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Lupus Treatments

Tuyen Ngo

State University of New York Polytechnic Institute

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Lupus Treatments

Lupus is an autoimmune disease that triggers inflammation in different tissues of the

body. The most common type of lupus is systemic lupus erythematosus (SLE), which affects

different parts of the body including the skin, joints, kidneys, heart, lungs, blood vessels, and

brain. It is a disease of remissions and exacerbations. SLE can be mild or aggressive and even

life-threatening in presentation. The exact cause is unknown but genetic factors, ethnic origin,

. environmental factors, and medications may all be involved in its developments (CDC, 2015).

. Although lupus can strike men and women of all ages, 90 percent of individuals diagnosed with

. the disease are women. Women of childbearing ages between 15-44 are at greatest risk of

. developing SLE. Lupus is two to three times more prevalent among women of color: African

. Americans, Hispanics/Latinos, Asians, Native Americans, Alaska Natives, Native Hawaiians and

. other Pacific Islanders as compared to among Caucasian women.

. The Lupus Foundation of America estimates that 1.5 million Americans, and at least five

. million people worldwide, have a form of lupus (Lupus Foundation of America, 2016). The

. Centers for Disease Control and Prevention (CDC) estimated the annual number of deaths in the

United States from SLE in 1979 to 1998 increased from 879 to 1, 406. Hospitalization was

estimated 39,400 among adults in 2010. According to the CDC, no national cost estimates exist

specifically for SLE. However, the average hospital charges for diffuse connective tissue

disease, which includes SLE, was about 13.3 billion US dollars in 2011 (CDC, 2015). The

leading cause of death in patients with SLE is kidney failure; however other causes include

infections, cerebrovascular disease, cardiovascular disease, and cancer (Sweet et al, 2013).

. According to Lupus of America, lupus is a widespread disease; however, the awareness

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. of the disease lags behind many other illnesses. Among Americans aged 18-34, 72% of those

. surveyed have either not heard about lupus or know little or nothing about lupus beyond the

. name. This is particularly disturbing because this is the age at greatest risk for the disease

. (Lupus of American, 2016). In addition, the treatment options for patients with SLE remain

limited and existing therapies are ineffective or poorly tolerated in a large number of patients.

SLE is relative rare, however; it is a complex disease. It is a global burden in terms of incidence

and prevalence, economic costs and health disparities. It is therefore imperative that further

research applies a consistent disease definition and uses appropriate data in improving patient

outcomes through appropriate health care planning and effective treatment for lupus (Carter, Barr

& Clarke, 2016).

The goals of therapy for lupus are to ensure long-term survival, achieve the lowest

possible disease activity, prevent organ damage, minimize drug toxicity, improve quality of life,

and educate patients about their role in disease management. There are many different treatment

options for lupus. Treatment of lupus is guided by the patients manifestations, pattern of disease

and the severity of organ involvement. Numerous therapies include non-pharmacologic and

pharmacologic. Non-pharmacologic therapies include: sun sunscreen, avoiding smoking

cigarettes, exercise, and vitamin D supplement. Pharmacologic therapies include nonsteroidal

anti-inflammatory drugs (NSAIDs), antimalarial agent (hydroxychloroquine), corticosteroids,

immunosuppressant (methotrexate), b-cell depletion (Rituxan) and targeted biologic therapies

(belimumab) (Robinson, Cook & Currie, 2011). In addition to these therapies, patient

attachment and working alliance affects patient adherence, satisfaction, and health-related quality

of life in lupus treatment (Bennet, Fuertes, Keitel & Philips, 2011).

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The purpose of this literature review is to investigate and analyze the current

therapies available using up to date scientific literature and available guidelines to determine the

efficacy and effectiveness of treatments for lupus. Goals of this literature review are to provide

information to primary care providers on the effectiveness of non-pharmacological,

pharmacological, and combination therapies as well as compare various therapeutic treatments.

Methods

Search Strategy

The State University of New York Polytechnic Institute Cayan Library electronic

databases were searched for relevant randomized control trials and articles dating from 2011-

2016. Databases included Medline CINAHL plus with Full Text. Google scholar, Sage Journal,

Lupus Journal and the Center for Disease Control databases were also searched.

Search terms included the keywords and combination key terms of lupus, systemic

lupus erythematosus, SLE, treatment, intervention, therapy, smoking cessation in

SLE, risk factors, vitamin D in SLE, sunscreen in SLE, antimalarial in lupus,

hydroxychloroquine, HCQ, NSAIDs, Corticosteroids, methotrexate. Literature was

sorted by study type, measurement scale, treatment type, and control type (see Appendix A non-

pharmacologic and Appendix B pharmacologic). All searches were limited to articles in peer-

reviewed journals, studies of humans and those published in the English language.

Results

Non-Pharmacological Therapies

Vitamin D

Vitamin D regulates the growth and differentiation of immune system cells and acts as an
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immunosuppressive agent. Vitamin D deficiency has been associated with pathogenesis of

autoimmune diseases including SLE. Low levels of sunlight exposure due to photosensitivity

may trigger SLE disease flares. Many studies found that vitamin D levels to be lower in lupus

patients than those without lupus (Barbhaiya & Costenbader, 2014 & Breslin et al, 2011).

Souza et al. (2014) evaluated the association between vitamin D insufficiency with SLE

and inflammatory markers. The patients diagnosed with SLE and control group (healthy

individuals) completed a structured questionnaire addressing age, gender, self-reported race,

exposure to sunlight (hours/week) and the use of sunscreen and smoking. The patient also stayed

off their calcium and vitamin D pills for 6 weeks before joining the study. Serum levels of 25-

hydroxy vitamin D were established by high performance liquid chromatography (HPLC) tests.

The levels of 25 (OH)D greater or equal 30 ng/mL is considered sufficient, 15- 29 ng/mL is

insufficient and deficient when levels were 15 ng/mL or less. The Kruskal-Wallis test was used

to compare the level of vitamin D from patient and control group. This cross-sectional study

concluded that vitamin D deficiency was more prevalent in patient with SLE and was associated

with higher level of Interleukin-6 (IL-6), proteinuria and hematuria compared to the control

group. The limitations of this study are small sample size (n =45) and low levels of disease

activity. Future enrolling a larger number of patients with more severe disease could potentially

provide more results with regard to the association between insufficient levels of vitamin D and

disease activity.

In another study Bonakdar, Jahanshahifar, Jahanshahifar & Gholamrezaei (2011) reported

that most of the SLE patients have vitamin D deficiency at the time of diagnosis that is

associated with a level of higher disease. This cross-sectional study was conducted in Isfahan
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city, Iran. Forty women with newly diagnosed SLE were enrolled, based on American College

of Rheumatology (ACR) criteria. Disease activity was measured by the British Isles Lupus

Assessment Group (BILAG) index and serum concentration of 25-hydroxyvitamin D (25(OH)D)

was measured by radioimmunoassay method. The results of the study showed a vitamin D

deficiency in new cases of SLE in Iran. Also, an increased disease activity associated with

vitamin D deficiency. Therefore. routine screening for vitamin D deficiency and prompt

treatment in patients with newly diagnosed SLE is recommended. Study limitations included

lack of control group and small sample size.

Abou-Raya, Raya & Helmii (2013) used a randomized, double-blinded, placebo-

controlled study assessing vitamin D status in patients with SLE and determined alterations in

inflammatory and hemostatic markers and disease activity before and after vitamin D

supplementation. Two hundred sixty-seven patients with SLE participated in this study (228

women, 39 men). The mean age was 38.8 years. All patients must meet at least 4 of the ACR

criteria for SLE. The patient was randomized into 2 groups: 178 patients assigned to received

oral cholecalciferol 2000 IU/day and 89 patients who were given placebo tablets for 12 months.

Both groups were allowed to continue their ongoing standard therapy (corticosteroids <10

mg/day, hydroxychloroquine (HCQ), immunosuppressants, and ace-inhibitors/ace receptor

blockers. None of the patients were taking a statin or vitamin D prior to the study. Vitamin D

levels were measured by Liaison immunoassay (normal 30-100 ng/ml, insufficiency 10-30

ng/ml, deficiency <10 ng/ml). Outcome measures included assessment of alterations in levels of

proinflammatory cytokines and hemostatic markers, and improvement in disease activity before

and after 12 months of supplementation. Disease activity was measured by SLE Disease Activity
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Index. Of the 267 patients, 236 completed the study.

The study showed that all baseline markers were significantly higher in patients with

SLE compared to healthy controls. There was significant decreased in levels of inflammatory,

hemostatic, and disease activity markers in the vitamin D group compared to the placebo group

after 12 months of therapy. Deficient 25 (OH)D serum levels were found in 33% of patients with

SLE at baseline, and after 12 months of therapy none of the patients in this group had deficiency.

There was a significant improvement disease activity as well as a significant reduction in the

levels of autoantibodies (anti-Sm, anti-dsDNA) and ESR levels. Further, the study also observed

a significant improvement in the levels of proinflammatory cytokines (IL-1, IL-6, IL-18, and

TNF-x). Changes in the concentration of these proinflammatory mediators reduced the disease

activity in SLE patients. The study concluded that vitamin D supplementation in patients with

SLE is recommended because it is safe, it provides anti-inflammatory effect and improve clinical

disease activity in lupus patients.

Sunscreen

Protection from direct or reflected sunlight and other sources of ultraviolet light must be

emphasized with lupus patients as well as the sunscreens, which blocks both ultraviolet A (UVA)

and ultraviolet B (UVB) protection. This is important because the majority of lupus patients are

photosensitive and have an increased greater risk of skin cancer because of immunosuppressive

therapy. In addition, lupus patient are encouraged to avoid excessive sun exposure, put them at

risk for vitamin D deficiency (Robinson, Cook & Currie, 2011).

Kuhn et al. (2011) assessed the use of broad-spectrum sunscreen can prevent skin lesions

in patients with different subtypes of cutaneous lupus erythematosus (CLE) induced by

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ultraviolet (UV) irradiation under standardized conditions. A total of 25 patients with a medical

history of photosensitive CLE were included in this monocentric, randomized, vehicle-

controlled, double-blind, intraindividual study. Patients were asked to stop any disease-

modifying medication including antimarials agents at least 6 weeks before the start of the study.

Furthermore, sun exposures were not permitted during this study course. The test product and its

vehicle were applied 15 minutes before UVA and UVB irradiation of uninvolved skin areas (4 x

5 cm) on the upper aspect of the back in a random order (untreated area, vehicle-treated area,

sunscreen area), and standardized phototesting was performed daily for 3 consecutive days. A

high-pressure metal halide lamp (340-440 nm) was used for UVA phototesting and a UV-800 unit

lamp with fluorescent bulbs (285-350 nm) for UVB phototesting. Irradiation output was

measured using a UV spectrometer. Patient were instructed to report any local or systemic

adverse event to the investigator during the study period. The X2 test, Fisher exact test and

McNemar test was performed to determine the photoprovation results.

The study showed a significant result in 25 CLE patients treated with the broad-spectrum

sunscreen and they did not develop any skin lesions compared to untreated or vehicle-treated

areas. Skin lesions were induced by UVA and UVB irradiation in 16 patients with CLE in the

untreated area, and14 showed a positive test result in the vehicle-treated area. In addition,

patients who were younger than 40 years at onset of CLE reported photosensitivity significantly

more often than patients with a higher age of disease onset. None of the patients showed any

adverse events from application of the test product or the vehicle. This study confirms that the

use of a broad-spectrum (UVB and UVA) sunscreen can effectively protect photosensitive

patients with CLE from developing skin lesions. Study limitation include data resulting from
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standardized experimental phototesting might not be transferable to a clinical testing.

In another study Zahn et al. (2014) demonstrated the ability of a broad-spectrum

liposomal sunscreen to prevent UV-induced damage to both patients with different CLE subtypes

and in healthy controls (HCs) using a standardized photovocation protocol. Twenty patients with

participated in this prospective open-label study. The areas on the upper back were treated with a

broad-spectrum liposomal sunscreen 20 minutes prior to a combined standardized UVA/UVB

irradiation. Skin biopsies were taken before (baseline) and 24 and 72 hours after standardized

UV irradiation from unprotected and sunscreen-protected areas of 20 CLE patients and 10 HCs.

Immunohistological analyses using antibodies directed against myxovirus protein A (MxA), type

I and III interferons (IFNs). These are cell molecules have been shown to be important

biomarkers in the inflammatory of lupus disease. The result showed significant higher level of

MxA in patients after 72 hours after UV irradiation compared to skin samples taken at baseline.

In sunscreen-protected skin patients, expression of MxA was significantly reduced compared to

unprotected skin 72 hours after UV irradiation and was completed negative in HCs by the use of

the sunscreen 24/72 hours after UV irradiation. No specific eruptions or skin damage were

observed in sunscreen-protected areas of CLE patients and HCs after combined UVA and UVB

irradiation. The study concluded that effective UV protection blocks the development of UV-

triggered CLE skin lesion by a reduction in lesional tissue damage and the inhibition of the

typical IFN-driven inflammatory response. There was no limitation recorded in this study.

Possible limitation is the sample size was small and there was no breakdown in gender.

Smoking cessation

It is widely believed that interactions between genetic and environmental factors

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contribute to the development of SLE. One of these environmental exposures is cigarette

smoking. Several studies have shown that smokers, particularly current smokers, have an

increased of developing SLE. Cigarette smoke contains numerous potentially toxic components,

including tars, nicotine, carbon monoxide and polycyclic aromatic hydrocarbons. Exposure to

such toxins, can directly damage cell proteins and DNA. Further, cigarette smoke also modulate

genes involved in pathways of inflammation and autoimmunity, increase production of pro-

inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL08

and macrophages factor and decrease levels of anti-inflammatory cytokines such as IL-10.

Cigarette smoking is associated with worse disease activity and severity, including more

extensive organ system involvement, perhaps triggering SLE (Takvorian, Merola & Costenbader,

2014).

Piette at el. (2012) investigated cigarette smoking in cutaneous lupus erythematosus. A

total of 197 individuals with CLE or SLE and lupus nonspecific skin disease participated in this

prospective longitudinal cohort study between January 2, 2007 and July 30, 2010. Cutaneous

Lupus Erythematosus Disease Area and Severity Index (CLASI) scores to assess disease severity

and response to treatment and Skindex 29+3 scores (function, emotion, symptoms and

photosensitivity) to assess patient quality of life. Participants with CLE were divided into 2

different treatment groups: those who were treated with only antimalarial drugs during

enrollment (Am only) and those were treated with at least one additional immonomodulator drug

(Am + IM). The result showed that current smokers with lupus erythematosus had higher median

CLASI scores than did never and past smokers with CLE. Current smokers had higher median

scores on all the Skindex 29+9 subsets. Current smokers taking hydroxychloroquine (HCQ) had
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higher quinacrine hydrochloride use than never and past smokers. Current smokers in the AM

only group had greater improvement than did never or past smokers at the 2 to 7 month (p=.2)

and 8-month and longer (P=.24) follow-up visits. In the AM+ IM group, never smokers had

greater improvement than past or current smokers at the 2-7 month (P=.07) and 8-month and

longer (P=.04) follow-up visit. However, current smokers are more likely to have refractory

disease than are nonsmokers and that antimalarial agents may be less effective in patients with

CLE who smoke. Nonsmokers had significantly lower rates of quinacrine and

hydroxychloroquine use compared with current smokers. The study concluded that current

current smokers with lupus had worse disease, has worse quality of life, and were more often

treated with a combination of HCQ and quinacrine than were nonsmokers. It is therefore, the

need for smoking cessation in the CLE population is recommended.

In another study Chasset et al. (2014) compared the efficacy of antimalarials among

smoker versus nonsmoker patients with CLE. The study conducted a systematic review of

literature and a meta-analysis of 240 citations, 10 studies met inclusion criteria, for a total of

1398 patients. The study showed that smoking is negative association between smoking and

response of CLE to antimalarials. There was 2-fold decrease in the proportion of smoker versus

nonsmoker patients who reached cutaneous response to animalarials in CLE. The study

concluded that smoking cessation should be considered in patients with CLE and refractory

cutaneous involvement. Study limitation include data about CLE subtypes were not available and

therefore no subgroup analysis base on these subtypes could be performed.

Bourre-Tessier et al. (2013) also examined the association between smoking and

cutaneous involvement in SLE. This prospective cohort study included 1,346 patients, the
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majority of patients were women (91.0%) and 62.6% were white. The mean age at the time was

47.1. A total of 554 patients reported ever smoking, 34.1% were current smokers and 65.9%

were past smokers. The majority of patients (69.6%) were receiving antimalarials (63.5%

receiving HCQ and 6.4% receiving chloroquine), while 34.8% were taking immunosuppressant

drugs. Mucocutaneous involvement was recorded using the SLEDAI 2K (rash, alopecia, and oral

ulcers) and Systemic Lupus International Collaborating Clinics/American College of

Rheumatology (ACR) Damage Index. (alopecia, extensive scarring, and skin ulceration), and the

ACR criteria for SLE (malar rash, discoid rash, photosensitivity, and mucosal involvement). The

study showed that being a current smoker is a risk factor for active skin manifestations as

recorded by SLEDAI-2K. The number of pack-years among current smokers was associated

with the presence of discoid rash according to ACR criteria. Past smoking was not associated

with active skin rash on the SLEDAI-2K. There was no association found between smoking and

cutaneous damage or mucosal ulcers. In addition, there was no interaction was seen between

smoking and antimalarials. The study concluded that tobacco smoking is serious and preventable

health hazard that can cause and exacerbate SLE patients. The need to counsel patients on

smoking cessation should be emphasized. Limitation in this study was that medication

nonadherence and sun exposure were not considered in the analyses. The estimates of cigarette

smoking were based on self-report and were not validated with biochemical test, therefore

leading to to an underestimation of the real association between smoking and cutaneous

manifestations.

Multiple Nonpharmacologic Interventions

Patient with SLE has numerous of clinical manifestations including fatigue. This can
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affect individuals physically, emotionally, cognitively, and behaviorally. Therefore, every effort

should be made to relieve fatigue in this population. Other nonpharmacologic therapy that can

reduce fatigue in SLE patients including exercise (Robinson, Cook & Currie, 2011).

In the study of Pino-Sedeno at al. (2016) conducted a systemic review to analyze the

effective of nonpharmacologic interventions to reduce fatigue in SLE patients. The databases

were searched with a total of 12 studies. The study assessed 5 main intervention categories:

exercise, behavioral and psychological approaches, diets, acupuncture, and phototherapy. All

interventions produced reductions in fatigue; however, aerobic exercise was found to be effective

and suitable for reducing fatigue in SLE patients. The aerobic exercises including walking,

jogging, cycling, and swimming. The appropriate exercise should start early in the disease

course, begin with low-intensity activities at least 3 times weekly for 15-30 minutes as tolerated.

A number of psychological interventions also appeared effective in reducing fatigue in SLE

patients included cognitive-behavior therapy, psychoeducational programs, relaxation, and self-

management. There were no differences with acupuncture or diet and ultraviolet. Overall the

study suggested at least one effect in reducing fatigue in SLE patients. However, methodological

differences between studies make it difficult to draw solid conclusions. More studies are needed

to verify the promising results shown in this review in order to recommend specific interventions

treat this this population.

Patient attachment and Working Alliance

SLE is a complex autoimmune disease that affect many different organ systems.

Pharmacotherapy is very essential and is highly individualized. Poor adherence to therapeutic

regimens is associated with a higher risk of flares, morbidity, hospitalizations and poor renal
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outcome. It is important that health care providers to educate patients with SLE in medication

adherence to achieve better outcome and quality of life (Costedoat-Chalumeau et al., 2013)

Bennett et al. (2011) tested the hypothesis that patients working alliance with their

physicians, and patients attachment styles would predict patients adherence, satisfaction, and

health-related quality of life. One hundred ninety-three patients diagnosed with lupus

participated in an online survey. They completed measures of the Physician-Patient Alliance

Inventory, Experiences in Close Relationships Scale, SF-36, General Adherence Inventory, and

the Medical Patient Satisfaction Questionnaire. The result showed that a working alliance

between patient and physician was positively associated with a significant increased all three

outcome variables of adherence, satisfaction, and quality of life. Attachment avoidance was

significantly and negatively related to adherence, and attachment anxiety was significantly and

negatively related to health-related quality of life. The study also concluded that a working

alliance between physician and patient should be in agreement on both goals and tasks of

treatment along with trust relationship. This strong relationship increase treatment efficacy and

effectiveness and improve outcome for individuals in lupus patients.

Pharmacologic Therapies

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAID are inhibitors of cyclooxygenases Cox-1 and Cox-2. Ninety percent of patients

with SLE experience arthralgia and polyarthritis. NSAIDs are often used first to mediate

inflammation and pain. For instance, Celebrex is a Cox-2 inhibitor, 100-200 mg/daily, ibuprofen

800 mg four times a day, naproxen 500 mg daily, or nabumetone 1 gram twice daily (Sweet et al,
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2013). There was no current research literature found during the year of 2011-2016. According

to Lupus Journal, NSAID is effective in treating arthritis/arthralgia, soft tissue pain, headache

and serositis in SLE. However, some toxic effects of NSAID are increased in SLE such as

hepatotoxicity, gastrointestinal bleeding/ulcers, renal failure, cutaneous allergic reactions, and

cerebral symptoms. Therefore, monitoring of NSAID therapy in SLE patient should include a

complete blood count, hepatic function test at regular intervals, and surveillance of renal

function, particularly in the presence of renal lupus (Ostensen & Villiger, 2001). Although this

literature review is outdated, it provides important information about NSAIDs that health care

provider should consider when prescribing this type of drug to SLE patients.

Antimalarials

The efficacy of antimalarials, especially hydroxychloroquine (HCQ), in preventing

systemic lupus erythematosus (SLE) flares is well demonstrated. HCQ is lipophilic, weak bases

that easily pass across cell membranes and into acidic intracellular vesicles. HCQ blocking the

toll-like receptor (TLR), anti-inflammatory, suppress autoantigen, photoprotective, inhibits

interferon-alpha production which plays a crucial role in SLE pathogenesis. In addition, HCQ

appears to protect against the occurrence of diabetes, thrombotic events and dyslipidemia. HCQ

is now recommended long-term for all patients with SLE. Patient should be counselled the risk

of retinal toxicity. Patient must have eye examinations at baseline and annually after 5 years of

HCQ (Lee, Silverman & Bargman, 2011)

Willis et al. (2012) determined the effect of hydroxychloroquine therapy resulted

significant clinical improvement in SLE patients by monitoring the level of proinflammatory

markers and disease activities. The patients in this study were selected from the Lupus in
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Minorities, Nature versus Nurture (LUMINA) cohort. It is a longitudinal study of multiethnic

(Hispanic, African American and Caucasian) SLE patients. Thirty-five patients were

participated. Plasma samples from participants were evaluated at baseline and after HCQ

treatment. Disease activity was assessed using Systemic Lupus Activity Measure-Revised

(SLAM-R) scores. Interferon (IFN)-x2, interleukin (IL)-1b, IL-6, IL-8, inducible protein (IP)-

10, monocytes chemotactic protein-1, tumor necrosis factor (TNF)-x and soluble CD40 ligand

(sCD40L) levels were determined by a multiplex immunoassay. The result showed that levels of

IL-6, IP-10, sCD40L, IFN-x and TNF-x were significantly elevated in SLE patients versus

control groups. HCQ therapy resulted in a significant decreased in SLAM-R scores (p=0.0157)

compared to baseline level (p=0.0546). The study concluded that HCQ treatment decreased

disease activity levels in SLE patients. Study limitation included small number of patients were

selected. Furthermore, there were several patients that met inclusion criteria but could not be

included due to insufficient volumes of stored serum samples.

Corticosteroids

Feng et al. (2012) demonstrated the elevated circulating T follicular helper (Tfh) cells and

plasma cells and ANA level in patient with SLE. Forty-two SLE patients (35 women and 7 men,

mean age 33.7 years) and 22 healthy volunteers control group were enrolled. Peripheral blood

mononuclear cells (PBMCs) were collected to assess proportions of circulating (cells)

CXCR5+PD1+CD4, T cells (Tfh), and CD19 and CD138 at baseline and after

methylprednisolone pulse treatment was assessed by rheumatologists using SLEDA. These cells

are believed to be crucial role in the pathogenesis of SLE. Percentage of peripheral blood were

analyzed by flow cytometry. The result showed percentage of CXCR5+ PD1+/CD4+ Tfh cells
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were higher in the SLE patients compared to normal controls. Tfh cell numbers dramatically

reduced after the patients received methylprednisolone pulse treatment (in addition to

dexamethasone). The study indicated that Tfh cells might interact with B cells and facilitated

autoantibodies production in SLE. The proportion of circulating Tfh cells was down-regulated by

corticosteroids, and therefore, this could be a new target in the treatment of SLE patients.

Methotrexate

Methotrexate is an immunosuppressive drug are usually prescribed to patients with

severe organ dysfunction or if they partially respond to glucorticoids (Robinson, Cook & Currie,

2011).

Islam et al. (2012) evaluated the efficacy and safety of methotrexate (MTX) compared

with chloroquine (CQ) to improve in articular and cutaneous manifestations of systemic lupus

erythematosus patient. Subjects (n=41) were randomly assigned to either 10 mg MTX weekly or

150 mg CQ daily during 24 weeks (n=15 MTX, n=26 CQ). Four patient dropped out due to

central nervous system and psychosis involvement. The study ended up with 37 patients, 36 were

female. Outcome measures were: numbers of swollen and tender joints, duration of morning

stiffness, visual analog scale (VAS) for articular pain, physician global assessment index, patient

global assessment index, SLE Disease Activity Index (SLEDAI), disappearance of skin rash and

erythrocyte sedimentation rate (ESR). The patients were allowed to continue corticosteroids in a

fixed dose, and dose not exceeding 10 mg/day orally. The study showed that both MTX and CQ

are effective in treatment of articular and cutaneous lupus patients. In both groups, the clinical

and laboratory parameters improved significantly over 24 weeks, except the ESR in the MTX

group. This may reflect ESR is not correlate with disease activity in SLE. The finding also
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. indicated that MTX can be used as a steroid-sparing agent when antimalarial drugs that often not

. responded with long-term higher dose of corticosteroids. There were several limitations

. including the small sample size, no double-blinded to treatment, many patients were illiterate and

. study was done without any funding or government. In addition, CQ used instead of

. hydrochloroquine (HCQ) because HCQ is more expensive and not available in Bangladesh.

. Although CQ is more effective but more toxic than HCQ. Future more research is needed in

. larger sample size in order to achieve enough difference between the two treatments.

Newer Treatments

There are several medications undergoing investigating to determine their role in the

current management of SLE. The monoclonal antibodies (belimumab and Rituximab) that

targets both B and T lymphocytes, which are the white blood cells associated with autoantibody

production in lupus. These treatments may be beneficial for patients that have failed other

therapy (Sweet et al, 2013).

Navarra et al. (2011) evaluated the efficacy and safety of belimumab in patients with

active SLE patients. The study included 867 patients were randomly assigned to belimumab

1 mg/kg (n=289) or 10mg/kg (n=290), or placebo (n=288) by intravenous infusion in 1 hour on

days 0, 14, and 28, and then every 28 days until 48 weeks. Two patients were excluded because

never received any study treatment. The response rate was assessed with SLE Responder Index

(SRI) at 52 weeks, SLEDAI score, British Isle Lupus Assessment Group (BILAG), and

Physicians Global Assessment (PGA) score. The study showed that Belimumab 1 mg/day and

10 mg/day significantly higher response rate than did placebo at week 52. The clinical

improvement and flare reduction was noted as early as week 16. Belimumab has the potential to
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be the first target biological treatment that is approved for SLE, providing a new option for the

management of this important autoimmune disease. Study limitation was that safety result cannot

rule out until as much larger number of patients is treated with belimumab for longer than 52

weeks.

Turner-Stokes et al. (2013) evaluated the efficacy of B-cell depletion therapy (BCDT)

with rituximab (RTX) in systemic lupus erythematosus patients. Subjects (n=18), all female;

mean age 29.9 years; mean duration of follow-up 58.7 months. BCDT was administered using

cyclophosphamide (CYC) 750 mg, methylprednisolone 124-250 mg and rituximab 1 g given

intravenously on two occasion, 2 weeks apart. Patient were reviewed at 1-2 monthly intervals

and disease activity assessed using the British Isles Lupus Assessment Group (BILAG) activity

index and serological markers (Anti-dsDNA, complement (C3). Clinical response was

categorized as completed or partial remission, or no response, based on the change in BILAG

scores. The result showed that disease activity was significantly reduced after both cycles of

BCDT at 6 months. More patients achieved disease remission after second cycle (82% vs 61%

first cycle). Based on this findings, repeated cycles of BCT with rituximab ware effective in

treating refractory SLE and has a favorable safety profile. Further, retreatment may produce a

more sustained clinical response. Limitation in this study was small sample size with a diverse

range of disease manifestations, which limits the extent to which the study can generalize the

result. Furthermore, there was patients dropping out, which unable to follow up completely. The

study concluded that rituximab is a safe and effective treatment for active and refractory SLE.

Further study in larger patient population is needed.

Nursing Implication
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The review of literature has important implication for clinical practice, research, and

education. One of the most important roles of the nurse practitioner is to provide education and

counseling regarding disease processes and treatments. This review provides information on

current practice management of lupus disorder as well as information on newer treatments.

Lupus is one of the most diverse immune disease with many different manifestations. Nurse

practitioners need to address any concerns a client may have regarding their disease and other

specific needs. In addition, nurse practitioners are able to offer a variety of treatments that

complement medical management.

Conclusion

The effective of pharmacologic and non-pharmacologic treatments in the reduction of

symptoms in lupus patients is well documented in the literature. Although some studies are

promising, they were limited and require additional research. Non-pharmacotherapy includes

protecting against ultraviolet light, adequate vitamin D supplement, exercise and smoking

cessation. Treatment options like NSAID, antimalarial, methotrexate are currently available to

patients, whereas newer treatments are undergoing investigation for SLE. Both kinds of

treatments are important to maintain a state of remission. Patients should be adequately

counseled on medication adherence to reduce health disparities and improve outcomes in patients

with lupus.
TREATMENTS 21

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doi: 10.1111/exd.1242
 Appendix A

Study Focus Size Demographic Intervention Method Findings

Souza et al. Evaluated P=45 18 years and older Serum levels Cross-sectional VD deficiency higher in
(2014) hypovitamin D in C=24 Gender not given 25 (OH) D measured Kruskal- study SLE compared to
SLE Wallis test compare the level of controls
patient and controls
Bonakdar et al. Evaluated VD P=40 Newly diagnosed Serum levels 25(Oh) D measured Cross-sectional VD deficiency a
(2011) deficiency & with SLE in Iran study over 1 year associated with higher
association with All women disease activity.
disease activity Mean age 25.3
Abou-Raya, Vitamin D P=267 F: 228 Randomized to receive 2000 IU Randomized, significant
Raya & Helmii supplement on C=175 M: 39 cholecalciferol or placebo x 12 double blinded, improvement disease
(2013) inflammatory & months placebo- activity & reduction
hemostatic markers controlled levels of autoantibodies
& disease activity (anti-Sm, anti-dsDNA)
in SLE and ESR levels.
Improvement level
proinflammatory
cytokines (IL-1, IL-6,
IL-18, and TNF-x) level
Kuhn et al. Broad-spectrum P=25 (LET) F:9 M:8 Product test & vehicle applied Monocentric, broad-spectrum (UVB
(2011) sunscreen in (DLE) F:2 M:3 15m before UVA & UVB randomized, and UVA) sunscreen
different type of (CLE) F:2 M:1 irradiation skin area upper back & vehicle- can effectively protect
CLE phototesting performed x 3 days. controlled, photosensitive patients
18 years or older double-blinded, with CLE from
intraindividual developing skin lesions.
Zahn et al. Ultraviolet light P= 20 CLE upper back treated with broad- Prospective No specific eruptions or
(2014) protection in CLE C=10 HCs spectrum liposomal sunscreen 20 open-label study skin damage in
Gender not given min prior UVA/UVB irradiation. sunscreen-protected
Skin biopsies were taken before areas of CLE patients
(baseline) and 24 and 72 h and HCs after UVA/
UVB
Piette et al. Cigarette smoking P=197 Gender not given 2 different treatment groups: group Prospective current smokers with
(2012) in CLE Never smokers=34% with only antimalarial drugs (Am longitudinal lupus had worse
Past smokers=27% only) and group with at least one cohort study disease, worse quality
Current additional immonomodulator drug of life &more often
smokers=39% (Am + IM). treated with a
combination of HCQ
and quinacrine than
were nonsmokers.
Chasset et al. Interaction between P=1398 Smokers=832 Compared the efficacy of Systematic smoking is negative
(2014) smoking & Nonsmokers=566 antimalarials drugs between review of the association between
antimalarials in F=76.6% smoker & nonsmoker patients with literature & smoking and response
CLE CLE Meta-analysis of CLE to antimalarials.
Sources: EMBASE, MEDLINE, literature
Cochrane Database of Systematic
review articles

Bourre-Tessier Association of P=1,346 F=91.0% SLEDAI-2K Prospective Tobacco smoking is

et al. smoking & W=62.6% SLICCS multicenter serious and preventable
(2013) antimalarial with MA=47.1 y ACR cohort health hazard that can
SLE MDD=13.2 y cause and exacerbate
Ever SLE patients
smoking=41.2%
Past smokers=65.9%
Current
smokers=34.1%
Pino-Sedeno et Nonpharmacolgic N=549 Not given Medline/Premedline, Embase, Systematic All interventions
al. interventions for PsychINFO, SCI-Expanded, Social review produced reductions in
(2016) decreasing fatigue Science Citation Index & fatigue; however,
in adult with SLE Cochrane. 12 studies: aerobic exercise was
7 randomized found to be effective
1 nonrandomized trial and suitable for
4 POS reducing fatigue in SLE
Assessed interventions: exercise, patients.
behavioral/psychological, diets,
acupuncture & phototherapy
Bennett et al. Patient attachment P=193 F=188 Online survey completed by Systematic Working alliance was
(2011) & working alliance M=5 patient on working alliance, Review positively associated
between patient & Age range-25-60 attachment orientation, treatment with a significantly
physicians White/Non- adherence, treatment satisfaction increase treatment
Hispanic=152 & quality of life adherence, satisfaction
Black/Non- & quality of life
Hispanic=13
Hispanic=12
Asian/Pacific
Islander=5
Native American=4
Other=7

Note: 25-Hydroxyvitamin D= 25 (OH) D; SLE=systemic lupus erythematosus; VD=Vitamin D

C=control; CLE= cutaneous lupus erythematosus; DLE= discoid lupus erythematosus; P=patients; M=male; F=female;
HCs=healthy controls; HCQ=hydroxychloroquine; POS=prospective observational studies; SLEDAI-2K=systemic lupus
erythematosus disease index 2000; SLICCs=systemic lupus international collaborating clinics; ACR=American college of
rheumatology
 Appendix B

Study Focus Size Demographic Interventio Method Findings

n
Willis et al. Effect of HCQ P=35 F=85% Patients place LUMINA HCQ TX decreased disease
(2012) TX on pro- Age=18-65 on HCQ & longitudinal activity levels In SLE
inflammatory MA=33.9 serum plasma cohort study
cytokines and Hispanic samples taken
disease activity (Mexican/Central before & after
in SLE American & therapy at least
Puerto Rican), 6 months
African American
& Caucasian
Feng et al. Inhibiting P=42 SLE SLE PBMCs were Not given percentage of CXCR5+
(2012) circulating Tfh HCs=22 MA=33.7y collected to PD1+/CD4+ Tfh cells higher in
cells in SLE by F=35 assess the SLE patients compared to
corticosteroids MDD=7.05y circulating cells normal controls. Tfh cell
in SLE and numbers dramatically reduced
HCs HCs after the patients received
F=20 methylprednisolone pulse
MA=34.1 treatment (in addition to
dexamethasone).
Islam et al. Efficacy and P=37 F=36 Randomly Prospective Both MTX & CQ are effective in
(2012) safety of MTX assigned either open-label TX of articular& CLE.
& HCQ in 10 mg MTX study
articular & weekly or 150
cutaneous of mg CQ for 24
SLE weeks.
Navarra et al. Evaluated the P=867 Randomly Randomized, Belimumab 1mg/kg and
(2011) efficacy & assigned to placebo- 10mg/kg significantly higher
safety of belimumab controlled, response rate than did placebo at
belimumab in 1mg/kg or phase 3 trial week 52. Clinical improvement
patient with 10 mg/kg or & flare reduction at week 16.
active SLE placebo by IV
in 1h on day 0,
14, 28 & q28
days until 48
weeks
Turner-Stokes et al. Evaluated P=18 All female BCDT Evaluation Disease activity significantly
(2013) efficacy of MA=29.9 administered study reduced after both cycles of
repeated TX of via IV 2 wks BCDT with RTX at 6 months.
BCDT with apart. P were Disease remission after 2nd cycle.
RTX in SLE reviewed at 1-2
monthly
intervals. DA
assessed by
BILAG &
serological
markers.

Note: P=patient; W=white; Y= year; MA=mean age; MDD=mean disease duration; DA=disease activity; SLE=systemic lupus
erythematosus; CLE=cutaneous lupus erythematosus; SLEDAI-2K=systemic lupus erythematosus disease index 2000;
SLICCs=systemic lupus international collaborating clinics; ACR=American college of rheumatology;
HCQ=hydroxychloroquine; CQ=chloroquine; MTX=methotrexate; RTX=rituximab; BCDT=b-cell depletion therapy;
TX=treatment; PBMCs=peripheral blood mononuclear cells: LUMINA=lupus in minorities, nature versus nurture;
BILAG=British Isle lupus assessment group; IV=intravenous; MD=mean duration; F/U=follow-up; HCP=health care provider;
PPAI=the physician-patient alliance inventory; ERS=the experiences in close relationship scale; GAI=the general adherence
inventory; MPSQ=the medical patient satisfaction questionnaire.