Lupus or Systemic Lupus Erythematosus (SLE) is an autoimmune multisystem disease that can affect

many different tissues and organs in the body, including skin, joint, kidney, blood cells, heart, and
lungs. Some patients have mild form of the disease whereas others have serious life-threatening
complications. Lupus is a chronic disease and is characterized by periods of remissions and relapses
or flare.

Risk factors:

The exact cause of Lupus is unknown. Although there are certain factors that trigger the immune
system to attack various parts of the body.
Factors that may play a role in development of Lupus:

 Sex- more common in women (90%).

 Age- Although it affects people of all age, it is more common between age of 15 and 40.
 Hormonal factor- As most affected women are in there reproductive age group.

 Race- More common in people of African, Asian, and Native American descent.
 Genetic factor - An identical twin has a 3-10 fold greater risk of getting lupus than a non-
identical twin. Also, first-degree relatives (mother, father, brother, sister) of people with lupus
have an 8- to 9-fold increased risk of having lupus than the general public.

 Environmental factors- Certain environmental factors such as diet, drugs, toxins, viral
infection (Epstein-Barr virus), and sun-exposure may trigger autoimmune response in
genetically susceptible individuals.
 Reversible drug induced Lupus- Most frequently responsible drugs are hydralazine
(Apresoline), procainamide (Procanbid), and isoniazid (Laniazid).

Symptoms:

 The most common initial symptoms are fatigue, fever (rarely exceeding 102°F), and joint and
muscle pain.
 Skin and hair- Malar flush, alopecia
 Kidney system-
 Heart and blood vessels- Chest pain due to Pericarditis. Atherosclerosis leading to angina
and heart attack. Some people develop Raynaud syndrome.
 Nervous system- Seizure, nerve paralysis, severe depression, psychosis, and stroke.
 Lungs- Pleurisy leading to chest pain and shortness of breath. Pleural effusion or Pneumonia
may develop as well.
 Blood and lymph system- Anemia, thrombocytopenia, and leukopenia leading to bleeding and
bruising from the skin and in severe cases, it can cause internal bleeding. Some may develop
blood clots in veins (leading to phlebitis) or arteries (leading to strokes or other problems).
This is due to presence of auto antibodies called antiphospholipid antibodies.
 Stomach, intestine, liver, and associated organs- Painless ulcers in the mouth and nose,
abdominal pain, and liver is rarely involved.

Treatment:

There is no treatment cure for SLE, but there are medications that may control many
symptoms and often can prevent or slow organ damage. Although many medications are
used for management of SLE and its complication, only corticosteroids, aspirin and
hydroxychloroqine (HCQ) are specifically approved by FDA.
Most other medications are available off label-
 Cyclophosphamide
 Azathioprine
 Abatacept
  Cyclosporine
 Leflunomide
 Methotrexate
 Mycophenolate mofetil
 Rituximab
 Tacrolimus
 Thalidomide

Medication choices-

A. Mild disease or symptoms:

 NSAIDs: Aspirin or other NSAIDs such as ibuprofen (Advil, Motrin) and naproxen
sodium (Aleve) may be used to treat variety of signs and symptoms associated
with Lupus. NSAIDs are available over the counter, or stronger versions can be
prescribed by the physician.
Some people have been associated with serious side effects due to NSAIDs.
Side effects of NSAIDs include stomach bleeding, kidney problems, and
increased risk of heart problems.
 Corticosteroids: These drugs counter the inflammation of Lupus. Steroid creams
can be applied directly to rashes. The use of steroid cream and tablets in low
doses can be effective for mild to moderate cases of Lupus.
Corticosteroids can have serious long term side effects such as weight gain,
osteoporosis, high blood pressure, easy bruising, and increased risk of infections.
The risk of side effects increases with higher doses and long term therapy. So
corticosteroids are sometimes given in combination with other medication to help
reduce its dose and thus the toxicity. Calcium and vitamin D supplements are
given to reduce risk of osteoporosis.
 Antimalarial drugs: Hydroxychloroqine (HCQ) is used in case of mild symptoms
such as skin and joint diseases. This is also effective to prevent Lupus flares.
Side effects of include vision problem and muscle weakness. So it is important
that patients get eye check-up done at regular interval.

Treatment for specific signs and symptoms-

 Joint pain and swelling: Initially controlled with NSAIDs. In case of significant joint
pain corticosteroids or Antimalarial drugs are used.
 Fatigue: It is treated by determining the treating the underlying cause. In case the
cause can`t be determined medications such as corticosteroids and Antimalarial
drugs can be considered.
 Swelling around heart and lungs: NSAIDs, Antimalarial drugs or corticosteroids.
 Skin rashes- Avoid sun and use sunblock. Treat rashes with topical
corticosteroids. Oral steroids and Antimalarial drugs can also be used.

B. Life threatening cases of Lupus, those including inflammation in the blood vessels, kidney
problems, and CNS symptoms such as psychosis and seizures, may require aggressive
course or treatment.

 High dose corticosteroids taken orally or intravenously. High dose is

associated with serious side effects, including infection, high blood pressure,
osteoporosis, and mood swings.
 Immunosuppressive drugs:
1. Cyclophosphamide (Cytoxan) is a chemotherapy drug which has powerful
effect on reducing the immune system activity. It is used in severe cases,
such as those affecting the brain or kidney.
2. Azathioprine (Imuran, Azasan) lowers body`s immune system.
3. Methotrexate (Rheumatrex) is another chemotherapy drug that is used to
suppress the immune system. It is used for arthritis, skin diseases, and other
 non –life threatening forms of Lupus that have not responded to HCQ or low
doses of steroids.
4. Mycophenolate mofetil (CellCept) is another drug that suppresses the
immune system.

Depending in drug, immunosuppressive medication can be taken orally or

intravenously. Side effects of immunosuppressive drugs include increased
risk of infections, liver damage, increased risk of cancer and infertility.
High-dose corticosteroids can be combined with immunosuppressive drugs to
reduce dosage of each drug, and thus reduce the risk of side effects.
 Rituximab (Rituxan) is a biologic agent originally used to treat lymphoma and
RA. It is used to treat the most serious types of Lupus when other therapies are
not effective.
 Anticoagulants are prescribed in patients with antiphospholipid antibody
syndrome who have previously had clots in a vein or artery. In case of
antiphospholipid antibody syndrome but no blood clot, aspirin is prescribed.

Novel treatment therapy for SLE: Biological therapies:

In last decade or so there have been significant advances in the treatment of SLE, and there are a
variety of immunologic therapies at various stages of clinical development. The improved
immunobiology and immunopathology of SLE, though incomplete, has led to identification of several
important cellular and molecular targets, such as cytokines, co-stimulatory molecules etc. These
potential target mechanisms are summarized in Fig.1.

It is important to develop new improved immunotherapeutic agents to try reducing some of the well
known side effects associated with current treatment therapy and also to increase the efficacy of the
therapy.
 A. Biologic agents:
Biologic agents currently under trails target various immunological process, such as B-cell and T-cell
function, cytokine production etc. These medications can lead to B-cell depletion, act as modulators
and tolerogens and block costimulatory and cytokine pathways. These agents are still under trials and
their efficacy is yet to be proven.

Various biologic agents:

1. B-cell depleters:
 Rituximab- CD20 is a B-cell specific surface molecule that plays important role in B-
cell activation, proliferation and differentiation. Rituximab is a chimeric anti-CD20
monoclonal antibody, which depletes B-cells from peripheral circulation, but allows
regeneration from stem cells. Trials have shown significant improvement in fatigue,
arthritis and rash.
The most common side effects observed in patients treated with Rituximab were
infections (viral, bacterial and fungal), infusion reactions, skin rash and pruritus,
nausea and abdominal pain. Human anti-chimeric antibodies (HACAs) responses
can be produced, though as yet have not caused major clinical problem. The HACA
response has theoretical potential to cause problems in re-treatments.
 Ocrezulimab- Ocrelizumab is a 'humanized' monoclonal antibody to CD20. The
rationale is that it should avoid the potential problems of HACA responses with
Rituximab.
 Epratuzumab is a humanized recombinant monoclonal antibody against CD22, a
molecule expressed on the surface of mature B cells. Epratuzumab, unlike rituximab,
does not lead to complete B-cell depletion.

2. B-cell modulators:
 Belimumab: B-lymphocyte stimulator protein (BLyS), also known as B-cell activating
factor (BAFF), is a cytokine of the TNF ligand superfamily, which acts as an important
growth factor for B cells. BLyS binds to three different receptors, transmembrane
activator and calcium-modulating cyclophilin ligand interactor (TACI), BAFF receptor
(BAFF-R) and B-cell maturation protein (BCMA). Studies have shown that levels of
BLyS are elevated in SLE, as demonstrated by the presence of BLyS mRNA and also
by cell surface expression. Belimumab, a human monoclonal antibody specific for
BLyS, was added to standard-of-care therapy in a placebo-controlled trial of patients
with active lupus. The drug was well tolerated with no increase in adverse events.
 Atacicept: A proliferation-inducing ligand (APRIL) is another member of the TNF
ligand superfamily, which binds to both TACI and BCMA, but not to BAFF-R. Hence,
APRIL may be able to influence the effects of BLyS. Interestingly, APRIL levels seem
to correlate inversely with both SLE disease activity and levels of BLyS in lupus
patients. TACI-IgG (Atacicept) is a soluble receptor that binds to BLyS and APRIL.

3. B-cell tolerogens:
 Abetimus: LJP-394 (Abetimus), an immunomodulating B cell tolerizing agent,
consists of four double-stranded oligonucleotides attached to a nonimmunogenic
polyethylene glycol as carrier. This synthetic B-cell toleragen molecule, which acts as
an 'anti-anti DNA', by cross-linking surface anti-dsDNA antibody molecules, with
consequent decrease in anti-dsDNA antibody production. One drawback is the
frequency of administration—as a weekly infusion over a period of over 4 months—
but no major toxicity has been shown in almost 1000 patients.

4. Costimulatory pathway blocker:

Above Figure demonstrates costimulatory molecules important For B and T cell activation. Upon
interaction with antigen APCs (antigen presenting cells), such as B-cells and macrophages stimulate
to express specific surface molecule not present on resting APCs. Among these, the B7 molecules
(B7-1 and B7-2) play an important role in T cell activation. The interaction of B7 on APCs and CD28
on T cells provides an important second signal for T cell activation, the first being interaction of
antigen with T-cell receptor complex.

 Anti- CD4 Ligand antibody: While B7 is expressed on activated APCs, a molecule

designated as CD40 ligand (CD40L) is expressed on activated but not resting helper
T cells. CD40L binds to a complementary molecule designated as CD40 on B cells
and is responsible for antibody production. CD40L is expressed in a higher
percentage of T cells and for longer periods of time in patients with lupus compared
with controls. Preliminary studies in animal models of SLE demonstrated that
selective blockade of the CD40L/CD40 interaction early in life inhibits autoantibody
production, reduces nephritis, and improves survival.
 Abatacept: CD28 and CTLA4 are costimulatory molecules expressed on the T-
lymphocyte surface; CD28 is normally expressed in resting T-cells and CTLA4 is
expressed after initial T-cell activation. They both bind to CD80(B7.1)/CD86(B7.2)
receptors present on the surface of APCs. The engagement of CTLA4 with B7
receptors appears to down-regulate the immune responses, thus CTLA4 plays a role
in terminating T-cell responses. In contrast, signalling through CD28 prevents anergy
and apoptosis induced by T-cell receptor signalling alone.
CTLA4-Ig (Abatacept) works by blocking the T-cell costimulatory pathway. It is a
recombinant molecule consisting of the extracellular domain of CTLA4 receptor linked
to CH2–CH3 domains of IgG, which specifically blocks the interactions between
CD28 and B7.1/B7.2 receptors expressed on APC. Although this agent is FDA-
approved for rheumatoid arthritis (RA), clinical trials of preventing flares of
generalized SLE did not meet primary or secondary end points. Abatacept currently is
being studied in patients with LN maintained on a background of Mycophenolate
mofetil (MMF) and corticosteroids. Trials of agents that block CD40:CD40L interaction
was unsuccessful because of adverse thrombotic events.


5. Anticytokine therapy:
  Infliximab: It is an anti TNF alpha monoclonal antibody. . Anti–TNF-α agents have been
used in patients who have mild SLE with arthritis as the predominant feature. Anti–TNF-α
agents also are in trials for treatment of patients with LN and cutaneous lupus.
 Etanercept: It is a TNF alpha inhibitor.

6. Immune modulator:
 Lupuzor: It`s action aimed at modulating the body’s immune system so it does not
attack healthy cells without causing adverse side effects. It  has successfully
completed phase I, Phase IIa and Phase IIb studies and is now in preparation for
phase III.

B. Intravenous Immunoglobulin:
Clinical trials have shown improvement in proteinuria in most of the cases treated with IVIg. A
numbers of other features of Lupus have been treated with IVIg including, cytopenias,
cerebritis, neurological involvement, and secondary APS. Fever, arthritis, thrombocytopenia,
and neuropsychiatric lupus responded better to IVIg therapy.

C. Peripheral blood stem cell transplantation:

The concept of this therapy is to try resetting the aberrant immune system.

D. Hormonal therapies:
Sex hormone may have a role in development of Lupus. Oral formulation (Prasterone) of
adrenal steroid hormone dihydroepiandrosterone (DHEA) is investigated upon as possible
treatment of SLE. Various trials and clinical trials are ongoing over the last 10 years, but
controversy still exists regarding the efficacy of Prasterone.

Other novel treatment therapy:

A. Immunoablation with or without stem cell transplantation:

Immunoablative therapy is often effective in inducing remission in SLE patients, but there are
cases of incomplete response and relapse.

Conclusion:
The current treatment therapy of SLE is not very effective in treating the disease symptoms
and is also associated with significant adverse effects.
The future holds promise as various novel therapies discussed in the presentation are under
clinical trials and at various stages of development. These newer therapies, especially
biologic therapy, have shown potential to have better efficacy and/or better side effect profile.
Hopefully next 5-7 years will see some of these therapies being approved by FDA which
should improve disease control and quality of life.

http://lupus.webmd.com/lupus_systemic_lupus_erythematosus_article
http://lupus.webmd.com/arthritis-lupus
http://lupus.webmd.com/guide/lupus-systemic-lupus-erythematosus-other-treatment
http://www.mayoclinic.com/health/lupus/DS00115/DSECTION=treatments-and-drugs
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