2011;20:151825.
33. El-Magadmi M, Bodill H, Ahmad Y, Durrington PN, Mackness
M, Walker M, et al. Systemic lupus erythematosus an independent risk factor for endothelial dysfunction in women. Circulation. 2004;110:399404.
34. Adhikari T, Piatti A, Luggen M. Cognitive dysfunction in SLE:
development of a screening tool. Lupus. 2011;20:11426.
35. Auerbach C, Beckerman N. What social workers in health care
should know about lupus: a structural equation model. Health Soc
Work. 2011;36:26978.
36. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:12717.
37. Smith E, Shmerling R. The American College of Rheumatology
criteria for the classification of systemic lupus erythematosus:
strengths, weaknesses, and opportunities for improvement.
Lupus. 1999;8:58695.
38. Egner W. The use of laboratory tests in the diagnosis of SLE.
J Clin Pathol. 2000;53:42432.
39. Hull C. Systemic lupus erythematosus: a clinical review. Clin
Rev. 2010;20:1823.
40. Kalunian K, Merrill JT. New directions in the treatment of systemic lupus erythematosus. Curr Med Res Opin. 2009;6:150114.
41. Common symptoms of lupus. Lupus Foundation of America 2012.
learndiagnosing.aspx?articleid=2241&zoneid=524. Accessed 9
May 2012.
42. Ginzler E. Systemic lupus erythematosus (Lupus), American
College of Rheumatology Patient Fact Sheet, 2012. http://www.
lupus.asp. Updated Feb 2013.
43. Gladman DD, Urowitz MB, Esdaile JM, Hahn H, Kippel J, Lahita
R, et al. Guidelines for referral and management of systemic
lupus erythematosus in adults. Arthritis Rheum. 1999;9:178596.
44. Bertsias G, Loannidis JP, Boletis J, Bombardieri S, Cervera R,
Dostal C, et al. EULAR recommendations for the management of
systemic lupus erythematosus. Report of a task force of the
EULAR standing committee for international clinical studies
including therapeutics. Ann Rheum Dis. 2008;67:195205.
45. Amissah-Arthur MB, Gordon C. Contemporary treatment of
systemic lupus erythematosus: an update for clinicians. Ther Adv
Chronic Dis. 2010;1:16375.
46. The Medical Letter Volume 10 (Issue15) March 2012.
47. The Medical Letter Volume 53 (Issue 1366) June 2011.
48. Mycophenolatemofetil capsules and tablets. Pennington, NJ:
Zydus Pharmaceuticals USA,Inc; 2011 April.
49. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta
MA. Clinical efficacy and side effects of antimalarials in systemic
lupus erythematosus: a systemic review. Ann Rheum Dis.
50. Mazzoni D, Cicognani E. Social support and health in patients
with systemic lupus erythematosus: a literature review. Lupus.
51. Sostres C, Gargallo CJ, Arroyo MT. Adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs)
on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol.
52. Lander SA, Wallace DJ, Weisman MH. Celecoxib for systemic
lupus erythematosus: case series and literature review of the use
of NSAIDs in SLE. Lupus. 2002;11:3407.
53. Horizon AA, Wallace DJ. Risk: benefit ratio of nonsteroidal antiinflammatory drugs in systemic lupus erythematosus. Expert
Opin Drug Saf. 2004;3:2738.


54. Scheiman JM, Hindley CES. Strategies to optimize treatment
with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther. 2010;32:66777.
55. Tam LS, Gladman DD, Hallett DC, Rahman P, Urowitz MB.
Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol. 2000;9:21425.
56. Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R.
Mechanism of endosomal TLR inhibition by antimalarial drugs
and imidazoquinolines. J Immunol. 2011;186:111.
57. Fortin PR, Abrahamowicz M, Ferland D, Lacaille D, Smith CD,
Zummer M, et al. Steroid-sparing effects of methotrexate in
systemic lupus erythematosus: a double blind, randomized, placebo-controlled trial. Arthritis Rheum. 2008;59:1796804.
58. Islam N, Hossain M, Haq SA, Alam MN, Peter M, Klooster T,
et al. Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus. Int J
Rheum Dis. 2012;15:628.
59. Shum K, Askanase A. Treatment for lupus nephritis. Curr
Rheumatol Rep. 2011;13:28390.
60. Popescu A, Kao AH. Neuropsychiatric systemic lupus. Erythematosus. Curr Neuropharmacol. 2011;9:44957.
61. Kamanamool N, McEvoy M, Attia J, Ingsathit A, Ngamjanyaporn P, Thakkinstian A. Efficacy and adverse events of mycophenolate mofetil versus cyclophosphamide for induction therapy
of lupus nephritis. Medicine. 2010;89:22735.
62. Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy
D, et al. Mycophenolate versus azathioprine as maintenance
therapy for lupus nephritis. N Engl J Med. 2011;365:188695.


Int J Clin Pharm (2014) 36:684692

63. Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA,
Jimenez RE, et al. Efficacy and safety of Belimumab in patients
with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:72131.
64. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D,
et al. A phase III, randomized, placebo-controlled study of Belimumab, a monoclonal antibody that inhibits B lymphocyte
stimulator, in patients with systemic lupus erythematosus.
Arthritis Rheum. 2011;12:391830.
65. Day RO, Graham GG, Champion GD, Lee E. Anti-rheumatic
drug interactions. Clin Rheum Dis. 1984;2:25175.
66. Johnson AG, Seideman P, Day RO. Adverse drug interactions
with nonsteroidal anti-inflammatory drugs (NSAIDs), recognition, management and avoidance. Drug Saf. 1993;8:99127.
67. Kamen DL. Vitamin D in lupus: new kid on the block. Bull NYU
Hosp Jt Dis. 2010;68:218.
68. Toloza S, Cole D, Gladman DD, Ibanez D, Urowitz MB. Vitamin
D insufficiency in a large female SLE cohort. Lupus.
69. Grossman JM, Gordon R, Ranganath VK, Deal C, Chen W,
Curtis JR, et al. American college of rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res. 2010;62:151526.
70. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA,
Tugwell P. Folic acid and follinic acid for reducing side effects in
patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews 1999, Issue 4. Art. No.: