TUTORIAL REPORT

HEMATOIMMUNOLOGI

Scenario 4

The afro-carribean lady with using new chemical hair relaxation treatment

Composed by :

Agam Anggoro (1218011005)

Azmy Hanimah (1218011027)
Fairuz Rabaniyah (1218011048)
Farida Hakim (1218011050)
Ika Noverina Sihotang (121801177)
Lana Asfaradilla (1218011094)
M. Ridho Ansori (1218011
Radian Pandhika (1218011118)
Rana Raydian (1218011
Rembulan Ayu NP (121801126)
Sevfianti Jamil (1218011141)
Zaras Obella (1218011164)

MEDICAL FACULTY

LAMPUNG UNIVERSITY

2014
 PREFACE

Thank God we pray to the presence of Almighty God, who presumably should say the
authors, because of the blessings of His grace and guidance we can finish this report. In this
report explains the result of the discussion in tutorial. This report was made in order to meet
the duty of this blok HematoImmunology.

We recognize, in this report there are many mistakes and shortcomings. these are due to the
limited ability, knowledge and experience that we have, however, there are many people who
have helped us by providing documents or resources, provide thought input. Therefore we
expect criticism and suggestions for the improvement and perfection of this report in the
future. Hopefully, this report can be useful for us in especially and readers in general.
Scenario 4

The afro-carribean lady with using new chemical hair relaxation treatment

A 41 years old afro-carribean lady presented a 72 hours history of sore red eyes, oral mucous
ulceration,, labial crusting, feverish arthalgia, and wishpread rush. She was normally fit and
well, had no symptoms prior to the above, and normally workedas a retail assintant in a
departement store. She had no past medical history of note, took no regular medicationor
supplements andhad no recent travel abroad. At presentationshe was noticed to be febrile at
39C, but otherwise haemodynamically stabele. Examination revealda pseudo-membranous
conjuntivitis, extensive oral ulcerations and non-vesicular lip crusting with a muco-serous
discharge. She had widespread target lesions over her arms, legs, and trunk, highly
characteristic of erythema multiform. Retrospesificly, the only unusual contack the patient
recollect was having used a new chemical hair relaxation treatment3 days prior to the
symptoms araising. She recalls noticing some scalp irritation commencing a few hours after
the treatment, but dismissed the significance of this initially.

In the absence of any infective or medication related precipitant, what happened with this
lady?
STEP 1 Define unfamiliar word

1. Oral mucous ulceration is an ulcer that occurs on the mucous membrane of the oral
cavity.
2. Arthalgia it is a symptom of injury, infection, illnesses (in particular arthritis) or an
allergic reaction to medication.
3. Erytema multiforme is a type of hypsersensitivity reaction. It occurs in response to
medicines, infections, or illness.

STEP 2 Define the problem

1. How Imune and hypersensitivity mechanism?

2. What the Diagnosis and Differential diagnosis in scenario?
3. How SJS and SLE disease?
4. Explain therapy medication in SJS and SLE?

STEP 3 Brain Storming

1. The immune system is typically divided into two categories--innate and adaptive--
although these distinctions are not mutually exclusive.
Innate immunity
Innate immunity refers to nonspecific defense mechanisms that come into play
immediately or within hours of an antigen's appearance in the body. These
mechanisms include physical barriers such as skin, chemicals in the blood, and
immune system cells that attack foreign cells in the body. The innate immune
response is activated by chemical properties of the antigen.
Adaptive immunity
Adaptive immunity refers to antigen-specific immune response. The adaptive immune response is
more complex than the innate. The antigen first must be processed and recognized. Once an antigen
has been recognized, the adaptive immune system creates an army of immune cells specifically
designed to attack that antigen. Adaptive immunity also includes a "memory" that makes future
responses against a specific antigen more efficient.

The cellular system

 T-cells differentiate in the thymus, and have a specific receptor for a fragment of antigen..
Cytotoxic T-cells contain a surface protein called CD8 and destroy pathogen infected cells,
cancer cells, and foreign cells (transplanted organs).
Helper T-cells contain a surface protein called CD4 and regulate both the cellular and
humoral immune systems. This regulation reduces autoimmunity.
Autoimmune disease- self immunity. Some examples include rheumatic fever, rheumatoid
arthritis, ulcerative colitis, myasthenia gravis, etc.

Microscopic movie of
cytotoxic
lymphocytes killing a
tumor cell
(1257 kb)

Immunological response

The graph shows a very important feature of the immune

response. When first exposed to antigen "A", we begin to
make low levels of antibody in about a week However, a
second exposure to antigen "A" produces a much faster
response, and several orders of magnitude higher levels of
antibody. The ability of antibody to bind antigen also
increases dramatically in the secondary response. Injecting a
new antigen "B" with "A" shows that a memory or prior
exposure is required for the accelerated response. The
memory of antigen and the stimulated response is the basis
for success in vaccination programs. We explain memory by
the clonal selection theory of the immune response.

The Clonal Selection Theory

The immune systems produces Billions of kinds of B-cells each making one kind of
antibody receptor.
The presence of antigen leads to the proliferation and differentiation of clones that have
 antibody capable of binding the antigen. In the diagram the "green" antigen binds to the
green antibody on a B-cell. The color code means that only this antibody receptor on the cell
binds free antigen.
The "green" helper T-cell must give a stimulatory signal to allow a particular B-cell to be
selected. This step allows a regulation or control of the process.
The antigen driven selection produces memory cells and plasma cells secreting antibody
capable of binding the original selecting antigen with high affinity..
If antigen appears in the organism a second time, then the memory cells are already present
at high levels, and produce a more rapid and much stronger immune response.

We will discuss the Humoral System, and in particular how we can produce so many kinds of
antibody, and the differences between a primary and secondary immune response. Regulation of the
immune response requires the participation of a set of cell surface glycoproteins called the MHC or
Major Histocompatibility Complex. The Cellular System recognizes the MHC to regulate both B-cell
and T-cell responses.

HYPERSENSITIVITY

Hypersensitivity refers to excessive, undesirable (damaging, discomfort-producing and

sometimes fatal) reactions produced by the normal immune system. Hypersensitivity
reactions require a pre-sensitized (immune) state of the host. Hypersensitivity reactions can
be divided into four types: type I, type II, type III and type IV, based on the mechanisms
involved and time taken for the reaction. Frequently, a particular clinical condition (disease)
may involve more than one type of reaction.
TYPE I HYPERSENSITIVITY

Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The

reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx
(rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract
(gastroenteritis). The reaction may cause a range of symptoms from minor inconvenience to
death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen,
although sometimes it may have a delayed onset (10 - 12 hours).

Immediate hypersensitivity is mediated by IgE. The primary cellular component in this

hypersensitivity is the mast cell or basophil. The reaction is amplified and/or modified by
platelets, neutrophils and eosinophils. A biopsy of the reaction site demonstrates mainly mast
cells and eosinophils.

The mechanism of reaction involves preferential production of IgE, in response to certain

antigens (often called allergens). The precise mechanism as to why some individuals are
more prone to type-I hypersensitivity is not clear. However, it has been shown that such
individuals preferentially produce more of TH2 cells that secrete IL-4, IL-5 and IL-13 which
in turn favor IgE class switch. IgE has very high affinity for its receptor (Fc; CD23) on mast
cells and basophils.

A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the
release of various pharmacologically active substances (figure 1). Cross-linking of IgE Fc-
receptor is important in mast cell triggering. Mast cell degranulation is preceded by increased
Ca++ influx, which is a crucial process; ionophores which increase cytoplasmic Ca++ also
promote degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress
degranulation.

The agents released from mast cells and their effects are listed in Table 1. Mast cells may be
triggered by other stimuli such as exercise, emotional stress, chemicals (e.g., photographic
developing medium, calcium ionophores, codeine, etc.), anaphylotoxins (e.g., C4a, C3a, C5a,
etc.). These reactions, mediated by agents without IgE-allergen interaction, are not
hypersensitivity reactions, although they produce the same symptoms.
TYPE II HYPERSENSITIVITY

Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and
tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to
cell membranes can also lead to type II hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia
and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is
primarily mediated by antibodies of the IgM or IgG classes and complement (Figure 2). Phagocytes and K
cells may also play a role.

The lesion contains antibody, complement and neutrophils. Diagnostic tests include detection of circulating
antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by
immunofluorescence. The staining pattern is normally smooth and linear, such as that seen in Goodpasture's
nephritis (renal and lung basement membrane) (figure 3A) and pemphigus (skin intercellular protein,
desmosome) (figure 3B).

Treatment involves anti-inflammatory and immunosuppressive agents.

TYPE III HYPERSENSITIVITY

Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general
(e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus,
Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis),
joints (e.g., rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases
caused by many microorganisms.

The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by
soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The
antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific
autoimmunity: e.g., systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ
involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage
is caused by platelets and neutrophils (Figure 4). The lesion contains primarily neutrophils and deposits of
immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing
process.
The affinity of antibody and size of immune complexes are important in production of disease and
determining the tissue involved. Diagnosis involves examination of tissue biopsies for deposits of
immunoglobulin and complement by immunofluorescence microscopy. The immunofluorescent staining in
type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture's syndrome).
The presence of immune complexes in serum and depletion in the level of complement are also diagnostic.
Polyethylene glycol-mediated turbidity (nephelometry) binding of C1q and Raji cell test are utilized to detect
immune complexes. Treatment includes anti-inflammatory agents.

TYPE IV HYPERSENSITIVITY

Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The
classical example of this hypersensitivity is tuberculin (Montoux) reaction (figure 5) which
peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is
characterized by induration and erythema.

2. Diagnosis : SJS

Symptoms and Clinical Manifestations

The theory is based on the fact Patients
between 1-14 day prodrome of fever , lethargy , stone , cold , painful swallowing ,
chest pain , muscle aches , arthralgia .
after taking the drug 2 times , the patient complained of his body felt hot
accompanied with fever , dizziness , and nausea
Incurred skin symptoms such as macular erythematous rash that resembles
morbiliform , arise on the face , neck , chin , body , and extremities
reddish splotches appeared originally appeared in the face and then spreads
throughout the body . Eventually , fluid-filled blisters form in selurih body . The
fluid-filled bumps multiplied and grew in size .
The existence of the target lesion , however , in contrast to the typical lesions of
erythema multiforme , these lesions have only two color zones . core may be vesicular
, purpuric , or necrotic , the zone surrounded by macular erythema
epidermolysis sign ( - )
Abnormal mucous membranes : the lips , oral mucosa felt pain , accompanied by
 mucosal abnormalities erythematous , swollen , accompanied by a bull , which then
rupture causing erosion pseudomembrane covered . Lips covered with massive
hemorrhagic crust .
Abnormalities in the mouth causing difficulty eating , breathing , and
hypersalivation occurred .
The patient also complained of soreness in the mouth with lips feel swollen . The
patient also complained of the emergence of black splotches . Patients have difficulty
eating due to pain .
On physical examination found oral mucosal erythema and edema and hemorrhagic
crust on his lips .
. Abnormalities in the eye conjunctiva obtained stinging , conjunctivitis , anterior
uveitis , and panophthalmitis , in severe cases erosion and perforation of the cornea .
Abnormalities in sex often obtained hemorrhagic bullae and erosions . The patient
also complained of pain and the amount of viscous fluid out of the eye that causes the
eyes difficult to open his eyes .
Conjunctivitis ( + )

Differential diagnosis : SLE, Erythema multiforme, Hypersensitivitas type 4,TEN

SLE is based on a combination of clinical findings and laboratory evidence. Familiarity with
the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex
disease based on the pattern of target-organ manifestations.

The presence of 4 of the 11 American College of Rheumatology (ACR) criteria yields a

sensitivity of 85% and a specificity of 95% for SLE.

When the Systemic Lupus International Collaborating Clinics (SLICC) group revised and
validated the ACR SLE classification criteria in 2012, they classified a person as having SLE
in the presence of biopsy-proven lupus nephritis with ANA or anti-dsDNA antibodies or if 4
of the diagnostic criteria, including at least 1 clinical and 1 immunologic criterion, have been
satisfied
3. Steven - Johnson Syndrome ( SJS ) is a hypersensitivity reaction mediated immune
complex which is a severe form of erythema multiforme . SJS is also known as
erythema multiforme major. SJS usually involves the skin and mucous membranes .
When the minor forms occur , significant involvement of the mouth , nose , eyes ,
vagina , urethra , gastrointestinal tract , respiratory tract and mucous membranes
under can develop into a disease . Involvement of the gastrointestinal tract and
respiratory tract may progress to necrosis . SJS is a serious systemic illness potentially
be a very serious illness and even be a death .
Stevens - Johnson Syndrome ( SJS ) and Toxic Epidermal necrolysis ( TEN ) long ago
regarded as a severe form of erythema multiforme . Recently proposed that erythema
multiforme major is different from SJS and TEN in determining the basis of clinical
criteria . The proposed concept is to separate the spectrum of erythema multiforme
spectrum of SJS / TEN . Erythema multiforme , target lesions characterized by
common , occurring post- infection , often recurrent but morbidity is low . While SJS
/ TEN is characterized by extensive blisters and maculopapular , usually occurs due to
reactions induced by drugs with high morbidity and poor prognosis .

Pathophysiology

Stevens - Johnson Syndrome is a hypersensitivity disease mediated by immune

complexes that may be caused by some medications , viral infections , and
malignancies . Cocaine is currently added to the list of drugs capable of causing this
syndrome . Until the majority of cases are detected , there is no specific etiology can
be identified .

Approximately 50% of the cause of SJS is a drug . The highest ranking is

Sulfonamides drugs , beta- lactams , imidazole , and NSAIDs , while the middle rank
is quinolones , aromatic anticonvulsants and allopurinol . Some of the factors causing
SJS include : infection ( herpes simplex virus , and Mycoplasma pneumonia , eating (
chocolate ) , and vaccination . Physical factors ( cold, whole solar rays , X-rays)
apparently acts as originator ( the trigger ) . Pathogenesis of SJS to date unclear
although often associated with hypersensitivity reactions type III and IV . therefore
hypersensitivity process , then there is damage to the skin resulting in :
1 . Skin malfunction that causes fluid loss
2 . Hormonal stress followed by an increase in insulin resistance , hyperglycemia and
glucosuria
3 . failure of thermoregulation
4 . Failure of immune function
5 . Infection .

In East Asia , a syndrome caused by carbamazepine and phenytoin are closely

 connected with ( B * 1502 allele of the HLA - B ) . A European study found that the
gene marker is only relevant for East Asia . Based on the findings in Asia , conducted
a similar study in Europe , 61 % of SJS / TEN induced allopurinol carry HLA- B58 (
B * 5801 allele - frequency of phenotypes in Europe is generally 3 % ) , indicating
that the risk allele differs across ethnic / ethnicity , locus HLA - B is closely related to
genes related.

Steven-Johnsons Syndrome (with <10% body surface involved) had a mortality rate
of about 5%. The risk of death can be estimated using SCORTEN scale, by using a
number of prognostic factors were summed. Other outcomes include organ damage
and death.

cause

Etiology SSJ difficult to determine with certainty because it can be caused by various
factors, although in general often associated with immune response to the drug.
Some of the factors causing SSJ include: infection (viral, fungal, bacterial, parasitic),
drugs (salicylates, sulfa, penicillin, ethambutol, Tegretol, tetracycline, digitalis,
contraceptives), food (chocolate), physical (cold air, sunlight, X-rays), others (polagen
disease, malignancy, pregnancy).

SLE

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that has protean
manifestations and follows a relapsing and remitting course. More than 90% of cases of SLE
occur in women, frequently starting at childbearing age.

Signs and symptoms

SLE is a chronic autoimmune disease that can affect almost any organ system; thus, its
presentation and course are highly variable, ranging from indolent to fulminant.

In childhood-onset SLE, there are several clinical symptoms more commonly found than in
adults, including malar rash, ulcers/mucocutaneous involvement, renal involvement,
proteinuria, urinary cellular casts, seizures, thrombocytopenia, hemolytic anemia, fever, and
lymphadenopathy.
In adults, Raynaud pleuritis and sicca are twice as common as in children and adolescents

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing
age should prompt investigation into the diagnosis of SLE.

Patients may present with any of the following manifestations

Constitutional (eg, fatigue, fever, arthralgia, weight changes)

Musculoskeletal (eg, arthralgia, arthropathy, myalgia, frank arthritis, avascular
necrosis)
Dermatologic (eg, malar rash, photosensitivity, discoid lupus)
Renal (eg, acute or chronic renal failure, acute nephritic disease)
Neuropsychiatric (eg, seizure, psychosis)
Pulmonary (eg, pleurisy, pleural effusion, pneumonitis, pulmonary hypertension,
interstitial lung disease)
Gastrointestinal (eg, nausea, dyspepsia, abdominal pain)
Cardiac (eg, pericarditis, myocarditis)
Hematologic (eg, cytopenias such as leukopenia, lymphopenia, anemia, or
thrombocytopenia)

In patients with suggestive clinical findings, a family history of autoimmune disease should
raise further suspicion of SLE.

4. Therapy SJS and SLE

Supportive therapy is the standard of governance in patients SSJ . Patients generally

come with a heavy general condition requiring fluid and electrolytes , as well as
calorie and protein needs appropriate parenterally . Fluid administration depends on
the extent of skin and mucosal abnormalities involved . Nutrition through a
nasogastric tube is done to return to normal oral mucosa . Lesions in the oral mucosa
are given medication and ointments glycerin dessert .
For infection , given broad-spectrum antibiotics , usually used gentamicin
intramuscularly in two doses 5mg/kgBB/hari . Subsequent antibiotic treatment based
on culture results and test the resistance of germs skin lesions and blood preparations .
 Corticosteroids administered parenterally , usually dexamethasone at a starting dose
of 1 mg / kg bolus , then for 3 days 0.2-0.5 mg / kg every 6 hours , after it was
revealed gradually and when it may be replaced with oral prednisone . Systemic
corticosteroids as therapy remains controversial SSJ . Some assume that the use of
systemic steroids in children can slow healing and cause significant side effects , but
some are considered steroid benefit and saves lives .
Use of Intravenous Human Immunoglobulin ( IVIG ) may stop the progression of the
disease SSJ with a total dose of 3 g / kg for 3 consecutive days ( 1 g / kg / day for 3
days ) .
Do the eyes as well as skin care and topical administration antibitik . Leather can be
cleaned with physiological saline solution or compressed with Burrow . On the skin or
epidermis necrosis debridement can be done . To prevent ocular sequelae can be given
eye drops with antiseptic .
Causal factors ( drugs or other factors suspected as the cause ) should be discontinued
or resolved . Detection of the most common causes such as a history of drug use last ,
and its relationship to disease progression , especially the episode SSJ , SSJ proved
useful in management .
Broad-spectrum antibiotics , then based on the results of bacteria culture and test the
resistance of the skin lesions and blood preparations .
Antihistamines , if necessary . Especially when there is intense itching . Feniramin
hydrogen maleate ( Avil ) can be administered at a dose for ages 1-3 years 7.5 mg /
dose , for ages 3-12 years 15 mg / dose , administered 3 times / day . As for cetirizine
dose can be given to children aged 2-5 years : 2.5 mg / dose , 1 time / day ; > 6 years :
5-10 mg / dose , 1 time / day . Eyes as well as skin care and topical antibiotics .
Bullae in skin treated with wet compresses Burowi solution .
Not allowed to use topical steroids on skin lesions .
Lesions in the mouth given kenalog orabase .
Secondary infection with antibiotic therapy rarely cause allergies , broad spectrum,
bactericidal and is not nephrotoxic , eg intravenous clindamycin 8-16 mg / kg / day
intravenously , administered 2 times / day .

STEP 4

1.) Immunology is the study of specific defense mechanisms.

Two major kinds of defense have evolved to counter the thread of infection.

1. Innate immunity: rapid response to a broad range of microbes.

2. Acquired immunity: slower response to specific microbes; it is also called adaptive
immunity; it includes lymphocytes and antibodies.

There are specific defense mechanisms and nonspecific defense mechanisms also known as
innate immune response.

INNATE IMMUNITY

It provides a wide range of defenses. These defenses are not specific for a type of pathogen.

External Defense Mechanisms

These mechanisms are nonspecific and include mechanical and chemical barriers.

Mechanical barriers include skin, hair, mucous.

Chemical barriers include sweat, sebum, tears, and stomach acid; lysozymes digest
the cell wall of bacteria.
Intact skin is barrier that prevents pathogens from penetrating into the body. Secretions from
sweat and sebaceous glands give the skin a pH of 3 to 5, which is acidic enough to prevent
colonization by many microbes. Saliva, tears and mucus also kill bacteria. Lysozymes are
enzymes found in tears, sebum and tissues that attack the cell wall of bacteria. Acid
secretions and enzymes in the stomach kill most ingested pathogens.

Internal Cellular And Chemical Defenses.

Invading organisms are ingested and destroyed trough phagocytosis. White blood cells or
leukocytes are involved in this process.

1. Phagocytes destroy bacteria and other cells.

There are four types of white blood cells (leukocytes) that are phagocytes.

Neutrophils are the first phagocytes to arrive usually within an hour of injury.
Neutrophils make about 60%-70% of all white blood cells.
Damaged cells secrete chemical signals that attract neutrophils: chemotaxis.
Monocytes arrive next and become large macrophages.
 Monocytes make about 5% of WBC.
Macrophages are long-lived cells.
Ingest the bacterium into a food vacuole that fuses with a lysosome which secrets
superoxide ions, O2-, and nitric oxide, NO, both strong antimicrobial substances;
hydrolytic enzymes digest the microbial components.
Macrophages are found in the lungs, liver, lymph nodes, kidney, brain, spleen, and
connective tissues.
Both phagocytize pathogens, their products and dead and injured cells.
A neutrophil can phagocytize about 20 cells and a macrophage 100 cells before they
become inactive and die.
Pus consists of dead phagocytic cell, fluid and proteins leaked out of capillaries.
Some bacteria are resistant to macrophage digestion.
Eosinophils make about 1.5%of all leukocytes.
They attack large parasitic invaders like blood flukes.
They discharge hydrolytic enzymes on the surface of the parasite.
They have limited phagocytic activity.

2. Antimicrobial proteins

Complement system proteins are regulatory proteins secreted by cells of the immune system.

There are about 30 of these serum proteins.

Two types of interferon provide innate defense against viral infection.
Some lymphocytes secrete a third type of interferon that activates microphages.
They are important signaling cells during immune responses and lead to the lysis of
the viruses, yeast and bacteria, and enhance their phagocytosis by macrophages.
They are inactive until an infection occurs.
Defensins are secreted by activated macrophages.
Interferons are proteins produced by virus infected cells. They signal other cells to produce
chemicals that inhibit viral replication.

3. Inflammation is a protective mechanism.

 Damage to tissue by physical injury or by infection triggers the inflammatory
response.
It is regulated by proteins in the plasma, by cytokines, and by substances called
histamines released by platelets, by basophils (WBC), and by mast cells.
Blood flow increases bringing phagocytic cells to the site of infection. This is
probably the most important element of inflammation.
Histamines released in response to injury cause vasodilation and make capillaries
more permeable allowing antibodies to enter the tissues; postcapillary venules
constrict.
Histamines are released by circulating leukocytes called basophils and by mast cells
found in connective tissue.
Leukocytes and damaged cells release prostaglandins that increase blood flow to the
injured area.
Chemokines secreted by flood vessel endothelial cells and monocytes attract
phagocytes to the injured area.
Blood flow to the injured area brings clotting elements to initiate tissue repair, makes
the skin feel warm, and may causes redness.
Edema (swelling) occurs.
Injured cells put out chemical signals that cause the release of leukocytes from the bone
marrow.

4. Natural Killer Cells

Natural killer cells (NK) are large, granular lymphocytes that originate in the bone
marrow.
Attack cancer cells, infected cells and pathogens including certain fungi.
Release proteins that destroy target cells by lysing the cells.
NK cells trigger apoptosis of infected cells

ACQUIRED IMMUNITY - LYMPHOCYTES

Pathogens always come in contact with lymphocytes when they invade a vertebrate.
Phagocytes secrete cytokines that activate lymphocytes when they phagocytose microbes.
Pathogens have macromolecules on their cell surfaces that the body recognizes as foreign.
These foreign substances stimulate an immune response. They are called antigens.
Lymphocytes recognize and bind to a small portion of the antigen called the epitope. An
antigen that is a protein has a specific sequence of amino acids that makes up the epitope or
antigenic determinant. An antibody interacts with a small, accessible portion of the antigen,
the epitope. An epitope interacts with a specific antibody and is capable of inducing the
production of the specific antibody. These antigen determinants vary in number from 5 to
more than 200 on a single antigen. The shape of the epitope can be recognized by the
antibody or a T cell receptor.

ANTIGEN RECOGNITION BY LYMPHOCYTES

Cells of the immune system include lymphocytes: T lymphocytes or T cells, B lymphocytes

or B cells, natural killer (NK) cells and phagocytes. These cells circulate throughout the body
in the blood and lymph, and are concentrated in the spleen, lymph nodes and other lymphatic
tissues. T lymphocytes and B lymphocytes target specific invaders. B cells and T cells
recognize antigens by means of antigen-specific receptors embedded in their plasma
membranes. Each of these cells bears about 100,000 of these antigen receptors. All the
receptors on a single cell are identical, that is, they all recognize the same epitope. Each
lymphocyte displays specificity of a particular epitope on an antigen and defends against that
antigen or a small set of closely related antigens.

B Cells Receptors For Antigens

A typical B-cell receptor or antibody is a Y-shaped molecule consisting of four polypeptide

chains:

Two identical heavy chains and two identical light chains joined by disulfide
bridges to form the Y-shaped molecule.
The transmembrane region of the tail portion anchors the receptor in the plasma
membrane and a short portion penetrates into the cytoplasm.
The tips of the Y are the variable regions, V regions, of the heavy and light chains.
The tail of the Y shaped antibody is made of the constant or C regions of the
heavy chains.
The interaction between the antigen-binding site and its corresponding antigen is stabilized
by multiple noncovalent bonds between chemical groups on the respective molecules. The
receptor binds to molecules that are on the surface of the infectious agent. Antibodies have
two main functions:

1. Combine with antigen and labels it for destruction.

2. Activates processes that destroy the antigen that binds to it.

Antibodies do not destroy the antigen. It labels the antigen for destruction. Secreted
antibodies are serum globular proteins also known as immunoglobulins, Ig.

T Cell Receptors For Antigens And The Role Of The MHC

T cell receptors consist of two polypeptide chains, and chains linked by disulfide
bridge.
They have a straight shape, not a Y shape like the B-cell receptors.
The transmembrane region anchors the antibody to the plasma membrane.
The variable V regions at the other end of the antigen form a single antigen-binding
site.
The remainder of the molecule is made up of the constant C region.
The T cell receptors bind with antigens like the B cell receptors. T cell receptors are capable
of recognizing small fragments of the antigen that are bound to normal cell-surface proteins
called MHC molecules.

B cell receptors recognize intact antigens on the surface of the pathogen.

T cell receptors recognize fragments of antigens presented by the MHC complex.

2.) Diagnose : Stevens Johnson Syndrome

Differential Diagnose : SLE (Sistemic Lupus Erythemathosus) and Contact Dermatitis

Stevens-Johnson syndrome is an immune-complexmediated hypersensitivity complex that

typically involves the skin and the mucous membranes. Although several classification
schemes have been reported, the simplest classification breaks the disease down as follows :
 Stevens-Johnson syndrome: A minor form of toxic epidermal necrolysis, with less
than 10% body surface area (BSA) detachment
Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis: Detachment of
10-30% of the BSA
Toxic epidermal necrolysis: Detachment of more than 30% of the BSA

Signs and symptoms

Typical prodromal symptoms of Stevens-Johnson syndrome are as follows:

Cough productive of a thick, purulent sputum

Headache
Malaise
Arthralgia

Patients may complain of a burning rash that begins symmetrically on the face and the upper
part of the torso. The cutaneous lesions are characterized as follows:

The rash can begin as macules that develop into papules, vesicles, bullae, urticarial
plaques, or confluent erythema
The typical lesion has the appearance of a target; this is considered pathognomonic
In contrast to the typical lesions of erythema multiforme, these lesions have only 2
zones of color
The lesions core may be vesicular, purpuric, or necrotic; that zone is surrounded by
macular erythema
Lesions may become bullous and later rupture, leaving denuded skin; the skin
becomes susceptible to secondary infection
Urticarial lesions typically are not pruritic
Infection may be responsible for the scarring associated with morbidity
Although lesions may occur anywhere, the palms, soles, dorsum of the hands, and
extensor surfaces are most commonly affected
The rash may be confined to any one area of the body, most often the trunk

Signs of mucosal involvement can include the following:

Erythema
 Edema
Sloughing
Blistering
Ulceration
Necrosis

The following ocular signs may be noted on slit-lamp examination:

Eyelids: Trichiasis, distichiasis, meibomian gland dysfunction, blepharitis

Conjunctiva: Papillae, follicles, keratinization, subepithelial fibrosis, conjunctival
shrinkage, foreshortening of fornices, symblepharon, ankyloblepharon
Cornea: Superficial punctate keratitis, epithelial defect, stromal ulcer,
neovascularization, keratinization, limbitis, conjunctivalization, stromal opacity,
perforation

Diagnosis

Minimal dermal inflammatory cell infiltrate and full-thickness necrosis of the epidermis are
typical histopathologic findings in patients with Stevens-Johnson syndrome. Histopathologic
examination of the skin can also reveal the following:

Changes in the epidermal-dermal junction ranging from vacuolar alteration to

subepidermal blisters
Dermal infiltrate: Superficial and mostly perivascular
Apoptosis of keratinocytes
CD4+ T lymphocytes predominating in the dermis; CD8+ T lymphocytes
predominating in the epidermis; the dermoepidermal junction and epidermis is
infiltrated mostly by CD8+ T lymphocytes

Ocular examination can demonstrate the following:

Conjunctival biopsies from patients with active ocular disease show subepithelial
plasma cells and lymphocyte infiltration; lymphocytes also are present around vessel
walls; the predominant infiltrating lymphocyte is the helper T cell
Immunohistology of the conjunctiva reveals numerous HLA-DRpositive cells in the
substantia propria, vessel walls, and epithelium
3.) Hypersensitivity refers to excessive, undesirable (damaging, discomfort-producing and
sometimes fatal) reactions produced by the normal immune system. Hypersensitivity
reactions require a pre-sensitized (immune) state of the host. Hypersensitivity reactions can
be divided into four types: type I, type II, type III and type IV, based on the mechanisms
involved and time taken for the reaction. Frequently, a particular clinical condition (disease)
may involve more than one type of reaction.

TYPE I HYPERSENSITIVITY

Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The

reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx
(rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract
(gastroenteritis). The reaction may cause a range of symptoms from minor inconvenience to
death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen,
although sometimes it may have a delayed onset (10 - 12 hours).

Immediate hypersensitivity is mediated by IgE. The primary cellular component in this

hypersensitivity is the mast cell or basophil. The reaction is amplified and/or modified by
platelets, neutrophils and eosinophils. A biopsy of the reaction site demonstrates mainly mast
cells and eosinophils.

The mechanism of reaction involves preferential production of IgE, in response to certain

antigens (often called allergens). The precise mechanism as to why some individuals are
more prone to type-I hypersensitivity is not clear. However, it has been shown that such
individuals preferentially produce more of TH2 cells that secrete IL-4, IL-5 and IL-13 which
in turn favor IgE class switch. IgE has very high affinity for its receptor (Fc; CD23) on mast
cells and basophils.

A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the
release of various pharmacologically active substances. Cross-linking of IgE Fc-receptor is
important in mast cell triggering. Mast cell degranulation is preceded by increased Ca++
influx, which is a crucial process; ionophores which increase cytoplasmic Ca++ also promote
degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress degranulation.
Mast cells may be triggered by other stimuli such as exercise, emotional stress, chemicals
(e.g., photographic developing medium, calcium ionophores, codeine, etc.), anaphylotoxins
(e.g., C4a, C3a, C5a, etc.). These reactions, mediated by agents without IgE-allergen
interaction, are not hypersensitivity reactions, although they produce the same symptoms.

TYPE II HYPERSENSITIVITY

Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety
of organs and tissues. The antigens are normally endogenous, although exogenous chemicals
(haptens) which can attach to cell membranes can also lead to type II hypersensitivity. Drug-
induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The
reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies
of the IgM or IgG classes and complement. Phagocytes and K cells may also play a role.

The lesion contains antibody, complement and neutrophils. Diagnostic tests include detection
of circulating antibody against the tissues involved and the presence of antibody and
complement in the lesion (biopsy) by immunofluorescence. The staining pattern is normally
smooth and linear, such as that seen in Goodpasture's nephritis (renal and lung basement
membrane) and pemphigus (skin intercellular protein, desmosome).

Treatment involves anti-inflammatory and immunosuppressive agents.

TYPE III HYPERSENSITIVITY

Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction
may be general (e.g., serum sickness) or may involve individual organs including skin (e.g.,
systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g.,
aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other
organs. This reaction may be the pathogenic mechanism of diseases caused by many
microorganisms.

The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). It is
mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may
also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic
infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus
erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary
components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is
caused by platelets and neutrophils. The lesion contains primarily neutrophils and deposits of
immune complexes and complement. Macrophages infiltrating in later stages may be
involved in the healing process.

The affinity of antibody and size of immune complexes are important in production of
disease and determining the tissue involved. Diagnosis involves examination of tissue
biopsies for deposits of immunoglobulin and complement by immunofluorescence
microscopy. The immunofluorescent staining in type III hypersensitivity is granular (as
opposed to linear in type II such as seen in Goodpasture's syndrome). The presence of
immune complexes in serum and depletion in the level of complement are also diagnostic.
Polyethylene glycol-mediated turbidity (nephelometry) binding of C1q and Raji cell test are
utilized to detect immune complexes. Treatment includes anti-inflammatory agents.

TYPE IV HYPERSENSITIVITY

Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The
classical example of this hypersensitivity is tuberculin (Montoux) reaction which peaks 48
hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by
induration and erythema.

Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious

diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis,
etc.) and granulomas due to infections and foreign antigens. Another form of delayed
hypersensitivity is contact dermatitis (poison ivy), chemicals, heavy metals, etc.) in which the
lesions are more papular. Type IV hypersensitivity can be classified into three categories
depending on the time of onset and clinical and histological presentation.

Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes

and/or macrophages. Cytotoxic T cells (Tc) cause direct damage whereas helper T (TH1)
cells secrete cytokines which activate cytotoxic T cells and recruit and activate monocytes
and macrophages, which cause the bulk of the damage. The delayed hypersensitivity lesions
mainly contain monocytes and a few T cells.
Major lymphokines involved in delayed hypersensitivity reaction include monocyte
chemotactic factor, interleukin-2, interferon-gamma, TNF alpha/beta, etc.

Pathophysiology of SJS

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but
potentially life threatening, diseases characterized by widespread epidermal necrosis, and are
predominantly medication-induced. Unfortunately, though they are often associated with
long-term debilitating sequelae, there are currently no efficacious pharmaceutical
interventions proven through large clinical trials. It has been well established that the
epidermal damage in these diseases is due to keratinocyte apoptosis. Although drug-specific
T cells are implicated in this process, our understanding of the immunopathology is far from
complete. The scenario suggested by today's literature points towards drug-specific CD8+
cytotoxic T cells utilizing perforin/granzyme B trigger keratinocyte apoptosis. Subsequently,
there may be an expansion of apoptosis involving the interaction of either membrane-bound
or soluble Fas ligand (sFasL) with its receptor Fas. The cellular source of sFasL remains
controversial, with both peripheral lymphocytes and keratinocytes themselves as potential
candidates. Cytokines produced by T lymphocytes, macrophages or keratinocytes may
participate by activating keratinocytes and enhancing their expression of Fas and FasL, or by
promoting the skin recruitment of lymphocytes by upregulating adhesion molecules. A better
understanding of the underlying immunological mechanisms is required to identify
appropriate therapeutic interventions. Finally, clinicians must remain vigilant about drug
hypersensitivity to prevent SJS/TEN.

While in SLE, SLE is an autoimmune disorder characterized by multisystem inflammation

with the generation of autoantibodies. Although the specific cause of SLE is unknown,
multiple factors are associated with the development of the disease, including genetic,
epigenetic, ethnic, immunoregulatory, hormonal, and environmental factors. Many immune
disturbances, both innate and acquired, occur in SLE.

In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental

triggers, antigen-antibody (Ab) responses, B-cell and T-cell interactions, and immune
clearance processes interact to generate and perpetuate autoimmunity. HLA = human
leukocyte antigen; UV = ultraviolet light.

Potential mechanisms

It is important to note that antibodies may be present for many years before the onset of the
first symptoms of SLE. One longstanding proposed mechanism for the development of
autoantibodies involves a defect in apoptosis that causes increased cell death and a
disturbance in immune tolerance. The redistribution of cellular antigens during
necrosis/apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form
of nucleosomes. Subsequently, dysregulated (intolerant) lymphocytes begin targeting
normally protected intracellular antigens. The defective clearance of the apoptotic cell debris
allows for the persistence of antigen and immune complex production.

T cells have long been thought to play a central role in SLE pathogenesis, and T cells from
patients with lupus show defects in both signaling and effector function. These T cells secrete
less interleukin (IL)-2, and one defect in signaling seems to be linked to an increase in
calcium influx, possibly due to changes in the CD3 signaling subunits. The following seem to
be adversely affected in T cells from patients with SLE: effector activity such as CD8
cytotoxicity; T-regulatory, B-cell help; migration; and adhesion. However, the method by
which each of these deficits contributes to the exact clinical syndrome seen in an individual
patient is still unknown. These T-cell abnormalities are currently being explored as targets for
therapy, as seen with the recent approval of belimumab, which targets the B-lymphocyte
stimulator (BLys) signaling pathway.

Many clinical manifestations of SLE are mediated by circulating immune complexes that
form with antigens in various tissues or the direct effects of antibodies to cell surface
components. Immune complexes form in the microvasculature, leading to complement
activation and inflammation. Moreover, antibody-antigen complexes deposit on the basement
membranes of skin and kidneys. In active SLE, this process has been confirmed by
demonstration of complexes of nuclear antigens such as DNA, immunoglobulins, and
complement proteins at these sites. Autoantibodies have been found to be biomarkers for
future neuropsychiatric events in SLE. A prospective study (=10 years) of 1047 SLE patients
demonstrated that individuals who had evidence of lupus anticoagulant (LA) had an increased
future risk of intracranial thrombosis and that those with anti-ribosomal P antibodies had an
increased future risk of lupus psychosis.

Serum antinuclear antibodies (ANAs) are found in nearly all individuals with active SLE.
Antibodies to native double-stranded DNA (dsDNA) are relatively specific for the diagnosis
of SLE. Whether polyclonal B-cell activation or a response to specific antigens exists is
unclear, but much of the pathology involves B cells, T cells, and dendritic cells. Cytotoxic T
cells and suppressor T cells (which would normally down-regulate immune responses) are
decreased. The generation of polyclonal T-cell cytolytic activity is impaired. Helper (CD4+)
T cells are increased. A lack of immune tolerance is observed in animal lupus models.
Reports pointing to important roles of interferon-alpha, transcription factors, and signaling
variations also point to a central role for neutrophils.

Genetics

There is a clear genetic component in SLE, with a sibling risk ratio 8-fold to 29-fold higher
than that in the general population and a 10-fold increase in disease concordance in identical
twins. In addition, there is a 24-56% concordance rate in monozygotic twins, compared with
a 2-5% risk in dizygotic twins. Although some single genes have been implicated to play a
causative role in SLE, current knowledge points toward a large number of genes being
involved in a multifactorial-type inheritance pattern in most patients.

Genetic studies also point to disruptions in lymphocyte signaling, interferon response,

clearance of complement and immune complexes, apoptosis, and DNA methylation.
Genome-wide association studies (GWAS) have identified several loci with a strong
association with SLE, many of which are involved in the immune and related biologic
systems. Genes previously associated with other autoimmune diseases have been associated
with SLE (eg, PTPN22 and diabetes; STAT4 and rheumatoid arthritis). Several genes
associated with T-cell function and signaling have also been associated with SLE, including
PTPN22, TNFSF4, PDCD1, IL10, BCL6, IL16, TYK2, PRL, STAT4, and RASGRP3, as have
immune-complex processing and innate immunity genes, including several complement
genes (eg, C2, C4A, and C4B).

A meta-analysis of the association of interferon regulatory factor 5 (IRF5) with SLE found
that a specific T allele, IRF5 rs2004640, is significantly associated with SLE in populations
of European, Asian, and Latin American origins, whereas the A allele IRF5 rs10954213 is
associated with SLE in patients of European origin but not in those of Asian origin. Overall,
the IRF5 gene polymorphism was found to be associated with SLE in multiple ethnic
populations. The results also offer insights into the epigenetics of SLE: Hypomethylation (a
form of epigenetic modification) of genes involved in osmotic lysis, apoptosis, inflammation,
and cytokine pathways, among other immunologic functions, have been associated with this
disease.

4.) Management of patients with Stevens-Johnson syndrome is usually provided in intensive

care units or burn centers. No specific treatment of Stevens-Johnson syndrome is noted;
therefore, most patients are treated symptomatically. In principle, the symptomatic treatment
of patients with Stevens-Johnson syndrome does not differ from the treatment of patients
with extensive burns.

Prehospital and emergency department care

Paramedics should recognize the presence of severe fluid loss and should treat patients with
Stevens-Johnson syndrome as they would patients with thermal burns.

Most patients present early and prior to obvious signs of hemodynamic compromise. The
single most important role for the ED physician is to detect Stevens-Johnson syndrome/toxic
epidermal necrolysis early and initiate the appropriate ED and inpatient management.

Withdrawal of the suspected offending agent is critically important. Timing of withdrawal

has been linked to outcome. Underlying diseases and secondary infections must be identified
and treated.

Patients should be treated with special attention to airway and hemodynamic stability, fluid
status, wound/burn care, and pain control. Care in the ED must be directed to fluid
replacement and electrolyte correction. Treatment is primarily supportive and symptomatic.
Some have advocated corticosteroids, cyclophosphamide, plasmapheresis, hemodialysis, and
immunoglobulin.

Manage oral lesions with mouthwashes. Topical anesthetics are useful in reducing pain and
allowing the patient to take in fluids. Skin lesions are treated as burns. Areas of denuded skin
must be covered with compresses of saline or Burow solution.
STEP 5

Learning objective

1. Steven Johnson Syndrome

2. Characteristic and criteria definitions of SLEs Symptoms

3. What kind of drug can make trigger for Steven Johnson Symptoms

4. Other kind of hipersensitivity disease

Step 6
STEP 7

1. Steven Johnson Syndrome

INTRODUCTION AND TERMINOLOGY Stevens-Johnson syndrome (SJS) and toxic

epidermal necrolysis (TEN) are severe idiosyncratic reactions, most commonly triggered by
medications, which are characterized by fever and mucocutaneous lesions leading to necrosis
and sloughing of the epidermis. SJS and TEN are distinguished chiefly by severity and
percentage of body surface involved. In this review, the term "SJS/TEN" is used to refer
collectively to SJS, TEN, and SJS/TEN overlap syndrome.

The clinical manifestations, pathogenesis, evaluation, and diagnosis of SJS/TEN will be

presented in this topic review. The treatment, prognosis, and long-term complications are
discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Management, prognosis, and long-term sequelae".)

Stevens-Johnson syndrome SJS is the less severe condition, in which skin sloughing is
limited to less than 10 percent of the body surface [1]. It is characterized by a prodrome of
malaise and fever, followed by the rapid onset of erythematous or purpuric macules and
plaques [1,2]. The skin lesions progress to epidermal necrosis and sloughing (picture 1A-B).
Mucosal membranes are affected in 92 to 100 percent of patients, usually at two or more
distinct sites (ocular, oral, and genital) [3].

Toxic epidermal necrolysis Toxic epidermal necrolysis (TEN), or Lyell's syndrome,

involves sloughing of greater than 30 percent of the body surface area [1]. TEN also begins
with a prodrome of fever and malaise, although temperatures are typically higher than those
seen with SJS, often exceeding 39 degrees Celsius. Mucous membranes are involved in
nearly all cases [4]. The skin lesions are widely distributed erythematous macules and
patches, although about 50 percent of cases begin with diffuse erythema [1,5,6]. In the early
stages, skin pain may be prominent and out of proportion to clinical findings [7]. The skin
lesions progress to full-thickness epidermal necrosis leads. The ultimate appearance of the
skin has been likened to that of extensive thermal injury (picture 2A-B) [5].

SJS/TEN overlap syndrome SJS/TEN overlap syndrome describes patients with

involvement of greater than 10 percent, but less than 30 percent of body surface area [1].

There is a lack of consensus regarding whether SJS and TEN represent different severities of
the same condition or separate disorders, primarily because the pathogenesis of these
disorders is not well-understood. Likewise, there are differing opinions about the degree to
which SJS overlaps with severe erythema multiforme (EM), a condition with similar
presentation. The most widely employed criteria, which are presented herein, propose a
continuum between TEN and SJS, and distinguish SJS from severe EM (table 1) [1,3,8]. The
nosologic controversies surrounding these disorders are discussed below. (See 'Nosologic
controversies' below.)

EPIDEMIOLOGY Various estimates of the incidence of SJS, SJS/TEN overlap, and TEN
are reported in the literature, and the imprecise distinctions among these disorders has
impeded more definite figures. SJS is the more common disorder, outnumbering TEN by as
much as three cases to one [9]. Estimates of incidence for all three disorders range from two
to seven cases per million people per year [10-14]. Incidence may be highest in the spring
months [15].

SJS and TEN can occur in patients of any age. The mean age of patients with SJS has varied
from 25 to 47 years, depending upon the series [14,16,17]. Patients affected by TEN tend to
be slightly older, with a mean reported age between 46 and 63 years [13,14]. Women account
for over 60 percent of cases [14].

ETIOLOGIES Medications are the leading trigger of SJS and TEN in both adults and
children, although in children, infections are responsible for a relatively higher percentage of
cases of SJS.

In adults In adults, medications cause 30 to 50 percent of cases of SJS and up to 80

percent of cases of TEN [1,7,8,18,19]. Infections are the next most common trigger of adult
SJS (up to 15 percent). In contrast, it is unusual for infections to trigger TEN in adults
[4,20,21]. Rare causes of SJS and TEN include vaccinations, systemic diseases, chemical
exposure, herbal medicines, and foods [8,22-24].

Medications The following groups of agents are most commonly implicated (table
2) [14,25-27]:

Anti-gout agents (especially allopurinol)

Antibiotics (sulfonamides >> penicillins > cephalosporins)
Antipsychotics and anti-epileptics (including carbamazepine, dilantin, lamotrigine,
and phenobarbital)
Analgesics and non-steroidal anti-inflammatory agents (especially piroxicam)

A case control study published in the 1990s quantified the relative risk of SJS/TEN
corresponding with common medications (table 3) [28]. A 2007 multinational study from
Europe and Israel indicated that allopurinol was the most common cause of SJS and TEN in
these areas [29]. Newer drugs that have been associated with SJS and TEN include
nevirapine, lamotrigine, sertraline, pantoprazole, and tramadol [27].

Many other types of agents have been implicated in smaller numbers of cases. These are
discussed in other topic reviews. (See "Cutaneous complications of conventional
chemotherapy agents" and "Rituximab and other B cell targeted therapies for rheumatoid
arthritis".)

In children Medications are the leading cause of SJS and TEN in children, as in adults.
However, infections, particularly Mycoplasma pneumonia and herpes viruses, are associated
with a greater proportion of pediatric cases of SJS [30,31].

The medications most often implicated in pediatric SJS/TEN are sulfonamide antimicrobials,
phenobarbital, carbamazepine, lamotrigine, valproic acid, and acetaminophen/paracetamol
[32]. The combination of azithromycin and ibuprofen has also been associated [33].

HISTORY AND CLINICAL PRESENTATION Drug exposure commonly precedes the

onset of symptoms by one to three weeks (average 14 days) in medication-related cases [34].
Reexposure may result in onset of symptoms in as little as 48 hours [35].

Signs and symptoms

Prodrome SJS and TEN typically have a prodrome of fever and influenza-like symptoms
one to three days before the development of mucocutaneous lesions [36]. Fever is usually
higher with TEN, and often exceeds 39 degrees Celsius [34]. Skin tenderness, photophobia,
and conjunctival itching or burning may be early symptoms in both conditions.

The following signs and symptoms, when present early in the course of a drug reaction or
illness, should alert clinicians to the possibility of SJS/TEN [36]:

Confluent erythema (erythroderma)

Facial edema or central facial involvement
Skin pain
Palpable purpura
Skin necrosis
Blisters and/or epidermal detachment
Mucous membrane erosions and crusting
Swelling of tongue

Skin The skin lesions typically begin as ill-defined erythematous macules with purpuric
centers, although about 50 percent of cases of TEN begin with diffuse erythema [1,5,6]. In
SJS, the lesions are often quite targetoid, while in TEN, the targets may be more atypical and
less well-demarcated. A burning sensation or other paresthesias may be noted. In the early
stages, skin pain can be prominent and out of proportion to clinical findings, particularly in
TEN [7,34]. Lesions are symmetrically distributed, and start upon the face and thorax before
spreading to other areas [7]. The scalp is typically spared, and palms and soles are less often
involved [37,38].

Vesicles and bullae then form, which spread laterally with pressure. The skin begins to
slough within days. Sloughing progresses rapidly for two to three days and then usually
stabilizes [39]. Fulminant cases of TEN have been described, in which nearly 100 percent of
the epidermis sloughed over a matter of hours [37,38].

Mucosa Mucous membranes are involved in more than 90 percent of cases of SJS/TEN
[3]. Typically, at least two mucus membranes are affected, although this may not always
include the oral mucosa [36,40]. Painful crusts and erosions may occur upon any mucosal
surface [34,36].
 Ophthalmologic - Conjunctival lesions have been reported in 85 percent of patients
[34,41]. Excessive tearing sometimes occurs from obstruction of the tear punctae [36].
Ocular involvement may range from simple hyperemia and congestion of vessels to
scarring with the development of synechiae between the eyelids and conjunctiva
[7,41].
Urogenital - Urethritis may result in dysuria or even urinary retention [8].
Pulmonary - Pulmonary complications of TEN may include dyspnea, hypoxia,
bronchial hypersecretion, tracheobronchitis, pulmonary edema, bacterial pneumonitis,
and bronchiolitis obliterans [42,43].

Laboratory abnormalities Hematologic abnormalities, particularly anemia and

lymphopenia, are common in TEN [7]. Eosinophilia is unusual, despite the strong association
of TEN with drug ingestion. Neutropenia is noted in about one-third of patients, and is
correlated with a poor prognosis [7,44]. Glucocorticoids can cause demarginalization and
mobilization of neutrophils into the circulation, and this must be considered in patients who
received these agents prior to testing, as this may obscure neutropenia. (See "Stevens-
Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term
sequelae", section on 'Prognosis'.)

Mild elevations in serum aminotransferase levels (two to three times normal) are present in
about one-half of patients with TEN, while overt hepatitis occurs in approximately 10 percent
[34].

Time course The time course of SJS/TEN, from prodrome to hospital discharge in the
absence of significant complications, is typically two to four weeks.

Reepithelialization Reepithelialization may begin after several days, and typically requires
two to three weeks; corresponding to the usual duration of hospitalization [45]. Skin that
remained attached during the acute process may peel gradually and nails may be shed.

RISK FACTORS Risk factors for SJS and TEN include HIV infection, genetic factors,
concomitant viral infections, underlying immunologic diseases, and possibly physical factors.

HIV infection Patients with HIV infection have been reported to be at three times
increased risk for SJS/TEN. The reasons for this susceptibility are not fully understood,
although exposure to multiple medications (including sulfonamide antibiotics), "slow
acetylation" status, immune dysregulation, and the presence of concomitant infections may
contribute [46-48].

A 40-fold increased risk for SJS/TEN due to trimethoprim-sulfamethoxazole specifically has

been reported in HIV-infected patients, as compared to the risk among the general population
taking this same medication [49]. Toxic hydroxylamine metabolites and depleted systemic
glutathione reserves have been implicated in this toxicity [50].

Genetic factors Genetic factors associated with an increased risk of SJS/TEN include the
following:

Certain HLA-types (table 4) [51-55]: Patients with HLA-B* 1502 are at sufficiently
increased risk for SJS/TEN due to carbamazepine and other aromatic anticonvulsants
(eg, phenytoin, phenobarbital) that the United States Food and Drug Administration
has suggested screening patients of Asian and South Asian ancestry (in whom the
prevalence of this allele is significant) if use of carbamazepine is under consideration
[56].
Lower N-acetylation capacity ("slow acetylators"), which may be congenital or
acquired (eg, with HIV infection): Patients with this condition may have prolonged
exposure to immunogenic or toxic drug metabolites [46].
Polymorphisms in the IL4 receptor gene, which are biologically linked to Th2
cytokine-driven inflammatory mediators [57].

Other factors

Malignancy may increase the risk of SJS and TEN, although data are conflicting as to
whether malignancy truly increases the risk, or is simply associated with increased
exposure to causative medications [7,58,59].
Higher doses and more rapid introduction of medications may increase the risk of SJS
or TEN. As examples, allopurinol doses below 200 mg/dL were associated with a
lower risk of SJS/TEN than higher doses [29]. Similarly, lamotrigine was associated
with high rates of severe skin reactions when it was initially introduced [60].
Recommendations were subsequently made for gradual titration when beginning
therapy, and more recent studies suggest much lower rates of SJS/TEN [61].
 Coincidental viral infections or other coingestants [62]
Patients with systemic lupus erythematosus appear to experience higher rates of SJS
and TEN [63]
Physical stimuli, such as ultraviolet light or radiation therapy, may be co-factors in
some cases [58,64,65]

PATHOGENESIS The pathologic mechanisms that induce skin damage in SJS/TEN are
incompletely understood. The shortened interval between a recurrent exposure and the onset
of symptoms is consistent with an immunologic process [34].

Granulysin A promising line of investigation has implicated granulysin, a cytolytic protein

produced and secreted by cytotoxic T lymphocytes and natural killer (NK cells) [66]. Cells
from five patients with SJS or TEN were analyzed with gene expression profiling. Granulysin
was identified as the most highly expressed cytotoxic molecule. Both fluid and cells from
SJS/TEN patient blisters demonstrated cytotoxicity when incubated with keratinocytes, and
depletion of granulysin reduced the effect. Control fluid/cells from patients with burns
showed no such activity. The levels of granulysin in blister fluid correlated with the severity
of disease. In addition, injection of granulysin from patient blisters into mouse skin caused
dose-dependent blistering and necrosis.

The mechanism through which cytotoxic T lymphocytes and natural killer cells are
stimulated to release granulysin is unknown. The results of one study suggest that interaction
between the CD94/NKG2C receptor on these cells and HLA-E, an MHC class Ib molecule
expressed by keratinocytes in patients with SJS or TEN, may promote degranulation [67].

Other factors A role for reactive drug metabolites has been supported by the finding that
many patients with SJS and TEN demonstrate altered metabolic capabilities, such as slow N-
acetylation [46,47,68]. This may result in prolonged exposure to toxic and/or immunogenic
metabolites in these individuals. (See 'Genetic factors' above.)

Other hypothesized mechanisms for SJS/TEN have involved mixed drug-induced and
immunologically-mediated phenomenon. Keratinocytes normally express the death receptor,
CD95 (fas). When fas interacts with its ligand (fas ligand), the affected cell undergoes
apoptosis, a highly-controlled process that eliminates unwanted cells without creating an
inflammatory reaction. Mass triggering of apoptosis among keratinocytes may explain the
pauci-inflammatory nature of the epidermal necrosis observed in SJS/TEN. Serum levels of
soluble fas ligand were reported to be elevated in 5 of 7 patients with early drug reactions
who subsequently developed SJS/TEN, even before skin detachment or mucosal lesions
appeared [69]. In contrast, soluble fas ligand levels were normal in a group of 32 control
patients with less severe drug reactions. (See 'Histology' below.)

Perforin, TNF-a, and granzyme B, which are involved in distinct non-apoptotic cell death
pathways, are also found in the high concentrations in the peripheral mononuclear cells and
blister fluid of SJS/TEN patients [70]. However, elevations in these mediators are not specific
to SJS/TEN.

NOSOLOGIC CONTROVERSIES The categorization, or nosology, of SJS, TEN, and

severe EM, is an area of ongoing controversy that will only be resolved once the
pathophysiology of these disorders has been revealed. An understanding of the controversy
requires a brief historical review.

Erythema multiforme, the least severe of the disorders, was described by von Hebra in 1866
as acral (peripheral), targetoid, edematous papules and/or plaques without mucosal
involvement (picture 3) [71]. It is associated with infections, particularly herpes simplex virus
[72].

Stevens-Johnson syndrome was subsequently described as a pediatric affliction by Stevens

and Johnson in 1922 [2]. These authors reported on two cases consisting of a "generalized
eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis."
The cases were distinguished from EM (von Hebra) by the "character of the lesionsthe
prolonged high fever and the terminal heavy crusting."

Two categories of EM were later suggested: erythema multiforme minor (von Hebra), and a
severe form, erythema multiforme major (EM major), which encompassed SJS [73].
Subsequently, SJS came to be used synonymously with EM major, a view which is still held
by many dermatologists [6,74].

However, this categorization did not address cases with predominantly acral, targetoid
eruptions, characteristic of EM minor (von Hebra), but with mucosal involvement more
characteristic of EM major. To encompass this variant, it was proposed that EM major and
SJS be considered distinct conditions with the term EM being restricted to acral, targetoid
lesions, either with or without mucosal involvement, and the term SJS applied to mucous
membrane involvement and widespread vesicles arising upon erythematous skin, without
classic targetoid lesions [1,18]. Distinguishing the two conditions is also consistent with
observations about etiology, as there is a strong association between herpes virus infections
and EM, while SJS is more often associated with exogenous agents (eg, drugs) [19]. While
differing slightly in definitional characteristics of the diseases, studies of the expression of
IL-13 and other cytokines lends further support to the notion that SJS and TEN are diseases
akin to one another, but distinct from classic erythema multiforme [75,76].

TEN was first described in 1948, with a small series appearing a decade later [5]. TEN was
distinguished by an acute, diffuse, erythematous rash followed by widespread full-thickness
epidermal sloughing, and was initially believed to be distinct from SJS.

It was later proposed that SJS and TEN were varying degrees of the same process, differing
only in the extent of involvement [37,77]. However, this unifying concept has not been
universally accepted. Some have cited subtle histologic differences between SJS and TEN
[9]. In addition, one report demonstrated that serum from TEN patients was directly cytotoxic
to cultured keratinocytes, while serum from SJS patients was toxic only in the presence of
lymphocytes [78]. This observation supported the original hypothesis that the conditions were
different, with a toxic metabolite triggering TEN and an immunologic cellular response
mediating SJS [5].

Summary Severe EM (EM major) and SJS are viewed by many experts as separate
entities, based on etiologic and clinical distinctions. In contrast, the concept that SJS and
TEN exist along a continuum of a single disease process appears well-supported by the
majority of evidence and is accepted by most, although not all.

EVALUATION AND DIAGNOSIS SJS, TEN, and SJS/TEN overlap are clinical
diagnoses supported by compatible histologic findings. There are no universally-accepted
diagnostic criteria, and histology findings are neither specific nor diagnostic. Despite these
limitations, the diagnosis of SJS or TEN would be appropriate in a patient with:

A suggestive history of antecedent drug exposure or illness

A prodrome of acute-onset febrile illness and malaise
 Erythematous macules, targetoid lesions, or diffuse erythema progressing to vesicles
and bullae
Necrosis and sloughing of the epidermis (of varying degrees)

Histology Skin biopsy is useful in excluding or including many of the conditions in the
differential diagnosis. An appropriate sample may be obtained using a large (>4 mm) punch
biopsy or by deep shave biopsy ("saucerization") technique.

The earliest histologic finding in SJS is a perivascular mononuclear inflammatory infiltrate

comprised primarily of T-lymphocytes [79,80]. This infiltrate is not diagnostic, and it may be
seen in a wide variety of conditions, including a simple drug-induced exanthem. A sparse
infiltrate of lymphocytes develops at the dermoepidermal junction, with lymphocytes
clustered around dying basal keratinocytes ("satellitosis") [9]. As the lesions progress, frank
subepidermal vesiculation develops, with full thickness epidermal necrosis.

Fully developed SJS is distinguished by full thickness epidermal detachment with

splitting above the basement membrane, minimal inflammatory infiltrate, and normal
immunofluorescence.
The histopathology of TEN is similar. In addition, abnormalities of the underlying
sweat ducts have been described in TEN, including lymphocytic infiltration, basal cell
hyperplasia, and necrosis [81].

Cultures Appropriate cultures should be performed on blood, wounds, and mucosal lesions
to evaluate for the presence of staphylococcal species, in particular. In children, serologies for
Mycoplasma pneumoniae infection should also be obtained. (See "Mycoplasma pneumoniae
infection in children", section on 'Diagnosis'.)

Investigational tests A small pilot study has suggested that measurement of serum
granulysin (a cytotoxic molecule present in the blister fluid of patients with SJS or TEN)
might assist with early diagnosis [82]. Serum granulysin levels were found to be elevated in
four out of five patients with SJS or TEN two to four days prior to the onset of skin erosions.
However, the proportion of patients with elevated granulysin levels decreased rapidly with
disease progression. Further studies are necessary to determine whether serum granulysin
levels will be a useful early diagnostic test for SJS and TEN. (See 'Pathogenesis' above.)
DIFFERENTIAL DIAGNOSIS The differential diagnosis of SJS/TEN includes:

Erythema multiforme (see 'Nosologic controversies' above)

Erythroderma and other erythematous drug eruptions
Acute generalized exanthematous pustulosis (AGEP) and other pustular drug
eruptions
Phototoxic eruptions
Toxic shock syndrome (TSS)
Staphylococcal scalded skin syndrome (SSSS) (in children)
Paraneoplastic pemphigus

Erythroderma and erythematous drug eruptions - Erythematous drug reactions are

commonplace. The generalized and symmetric maculopapular erythema of a drug
eruption can mimic early SJS/TEN. However, erythematous drug eruptions lack
mucosal involvement as well as the ill-defined but prominent skin pain of TEN.
Treatment of erythematous drug reactions includes withdrawal of possible causative
agents and supportive measures (eg, antihistamines for pruritus). (See "Drug
eruptions".)
Pustular drug eruptions - Pustular drug reactions, including acute generalized
exanthematous pustulosis (AGEP), may also be severe and mimic early SJS/TEN
[83]. AGEP is an eruption consisting of non-follicularly centered pustules that often
begin on the neck and intertriginous areas. Most commonly, AGEP is caused by beta-
lactam antibiotics, occurring within a few days of ingestion. The lesions are not
associated with pain, and mucosal involvement is rare. The pustules of AGEP may
coalesce and slough, but this occurs during resolution of the disorder, and is not
present during the evolving phase of the disease. Treatment of pustular drug reactions
includes withdrawal and supportive measures.
Phototoxic eruptions - Phototoxic eruptions are caused by direct interaction of a
chemical with sunlight to yield a byproduct toxic to the skin. The most common
phototoxic reactions to be confused with SJS/TEN are those that are due to oral
ingestants. As an example, fluoroquinolones may yield a phototoxic reaction, which
can lead to widespread epidermal sloughing. Important clues to the presence of a
phototoxic eruption include recent sun exposure, known phototoxic qualities of
certain medications, and locations of the lesions on sun-exposed areas. When
 sloughing is marked, the patient with a severe phototoxic reaction is managed in a
burn unit, much like a patient with SJS/TEN. (See "Drug eruptions".)
Toxic shock syndrome - Toxic shock syndrome (TSS) is classically caused by
Staphylococcus aureus, although a similar disorder can be caused by toxin-elaborating
strains of Group A streptococci. Compared to SJS/TEN, TSS presents with more
prominent involvement of multiple organ systems.

TSS is caused by elaboration of specific bacterial toxin(s) from staphylococci or

streptococci that act as superantigens, non-specifically activating large numbers of T
lymphocytes [84]. These disorders are described briefly here and presented in detail
elsewhere. (See "Staphylococcal toxic shock syndrome" and "Epidemiology, clinical
manifestations, and diagnosis of streptococcal toxic shock syndrome".)

TSS develops acutely in healthy individuals, particularly young women, typically (but
not always) within days of menstruation or a surgical procedure.

Cutaneous manifestations may include a diffuse, red, macular rash resembling

sunburn that may involve the palms and soles. This eruption may be subtle or fleeting
(picture 4). Petechiae, vesicles, and bullae may develop in severe cases.
Desquamation occurs one to two weeks after the onset of illness and chiefly affects
the palms and soles (picture 5). Mucosal involvement in TSS includes hyperemia of
the vaginal and oropharyngeal mucosa and conjunctival-scleral suffusion and
hemorrhage (picture 6) [85].

Systemic signs and symptoms include fever, nonpitting edema of the face and hands,
diarrhea and vomiting, myalgias, hypotension, mental status changes, and multi-organ
failure. Early laboratory findings include elevations of creatinine phosphokinase,
elevated transaminases, and elevated creatinine. The diagnosis of TSS is based upon
clinical presentation, utilizing the CDC case definition (table 5).

Staphylococcal scalded skin syndrome - Staphylococcal scalded skin syndrome

(SSSS), also known as Ritter disease, is caused by epidermolytic toxins produced by
certain strains of Staphylococci [86]. This toxin is distributed systemically and results
in dissolution of keratinocyte attachments in only the upper layer of the epidermis
 (stratum granulosum). SSSS usually affects newborns and children [87]. Adults are
less commonly affected because improved renal function allows for clearance of the
toxins from the body, although adults with renal failure are more susceptible [88].
(See "Vesiculobullous and pustular lesions in the newborn".)

SSSS presents with fever, irritability, and a generalized, erythematous, micromacular

to maculopapular rash (picture 7 and picture 8) [86-88]. The exfoliative phase is
heralded by perioral exudation and crusting with large radial fissures, likened to an
"unhappy clown," appearing around the mouth. However, mucosal membranes are not
involved. There is usually no history of drug exposure.

SSSS is distinguished clinically from SJS/TEN chiefly by its epidemiology and

sparing of mucous membranes. The diagnosis is supported by histologic examination,
which reveals sloughing of only the upper layers of the epidermis. Frozen section
examination of sloughing epidermis can often distinguish SSSS from TEN as
histology in TEN will reveal a subepidermal split with full thickness epidermal
necrosis, while only partial thickness epidermal sloughing and minimal keratinocyte
necrosis will be noted in SSSS [89,90].

Treatment of SSSS involves eradication using intravenous antibiotics [86]. (See

"Treatment of invasive methicillin-resistant Staphylococcus aureus infection in
children".)

Paraneoplastic pemphigus Paraneoplastic pemphigus (PNP) is a rare disorder that

can represent the initial presentation of a malignancy or occur in a patient with a
known neoplastic process, such as non-Hodgkin lymphoma in adults or Castleman's
disease in children. Patients may develop severe mucocutaneous disease with ocular
and oral blisters and skin lesions that resemble erythema multiforme, bullous
pemphigoid, or lichen planus. (See "Pemphigus", section on 'Paraneoplastic
pemphigus'.)

SUMMARY AND RECOMMENDATIONS

 SJS, TEN, and SJS/TEN overlap syndrome represent disorders of uncertain etiology
that are characterized by desquamative lesions of the skin and mucous membranes.
Cases with less than 10 percent epidermal involvement are classified as SJS; those
with 30 percent or more involvement are classified as TEN; cases with between 10
and 30 percent involvement are considered overlap SJS/TEN. (See 'Introduction and
terminology' above.)
TEN is almost invariably drug-induced, while SJS is associated with infections, as
well as drug administration. (See 'Etiologies' above.)
SJS and TEN begin with a prodrome of fever and influenza-like symptoms one to
three days before the development of mucocutaneous and skin lesions. Characteristic
vesicular and bullous skin lesions then appear and progress over several days,
followed by sloughing. There may be multiorgan involvement. In the absence of
complications, the disorder generally resolves sufficiently that the patient can be
discharged from the hospital in two to four weeks. (See 'History and clinical
presentation' above.)
Risk factors for SJS and TEN include HIV infection, genetic factors, concomitant
viral infections, underlying immunologic diseases, and possibly physical factors. (See
'Risk factors' above.)
The diagnosis of SJS or TEN is clinical. Histologic findings on skin biopsy are
supportive, but not independently diagnostic. (See 'Evaluation and diagnosis' above.)
The differential diagnosis includes erythema multiforme, other types of severe
medication reactions, severe reactions to bacterial toxins (eg, toxic shock syndrome,
staphylococcal scalded skin syndrome), and Kawasaki disease. (See 'Differential
diagnosis' above.)

2. Characteristics and criteria Definitions of SLEs symtomp

Criteria definitions :

1 . Malar rash / erythema rash on the face that give rise flat or slightly above the surface of
the skin of the face , resembling a butterfly , the cords are usually not nasolabialis
2 . Discoid lupus rash shaped spheres give rise above the skin 's surface with a layer of
follicle blockage with flaky . In long lesions may form scar tissue .
3 . Photosensitive skin rash occurs as a hypersensitivity reaction to sunlight , is obtained from
the history or physical examination .
4 . Oral or nasopharyngeal ulceration is usually not painful , obtained from physical
examination
5 . Non- erosive arthritis Arthritis about 2 or more joints , swollen and painful or there is a
synovial effusion .
6 . Serositis a) Pleurisy - a history of pleural pain or pleural friction sound proofing or no
pleural effusion
or
b ) Pericarditis - of ECG or acquired pericardial friction sound or no pericardial effusion
7 . A kidney disorder ) settled proteinuria > 0.5 g / day proteinuria or urine examination as >
3+
or
b ) Cellular casts - may be the cells of erythrocytes , hemoglobin , granular , tubular or
mixed .
8 . Neurological abnormalities a) Seizures - not because of spontaneous or drug - obatatn
metabolic disorders such as uremia , ketoacidosis and electrolyte balance disorders .
or
b ) Psychosis in the absence of other causes such as drugs or metabolic disorders such as
uremia , ketoacidosis and electrolyte balance disorders .
9 . A hematologic disorder a) hemolytic anemia with reticulocytosis
or
b ) Leukopenia - less than 4000/mm3 on 2 / more measurements
c ) lymphopenia - less than 1500/mm3 on 2 / more measurements
d ) Thrombocytopenia - less than 100.000/mm3 without drugs that can cause
thrombocytopenia
10 . Immunological abnormalities ba ) Anti - DNA : abnormal titers of antibodies to native
DNA
or
b ) Anti - SM : presence of antibodies against the core antigen of smooth muscle or
c ) positive antiphospholipid antibodies based on
The others:
( 1 ) abnormal serum IgG titer or IgM antibodies or anti - kardiolipin ,
( 2 ) positive lupus anticoagulant using a standard method or
( 3 ) false positive serological test for at least 6 months and confirmed enumerated by
Treponema pallidum immobilization test or test fluorescence treponemal antibody absorption
11 . Antinuclear antibody titers checked with abnormal ANA imunoflurosensi method or
other equivalent means , which performed at the same time or the presence of lupus
syndrome due to drug
a. This classification consists of 11 criteria . For the purposes of clinical studies , a person is
said to LES obtained when 4 or more
of 11 criteria , either serially or sustained during the interval or observation .

Modified criteria no.10 made in 1997.

The onset of the disease can be spontaneous or preceded precipitation factors such as contact
with sunlight , infection , drugs , pregnancy termination , physical trauma / psikis.Setiap
attacks are usually preceded general symptoms such as fever , MALISE , weakness , anorexia
, weight loss , is the manifestation iritabilitas.Demam the most prominent sometimes with
chills .
Skin manifestations in the form of butterfly appearance.Manifestasi other skin lesions of
discoid form , palmar erythema , periungual erythema , alopecia.Mucous lession membranes
tend to appear in 20 % of patients exacerbasi.pada period also obtained Raynaud's
phenomenon .
Gastrointestinal manifestations such as nausea , diarrhea , GIT discomfort.Gejala disappear
quickly if systemic manifestations diobait with adekuat.Nyeri GIT may be caused peritonitis
sterildan arteritis of small blood vessels of the mesentery and intestine resulting in ulceration
usus.Arteritis can also cause pancreatitis .
Musculoskeletal manifestations in the form of athralgia , myalgia , myopathi .
Joint symptoms with or without active synovitis in 90 % penderita.Atritis there tends to be
deformed , and the picture is almost always found on radiographic examination .
Ocular manifestations , including conjungtivitis , photophobia , transient or permanent
blindness and sight monooculr kabur.Pada fundus examination can also be found cotton-wool
spots in the retina ( cytoid bodies) .
Pleurisi , pleural effusion , bronchopneumonia , pneumonitis often dijumpai.Pleural mild
unilateral effusion is more common than in the LE cells obtained bilateral.Mungkin
pleura.Pleural effusion fluid therapy adekuat.Restriktif disappeared with pulmonary disease
may also be encountered .
Manifestations in the heart may be due to cardiac failure and hipertensi.Cardiac micarditis
arrhythmias are often dijumpai.Valvular incompetence often encountered is mitral
regurgitation .
Vasculitis of the branching mesenterica often and associated with polyarteritis nodusa ,
including the presence of aneurysm found on percabangannya.Abdominal pain ( after eating )
, ileus , peritonitis , perforation may occur .
Neurological complications manifest as peripheral and central form of psychosis , epilepsy ,
organic brain syndrome , peripheral and cranial neuropathies , transverse myelitis ,
stroke.Depresi and psychosis may also be due to induction of drug kortikosteroid.Perbedaan
between them can be known by lowering or raising the dose steroid.Psikosis lupus improved
when the steroid dose is increased , and the steroid psychosis improved when the dosage is
reduced .
Glomerulonephritis and renal complications such as kidney failure kronik.Manifestasi most
frequent form of renal lesions ranged proteinuria.Histopatologi focal glomerulonephritis to
renal difus.Keterlibatan glomerulonfritis membranoploriferatif in SLE may be mild and
asymptomatic to progressive and mematikan.Karena mild cases are increasingly being
detected , the incidence more meaningful menurun.Ada 2 kinds of renal pathology in the
form of diffuse lupus nephritis and lupus nephritis is a manifestation of diffuse lupus
membranosa.Nefritis terberat.Klinis form as nephrotic syndrome , hypertension , chronic
renal failure .
Thorough Adenopathi can be found , especially in children , young dewassa , and skin
hitam.Splenomegali occurred in 10% of the spleen showed histological penderita.Secara
periarterial fibrosis ( onion skin lesion ) .
Hepatomegaly may also be found , but rarely accompanied by icterus .
Parotid gland can be enlarged to 6 % of SLE cases .
In Lupus Erythematosus Drug induce abnormalities in the kidneys and central nervous
system rarely ditemukan.Anti Ds - DNA , hipocomplementemia and immune complexes are
also rarely

3. What kind of drugs can trigger for Steven Johnson Syndrome?

The skin is one organ very easy to give a clinical manifestation if there are
disturbances in the body. One such disorder can be caused by allergic reaction to a drug.
Allergic drug eruptions or allergic drug eruption is an allergic skin reaction or
mucocutaneous area which occurs as as a result of drug delivery systemic manner (enter
through mouth, nose, rectum, vagina, and by injection or infusion). While allergic reactions
caused by use of drugs by way of topical, which is a drug used in surface of the body has
its own term called allergic contact dermatitis.

Not all drugs can lead to allergic reactions only a few namely; non-anti-
inflammatory drugs steroids (NSAIDs), antibiotics; for example penicillin and its
derivatives, sulfonamides, and anticonvulsant drugs.

Steven-Johnson Syndrome (SSJ) Toxic epidermal necrolysis (NET) is some form

serious reactions posed.

Factors which increase the risk of drug eruptions are :

1 . sex

Women at risk for this disorder is much higher when compared to men . However, no single
expertwere able to explain this mechanism .

2 . immune system

Drug allergic eruption is more apt to occur in someone who experienced a decline in the
immune system.

3 . Age

Drug allergies can occur in all age groups , especially in children and adults . In children may
be due to development of immunological system is not perfect . In contrast , in adults caused
by adults more frequent contact with antigenic material .Older age would slow emergence
drug eruption onset but cause higher mortality when exposed severe reactions .

4 . dose

Intermittent drug delivery with high doses will facilitate the incidence of sensitization . But if
it is through the induction phase , even very small doses can cause allergic reactions already .
The more commonly used drugs , The greater the likelihood of an allergic reaction in
patients who are sensitive .
5 . Infection and malignancy

Other high mortality was also found in patients with severe drug eruption accompanied by
malignancy . Reactivation of latent virus infection with human herpes virus ( HHV )
commonly found in those who drug hypersensitivity syndrome .

6 . atopic

Atopy are risk factors is still under debate .

Pathogenesis

There are two kinds of mechanisms. The first is an immunological mechanism and the second
is a non-immunological mechanisms. Generally, drug eruptions arise due to a
hypersensitivity reaction based on immunological mechanisms. Drugs and drug metabolites
serves as a hapten, which induces humoral antibodies. This reaction can also occur through
non-immunological mechanisms caused by
drug toxicity, overdose, drug-drug interactions and changes in metabolism.
 Drugs most commonly cause allergic reactions are penicillin and its derivatives.

A person who has responded IgE penicillin, if the person is injected with penicillin
will experience anaphylactic shock can even cause death. to avoid the use of penicillin to
patients who have a history of allergy to drugs especially those that have a similar structure.
Penicillin acting as a hapten, which is a small molecule such as -lactam ring highly reactive
a very important role as an antibacterial agent. The ring reacts with the amino acid groups the
host protein and form a covalent bond. When penicillin was injected or orally treated,
penicillin will immediately conjugation with host proteins.
Proteins or peptides that have been modified by penicillin on certain people would trigger a
TH2 response. TH2 cells will further activate B cells that bind to penicillin. Activated B cells
to produce IgE antibodies which will bind the hapten penicillin. So penicillin acts as an
antigen to B cells, and the T cell antigen with respect to nature is capable of modifying
proteins and host peptides. When someone is allergic to penicillin received an intravenous
injection of the drug, proteins that have been modified by penicillin will cause IgE molecules
perform crosslinking on the surface of mast cells located on the network. IgE crosslinking is
not just confined to the surface of mast cells but also occurs on the cell surface of basophils
being circulated, giving rise to an anaphylactic reaction.

4. Other kind of hypersensitivity disease

Sceloderma

Scleroderma is a disease affecting the skin and other organs of the body. Scleroderma is one
of the autoimmune rheumatic diseases, meaning that the bodys immune system is acting
abnormally. The main finding in scleroderma is thickening and tightening of the skin, and
inflammation and scarring of many body parts leading to problems in the lungs, kidneys,
heart, intestinal system and other areas.There is still no cure for scleroderma but effective
treatments for some forms of the disease are available.
 Scleroderma is relatively rare. Only 75,000 to 100,000 people in the US have it. More
than 75 percent of people with scleroderma are women.
The condition affects adults and children, but it is most common in women aged 30 to
50.
There are several types of scleroderma and related diseases and the names can be
confusing.
The two main types are localized (which affects the skin on the face, hands and feet)
and systemic (which can also affect blood vessels and major internal organs).
Although the underlying cause is unknown, promising research is shedding light on
the relationship between the immune system and scleroderma

Scleroderma (also known as systemic sclerosis) is a chronic disease that causes the skin to
become thick and hard, a buildup of scar tissue, and damage to internal organs such as the
heart and blood vessels, lungs, stomach and kidneys. The effects of scleroderma vary widely
and range from minor to life-threatening, depending on how widespread the disease is and
which parts of the body are affected.

The two main types of scleroderma are:

Localized scleroderma, which usually affects only the skin, although it can spread to
the muscles, joints and bones. It does not affect other organs. Symptoms include
discolored patches on the skin (a condition called morphea); or streaks or bands of
thick, hard skin on the arms and legs (called linear scleroderma). When linear
scleroderma occurs on the face and forehead, it is called en coup de sabre
Systemic scleroderma, which is the most serious form of the disease, affects the skin,
muscles, joints, blood vessels, lungs, kidneys, heart and other organs

The cause of scleroderma is not known. Genetic factors (different genes) appear be important
in the disease. Although exposure to certain chemicals may play a role in some people having
scleroderma, the vast majority of patients with scleroderma do not have a history of exposure
to any suspicious toxins. The cause of scleroderma is likely quite complicated.
Scleroderma is relatively rare. About 75,000 to 100,000 people in the U.S. have this disease;
most are women between the ages of 30 and 50. Twins and family members of those with
scleroderma or other autoimmune connective tissue diseases, such as lupus, may have a
slightly higher risk of getting scleroderma. Children can also develop scleroderma, but the
disease is different in children than in adults.

Diagnosis can be tricky because symptoms may be similar to those of other diseases. There is
no one blood test or X-ray that can say for sure that you have scleroderma.
To make a diagnosis, a doctor will ask about the patients medical history, do a physical
exam and possibly order lab tests and X-rays. Some symptoms he or she will look for
include:
Raynauds phenomenon. This term refers to color changes (blue, white and red) that
occur in fingers (and sometimes toes), often after exposure to cold temperatures. It
occurs when blood flow to the hands and fingers is temporarily reduced. This is one
of the earliest signs of the disease; more than 90 percent of patients with scleroderma
have Raynauds. Raynauds can lead to finger swelling, color changes, numbness,
pain, skin ulcers and gangrene on the fingers and toes. People with other diseases can
also have Raynauds and some people with Raynauds do not have any other disease.
Skin thickening, swelling and tightening. This is the problem that leads to the name
scleroderma (Sclera means hard and derma means skin). The skin may also
become glossy or unusually dark or light in places. The disease can sometimes result
in changes is personal appearance, especially in the face. When the skin becomes
extremely tight, the function of the area affected can be reduced (for example,
fingers).
Enlarged red blood vessels on the hands, face and around nail beds (called
telangiectasias).
Calcium deposits in the skin or other areas.
High blood pressure from kidney problems.
Heartburn; this is an extremely common problem in scleroderma
Other problems of the digestive tract such as difficulty swallowing food, bloating and
constipation, or problems absorbing food leading to weight loss.
Shortness of breath.
Joint pain.
While some treatments are effective in treating some aspects of this disease, there is no drug
that has been clearly proven to stop, or reverse, the key symptom of skin thickening and
hardening. Medications that have proven helpful in treating other autoimmune diseases, such
as rheumatoid arthritis and lupus, usually dont work for people with scleroderma. Doctors
aim to curb individual symptoms and prevent further complications with a combination of
drugs and self-care. For example:
Raynaud's phenomenon can be treated with drugs such as calcium channel blockers
or drugs called PDE-5 inhibors sildenafil (Viagra), tadalafil (Cialis), which
open up narrowed blood vessels and improve circulation. To prevent further damage,
its important to keep the whole body warm, especially fingers and toes. Its also
important to protect fingertips and other skin areas from injury, which can happen
even during normal daily activities.
Heartburn (acid reflux) can be treated with antacid drugs, especially proton-pump
inhibitors (omeprazole and others). These medications ease gastro-esophageal reflux
disease (known as GERD).
Scleroderma kidney disease can be treated with blood pressure medications called
angiotensin converting enzyme inhibitors (ACE inhibitors). These can often
effectively control kidney damage if started early and use of these drugs has been a
major advance for treating scleroderma.
Muscle pain and weakness can be treated with anti-inflammatory drugs such as
glucocorticoids (prednisone), intravenous immunoglobin (IVIg), and/or
immunosuppressive medications. Physical therapy may be useful to maintain joint
and skin flexibility.
Lung damage. There are two types of lung disease that patients with scleroderma may
develop. The first type is called interstitial lung disease (scarring). There is evidence
that cyclophosphamide is somewhat effective in treating the interstitial lung disease in
scleroderma. Clinical trials are underway assessing the effectiveness of several other
drugs for this problem.

The second type of lung disease seen in scleroderma is pulmonary arterial hypertension (high
blood pressure in the arteries in the lungs). In the last 10 years, a number of drugs have
become available to treat this condition, including prostacyclin-like drugs (epoprostenol,
treprostinol, iloprost), the endothelin receptor antagonists (bosentan, ambrisentan), and PDE-
5 inhibitors (sildenafil, vardenafil, tadalafil).

Much research is ongoing into new treatments for scleroderma. Patients and their families
should know that experts remain optimistic and take comfort in the fact that work towards a
cure will continue.

Scleroderma can involve almost every organ system in the body. Although symptoms vary
greatly from patient to patient, it can dramatically impact someones life.
Patients should consult a rheumatologistor a team of specialists---who are experienced in
dealing with this complicated disease. Several other diseases that affect the skin are
sometimes confused with scleroderma.

Living with scleroderma is quite challenging. Everyday activities can sometimes be difficult
due to physical limitations and pain. Problems with digestion may require changes in diet;
patients often have to eat several small meals rather than fewer large meals. Patients must
also keep the skin well-moisturized to lessen stiffness and be careful during activities such as
gardening, cookingeven opening envelopes---to avoid finger injuries. To keep the body
warm, patients should dress in layers; wear socks, boots and gloves; and avoid very cold
rooms. Unfortunately, moving to a warmer climate does not necessarily lead to dramatic
improvement. Exercise and/or physical therapy may ease stiffness in the joints.
Patients must also deal with the psychological setbacks that come from living with a disease
that is chronic, uncommon and currently incurable. Because scleroderma can cause
significant changes in appearance, a patients self-esteem and self-image are almost always
affected. The support of family and friends is vital in helping to maintain a good quality of
life.

Points to remember
Scleroderma differs from person to person but can be very serious.
There are medications, as well as steps individuals can take, to ease the symptoms of
Raynaud's phenomenon, skin problems and heartburn.
Effective treatments are available for those with severe disease, including acute
kidney disease, pulmonary hypertension, lung inflammation and gastrointestinal
problems.
 It is important to recognize and treat organ involvement early on to prevent
irreversible damage.
Patients should see physicians with specialized expertise in the care of this complex
disease.
A great deal of research is underway to find better treatments for scleroderma and,
hopefully, someday a cure.

Polyarteritis nodosa

Polyarteritis nodosa (PAN) is an inflammatory necrotizing vasculitis that tends to occur at

bifurcations & branchings of small and medium sized muscular arteries but not venules.
Fibrinoid necrosis of the vascular wall results in occlusion & infarction, aneurismal dilatation
or fracture & hemorrhage. Involvement of the renal and visceral arteries is characteristic but
involvement of the arterioles of the renal glomeruli or the pulmonary arteries does not occur.
PAN can affect almost any organ system in the body, but is classically seen in the skin,
kidneys, gastrointestinal tract, peripheral nerves, and joints. Glomerulonephritis and
pulmonary capillaritis are not associated with PAN, although hematurea resulting from renal
infarction is common.

Epidemiology: PAN is a rare condition in the US. Its incidence in the general population is
0.7 per 100,000 & the prevalence is 6.3 per 100,000. PAN predominantly affects persons
aged 40-60 with no racial or ethnic predilection. The mean age of onset is 48. It is rare in
children. A slightly higher incidence is found in males. Male-to-female ratio is 1.6:1. The
mortality rate can be as high as 20-30%, despite aggressive therapy.

Pathophysiology: PAN causes a segmental vasculitis and tends to involve the bifurcations of
small & medium sized arteries. The involvement of veins, venules, arterioles, and capillaries
is not usually seen in PAN, but is found in MPA . Acutely, polymorphonuclear leukocytes
infiltrate the layers of the vessel wall and the perivascular areas. This causes intimal
proliferation which then leads to degeneration of the vessel wall. Later mononuclear cells
infiltrate the vessel and then fibrinoid necrosis begins which causes occlusion of the vessel
lumen, thrombosis, and ischemia of the tissue supplied by the vessel. The lesions then heal
with collagen deposition which further exacerbates the occlusion. The lesions can produce an
aneurysmal dilatation of the artery or a hard nodule.
Immune Pathology: Studies in animal models dating back to the 1930s implicated the arterial
deposition of circulating immune complexes in the pathogenesis of PAN and other systemic
necrotizing vasculitides. Before widespread vaccination for hepatitis B, up to one third of all
cases of PAN were caused by HBV in about 10% of cases this is true today. In such cases
viral antigenantibody complexes are readily demonstrated in blood vessel walls in
conjunction with reductions in serum complement. Such immune complexes activate
compliment C5a which attracts neutrophils into the vessel wall. The immune complexes also
elicit a marked increase in interferon- and interleukin (IL)-2 and a moderate increase in
TNF & IL-1b. IL-1 & TNF activate endothelial cells & neutrophils. In vitro, ANCA (anti-
cytoplasmic neutrophil antibodies) can activate neutrophils to adhere more to endothelial
cells and to stimulate neutrophils that have been primed with tumor necrosis factor (TNF) to
lyse cultured endothelial cells. It is uncertain if this has any pathogenetic significance.
Nonetheless cANCA & pANCA are useful as diagnostic tests for cANCA is present in 90%
of Wegeners patients but rare in PAN or Churg-Straus Syndrome & unusual in MPA.
pANCA (Perinuclear ANCA; antimyeloperoxidase) is present in 75% of patients with MPA
& 48% with Churg-Straus Syndrome. This presence of ANCAs in MPA, Churg-Straus &
Wegeners suggests stronger relationship between MPA Churg-Straus & Wegeners than
with PAN & may also in some manner be related to the propensity for glomerulonephritis
and pulmonary capillaritis not shared by PAN.

Clinical Manifestations: PAN usually present with hypertension and symptoms or sign
suggesting ischemia but may also present with nonspecific complaints involving almost any
system of the body. Fever, weight loss and malaise are present in over one half of cases.
Often patients present with vague symptoms like those listed previously and headache,
abdominal pain, and myalgias. Any organ system, usually except the lungs (lungs are
involved in MPA) and the follicular arteries of the spleen, may be involved in PAN:

Nervous system: Peripheral disease has been noted early in 50-70% of patients as a
direct result of occlusion to the vasa vasorum. The most common manifestation is
mononeuritis multiplex, usually manifested by rapid development of focal neuritic
pain and associated sensorimotor deficits. Cranial neuropathies (most often CN III
and VIII) may also be observed. It is typically an early manifestation of the disease
and represents a major clue to the diagnosis. Central disease occurs 2-3 years after
onset of PAN and usually manifests as diffuse encephalopathy and can includes
motor deficits, strokes, brain hemorrhages, seizures and diffuse encephalopathy. In
 the brain, the most consistent changes are found in the small meningeal arteries with
less consistent involvement of parenchymal vessels. Cerebral angiography most
frequently shows alternating segments of narrowing and widening of small- and
medium-sized arteries or occlusion of small arteries.
Skin: Skin manifestations occur in approximately 40% of individuals with PAN.
Vascular purpura typically is papulopetechial but sometimes may be bullous or
vesicular. Any infiltration of subcutaneous nodules should be biopsied immediately.
Livedo reticularis, mottled reticular pattern over the skin or portions of the extremities
or torso is common. Distal gangrene may be observed as the consequence of
ischemia. Skin involvement is usually in the legs and is very painful.
Musculoskeletal: One half of patients complain of arthralgia or myalgia.
Renal: The kidney is the most frequently affected site occurring in 63% of individuals
with PAN and/or MPA. In persons with classic PAN, vascular nephropathy is a
common manifestation. Renal failure can occur because of multiple infarcts. Rapidly
progessing glomerulonephritis is more characteristic of MPA. Ureteral involvement,
which can be unilateral or bilateral, occurs because of periureteral vasculitis and
secondary fibrosis.
GI: GI involvement can be found in up to 50% of patients on autopsy. Abdominal
pain can be the first symptom of GI vasculitis. Abdominal pain syndromes are the
most common, followed by nausea or vomiting, melena, hematochezia, non-bloody
diarrhea, constipation, and overt gastrointestinal bleeding that requires transfusions.
Acute cholecystitis, gallbladder infarction, perforation of the bowel and infarction of
the bowel also occur. This can often be mistaken for inflammatory bowel disease.
Cardiac: There are usually no clinical symptoms from damage to the heart, but 26%
of individuals with PAN do have cardiac manifestations. Cardiomegaly, systolic
dysfunction, tricuspid and mitral valve regurgitation, pericarditis, and coronary artery
involvement leading to ischemia and infarction can all be found in PAN.
Ocular manifestations: Retinal vasculitis, retinal detachment, and cotton wool spots
(cytoid bodies) are signs of PAN.
Orchitis: Testicular biopsy reveals vasculitis in 25% of persons with PAN.

Diagnosis: 1990 Criteria For the Classification of Polyarteritis Nodosa The presence of any 3
criteria in Table 2 yields a sensitivity of 82% and a specificicy of 87% :for PAN:

Table 2: Diagnostic Criteria for Polyarteritis Nodosa

 Weight loss 4 kg not due to dieting or other factors
Livedo reticularis (A mottled reticular pattern over the skin of the extremities or
torso.)
Testicular pain or tenderness, not due to infection, trauma, or other obvious cause.
Myalgia, weakness or tenderness of leg muscles (excluding shoulder and hip girdle).
Mononeuropathy or polyneuropathies.
Diastolic BP >90 mm Hg.
BUN >40 mg/dl or creatinine >1.5 mg/dl, not due to dehydration or obstruction.
Hepatitis B virus antigen or antibody in the serum.
Arteriographic abnormalities showing aneurysms or occlusions of the visceral
arteries, not due to arteriosclerosis, fibromuscular dysplasia, or other non-
inflammatory cause. Biopsy of small or medium-sized artery showing granulocytes
&/or mononuclear leukocytes infiltrating the artery wall.

Laboratory:

The anemia of chronic disease may be found in PAN.

WBCs are elevated with predominance of polys in 75% of PAN patients.

Elevated ESR & Hypergammaglobulinemia but not increased ANA titer occurs in PAN.

30% of PAN patients have a positive test of Hep B surface antigen.

p-ANCAs are usually found in MPA & Churg-Straus Syndrome & cANCA in Wegeners.

Neither are common in patients with PAN.

Treatment: PAN related to hepatitis B infection is treated with a 2-week course of

prednisone, 1mg/kg/day, followed by antiviral therapy (interferon gamma-2b) plus ribavirin
(Rebetron) for 1 year or until seroconversion, whichever occurs first. Plasma exchange, 60
mL/kg/session, 34 sessions/week for a total of 30 sessions is recommended after the steroid
therapy. The principal treatment of idiopathic PAN is cyclophosphamide (Cytoxan). In most
cases, monthly intravenous pulses continued for 1 year (0.6 gm/m2, adjusted to achieve
leukopenia but maintain neutrophil counts above 1500/mm3) will suffice, and this mode of
administration is associated with significantly less infectious morbidity than daily oral
cyclophosphamide, which should be reserved for patients with refractory disease. A
combination of oral prednisone, 1mg/kg/day and cyclophosphamide, 2 mg/kg/day is a classic
treatment used for PAN. This treatment regimen has been reported to result in up to a 90%
remission rate even following discontinuation of therapy.

Prognosis: In untreated patients, the 5-year survival rate is 13%, with 40% to 50% of deaths
occurring in the first 3 months1,6. Death usually results from renal failure, GI complications,
bowel infarcts or perforations, or cardiovascular causes. In treated patients, 5-year survival
rate is increased to over 40%.

Juvenile rheumatoid arthritis (JRA) is the most common chronic rheumatologic disease in
children and is one of the most common chronic diseases of childhood. The etiology is
unknown, and the genetic component is complex, making clear distinctions between the
various subtypes difficult. A new nomenclature, juvenile idiopathic arthritis (JIA), is being
increasingly used to provide better definition of subgroups.

Signs and symptoms

History findings in children with JIA may include the following:

Arthritis present for at least 6 weeks before diagnosis (mandatory for diagnosis of
JIA)
Either insidious or abrupt disease onset, often with morning stiffness or gelling
phenomenon and arthralgia during the day
Complaints of joint pain or abnormal joint use
History of school absences or limited ability to participate in physical education
classes
Spiking fevers occurring once or twice each day at about the same time of day
Evanescent rash on the trunk and extremities
Psoriasis or more subtle dermatologic manifestations

Physical findings are important to provide criteria for diagnosis and to detect abnormalities
suggestive of alternative etiologies, as well as to indicate disease subtypes. Such findings
include the following:
 Arthritis: Defined either as intra-articular swelling on examination or as limitation of
joint motion in association with pain, warmth, or erythema of the joint; physical
findings in JIA reflect the extent of joint involvement
Synovitis: Characterized by synovial proliferation and increased joint volume; the
joint is held in a position of maximum comfort, and range of motion often is limited
only at the extremes

Types of JIA include the following:

Systemic-onset juvenile idiopathic arthritis

Oligoarticular juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis
Psoriatic arthritis
Enthesitis-related arthritis
Undifferentiated arthritis

Diagnosis

Diagnosis of JIA is based on the history and physical examination findings. When physical
findings do not document definite arthritis, further evaluation is warranted. Laboratory
studies that may be considered include the following:

Inflammatory markers: Erythrocyte sedimentation rate (ESR) or CRP level

Complete blood count (CBC) and metabolic panel
Liver function tests and assessment of renal function with serum creatinine levels
Antinuclear antibody (ANA) testing
Additional studies: Total protein, albumin, fibrinogen, ferritin, D-dimer, angiotensin-
converting enzyme (ACE), antistreptolysin 0 (AS0), anti-DNAse B, urinalysis

When only a single joint is affected, radiography is important to exclude other diseases. Basic
radiographic changes in JIA include the following:

Soft tissue swelling

Osteopenia or osteoporosis
Joint-space narrowing
Bony erosions
 Intra-articular bony ankylosis
Periosteitis
Growth disturbances
Epiphyseal compression fracture
Joint subluxation
Synovial cysts

Other imaging modalities that may be helpful include the following:

Computed tomography
Magnetic resonance imaging
Ultrasonography and echocardiography
Nuclear imaging

Other studies and procedures that may be considered include the following:

Dual-energy radiographic absorptiometry (DRA)

Arthrocentesis and synovial biopsy
Pericardiocentesis

Management

A team-based approach to the treatment of JIA can be helpful. Management may include 1 or
all of the following areas:

Pharmacologic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), disease-

modifying antirheumatic drugs (DMARDs), biologic agents, or intra-articular and oral
corticosteroids
Psychosocial interventions
Measures to enhance school performance (eg, academic counseling)
Improved nutrition
Physical therapy
Occupational therapy

American College of Rheumatology (ACR) criteria for complete remission are as follows[2] :
 No inflammatory joint pain
No morning stiffness
No fatigue
No synovitis
No progression of damage, as determined in sequential radiographic examinations
No elevation of the ESR and CRP level

The ACR recommends treatment approaches to JIA on the basis of the following 5 treatment
groups[3] :

A history of arthritis in 4 or fewer joints

A history of arthritis in 5 or more joints
Active sacroiliac arthritis
Systemic arthritis without active arthritis
Systemic arthritis with active arthritis

Within each group, choice of therapy is guided by the severity of disease activity and the
presence or absence of features indicating a poor prognosis.

Advances in medical treatment have reduced the need for surgical intervention. Procedures
that may be considered in specific circumstances include the following:

Synovectomy
Osteotomy and arthrodesis
Hip and knee replacement

Etiology and Pathophysiology

The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility
plays a major role, but there is significant overlap between loci associated with JIA and those
associated with other autoimmune diseases.

JIA is a genetically complex disorder in which multiple genes are important for disease onset
and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus,
as has the VTCN1 gene.Associations have been found between specific HLA alleles and
clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by
uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort).

Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. T lymphocytes
have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factoralpha
[TNF-], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A
disordered interaction between type 1 and type 2 T-helper cells has been postulated.

Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for

synovial nonself antigens. Evidence for abnormalities in the humoral immune system include
the increased presence of autoantibodies (especially antinuclear antibodies), increased serum
immunoglobulins, the presence of circulating immune complexes, and complement
activation.

Chronic inflammation of synovium is characterized by B-lymphocyte infiltration and

expansion. Macrophages and T-cell invasion are associated with the release of cytokines,
which evoke synoviocyte proliferation. A study by Scola et al found synovium to contain
messenger ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin
1, as well as for their receptors, suggesting that induction of angiogenesis by products of
lymphocytic infiltration may be involved in persistence of disease.

Some pediatric rheumatologists view systemic-onset JIA as an autoinflammatory disorder,

such as familial Mediterranean fever (FMF) or cryopyrin-associated periodic fever
syndromes, rather than a subtype of JIA. This theory is supported by work demonstrating
similar expression patterns of a phagocytic protein (S100A12) in systemic-onset JIA and
FMF, as well as the same marked responsiveness to IL-1 receptor antagonists.

FMF is associated with mutations in the MEFV gene; these mutations are associated with
activation of the IL-1b pathway, resulting in inflammation. A study by Ayaz et al found an
increased frequency of MEFV mutations in Turkish children who were diagnosed with
systemic JIA; this study has not been replicated in other populations.

Arthritis must be present for 6 weeks before the diagnosis of juvenile idiopathic arthritis
(JIA) can be made. Disease onset is either insidious or abrupt, with morning stiffness or
gelling phenomenon (ie, stiffness after long periods of sitting or inactivity) being a frequent
complaint and arthralgia occurring during the day. A morning limp that improves with time
may be noted, and a toddler may no longer stand in the crib in the morning or after naps.

Complaints of joint pain may not be predominant in the patients history, however; children
often stop using joints normally (eg, develop contractures of joints, decreased wrist range,
limp) rather than complain of pain. Up to a quarter of children with oligoarticular JIA have
no pain.

Individuals with JIA may have a history of school absences, and their ability to participate in
physical education classes reflects the severity of the disease or acute flares.

Systemic-onset JIA is characterized by spiking fevers, typically occurring once or twice each
day, at about the same time of day, with temperature returning to normal or below normal.
The fever pattern is very useful because infections, Kawasaki disease, and malignancy
usually do not have such a predictable pattern.

Systemic-onset JIA is usually accompanied by an evanescent rash (lasting a few hours),

which is typically nonpruritic, macular, and salmon colored on the trunk and extremities.
Occasionally, the rash is extremely pruritic and resistant to antihistamine treatment.

Children with psoriatic arthritis may have typical psoriasis but dermatological manifestations
may be subtle; careful attention should be paid to looking for nail pits. Dactylitis is
characteristic of psoriatic arthritis.

Enthesitis-related arthritis frequently presents as evening and post-exercise pain. Attention

should be given to buttock pain and back pain that improves with activity (inflammatory back
pain). These children cannot lie in bed all morning but have to get up due to back pain.

Physical Examination

JIA is a clinical diagnosis. A complete physical examination is critical for the diagnosis.
Physical findings are important to provide criteria for diagnosis and to detect abnormalities
suggestive of alternative etiologies. The diagnosis of JIA is based on the physical finding of
arthritis in at least 1 joint that has persisted for at least 6 weeks, with other causes excluded,
in an individual younger than 16 years.
No diagnostic serologic tests for JIA are recognized, aside from rheumatoid factor assay for
subclassification of polyarticular disease. Other tests, such as antinuclear antibody and HLA-
B27 assays, may help further define diagnosis and risk of complications.

Arthritis is defined as either intra-articular swelling on examination or as limitation of joint

motion in association with pain, warmth, or erythema of the joint. The hips,
temporomandibular joint, and small joints in the spine do not demonstrate swelling when
affected by synovitis but demonstrate the combination of loss of motion and pain. The
physical findings in JIA are a reflection of the extent of joint involvement.[18]

In synovitis, in which there is synovial proliferation and an increase in joint volume, the joint
is held in a position of maximum comfort. Limbs with synovitis are generally held in flexion.
Range of motion often is limited only at the extremes.

In synovitis, the fingers may appear swollen, and the range of motion becomes painful. The
wrist goes into flexion. In the knee, the parapatellar fossae often are obliterated, and a doughy
synovium may be palpable. A soft, boggy swelling is appreciated in the popliteal fossa.

The hip is held in an attitude of flexion, abduction, and external rotation. Attempted range of
motion will be painful to a varying degree. Guarding is an early sign of synovitis.

Cutaneous erythema is extremely rare in JIA. Its presence should alert one to look for another
diagnosis.

Glomerulonephritis

Definition

Glomerulonephritis is an inflammatory process affecting primarily the glomerulus, with

infiltration and proliferation of acute inflammatory cells. These are principally mononuclear
cells and neutrophils in post-infectious glomerulonephritis. The inflammation is
immunologically mediated with immune deposits in the glomerulus. Onset of symptoms is
usually acute. Symptoms include oliguria, hypertension, haematuria, proteinurai and renal
impairment.Acute post-streptococcal glomerulonephritis (APSGN) is the most common
glomerulonephritis affecting children. There are specific nephritogenic strains of group A
streptococcus which cause acute nephritis. It is usually sporadic and is uncommon in very
young children.Other infections - mycoplasma, staphylococcus, pneumococcus and viral
infections (parvovirus) may also cause acute glomerulonephritis.

Clinical Features

Pharyngitis precedes APSGN by 8-14 days. The time between purulent skin disease and
acute nephritis is very variable. Severity varies from asymptomatic microhaematuria to
anuric renal failure. Gross haematuria occurs in 30-50%. Volume overload occurs in up
to 2/3 of patients and may be severe enough to causecongestive heart failure and pulmonary
oedema. Hypertension occurs in up to 80%. Severity may not correlate with degree of
volumeoverload. Hypertensive encephalopathy (seizures, confusion, coma) is the
presenting feature in 5%.

Laboratory Features

Throat swabs are rarely positive. Leucocytes and red cell casts in urine. Proteinuria is
usually no more than 2+ on dipstix, however some children developnephrotic-range
proteinuria Mild normochromic, normocytic anaemia due to haemodilution. Depressed
C3 complement in 90%, normalises 2-6 weeks after onset. Prior penicillin therapy may
attenuate the fall in C3 Urea is raised disproportionately to creatinine Urine sodium
excretion is low compared with acute tubular necrosis Acidaemia and hyperkalaemia may
occur in those with severely depressed renal functio

Differential Diagnosis

IgA nephropathy, Alports disease, mesangiocapillary glomerulonephritis, Lupus nephritis,

Thin basement membrane nephropathy.

Management

Supportive care is all that is required in most. Bed rest does not influence rate of recovery.
Antibiotics do not change the course of illness once established but should be given to reduce
infectivity.
Complications

1. HypertensionMay cause seizures. Hypertension in the early stages of illness is usually

due to volume overload.

We suggest treating with salt and water restriction (400ml/m2/day)PLUSFrusemide 2- 4

mg/kg/dose IV.The dose needs to be titrated according to effect. Discuss with a senior if
giving an IV dose > 40 mg.

If additional acute hypertensive management is needed then add:

Isradipine 0.1 mg/kg/dose as required up to q6- 8h.This is a Hospital only medication. Will
need to be changed to a different medicationif hypertension persists at discharge

Patients with severe hypertension and encephalopathy should be admitted to PICU and
managed in consultation with the paediatric nephrologist and intensivist on call. (See
Management of Hypertensive Emergency - Hypertension guideline).

The choice of intravenous antihypertensive drug is at the discretion of the treating

physician:IV Labetalol: Bolus of 0.2 - 1 mg/kg, followed by a constant infusion (1 mg / ml
in 0.9% NaCl). Begin infusion at 1 mg / kg / hour. Increase the infusion rate at 10 -15 minute
intervals until there is an effect. If there is no effect at a dose of 2.5 mg / kg / hour, choose
another agent.

IV Hydralazine: Bolus 0.1 - 0.2mg/kg (max 20mg)

If BP falls too rapidly, give boluses of normal saline.

2. Electrolyte abnormalities.Usually not severe, potassium restriction may be required if

renal function significantly reducedIsradipine 0.1 mg/kg/dose as required up to q6- 8h.This
is a Hospital only medication. Will need to be changed to a different medicationif
hypertension persists at discharge.
3. Volume overloadTreat with fluid restriction -400ml/m2/day. Monitor weight and serum
sodium daily during acute phase.

Indications for Renal Biopsy

Persistently low C3 beyond 8 weeks Persistent heavy proteinuria after 6 months

Atypical presentation nephrotic syndrome, severe acute renal failure with estimatedGFR
<30ml/min/1.73m2 Atypical course failure of renal function to improve after initial
improvement during theacute phase which usually last no more than 2 weeks

Juvenile Idiopathic Arthritis (JIA)

Juvenile idiopathic arthritis (JIA) is defined by the Inter- national League of Associations for
Rheumatology (ILAR) as arthritis of unknown etiology that begins before the sixteenth
birthday and persists for at least 6 weeks withother known conditions excluded. JIA is one of
the more common chronic diseases of childhood, with a prev- alence of approximately 1 per
1,000. JIA often persists into adulthood and can result in significant long-term mor- bidity,
including physical disability. Recent majoradvances in treatment have greatly improved
short- and medium-term outcomes for children with JIA, yet no validated guidelines offer
recommendations for the treatment of JIA.To develop recommendations for the safest and
most effective treatment of JIA on behalf of the American Col- lege of Rheumatology
(ACR), we applied the established Research and Development/University of California at Los
Angeles (RAND/UCLA) Appropriateness Method to derive recommendations that are as
evidence based as possible. Similar methods were used recently in the de- velopment of the
ACR recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) for
rheumatoid arthritis and the management of glucocor- ticoid-induced osteoporosis. We
sought to give our recommendations additional strength by following the principles of the
Appraisal of Guidelines for Research and Evaluation instrument , a framework designed
specif- ically to assess the quality of clinical practice guidelines, including the methods used
for their development and the content of the final recommendations.Our effort focused on
the initiation and safety monitor- ing of therapeutic agents in the treatment of JIA, including
nonsteroidal antiinflammatory drugs (NSAIDs), intraartic- ular glucocorticoid injections,
nonbiologic DMARDs, bio- logic DMARDs, and systemic glucocorticoids for the treat- ment
of the systemic features of systemic arthritis. Th

indications for systemic glucocorticoids for the treatment of synovitis were not considered,
owing to a lack of pub- lished evidence. We did not consider all ILAR categories of JIA
individually and instead grouped children with JIA into distinct treatment groups (see
Materials and Meth- ods). We did not consider the economic costs of JIA or its treatment for
two reasons: first, too few economic analyses of JIA exist to permit conclusions; second, the
RAND/ UCLA Appropriateness Method specifically does not con- sider cost implications
(18). These recommendations were developed with international input and are intended to
inform and benefit health care providers caring for chil- dren with JIA throughout the world.
Many recommenda- tions fall outside the present bounds of regulatory agency approved
labeling, but reflect common and widely accepted practices in the field.The products of this
project are termed recommenda- tions rather than guidelines in order to reflect their non-
prescriptive nature. They are meant to function as a refer- ence and do not serve as a
substitute for individualized patient assessment and clinical decision making, espe- cially
when conducted by specialist clinicians familiar with the treatment of JIA. Importantly, these
recommen- dations are not intended to limit health care coverage for children with JIA

JIA treatment groups

JIA treatment groups. Chronic childhood arthritis is a heterogeneous condition. The most
recent ILAR disease classification criteria divide JIA into 6 distinct catego- ries. However,
this disease classification system was not strictly applied to the development of these
recommenda- tions for two reasons: currently, there is minimal evidence to support the
differential treatment of children with JIA for many of the category distinctions, and the
inclusion of all 6 categories would unnecessarily increase the total number of scenarios to an
unmanageable number for con- sideration by the TFP.

In place of the ILAR JIA classification, the CEP devel- oped treatment groups for these
recommendations with the goal of succinctly representing clinical decision mak- ing in the
treatment of JIA. The JIA category of systemic arthritis proved to be especially challenging
to evaluate. Attempts to exhaustively depict the myriad possible clin- ical presentations of
systemic arthritis were impractical. Therefore, recommendations for the treatment of signifi-
cant active systemic features (e.g., fever) and active arthri- tis for patients with systemic
arthritis were considered separately and independently by the TFP. Other authors have
suggested this dichotomy when considering thera- peutic choices for systemic arthritis. The
appropriate treatment of systemic arthritis patients with concurrentl

active systemic features and active arthritis may be ex- pected to incorporate elements of both
sets of recommen- dations, but this was not explicitly considered by the TFP. The 5 JIA
treatment groups used in these recommenda- tions are described below.

History of arthritis of 4 or fewer joints. This group in- cludes patients with the ILAR
categories of persistent oli- goarthritis, as well as patients with psoriatic arthritis, en- thesitis-
related arthritis, and undifferentiated arthritis who have developed active arthritis in only 4 or
fewer joints in total throughout the history of their disease course. Patients who currently
have 4 or fewer active joints, but who have a history of 5 or more active joints in total, are
considered in the history of arthritis of 5 or more joints treatment group. Patients with
systemic arthritis or active sacroiliac arthritis are considered in separate treat- ment groups.

History of arthritis of 5 or more joints. This group in- cludes patients with the ILAR
categories of extended oli- goarthritis, rheumatoid factor (RF)negative polyarthritis, RF-
positive polyarthritis, as well as patients with psoriatic arthritis, enthesitis-related arthritis,
and undifferentiated arthritis who have developed active arthritis in 5 or more joints in total
throughout the history of their disease. Pa- tients in this group need not currently have 5 or
more active joints. Patients with systemic arthritis or active sac- roiliac arthritis are
considered in separate treatment groups.Active sacroiliac arthritis. This group includes all
pa- tients with clinical and imaging evidence of active sacr

ntiated arthritis who have developed active arthritis in only 4 or fewer joints in total
throughout the history of their disease course. Patients who currently have 4 or fewer active
joints, but who have a history of 5 or more active joints in total, are considered in the history
of arthritis of 5 or more joints treatment group. Patients with systemic arthritis or active
sacroiliac arthritis are considered in separate treat- ment groups.History of arthritis of 5 or
more joints. This group in- cludes patients with the ILAR categories of extended oli-
goarthritis, rheumatoid factor (RF)negative polyarthritis, RF-positive polyarthritis, as well
as patients with psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis
who have developed active arthritis in 5 or more joints in total throughout the history of their
disease. Pa- tients in this group need not currently have 5 or more active joints. Patients with
systemic arthritis or active sac- roiliac arthritis are considered in separate treatment
groups.Active sacroiliac arthritis. This group includes all pa- tients with clinical and
imaging evidence of active sacro-iliac arthritis. This group is anticipated to include primar-
ily patients with the ILAR categories of enthesitis-related arthritis and psoriatic arthritis, but
may include patients from any of the ILAR JIA categories.Systemic arthritis with active
systemic features (and without active arthritis). This group includes all patients who fulfill the
ILAR criteria for systemic arthritis and who have active fever of systemic JIA with or
without other systemic features, but without active arthritis. An example of this clinical
phenotype would be a patient whose arthri- tis resolved spontaneously or rapidly upon
initiation of NSAIDs but who had persistent fever.Systemic arthritis with active arthritis
(and without ac- tive systemic features). This category includes all patients who fulfill the
ILAR criteria for systemic arthritis and who have active arthritis, but without active systemic
features. An example of this clinical phenotype would be a patient whose systemic features
resolved spontaneously or rap- idly upon initiation of NSAIDs but whose arthritis re- mained
active.

Therapeutic agent definitions

Therapeutic agent definitions. Medication classes used in the recommendation scenarios are
defined as follows: NSAID refers to all nonsteroidal antiinflammatory drugs used commonly
in clinical practice in the US and includes selective cyclooxygenase 2 inhibitors but not
aspirin. Cal- cineurin inhibitors refer to cyclosporine and tacrolimus. Tumor necrosis factor
(TNF )inhibitors refer to adali- mumab, etanercept, and infliximab.Clinical evaluation of
the effectiveness of a given thera- peutic agent may depend on the dose received. For all
recommendations, it is assumed that patients have re- ceived the maximum tolerated typical
dose of prior med- ications, as listed in Supplementary Appendix B (available in the online
version of this article at http://onlinelibrary. wiley.com/journal/10.1002/(ISSN)2151-4658).
Of note, the dose of methotrexate was assumed to be 15 mg/m2 (0.6 mg/kg) and administered
via the parenteral route. These specific doses were used as a guide for TFP mem- bers when
considering the scenarios; higher doses of these therapeutic agents may be appropriate in
some clinical situations.Clinical evaluation of the effectiveness of a given thera- peutic
agent may depend on the duration of therapy. Some scenarios explicitly stated the duration of
the current treat- ment regimen. In scenarios where duration of therapy was not defined, it
was assumed that the duration of therapy was sufficiently long to assess the response to
therapy.The recommendations assume that all medication regi- mens may contain a single
NSAID as adjunct therapy when considering the appropriateness of initiating new therapies.
For example, a patient described as currently receiving methotrexate is assumed to be taking
methotrex- ate with concurrent use of a single NSAID, as appropriate.Many of the
recommendations refer to initiating a new therapy for patients presently undergoing
treatment for JIA. In these cases, initiating is defined as either adding the new therapy
while continuing current therapy or switching to the new therapy while discontinuing the cur-
rent therapy. To limit the total number of scenarios, we made no distinction between adding
and switching for some of the recommendations. Of note, combination bio- logic DMARD
therapy was not considered by these recom- mendations, owing to concern from the reported
increased incidence of infections in studies of rheumatoid arthritisin adult populations.
Accordingly, initiation of a new biologic DMARD is always intended to be accompa- nied by
discontinuation of any current biologic DMARD.
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