18

▼
IMMUNOLOGIC DISEASES
KATHARINE N. CIARROCCA, DMD, MSED
MARTIN S. GREENBERG, DDS

▼ GENERAL PRINCIPLES OF ▼ GENERAL PRINCIPLES OF

IMMUNOLOGIC DISEASE IMMUNOLOGIC DISEASE
Immunity: Protection against Disease
Immunologic Disease The science of immunology, once a small branch of microbi-
ology, has grown into one of the principal sciences concerned
▼ PRIMARY IMMUNODEFICIENCIES with human disease. In recent years, the explosion of infor-
Immunodeficiency Disease with Primary Defect in Humoral mation in the field of immunology has both enhanced the
Immunity understanding of disease processes and provided tools with
Immunodeficiency Disease with Primary Defect in Cellular which to investigate a continually growing number of clinical
Immunity conditions. This wealth of knowledge has led to the develop-
Partial Combined Immunodeficiencies ment of better diagnostic tests and treatment specifically tar-
Oral Manifestations geted to the disease process.
Dental Management Concepts of disease are rapidly changing due to the ever-
increasing information gained in immunologic research. A
▼ SECONDARY IMMUNODEFICIENCIES competent clinician must understand the basic concepts of
Leukemia modern immunology and how they relate to disease. Much of
Hodgkin’s Disease the current research dealing with dental caries, periodontal
Non-Hodgkin’s Lymphoma disease, and oral ulcers uses the techniques of immunology to
Nephrotic Syndrome investigate the etiology and treatment of these diseases. In this
Multiple Myeloma chapter, pertinent basic principles of clinical immunology are
Sarcoidosis reviewed, diseases that involve the immune system are dis-
cussed, and the relationship of these diseases to oral mucosal
▼ CONNECTIVE-TISSUE DISEASES disease is highlighted.
Systemic Lupus Erythematosus
Scleroderma Immunity: Protection against Disease
Dermatomyositis The environment contains a large variety of microbial agents
Rheumatoid Arthritis (viruses, bacteria, fungi, protozoa, and parasites) that can cause
Mixed Connective-Tissue Disease disease if they multiply unchecked. The function of the
immune system is to distinguish these potentially infectious
▼ ALLERGY agents as foreign and to eliminate them from the body.
Localized Anaphylaxis An immune response involves both the recognition of the
Serum Sickness foreign substance and the reaction that serves to eliminate it.
Generalized Anaphylaxis This response can be divided into two functional systems: (1) the
Latex Allergy innate system, or first line of defense, and (2) the acquired or

478
Immunologic Diseases
adaptive system, the specific response to each infectious agent,
which eliminates the infection. These two systems work closely
together to eliminate pathogens. The innate immune response
is the immune defense system that lacks memory whereas the
acquired immune defense is dependent on previous encounters
with a pathogen. The unique characteristic of the acquired
immune response is its high specificity for a particular pathogen.
This specificity improves with each successive encounter with
the same pathogen, thus creating a “memory” that enables the
body to prevent the same infectious agent from causing disease
later. The innate response, however, does not change with
repeated exposure to a given infectious agent and therefore does
not possess the same antigen-specific recognition.
INNATE IMMUNITY
The major constituents of innate immunity are the cellular
components, represented by phagocytes; natural killer (NK)
cells; and the molecular component, which includes the com-
plement cascade and cytokines.
Phagocytic cells express surface glycoproteins and scav-
enger receptors that are used to recognize and engulf micro-
bial organisms and foreign particles.1 There are two types of
phagocytes: mononuclear phagocytes or tissue macrophages
and polymorphonuclear neutrophils.
Mononuclear phagocytic cells are derived from bone mar-
row stem cells, and their function is to engulf, internalize,
and destroy particles. Monocytes are strategically placed
where they will encounter foreign particles. In time, they
migrate into the tissues, where they develop into tissue
macrophages. Macrophages activate T lymphocytes by the
secretion of interleukins and present foreign antigens to lym-
phocytes. Macrophages act together with large granular lym-
phocytes to mediate both the lysis of cells coated with anti-
body and NK cells.
Neutrophils constitute the majority of the blood leuko-
cytes and develop from the same precursors as monocytes and
macrophages. They are activated by bacterial products to
phagocytize and kill bacteria. Phagocytosis is further increased
by the opsonization of bacteria with immunoglobulins and
complement products. Neutrophils are short-lived cells that
engulf and destroy material and then die.
Natural killer cells account for 10 to 15% of blood lym-
phocytes and are designed to kill any cells that do not express
self–major histocompatibility complex (MHC) antigens. They
are predominantly confined to the blood and spleen. Their
responsibility is to lyse virus-infected cells, foreign cells, or
malignant cells, without the help of antibodies.2
The complement system uses a simple self- or non-self-dis-
criminatory system: host tissues have cell surface molecules
that inhibit the activation of complement, and microbial organ-
isms lack these inhibitory molecules. The complement system
has multiple functions, including the direct killing of microor-
ganisms or tumor cells by lysis, the opsonization of microor-
ganisms for phagocytosis, the chemotaxis and activation of
leukocytes and mast cells, the processing of immunocomplexes,
and the regulation of antibody production by B cells.
479
ACQUIRED IMMUNITY
Lymphocytes are central to all adaptive immune responses as
they specifically recognize individual pathogens in host cells
and/or in the tissue fluids or blood. Lymphocytes are derived
from undifferentiated stem cell precursors that originate in the
bone marrow. These stem cells differentiate into two distinct
populations of lymphocytes, to form the two components of
adaptive immunity. One population of lymphoid stem cells
contacts the thymus and forms the thymus-dependent or T-cell
system. Other cells contact the human equivalent of the bursa
of Fabricius of birds, possibly the intestinal lymphoid tissue of
Peyer’s patches, to differentiate into the bursa or B-cell system.3
The diversity of these cells is extraordinary, and it has been
estimated that B and T lymphocytes are capable of respond-
ing to 10 to 15 different antigens.
T-Cell System (Cell-Mediated Immunity). T cells populate
the paracortical areas of lymph nodes and the white pulp of the
spleen and constitute 70 to 80% of lymphocytes in the periph-
eral blood. T cells have a wide range of activities. One group
interacts with B cells and helps them to divide, differentiate,
and make antibody. Another group interacts with phagocytic
cells to help them destroy pathogens they have engulfed. These
two groups are the T helper cells. A third group of T lympho-
cytes, the cytotoxic T cells, recognizes cells infected by virus
and destroys them. The T-cell system is responsible for cell-
mediated immunity, which serves as the body’s primary
defense against viruses and fungi and which is also responsi-
ble for delayed hypersensitivity reactions.
The use of monoclonal antibodies has permitted the fur-
ther subdivision of T lymphocytes by the detection of mole-
cules present on the cell surface. T lymphocytes are classified
as CD1 to CD8, according to cell surface molecules, with each
cell differing in function and stage of development. The two T-
cell types that are most important for clinicians to understand
are the CD4 (T4) and CD8 (T8) cells. Cells with CD4 surface
molecules (T4 lymphocytes) are important in directing the
immune response by inducing the proliferation of both T8
lymphocytes and B lymphocytes. The CD4 molecule present
on the T4 lymphocyte is the molecule used by human immun-
odeficiency virus (HIV) to penetrate and infect the cells. T8
lymphocytes (with CD8 surface molecules) suppress antibody
synthesis and are cytotoxic to tumor cells and cells infected
with viruses, fungi, or protozoa. They are also the cells that are
active in graft rejection.
T lymphocytes perform many of their functions by releas-
ing cytokines. Cytokines are proteinaceous mediators of cell-to-
cell interaction and act as local hormones. Cytokines are pro-
duced by virtually all nucleated cells and are called lymphokines
when produced by lymphocytes. Interleukins, colony-stimu-
lating factors, and interferons are among the main types of
cytokines. Interleukins are a large group of cytokines that are
mainly involved in directing other cells to divide and differen-
tiate. Colony-stimulating factors are involved in directing the
division and differentiation of bone marrow stem cells and the
precursors of blood leukocytes. Interferons are produced early
480
in infection and are the first line of resistance to many viruses.
Certain types of interferons and interleukins also play a role in
B-cell stimulation and modulation.
B-cell System (Humoral Immunity). The B cells populate the
follicles around germinal centers of lymph nodes, spleen, and
tonsils. B lymphocytes have immunoglobulin receptors on their
surfaces. When these receptors combine with an antigen, they
differentiate into plasma cells and produce antibodies, which
are vital to the body’s defense against bacterial infections and
other toxic foreign substances. Five major classes of antibodies
or immunoglobulins are now recognized: immunoglobulin
(Ig) M, IgG, IgA, IgD, and IgE. Each of these immunoglobulins
has different chemical and biologic properties.
IgM antibodies are macromolecules composed of five anti-
body monomers and are produced chiefly in the body’s pri-
mary response to a foreign antigen. IgM also plays an impor-
tant role in the activation of complement and in the formation
of immunocomplexes. IgG constitutes 75% of the serum
immunoglobulins and is the major component of the sec-
ondary antibody response. IgG is also the immunoglobulin
that crosses the placenta, giving protection to the newborn.
Four subgroups of IgG have been identified. IgA antibodies are
found in blood in small amounts, but secretory IgA is the main
antibody found in external secretions such as saliva, tears, and
bile. Levels of secretory IgA in saliva may have an important
role in protecting oral tissues against disease by preventing
microorganisms from attaching to the mucosa. Dysfunction of
the IgA system may help explain certain oral diseases, and in
the future, the induction of specific salivary secretory IgA anti-
bodies may protect patients from dental caries and periodon-
tal disease. Low quantities of both IgD and IgE are found in
normal human serum. IgD acts as a receptor for antigen on B
lymphocytes; IgE binds to mast cells and basophils, triggering
the release of histamine during allergic reactions such as ana-
phylaxis, hay fever, and asthma.
Immunologic Disease
The immune response, so necessary for protection against dis-
ease, can also cause disease or other undesirable consequences
when it reacts against tissues. The immune system can fail in
one of three ways:
IMMUNODEFICIENCY (INEFFECTIVE IMMUNE RESPONSE)
An immune response is comprised of a multitude of cells,
cytokines, and reactions. If any one part of an individual’s
immune system is defective, the individual may not be able
to fight infections adequately. Immunodeficiency may be
hereditary, manifesting shortly after birth, or may be
acquired as the result of viral (ie, HIV) infection or medica-
tion (ie, chemotherapy).
AUTOIMMUNITY (INAPPROPRIATE REACTION TO SELF)
A normally functioning immune system recognizes foreign
antigens and reacts against them; it simultaneously recognizes
its own tissues as self and mounts no reaction. If the system
Principles of Medicine
reacts against self-components, autoimmune disease occurs.
The body produces antibodies against its own tissues and
therefore causes damage. These autoantibodies play a signifi-
cant role in the pathogenesis of diseases such as pemphigus,
pemphigoid, and Hashimoto’s thyroiditis.
Immunocomplex disease is a subdivision of autoimmune
disorders. In these diseases, antigen-antibody complexes com-
bine with complement to cause a nonspecific vasculitis.
Systemic lupus erythematosus, glomerulonephritis, Behçet’s
syndrome, and erythema multiforme are examples of disor-
ders in which immunocomplexes play a significant role.
Antibodies may also cause disease by blocking the recep-
tor sites and preventing chemical agents that normally attach
at those sites from functioning. Myasthenia gravis and
insulin-resistant diabetes are caused by receptor sites blocked
by antibodies.
HYPERSENSITIVITY (OVERACTIVE IMMUNE RESPONSE)
Occasionally, immune reactions are out of proportion to the
damage caused by a pathogen, or the immune system pro-
duces a reaction to a harmless antigen, causing hypersensi-
tivity reactions. The immediate (type I) reaction responsible
for anaphylactic shock, angioedema, and hives is caused when
IgE and antigens bind to basophils and mast cells, resulting in
the release of chemical mediators such as histamine and
platelet-activating factor. These substances contract smooth
muscle and cause an accumulation of extravascular fluid by
increasing vascular permeability. The delayed-type hypersen-
sitivity reaction is mediated by a T-cell response rather than
by antibodies and leads to granulomatous inflammation. Two
examples of this reaction are inflammation resulting from a
tuberculin test and contact allergy to a topical antigen. The
immune nature of an allergic reaction is well accepted, but the
relationship of the immune response to other diseases
remains controversial.
Every immunologic disease can be classified with one of the
above immune-system malfunctions. The remainder of the
chapter discusses different examples of immunologic disorders
and their impact on oral disease and dental treatment.
▼ PRIMARY IMMUNODEFICIENCIES
Primary immunodeficiencies are hereditary abnormalities
characterized by an inborn defect of the immune system.
These diseases may involve only the B-cell system, with a
resultant deficiency of humoral antibodies, or only the T-cell
system, with a deficiency of cellular immunity. Since B-cell
function in humans is largely T-cell dependent, T-cell defi-
ciency also results in humoral immunodeficiency. Therefore,
T-cell deficiency can lead to a combined deficiency of both
humoral and cell-mediated immunity. The following is a dis-
cussion of various illustrative primary immunodeficiencies.
The oral manifestations of these deficiencies are discussed
together at the end of the section.
Immunologic Diseases
Immunodeficiency Disease with Primary Defect
in Humoral Immunity
X-LINKED AGAMMAGLOBULINEMIA
A hereditary disease of male children, X-linked agammaglob-
ulinemia (XLA), or Bruton’s agammaglobulinemia, occurs in
1 of 50,000 births and is caused by a defect in B-cell function.
Symptoms begin at 6 months of age, when transplacentally
acquired maternal antibodies have been metabolized. The
infant’s serum usually contains no IgA, IgM, IgD, or IgE and
only small amounts of IgG (< 100 mg/dL).4 Recent epidemi-
ologic studies have shown that most children develop clinical
problems during the first year of life but that as many as 21%
first present clinically as late as 3 to 5 years.5
The primary defect in XLA is a lesion on the gene that reg-
ulates the production of immunoglobulin heavy chains. The
affected individual lacks the ability to synthesize all classes of
antibodies, including the secretory immunoglobulins, making
the person considerably more susceptible to bacterial infec-
tions.6 The disease gene for XLA was identified in 1993 as
encoding Bruton tyrosine kinase (Btk).7 The exact role of Btk
in B-cell maturation is not yet understood, but defective Btk
results in an inability to develop B cells from pre-B cells.8
Patients with XLA experience severe recurrent bacterial
infections of the lungs, meninges, skin, and sinuses. The most
common organisms involved in these infections are pneumo-
cocci, streptococci, staphylococci, and Haemophilus influenzae.
Although recurrent sinopulmonary infection is the most com-
mon infection in patients with XLA, septicemia, septic arthri-
tis, and osteomyelitis may be present in untreated children.9
Untreated children also have an increased incidence of
rheumatoid arthritis, dermatomyositis with neurologic
involvement, lymphoma, and leukemia. The patient’s ability to
combat most viral and fungal infection is normal because of
the intact T-cell system.
A diagnosis of XLA is determined by the presence of very
little or no immunoglobulin and few or no B cells. Specific
mutation detection or measurement of Btk activity can con-
firm the genetic cause in a patient without an X-linked family
history.10 Examination of patients with XLA will reveal
hypoplasia of the lymph nodes, tonsils, and adenoids. Biopsy
specimens of lymphoid tissue reveal a lack of germinal centers
and plasma cells.
Even with careful therapy, the patient’s life span is
decreased because of repeated severe infections. Reductions in
hospitalization and infection rates have been well documented
in patients who receive high doses of intravenous
immunoglobulin (> 400 mg/kg every 3 weeks).11 Aggressive
antimicrobial therapy is often needed as adjunctive care in
spite of intravenous immunoglobulin replacement.
SELECTIVE IMMUNOGLOBULIN DEFICIENCIES
Selective immunoglobulin deficiencies are a group of disor-
ders characterized by an abnormality of the B-cell antibody
system that does not become clinically apparent until adult-
hood. Usually, only one or two immunoglobulin classes are
481
deficient, which accounts for the relatively asymptomatic
nature of the disease throughout childhood. There is evidence
that patients with deficiencies of one immunoglobulin will
compensate by the increased production of others. For this
reason, selective immunoglobulin deficiencies have been diffi-
cult to detect.12 Routine serum protein electrophoresis appears
normal, and specific tests for immunoglobulin levels must be
used in diagnosis.
The primary adult deficiencies rarely become apparent
until the third decade of life. The most common symptoms
include recurrent gram-positive bacterial infections, especially
of the respiratory tract. The infections are severe in patients
who lack all classes of immunoglobulins and are moderate to
mild in patients with a selective immunoglobulin deficiency.
Other organ systems commonly involved are the joints, gas-
trointestinal tract, and skin. Chronic compensatory hyperpla-
sia of the lymphoid tissue may occur, causing these disorders
to be confused with lymphomas.
IgA deficiency is the most common primary immunode-
ficiency, with an estimated 1 in 400 persons affected.13 One in
700 Caucasians have the defect; however, it is rarely found in
other ethnic groups. A majority of these patients are apparently
clinically normal and have no specific signs or symptoms
related to the deficiency and no obvious susceptibility to infec-
tion. The most common disorders related to selective IgA defi-
ciency are chronic sinusitis, chronic pulmonary infection, and
malabsorption syndromes. In addition, people with IgA defi-
ciency tend to develop malignant disorders. Finally, autoim-
mune and collagen vascular diseases such as systemic lupus
erythematosus and rheumatoid arthritis afflict people with
IgA deficiency more frequently.14 The reason for this is unclear,
but it has been speculated that in the normal patient, secretory
IgA blocks antigens that cause autoimmune diseases.
Approximately 20% of IgA-deficient individuals also lack
subclasses of IgG, specifically IgG2 and IgG4. In humans,
most antibodies to the capsular polysaccharides of pyogenic
bacteria are in the IgG2 subclass; therefore, a deficiency in
IgG2 alone also results in recurrent pyogenic infections. These
class and subclass deficiencies result from a failure in termi-
nal B-cell differentiation.
COMMON VARIABLE IMMUNODEFICIENCY
Individuals with common variable immunodeficiency (CVID)
have acquired agammaglobulinemia, which becomes apparent
in the second or third decade of life or later. As its genetic basis
and cause remain unknown, CVID is a diagnosis of exclusion.
It is clinically indistinguishable from the other primary B-cell
disorders and shares features of hypogammaglobulinemia,
recurrent pyogenic infections, and impaired antibody
responses. Both males and females are equally affected. Most
patients with CVID have B cells that are not fully mature and
thus do not function properly. The cells are not defective, but
they fail to receive proper signals from the T cells. T-cell defects
have not been well-defined in CVID. Many patients develop
autoimmune diseases (most prominently, pernicious anemia),
but the reason for this is unknown.
482
Immunodeficiency Disease with Primary Defect
in Cellular Immunity
DIGEORGE SYNDROME (VELOCARDIOFACIAL SYNDROME)
DiGeorge syndrome has recently been shown to be one of a
group of disorders caused by a deletion on chromosome
22q11.15 This genetic defect results in abnormal development of
the facial and neural crest tissues, causing abnormal develop-
ment of derivatives of the third and fourth pharyngeal pouches.
The result of this defect in embryonic growth are abnor-
malities of the thymus, the parathyroid glands, and the great
vessels of the heart. The subsequent malfunction of these
organs accounts for the respective features of DiGeorge syn-
drome: variable immunodeficiency, neonatal hypocalcemia
secondary to hypoparathyroidism, and congenital cardiac
defects. Abnormal ear, palatal (cleft palate), maxillary, and
mandibular development define the characteristic facies of
this disorder. These features include short palpebral fissures, a
small mouth, and a prominent forehead.16
The immunodeficiency associated with DiGeorge syn-
drome becomes apparent during the first few months of life.
Most patients have normal leukocyte function and normal
humoral immunity but a nearly total lack of cellular immunity.
As a result, patients have an increased susceptibility to infec-
tions with viruses and fungi. Infections with Candida albicans
are especially prominent (Figure 18-1).
DiGeorge syndrome was important in the development of
the concept of separate immune systems for humoral and
cellular hypersensitivity because hypoplasia of the thymus
produced impairment of only cellular immunity. The T-cell
deficiency is variable, depending on how severely the thymus
is affected. It is now believed that the thymus is completely
absent in less than 5% of patients with 22q11 deletion syn-
drome, but maldescent of the thymus leads to an absence of
thymus tissue in the mediastinum in most cases.17 Partial
DiGeorge syndrome exists with partial aplasia of the thymus
and parathyroid glands.
Spontaneous improvement in the immunologic defect of
DiGeorge syndrome has been described. Transplantation of fetal
or postneonatal thymic tissue may restore immune function.
SEVERE COMBINED IMMUNODEFICIENCY
Severe combined immunodeficiency (SCID) (Swiss-type
agammaglobulinemia) is a genetic disease that can be inher-
ited as either a sex-linked or autosomal recessive trait that
causes a variety of molecular defects.18 Because over 50% of
cases are caused by a genetic defect on the X chromosome,
SCID is more common in male infants than in female infants
(a ratio of 3:1). The remaining cases of SCID are due to reces-
sive genes on other chromosomes; one-half of these patients
have a genetic deficiency of adenosine deaminase or purine
nucleoside phosphorylase. A deficiency of these purine degra-
dation enzymes results in the accumulation of metabolites
that are toxic to lymphoid stem cells. These patients have low
peripheral lymphocyte counts, a severe deficiency of
immunoglobulins, and a lack of cellular immunity.
Principles of Medicine
The symptoms of this disease begin in the first few weeks
of life and include bacterial, viral, and fungal infections.
Localized or systemic candidiasis is common. Cutaneous
granulomas may also occur.19 Infants are also at risk for
lethal graft-versus-host disease (GVHD) if given transfu-
sions with nonirradiated blood products, and they can die
of progressive infection if vaccinated with live organisms.
The severity of these immunologic disorders has made them
logical candidates for treatments such as bone marrow
transplantation and gene replacement therapy. Gene therapy
has shown limited success in individuals with adenosine
deaminase deficiency. Early diagnosis and the availability of
matched donors for bone marrow transplantation remain
the most important factors in a hopeful prognosis for
patients with this group of disorders.
Partial Combined Immunodeficiencies
ATAXIA TELANGIECTASIA
Ataxia telangiectasia (AT) is a disorder characterized by cere-
bellar ataxia, oculocutaneous telangiectasia, and immunode-
ficiency. The ataxia usually begins in infancy and is progressive.
Telangiectasias of the skin and eyes become apparent between
3 and 6 years of age. Though not all patients with AT have
immunodeficiency, AT is clinically manifested by recurrent
and chronic sinopulmonary infections.
AT is inherited as an autosomal recessive trait. The AT gene
(ATM), identified in 1995, encodes a protein involved in the
repair of double-strand breaks in deoxyribonucleic acid
(DNA).20 Since radiosensitivity is a characteristic of AT in vitro,
understanding the mechanism of action of ATM may provide
additional information on radiation signaling in human cells;
it may be possible to sensitize tumor cells to radiation and sub-
sequently increase the therapeutic benefit of radiotherapy.21 In
addition, the ATM locus is a common event in some tumor
types, suggesting a general role for ATM in cancer. Defective
DNA repair mechanisms common to these patients may
account for the high incidence of malignancies. The ATM gene,
therefore, has the potential for wide-ranging roles such as
detecting DNA damage, preventing genomic re-arrangements
in malignancy, and preventing programmed cell death.
The immunologic abnormalities of AT include T-cell and
B-cell deficiencies, causing both an abnormal cellular response
and a deficiency of immunoglobulins. Due to a markedly
hypoplastic thymus, the peripheral T-cell pool is frequently
reduced in size. Although the number and class distribution of
B lymphocytes are usually normal, about 70% of AT patients
are serum IgA deficient and can also be deficient in IgG2 and
IgG4.9 These immunologic abnormalities may be the result of
cells that exhibit chromosomal breaks (usually in chromo-
somes 7 and 14) at the sites of the T-cell receptor genes and the
genes that encode the heavy chains of immunoglobulins.
Treatment for AT is limited to supportive care as no cure
is available. Unless a severe IgG deficiency is present, therapy
with gamma globulin is not indicated. Due to the highly vari-
able incidence of infection, bone marrow transplantation is
usually not advised.
Immunologic Diseases
A infection, on the hands. C, Lesions of the same infection, on the feet.
B C
WISKOTT-ALDRICH SYNDROME
Wiskott-Aldrich syndrome (WAS) is an X-linked disorder
characterized by lymphocytes and platelets that are faulty
due to an altered cell surface glycoprotein they share. The
classic clinical features include a microcytic thrombocy-
topenia, severe eczema, and pyogenic and opportunistic
infections. The immunologic findings of WAS are a result of
both T-cell defects and abnormal immunoglobulin levels.
The T cells have a uniquely abnormal appearance due to a
cytoskeletal defect. Moreover, the T cells are defective in
function, and this malfunction becomes progressively worse.
Impaired response to polysaccharide antigens, elevated
serum IgA and IgE levels, normal levels of IgG, and
decreased amounts of IgM are among the variable effects on
humoral immunity.
In addition, the collaboration among immune cells is also
faulty in patients with WAS. During the normal collaboration of
T cells and B cells in antibody formation, the cytoskeleton of the
T cells becomes polarized toward the B cells. This reorientation
of T cells to B cells fails to occur in patients with Wiskott-Aldrich
syndrome, most likely because of the cytoskeletal defect in the T
cells. The end result is a poorly collaborated immune response.
483
Figure 18-1 A, Chronic mucocutaneous candidiasis in patient with
DiGeorge syndrome, with lesions of the tongue. B, Lesions of the same
Oral Manifestations
Patients with T-lymphocyte abnormalities have a higher inci-
dence of oral disease than patients with B-lymphocyte dis-
orders have. T-lymphocyte abnormalities lead to chronic
fungal and viral infections, which are more likely to occur in
the oral mucosa than are the bacterial infections seen in B-
lymphocyte deficiencies.22 A consistent oral sign noted in
patients with T-cell diseases such as thymic hypoplasia or
AT is chronic oral candidiasis. Herpes simplex virus infec-
tions are also common in patients with T-cell disease. The
infections may be localized to the mouth but frequently
become disseminated and are potentially lethal if not treated
with antiviral medication.23 Other oral signs seen with T-cell
deficiencies include the dermal and mucosal telangiectases of
AT. Congenital defects of the mouth and jaws (including cleft
palate, micrognathia, bifid uvula, and short philtrum of the
upper lip) have also been seen in patients with thymic
hypoplasia. In patients with AT, hypotonia of facial muscles
and atrophy of the skin gives rise to a characteristic dull
expression; drooling can also be a problem.24
The major sign in patients with B-cell abnormalities is
recurrent bacterial infections25 that frequently involve the res-
484
piratory tract. The most common of these infections that comes
to the attention of dentists is chronic maxillary sinusitis.
The weight of evidence indicates that patients with primary
immunoglobulin deficiencies do not have an increase in den-
tal caries or periodontal disease.26,27 Although oral ulceration
has been occasionally described in patients with CVID and IgA
deficiency, it is not a characteristic finding.28 Neutropenia and
neutrophil dysfunction syndromes commonly cause oral
ulcers, but immunoglobulin deficiencies do not.
Factors other than primary immunodeficiency may
cause candidiasis and maxillary sinusitis, but for patients
with these infections who are not successfully treated by
antibiotic or antifungal therapy or who have a history of
other recurring infections, immunodeficiency should be
ruled out. This should be done with a careful history that
includes past episodes of pneumonia, recurrent otitis media,
autoimmune disease, severe asthma, malabsorption syn-
drome, and pyoderma.
Laboratory studies should be performed when the history
suggests immunodeficiency. With rare exceptions, a deficiency
of humoral immunity is accompanied by diminished serum
concentration of one or more classes of immunoglobulin.
Laboratory studies to rule out B-lymphocyte dysfunction
should include a quantitation of the major immunoglobulins,
using immunodiffusion techniques. In questionable cases, the
clinical immunologist will test the patient’s ability to synthe-
size specific antibodies after immunization with standard anti-
gens. Estimation of numbers of circulating B lymphocytes has
also been of great value in determining the pathogenesis of cer-
tain types of immunodeficiency.
Screening for T-lymphocyte dysfunction must be per-
formed by a clinician who is experienced in performing such
tests. Normal levels of serum immunoglobulins and antibody
responsiveness are reliable indices of intact T-helper-cell func-
tion. T-cell function can be measured directly by delayed hyper-
sensitivity skin testing, using a variety of antigens such as puri-
fied protein derivative (PPD) of tuberculin, Candida, and
Trichophyton. Negative reactions to these antigens suggest a
defect of cellular (T-cell) immunity. Laboratory studies that
are used to check T-cell activity include lymphocyte prolifera-
tion, T-cell subset quantification, and T-cell cytotoxicity assays.
Dental Management
Dental treatment for patients with primary immunodeficiency
must minimize the chances of local infection or bacteremia.
Patients with symptomatic B-cell abnormalities are usually
given monthly therapy with concentrated human gamma
globulin that has been screened for hepatitis B and HIV.29
Prior to instituting dental treatment, the gamma globulin level
should be checked to ensure that it is at least 200 mg/dL. When
oral surgery is necessary, an extra dose of gamma globulin
should be administered the day before surgery, in a dose usu-
ally between 100 and 200 mg/kg of body weight.30,31
Unusual transfusion reactions occur in patients with pri-
mary immunodeficiency and must be taken into account when
using blood replacement therapy. Patients with B-cell defi-
Principles of Medicine
ciency resulting in the absence of particular immunoglobulins
may experience severe transfusion reactions when receiving
blood from a patient who has normal immunoglobulin levels.
The immunoglobulin acts as a foreign protein and causes an
allergic response. For this reason, the patient with selective
IgA deficiency must be given IgA-depleted blood.32
Another problem in administering a transfusion to a
patient with primary immunodeficiency is the development of
GVHD. The immunocompetent cells in the transfused blood
will react against the tissues of the immunodeficient recipient.
Only fresh blood in which the immunocompetent lympho-
cytes have been destroyed can be used.
Dental infections in patients with primary immunodefi-
ciencies must be treated vigorously. A culture and sensitivity
for bacteria and fungi should be taken prior to instituting
antibiotic therapy. Few dentists do this routinely for normal
patients with abscesses, but it is particularly important for
immunodeficient patients because these patients get unusual
infections with fungi and gram-negative bacteria.33
▼ SECONDARY
IMMUNODEFICIENCIES
Secondary immunodeficiencies can be caused by immuno-
suppressive drug therapy, HIV infection, malignancy or gran-
ulomatous disease of the lymphoid system, or protein-deplet-
ing disorders. Specific diseases that result in secondary
immunodeficiency include leukemia, Hodgkin’s disease, non-
Hodgkin’s lymphoma, acquired immunodeficiency syndrome
(AIDS), nephrotic syndrome, multiple myeloma, and sar-
coidosis. (These disorders are discussed in detail in other chap-
ters of this text. This section confines itself to a discussion of
the immunologic aspects of these diseases. HIV infection and
AIDS are discussed in Chapter 20, “Infectious Diseases.”)
Leukemia
Infection is the major cause of death in patients with leukemia;
thus, it poses a major clinical management problem. The
majority of these infections are caused by microorganisms
that rarely cause fatal illness in normal individuals (eg, gram-
negative bacilli, fungi, and herpesviruses)34 (Figure 18-2).
Infections in patients with acute leukemia are caused by a
severe decrease in mature functioning granulocytes. Signs of an
infection may be present although typical findings of a puru-
lent infection or inflammatory response is muted in patients
with severe granulocytopenia. The function of the B lympho-
cytes and T lymphocytes appears to be intact until cytotoxic
chemotherapy is initiated. Studies of neutrophils from patients
with acute leukemia show both an impaired ability to migrate
and diminished bactericidal and chemotactic functions.
Chronic lymphocytic leukemia involves B lymphocytes in
most cases, affecting the humoral antibody response and
resulting in hypogammaglobulinemia with secondary bacter-
ial infection, particularly respiratory infection. Infections with
encapsulated bacteria (pneumococci, Haemophilus influenzae,
and group A streptococci) are common, presumably because
Immunologic Diseases
FIGURE 18-2 Extensive recurrent herpes simplex lesions of the buc-
cal mucosa and palate of a patient receiving chemotherapy for leukemia.
of the patient’s inability to produce antibodies. Serum
immunoglobulin levels are frequently low, and the circulating
antibody response to vaccines is impaired, but delayed hyper-
sensitivity reactions to recall antigens are usually intact.
Patients with chronic myelogenous leukemia have a lower
incidence of infection, consistent with laboratory studies that
show a good antibody response in these patients (see Chapter 16,
“Hematologic Diseases”).
Hodgkin’s Disease
Patients with Hodgkin’s disease have a loss of T-lymphocyte
function that worsens as the disease progresses. The radio-
therapy and chemotherapy used to treat the disease further
suppress normal immune function.
Studies of patients with advanced Hodgkin’s disease
reveal changes consistent with the deficient T-cell response,
including unresponsiveness to skin tests with previously
encountered antigens and prolonged skin graft survival
time. In vitro studies of lymphocytes from patients with
Hodgkin’s disease show an abnormal response to antigens.
The major clinical infections seen in patients with Hodgkin’s
disease are fungal, viral, and protozoal. The most common
fungal infections are histoplasmosis and infections with
Cryptococcus neoformans, Candida albicans, and actino-
mycetes. The viral infections are with herpes simplex virus,
varicella-zoster virus, and Cytomegalovirus. The protozoal
infections include toxoplasmosis and infections with
Pneumocystis carinii. Chemotherapy and radiotherapy may
suppress neutrophil and antibody function for years,
increasing the patient’s susceptibility to bacterial infection
(see Chapter 16, “Hematologic Diseases”).
Non-Hodgkin’s Lymphoma
Some patients with non-Hodgkin’s lymphoma have a defi-
ciency of the B-cell or T-cell system, caused by the disease
itself or by chemotherapy. This deficiency becomes more
severe late in the course of the disease. Lymphoma patients
485
FIGURE 18-3 Extensive condyloma acuminatum from human papil-
lomavirus infection in a patient receiving chemotherapy for non-Hodgkin’s
lymphoma.
have an increased rate of infections with bacteria, viruses, and
fungi (Figure 18-3) (see Chapter 16,“Hematologic Diseases”).
Nephrotic Syndrome
Patients with nephrotic syndrome lose large amounts of serum
protein through the destroyed or damaged glomeruli, which
causes secondary hypogammaglobulinemia. Bacterial infec-
tions secondary to hypogammaglobulinemia have been
described as a cause of death in children with nephrotic syn-
drome. The common sites of infection in these patients are the
oropharynx, the skin, and the lungs. The prophylactic use of
gamma globulin and antibiotics has decreased the incidence of
infection dramatically (see Chapter 15, “Renal Disease”).
Multiple Myeloma
Multiple myeloma is a malignancy of plasma cells, the cells pri-
marily responsible for the humoral antibody response. These
defective plasma cells produce large quantities of myeloma
proteins instead of the normal immunoglobulins. The
myeloma proteins offer no protection against infection, and
repeated bouts of bacterial infection, particularly pneumo-
coccal pneumonia, are common. Bone marrow suppression by
malignant plasma cells and chemotherapy further increases the
patient’s susceptibility to infection. A viral infection that occurs
with increased frequency in multiple myeloma patients is vari-
cella-zoster virus infection,which may occur as localized herpes zoster
or as generalized varicella (see Chapter 16,“Hematologic Diseases”).
Sarcoidosis
Sarcoidosis is a systemic granulomatous disease that primarily
affects the lungs and the lymphatic system but can also affect
mucocutaneous surfaces, the eyes, and the salivary glands. The
diagnosis is established when clinical and radiographic lesions
are supported by histologic evidence of noncaseating epithe-
lioid granulomas in more than one organ system and when
other disorders that are known to cause granulomatous disease
are excluded. Sarcoidosis commonly affects young and middle-
486
aged adults (between 20 and 40 years of age) and frequently
presents with bilateral hilar lymphadenopathy, pulmonary infil-
tration, and ocular and skin lesions.
Although the cause of sarcoidosis remains unknown, there
is evidence that it results from the exposure of genetically sus-
ceptible hosts to specific environmental agents.35 Frequently
observed immunologic features are depression of cutaneous
delayed-type hypersensitivity and a heightened helper T cell
type 1 (Th1) immune response at sites of disease. Circulating
immunocomplexes, along with signs of B-cell hyperactivity,
may also be found.36
Sarcoidosis is characterized by distinctive laboratory
abnormalities, including hyperglobulinemia, an elevated level
of serum angiotensin-converting enzyme, evidence of
depressed cellular immunity (manifested by cutaneous
anergy), and occasionally, hypercalcemia and hypercalciuria.
Systemic steroids remain the mainstay of therapy when treat-
ment is required although other anti-inflammatory agents are
being used increasingly often. (See Chapter 12,“Diseases of the
Respiratory System.”)
▼ CONNECTIVE-TISSUE DISEASES
Connective-tissue diseases are customarily grouped together
under names such as collagen disease, collagen vascular dis-
ease, hyperimmune disease, or autoimmune disease. They
include systemic lupus erythematosus, rheumatoid arthritis,
scleroderma (progressive systemic sclerosis), dermatomyositis,
and polyarteritis nodosa. Rheumatic fever is also sometimes
classified with these disorders.
The term “autoimmune” has been used to describe this group
of diseases because autoantibodies that react with normal tissue in
vitro have been detected in significant quantities in patients with
these diseases. This term appears to be justified when it is used to
describe pemphigus or Hashimoto’s thyroiditis, diseases in which
autoantibodies appear to cause direct and specific damage to tis-
sues.
In connective-tissue diseases, the term “immunocom-
plex” more accurately describes the source of most of the tis-
sue damage although autoantibodies appear to cause some
hematologic changes. In immunocomplex disease, a non-
specific inflammatory response results from the accumula-
tion of antigen-antibody complexes rather than from spe-
cific destruction by antibodies. When immunocomplexes
form, they activate the complement system, which attracts
neutrophils and macrophages. Vasculitis and tissue damage
result when immunocomplexes are present in sufficient
quantity. Serum sickness, a generalized allergic reaction, is
a classic example of a self-limiting disease caused by circu-
lating immunocomplexes.
The stimulus that causes the formation of the abnormal
antibodies that trigger the immunocomplexes is unknown,
but some investigators believe that viruses or other microor-
ganisms are responsible.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is the prototypical
autoimmune disease characterized by the production of
Principles of Medicine
numerous autoantibodies. Organ injury is secondary to either
the direct binding of autoantibodies to self-antigens or the
deposition of immunocomplexes in vessels or tissues. It is esti-
mated that 15 to 17% of lupus cases occur prior to the age of
16 years,37 with the peak incidence being in the age range of
20 to 40 years. SLE occurs ten times more frequently in females
and has a higher incidence among black people. The autoan-
tibodies of SLE may be directed against nucleoproteins, ery-
throcytes, leukocytes, platelets, coagulation factors, and organs
such as the liver, the kidneys, or the heart. SLE therefore has a
variety of clinical manifestations.
NOMENCLATURE (SUBTYPES)
Over the years, the classification of lupus has been modified to
include additional forms. Discoid lupus erythematosus (DLE)
is confined to the skin and mucosa; only approximately 10 to
20% of patients with DLE develop systemic manifestations
later in the course of the disease. The skin lesions of DLE begin
as erythematous scaling lesions with sharp borders that slowly
expand forming telangiectasias and (eventually) depigmented
scars. Follicular plugging that extends down into the skin fol-
licles can be observed when the scale is removed. The malar or
so-called butterfly rash is common, but does not always occur
and is not pathognomonic for DLE as it is also seen in other
dermatologic diseases such as seborrheic dermatitis.
Chronic cutaneous lupus erythematosus and subacute
cutaneous lupus erythematosus are mainly dermatologic dis-
eases that are almost always restricted to the skin (most often
the face and scalp) and to the oral mucosa.
Neonatal lupus erythematosus is most often a transient
self-limited disease. Dermatologic, hepatic, and hematologic
involvement usually disappears at the age of about 6 months,
in parallel with the decline in maternal antibodies in the
neonatal circulation.
Drug-induced lupus erythematosus has many features in
common with SLE and characteristically develops in people
who have no history of systemic rheumatic disease. By far, the
drugs with the highest risk are procainamide and hydralazine,
with incidences of approximately 20% for procainamide and
5 to 8% for hydralazine. The risk for developing lupuslike dis-
ease with other drugs is much lower: quinidine can be con-
sidered a moderate-risk drug, whereas sulfasalazine, chlor-
promazine, penicillamine, methyldopa, carbamazepine,
acebutalol, isoniazid, captopril, propylthiuracil, and mincy-
cline are relatively low-risk drugs.38
ETIOLOGY AND PATHOGENESIS
The specific etiology of SLE is not known with certainty, but
immunocomplexes, autoantibodies, and genetic, infectious,
environmental, and endocrine factors play significant roles.
Genetic Factors. Familial clustering and an increased rate
among identical twins (24 to 57%) demonstrate the important
role of genetic susceptibility. Relatives of SLE patients have
higher incidences of autoantibodies, immunodeficiency, and
connective-tissue disease. Genes that increase the risk of SLE
Immunologic Diseases
have been identified (specifically, HLA-DR2 and HLA-DR3).
Genetic linkage analyses yield consistent findings for linkage
of SLE on chromosome 1.39
Infectious and Environmental Factors. Viruslike particles of
ribonucleic acid (RNA) viruses have been detected in tissues
of SLE patients and are thought by some to initiate the
abnormal immune response. Epstein-Barr virus,
Cytomegalovirus, varicella-zoster virus, and other endoge-
nous/exogenous retroviruses have been reported to occur
with increased frequency in patients with SLE. This associa-
tion could result from the intrinsic susceptibility of lupus
patients to these infections, or virus-infected individuals may
simply be prone to developing lupus.
Endocrine Factors. A hormonal component to SLE is sug-
gested by its high incidence in women in their childbearing
years, the many reports of remission during pregnancy, and the
finding of increased estrogen levels in SLE patients.
Immunocomplexes and Autoantibodies. Immunocomplexes
consisting chiefly of nucleic acid and antibody account for the
majority of the tissue damage seen in SLE. These complexes set
off immunologic reactions that activate complement and
attract neutrophils and macrophages. The result is vasculitis,
fibrosis, and tissue necrosis. Patients with increased circulat-
ing immunocomplexes have more severe disease, particularly
of the kidney. Immunocomplexes also account for tissue dam-
age in the central nervous system, skin, and lungs.
The autoantibodies in SLE patients could be the actual
pathogenic agents of tissue destruction, or they could be the
consequence of tissue damage.40,41 Autoantibodies are a cause
of the hemolytic anemia, thrombocytopenia, and lymphope-
nia seen in SLE patients. The formation of autoantibodies is
thought to be related to the decreased functioning of sup-
pressor T lymphocytes and hyperreactive B lymphocytes.
A unified theory that accounts for many of the findings
described above has been developed. In this theory, many fac-
tors acting together result in SLE. An individual with a genetic
predisposition develops a chronic viral infection that releases
nucleic acid antigens. Sunburn or damage from chemicals may
also contribute to antigen release. A lack of normal suppres-
sor T-lymphocyte function and B-lymphocyte hyperactivity
leads to the formation of autoantibodies and immunocom-
plexes; widespread tissue damage results.
CLINICAL MANIFESTATIONS
SLE is a disease with multiorgan involvement. Immunocomplex
deposition causes small-vessel vasculitis, which then leads to
renal, cardiac, hematologic, mucocutaneous, and central ner-
vous system destruction. In addition, inflammation of the serous
membranes results in joint, peritoneal, and pleuropericardial
symptoms. As there is no typical pattern of presentation, one
patient may present with dermatitis and kidney disease whereas
another may present with arthritis, anemia, and pleurisy. Thus,
whenever a patient demonstrates signs and symptoms of mul-
487
tiorgan involvement, SLE should be considered in the differen-
tial diagnosis, especially for a female who is 20 to 40 years of age.
The following is a brief overview of the most frequently encoun-
tered clinical manifestations.
Renal Manifestations. Kidney involvement in the form of
glomerular destruction is seen in approximately 50% of
patients. The glomerulonephritis results from the deposition
of complement and immunocomplexes in the basement mem-
brane of the glomerulus. Five to twenty-two percent of SLE
patients progress to end-stage renal disease and require
hemodialysis or transplantation.42 Nephrotic syndrome results
from massive destruction and is a common cause of death in
SLE patients. The severity of kidney disease is often a good
indication of the overall prognosis of the patient.
Cardiac Manifestations. Accelerated atherosclerosis and
valvular heart disease constitute the primary cardiac manifes-
tations of SLE. The most common of all cardiac lesions in SLE
patients involves the endocardium and was originally
described (by Libman and Sacks) as verrucous valvular lesions.
Lupus-related valvular pathoses can include valve leaflet thick-
ening, with or without regurgitation.
Hematologic Manifestations. The primary hematologic dis-
eases among SLE patients are leukopenia, anemia, and throm-
bocytopenia. Leukopenia (< 4,000/mm3) is common and
usually reflects lymphopenia but can also be due to immuno-
suppressive therapies. Anemia of chronic disease occurs in
most patients during periods of disease activity but is also
often due to hemodialysis. Hemolytic anemia occurs in a small
proportion of patients with positive Coombs’ test results.
Thrombocytopenia (< 100,000/mm3) results from increased
phagocytosis of autoantibody-coated platelets by spleen, liver,
bone marrow and lymph node macrophages and can occur in
up to 25% of patients. When antiphospholipid antibodies or
the lupus anticoagulant and anticardiolipin antibodies are pre-
sent, patients are prone to episodic thrombosis, thrombocy-
topenia, and spontaneous abortion.
Mucocutaneous Manifestations. The cutaneous manifesta-
tions of SLE include photosensitive rashes, alopecia, periun-
gual telangiectasias, Raynaud’s phenomenon, and skin ulcer-
ation secondary to vasculitis (Figure 18-4). Cutaneous
involvement does not necessarily correlate with increased sys-
temic disease. The malar or “butterfly” rash (which affects
fewer than half of SLE patients) and the discoid rash are the
two most characteristic rashes of SLE. The malar rash is a fixed
flat or raised erythematous rash over the cheeks and bridge of
the nose, often involving the chin and ears (Figure 18-5). It is
usually exacerbated by ultraviolet light. A more diffuse macu-
lopapular rash, mainly in sun-exposed areas, is also common.
Vasculitic skin lesions include subcutaneous nodules, ulcers,
and infarcts of skin or digits. Oral mucosal lesions can be
found as annular leukoplakic areas and/or erythematous ero-
sions or chronic ulcerations, often resembling lichen planus.
488
FIGURE 18-4 Skin lesions in a patient with systemic lupus erythe-
matosus. (Courtesy of Dr. George Ehrlich)
Musculoskeletal Manifestations. Arthritis and arthropathies
are the primary musculoskeletal disorders associated with SLE.
Arthralgia with morning stiffness is the most common initial
manifestation of SLE. More than 75 % of SLE patients develop
a true arthritis, which is symmetrical and non-erosive and
which usually involves the hands, wrists, and knees. Deforming
arthritis is uncommon in SLE patients.
Central Nervous System Manifestations. Significant neu-
ropsychiatric signs and symptoms are found in 10 to 20% of
patients who have SLE.43 Diffuse and focal cerebral dysfunc-
tions (including psychoses, seizures, and cerebrovascular
accidents) in addition to peripheral sensorimotor neu-
FIGURE 18-5 “Butterfly” rash on the face of a patient with systemic
lupus erythematosus. (Courtesy of Dr. Robert Arm)
Principles of Medicine
ropathies, account for more than 60% of neuropsychiatric
manifestations.44 Central nervous system involvement is a
poor prognostic sign.
DIAGNOSIS AND LABORATORY EVALUATION
The most important diagnostic laboratory test for SLE is the
test for antinuclear antibody (ANA) in the serum, which is
positive for 96 to 100% of patients with SLE. The clinician
should remember that the ANA test is also positive in a
minority of patients with scleroderma or rheumatoid arthri-
tis; therefore, the diagnosis must be made on the total clini-
cal picture, not on a single laboratory test. In addition, SLE is
characterized by the production of numerous autoantibodies,
including ANAs, anti–native DNA, rheumatoid factor, anti-
body to Smith (Sm) antigen, antibody to Ro (SS-A) antigen,
and antibody to La (SS-B) antigen. Many of these autoanti-
bodies produce specific laboratory and clinical abnormalities
and can also be seen in a variety of other rheumatologic dis-
eases. An individual with elevated ANA and anti–native DNA
most likely has lupus (Table 18-1).
Important findings on routine laboratory tests include ane-
mia, thrombocytopenia, (which may occasionally be severe
enough to cause purpura), increased levels of globulins, and a
biologic false-positive result on the serologic test for syphilis
(STS). Depressed complement levels (particularly C3 and C4),
are also common.
ORAL MANIFESTATIONS
Patients with SLE are affected by a variety of orofacial disorders,
including characteristic oral lesions, nonspecific ulcerations,
salivary gland disease, and temporomandibular disorders. The
reported incidence of these manifestations varies considerably,
depending on the criteria of the investigators. The first report
of oral manifestations of SLE in the American dental literature
was in 1931, by the dermatologist Monash, who reported a
50% incidence of oral lesions.45 More recently, Rhodus and
Johnson reported a higher incidence (81.3 to 87.5%) of various
oral lesions, including ulceration, angular cheilosis, mucositis,
TABLE 18-1 Proportion of Autoantibodies Associated with
Lupus Erythematosus and Other Rheumatic Diseases
Presence in Autoimmune Disease (% of Cases)
Autoantibody Diffuse
Type SLE RA SS Scleroderma
Antinuclear antibodies 96–100 30–60 95 80–95
Anti–native DNA 60 0–5 0 0
Rheumatoid factor 20 72–85 75 25–33
Anti-Sm 10–25 0 0 0
Anti-Ro 15–20 0–5 60–70 0
Anti-La 5–20 0–2 60–70 0
Adapted from De Rossi SS, Glick M.43
Anti-Sm = antibody to Smith antigen; Anti-Ro = antibody to Ro (SS-A) antigen;
Anti-La = antibody to La (SS-B) antigen; DNA = deoxyribonucleic acid; RA = rheuma-
toid arthritis; SLE = systemic lupus erythematosus; SS = Sjögren’s syndrome.
Immunologic Diseases 489

and glossitis. They also reported a high incidence (75.0 to

87.5%) of signs and symptoms of oral conditions, including
glossodynia, dysgeusia, dysphagia, and dry mouth.46
The oral lesions of SLE are caused by vasculitis and appear
as frank ulceration or mucosal inflammation. Some individu-
als with SLE or discoid lupus have discoid-appearing oral
lesions.47 The lip lesions often have a central atrophic and
occasionally ulcerated area with small white dots, surrounded
by a keratinized border composed of small radiating white
striae (Figure 18-6). The intraoral lesions are somewhat dif-
ferent because of the thinner epithelium; they are composed
of a central depressed red atrophic area surrounded by a 2 to
4 mm elevated keratotic zone that dissolves into small white
lines (Figures 18-7 and 18-8).
The oral lesions of SLE are easily confused with the lesions
of lichen planus, both clinically and histologically. The World FIGURE 18-7 A chronic palatal lesion (the initial sign of systemic lupus
erythematosus in this patient).
Health Organization established criteria for the histologic
diagnosis of oral SLE, but these criteria often do not adequately
distinguish lupus from lichen planus. Karjalainen and
Tomich48 compared 17 cases of SLE with 17 cases of lichen whereas those deposits are rare in lichen planus or leuko-
planus and described five histologic criteria to distinguish plakia. There are a small number of cases, however, in which
these two disorders by light microscopy: (1) vascularization of DLE and lichen planus overlap.
keratinocytes, (2) subepithelial presence of patchy periodic Another oral sign of SLE is xerostomia secondary to
acid–Schiff (PAS)-positive deposits, (3) edema in the upper Sjögren’s syndrome.49 Xerostomia can significantly increase
lamina propria, (4) PAS-positive thickening of blood vessel the occurrence of dental caries and candidiasis, especially
walls, and (5) severe deep or perivascular inflammatory infil- when patients are being treated with steroids or immuno-
tration. Sanchez and colleagues demonstrated that the inflam- suppressive agents.
matory infiltrate in the oral lesions of SLE consists primarily Temporomandibular-joint involvement commonly occurs
of helper or inducer T lymphocytes.47 in SLE patients sometime during the course of their disease
Direct fluorescent antibody staining of biopsy specimens and may cause pain and mechanical dysfunction.
has become an important aid in the diagnosis of the mucosal
or skin lesions of SLE. More than 90% of patients with either TREATMENT
DLE or SLE have deposits of immunoglobulin and C3 in the With regard to the management of the oral lesions of SLE,
basement membrane zone. This lupus band test is an excel- there have been no reports involving the treatment of a large
lent means of differentiating lupus lesions from lichen series of patients. In general, the oral ulcerations of SLE are
planus, which is often clinically and histologically indistin- transient, occurring with acute lupus flares. Symptomatic
guishable from other forms of leukoplakia. Immunoglobulin lesions can be treated with high-potency topical corticosteroids
deposits are detected in oral lesions of SLE and of DLE or intralesional steroid injections.

FIGURE 18-6 Discoid lupus lesions on the lower lip. FIGURE 18-8 Chronic lesion of the dorsal tongue in a patient with sys-
temic lupus.
490
DENTAL CONSIDERATIONS
Because SLE can be a widespread disease affecting many organ
systems, the dental management of an SLE patient requires a
good understanding of general medicine. The more common
problems seen in SLE patients are discussed below.
Adrenal Suppression. Patients with SLE may be taking
adrenal-suppressive doses of corticosteroids, which makes
these patients susceptible to shock. Glucocorticosteroid ther-
apy will cause adrenal suppression that affects adrenal function
for up to 12 months, but the patient’s stress response will
return within 14 to 30 days. There is no need for replacement
therapy for dental treatment in patients who have not taken
glucocorticosteroids during the preceding 30 days. Patients
who are receiving alternate-day therapy can be treated on an
“off ” day without supplementation if they have been on the
alternate-day regimen for at least 2 weeks. Patients who are
receiving daily low-dose corticosteroid therapy (< 30 mg
hydrocortisone equivalent) will not need replacement therapy.
Patients who are receiving daily high-dose corticosteroid ther-
apy (> 30 mg hydrocortisone equivalent) should be treated as
if they were completely adrenally suppressed and were with-
out a normal stress response. The dose will need to be doubled
on the day of treatment. The patient’s primary care physician
should be consulted if the replacement dosage is uncertain or
when highly stressful procedures are to be done (eg, general
anesthesia)50 (Table 18-2).
Infection. Patients who are taking cytotoxic or immunosup-
pressive agents are at an increased risk of infection. Patients
with an absolute neutrophil count of between 500 and 1,000
cells/mm3 will need perioperative prophylactic antibiotics.
Although infection due to opportunistic pathogens should be
considered in patients who are on high steroid dosages (espe-
cially patients who are on adjuvant immunosuppressive ther-
TABLE 18-2 Protocol for Supplementation of Patients on Glucocorticoid Therapy Who Are Undergoing Dental Care
Dental Procedure Previous Systemic Steroid Use
Routine procedures If prior usage lasted for > 2 weeks
and ceased < 14–30 days ago,
give previous maintenance dose
If prior usage ceased > 14–30 days
ago, no supplementation needed
Extractions, surgery, or If prior usage lasted > 2 weeks and
extensive procedures ceased < 14–30 days ago, give
previous maintenance dose
If prior usage ceased > 14–30 days
ago, no supplementation needed
Adapted from De Rossi SS, Glick M.51
Principles of Medicine
apy), no protocol has been established for the prophylactic
use of antibiotics.
Hematologic Abnormalities. Patients with SLE can fre-
quently develop normochromic normocytic anemia,
hemolytic anemia, leukopenia, and thrombocytopenia. The
presence of an elevated partial thromboplastin time can result
from circulating anticoagulant. Prior to any extensive dental
procedures, a preoperative complete blood count can screen
for thrombocytopenia, anemia, and leukopenia, and a pro-
thrombin time/partial thromboplastin time measurement can
screen for a coagulopathy.
Cardiac Disease. Libman-Sacks vegetations under the
mitral-valve leaflets may occur in patients with SLE. These
vegetations rarely affect function but can lead to bacterial
endocarditis. Patients with SLE and heart murmurs should
have antibiotic prophylaxis prior to dental treatment that is
likely to cause bacteremia.
Renal Disease. Renal disease is common in SLE patients and
ranges from an asymptomatic state to frank renal failure;
therefore, the dentist should be aware of the patient’s renal
function (ie, creatinine clearance, serum creatinine, and blood
urea nitrogen). Patients who are undergoing hemodialysis
should receive dental treatment on nondialysis days.51
Exacerbation by Surgery. The dentist should proceed with cau-
tion in performing elective surgery or dental procedures, espe-
cially in patients who have a history of postsurgery lupus flares.
Exacerbation by Drug Therapy. Drugs that have been related
to acute lupus flares include penicillin, sulfonamides, and non-
steroidal anti-inflammatory drugs (NSAIDs) with photosen-
sitizing potential. All of these should be used judiciously.
Protocol
Current Systemic Daily Alternating
Steroid Use Systemic Steroid Use Current Topical Steroid Use
No supplementation needed Treat on steroid dosage day; No supplementation needed
no further supplementation
needed
Double daily dose on day Treat on steroid dosage No supplementation needed
of procedure day, and give double daily
dose on day of procedure
Double daily dose on first Give normal daily dose on first
postoperative day when postoperative day when
pain is anticipated pain is anticipated
Immunologic Diseases
Scleroderma
Scleroderma is a multisystem connective-tissue disease that
involves hardening of the skin and mucosa, smooth-muscle
atrophy, and fibrosis of internal organs. The prevalence of scle-
roderma is estimated to be about 250 per million, with women
being affected significantly more frequently than men.52
Several US studies have suggested that black patients have a
higher age-specific incidence rate and more severe disease than
have white patients.53
NOMENCLATURE (SUBTYPES)
Localized scleroderma refers to scleroderma primarily involv-
ing the skin, with minimal (if any) systemic features. Only
rarely have patients with localized scleroderma developed sys-
temic sclerosis. Three major types of localized scleroderma
exist: morphea, generalized morphea, and linear scleroderma.
Morphea begins with violaceous skin patches that enlarge,
become indurated, and eventually lose hair and the ability to
sweat. Later in the course of the disease, the lesion “burns out”
and appears as a hypo- or hyperpigmented area depressed
below the level of the skin.54 A small number of patients
develop numerous larger lesions that coalesce, and these
patients are said to have generalized morphea (Figure 18-9).
Patients with either type of morphea usually have a benign
course characterized by the softening of the lesions over time.
Linear scleroderma is a form of the localized disease that may
develop during childhood and that usually involves the arms,
legs, or head. This form of the disease develops as a thin band
of sclerosis that may run the entire length of an extremity,
FIGURE 18-9 Morphea of the face.
491
involving underlying muscle, bones, and joints. When the dis-
ease crosses a joint, limitation of motion is possible, along
with growth abnormalities. The lesion of linear localized scle-
roderma of the head and face is called en coup de sabre, and
these lesions may result in hemiatrophy of the face.
Scleroderma localized to the hands is called acrosclerosis.
Progressive systemic sclerosis (PSS) is a multisystem disease
characterized by the inflammation and fibrosis of many
organs. PSS occurs three to four times more frequently in
females, with its highest incidence occurring between the
ages of 25 and 50 years. There are two major subsets: limited
cutaneous scleroderma (previously called calcinosis cutis,
Raynaud’s phenomenon, esophageal dysmotility, sclero-
dactyly, and telangiectasia [CREST syndrome]) and diffuse
cutaneous scleroderma. The major difference between lim-
ited and diffuse scleroderma is the pace of the disease.
Patients with limited scleroderma often have a long history
of Raynaud’s phenomenon before the appearance of other
symptoms. They have skin thickening limited to hands and
frequently have problems with digital ulcers and esophageal
dysmotility. Although generally a milder form of disease than
diffuse scleroderma, limited scleroderma can have life-threat-
ening complications. Diffuse scleroderma patients have a
more acute onset, with constitutional symptoms, arthritis,
carpal tunnel syndrome, and marked swelling of the hands
and legs. They also characteristically develop widespread skin
thickening (progressing from the fingers to the trunk) as well
as internal organ involvement (including gastrointestinal and
pulmonary fibrosis) and potentially life-threatening cardiac
and renal failure. Other possible variants are an overlapping
syndrome with SLE, Sjögren’s syndrome, rheumatoid arthri-
tis, and dermatomyositis.
ETIOLOGY AND PATHOGENESIS
The etiology of PSS is unclear, but the pathogenesis is char-
acterized by vascular injury as well as the overproduction of
normal collagen. Vascular wall fibrosis of small and medium-
size arterioles is a prominent alteration in PSS and likely plays
a crucial role in the pathogenesis of pulmonary hyperten-
sion, renal crisis, myocardial dysfunction, and digital gan-
grene in this disease.55 Excessive collagen deposition in
affected tissues is also a central event in the pathogenesis of
PSS and is responsible for most of the clinical manifestations
of this disease. The up-regulation of collagen gene expres-
sion in PSS fibroblasts and the aberrant expression of
cytokines that positively or negatively influence fibroblast col-
lagen synthesis appear to be critical events in the development
of the pathologic tissue fibrosis that is characteristic of PSS.55
A role for environmental factors in the pathogenesis of PSS is
suggested by an increased rate of PSS and PSS-like disease
detected in individuals who are exposed to silica dust, vinyl
chloride, benzene, and tryptophan.56
CLINICAL MANIFESTATIONS
PSS sclerosis is a chronic multisystem disorder characterized
by intense fibrosis involving the skin, vasculature, synovium,
492 Principles of Medicine

skeletal muscles, and internal organs. The following is an

overview of frequently encountered clinical manifestations.

Raynaud’s Phenomenon. Raynaud’s phenomenon, a parox-

ysmal vasospasm of the fingers that results in a change in the
color of the fingertips as a response to cold or emotion, is the
most common finding of PSS. More than 95% of scleroderma
patients eventually experience the characteristic digital cyanosis
and blanching that results from intimal hyperplasia.57
Raynaud’s phenomenon may be nothing more than a nuisance,
but some patients have recurrent episodes that are associated
with digital pitting scars, nail fold infarcts, or digital ulcers.

Cutaneous Manifestations. The thickening of the skin of PSS

patients always begins in the fingers. Early skin changes, start-
ing with pitting edema, often involve the whole hand and the
extremities. In several months, the edema is replaced by a tight-
ening and hardening of the skin, which results in difficulty in
moving the affected parts. Hyperpigmentation, telangiectases
(Figure 18-10), and subcutaneous calcifications may also
occur, leading to deformity and severe cosmetic problems
(Figure 18-11).

Musculoskeletal Manifestations. Polyarthralgias and morning

stiffness affecting both small and large joints are frequent in
patients with scleroderma. Inflammatory joint pain with
A
markedly swollen fingers often appears to be true synovitis and
can lead to the premature diagnosis of rheumatoid arthritis.

Gastrointestinal Manifestations. Distal esophageal motor

dysfunction is the most frequent gastrointestinal finding; it
results from weakness and incoordination of esophageal

FIGURE 18-11 Manifestations of scleroderma. A, Severe tightening

of the skin and narrowing of the oral aperture of a patient with sclero-
derma. B, Extensive involvement of the fingers and hand of the same patient
causes a lack of mobility and the resorption of phalanges.

smooth muscle and leads to distal dysphagia. Intestinal fibro-

sis leading to severe intestinal malabsorption can also occur.

Cardiac Manifestations. Clinical evidence of myocardial

involvement in scleroderma cases is uncommon, but such
involvement is more frequent in patients with diffuse sclero-
derma. The clinical presentations of cardiac involvement can
FIGURE 18-10 Telangiectases in a patient with scleroderma. include pericarditis, conduction problems, and congestive
Immunologic Diseases
heart failure. Patchy replacement of the myocardium and the
conduction system by fibrous tissue occurs in most patients.
Pulmonary Manifestations. Pulmonary interstitial fibrosis is
now the most frequent cause of death in patients with sclero-
derma since renal disease has become a treatable complication.
Patients with either limited or diffuse scleroderma can develop
interstitial disease although it tends to be more severe in
patients with diffuse scleroderma. In patients with severe fibro-
sis, the greatest damage occurs during the first 5 years of illness,
often when there are no pulmonary symptoms. Pleural thick-
ening, pleural effusions, and pneumothorax are less frequent
manifestations of lung disease in patients with scleroderma.58
Renal Manifestations. Until recently, renal involvement was
the most dreaded and deadly complication of scleroderma.
The use of high-dose corticosteroids for the treatment of scle-
roderma has been implicated in precipitating renal crisis in
some patients. In addition, pathologic changes due to the dis-
ease itself typically show alterations resembling hypertensive
nephrosclerosis as well as mucinoid hyperplasia and vascular
fibrinoid necrosis in the interlobar arteries. Renal crisis is char-
acterized by malignant hypertension, which can rapidly
progress to renal failure. The use of angiotensin-converting
enzyme inhibitors has helped to make renal disease due to
scleroderma a very treatable condition.
LABORATORY EVALUATION
ANAs are present in approximately 90% of scleroderma
patients and are characteristically antinucleolar or anticen-
tromere antibodies. There are a few other important ANAs that
are specific for scleroderma but are not yet commercially avail-
able. Anti-ribonucleic acid (RNA) polymerase III may be the
most common antibody found in patients with scleroderma.
Other laboratory findings include anemia, an elevated ery-
throcyte sedimentation rate, and hypergammaglobulinemia.
TREATMENT
The treatment of PSS depends on the extent and severity of skin
and organ involvement. D-penicillamine, a drug effective for
both rheumatoid arthritis and Wilson’s disease, has shown
promise in the management of PSS by decreasing both skin
493
thickening and organ involvement. This drug has two mecha-
nisms of action: interference with cross-linking of collagen and
immunosuppression. Nifedipine is a calcium channel blocker
that has been shown to be effective in managing Raynaud’s
phenomenon and myocardial perfusion.59 Extracorporeal pho-
tochemotherapy has also shown promise in reversing cuta-
neous sclerosis in patients in the early stages of PSS.60
ORAL FINDINGS
The clinical signs of scleroderma of the mouth and jaws are
consistent with findings elsewhere in the body. The lips
become rigid, and the oral aperture narrows considerably.61
Skin folds are lost around the mouth, giving a masklike
appearance to the face. The tongue can also become hard
and rigid, making speaking and swallowing difficult.
Involvement of the esophagus causes dysphagia. 62 Oral
telangiectasia is equally prevalent in both limited and diffuse
forms of PSS and is most commonly observed on the hard
palate and the lips.63 When the soft tissues around the tem-
poromandibular joint are affected, they restrict movement of
the mandible, causing pseudoankylosis.64
The linear form of localized scleroderma may involve the
face as well as underlying bone and teeth. Dental radiographic
findings have been reported and widely described; these clas-
sic findings (which include uniform thickening of the peri-
odontal membrane, especially around the posterior teeth) are
found in less than 10% of patients (Figure 18-12). Other char-
acteristic radiographic findings include calcinosis of the soft tis-
sues around the jaws. The areas of calcinosis will be detected by
dental radiography and may be misinterpreted as radiographic
intrabony lesions. A thorough clinical examination will demon-
strate that the calcifications are present in the soft tissue.
When the facial tissues and muscles of mastication are exten-
sively involved, the pressure exerted will cause resorption of the
mandible. This resorption is particularly apparent at the angle
of the mandible at the attachment of the masseter muscle. The
coronoid process, condyle, or area of attachment of the digas-
tric muscles may also be damaged by the continual pressure.65
Patients may also have oral disease secondary to drug ther-
apy or xerostomia. Gingival hyperplasia can result from the use
of calcium channel blockers; pemphigus, blood dyscrasias, or
lichenoid reactions may result from penicillamine use. Salivary
FIGURE 18-12 Radiographs
showing thickening of the peri-
odontal membrane in a patient
with scleroderma.
494 Principles of Medicine

gland hypofunction that frequently correlated with kerato- ETIOLOGY AND PATHOGENESIS
conjunctivitis sicca occurred in 14 of 32 patients studied by
The etiology of DM is unknown, but genetic, immunologic,
Nagy and colleagues.61 Although some such patients have
and environmental factors are likely to play an important role.
overlapping Sjögren’s syndrome and have anti–SS-A antibody
Studies of histocompatibility antigen prevalence have demon-
and a lip biopsy which shows inflammation, most simply have
strated that human leukocyte antigens HLA-B8, HLA-B14,
fibrotic glands that cause the lack of saliva or tears. Xerostomia
and HLA-DR3 are associated with dermatomyositis, but these
results in an increased susceptibility to dental caries, Candida
studies have failed to link HLA haplotype with disease.67
infections, and periodontal disease.
Immune mechanisms play a significant role in the onset of the
DENTAL MANAGEMENT disease, particularly circulating immunocomplexes, cellular
immunity, and autoantibodies to skeletal-muscle myoglobin
The most common problem in the dental treatment of scle-
or myosin. The onset of the disease has been associated with
roderma patients is the physical limitation caused by the nar-
infections such as influenza, hepatitis, coxsackie virus infec-
rowing of the oral aperture and rigidity of the tongue.
tion, and infection with the protozoan Toxoplasma gondii. DM
Procedures such as molar endodontics, prosthetics, and
has also been linked to drug therapy and cancer.
restorative procedures in the posterior portions of the mouth
become difficult, and the dental treatment plan may some- CLINICAL MANIFESTATIONS
times need to be altered because of the physical problem of
DM usually begins with a symmetric and painless weakness of
access. The oral opening may be increased an average of
the proximal muscles of the arms, legs, and trunk. The weak-
5 mm by stretching exercises. One particularly effective tech-
ness is progressive and characteristically spreads to the face,
nique is the use of an increasing number of tongue blades
neck, larynx, pharynx, and heart. Muscle involvement may
between the posterior teeth to stretch the facial tissues. In
become severe enough to confine the patient to bed or to cause
addition, mechanical devices that assist the patient in per-
death due to failure of the respiratory muscles.
forming the stretching exercises are available. If these
The primary classic skin lesion is a violaceous macular ery-
approaches are insufficient, a bilateral commissurotomy may
thema distributed symmetrically. As the disease progresses,
be necessary.
the erythema may become progressively indurated due to
When treating a patient with diffuse scleroderma, the
mucin deposition. The pathognomonic skin manifestations,
extent of the heart, lung, or kidney involvement should be
occurring in approximately 70% of patients, are Gottron’s
considered, and appropriate alterations should be made
papules, which are violaceous papules overlying the dorsal
before, during, and after treatment.
elbow, knee, or interphalangeal or metacarpophalangeal joints.
Patients with extensive resorption of the angle of the
Facial changes may take on the “butterfly” distribution asso-
mandible are at risk for developing pathologic fractures from
ciated with SLE or may primarily involve the eyelids and the
minor trauma, including dental extractions. Patients with
forehead. Other skin changes are nonspecific diffuse erythema,
Sjögren’s syndrome should have daily fluoride treatments and
erythematous plaques, macules, papules, telangiectases, and
make frequent visits to the oral hygienist.
Raynaud’s phenomenon. Diagnosis from skin lesions alone is
Dermatomyositis rarely possible.
Noncutaneous manifestations of DM include interstitial
Dermatomyositis (DM) is a rare inflammatory degenerative
lung disease, cardiac conduction abnormalities, conjunctival
disease characterized by skin lesions and progressive muscle
edema, and renal damage.
atrophy. The disease occurs most frequently during childhood
and between the fourth and sixth decades of life. The true DIAGNOSIS AND LABORATORY EVALUATION
incidence and prevalence are difficult to ascertain because of
A diagnosis of definite PM or DM is given if any four of the
the rarity of the disease and the lack of consistent diagnostic
following criteria are met:
criteria. Most studies have found a preponderance of female
patients over male patients. Skin manifestations have been 1. Proximal symmetric muscle weakness, progressing
identified in 30 to 40% of adult patients and in 95% of affected from weeks to months
children.66 DM is classified with the connective-tissue diseases 2. Evidence of an inflammatory myopathy on muscle
because of many overlapping clinical features and the fact that biopsy
it is frequently seen together with scleroderma, SLE, rheuma- 3. Elevation of serum muscle enzymes
toid arthritis, or Sjögren’s syndrome. 4. Electromyographic features of myopathy
5. Cutaneous eruption that is typical of DM
NOMENCLATURE (SUBTYPES)
The three types of idiopathic inflammatory myopathies are A diagnosis of probable PM or DM is given if three criteria are
DM, polymyositis (PM), and inclusion body myositis. Specific met, and a diagnosis of possible PM or DM is given if two cri-
subtypes of DM or PM can be categorized as adult idiopathic, teria are fulfilled.
juvenile, or amyopathic DM. There is also a form of DM that Laboratory reports show evidence of muscle destruction by
is associated with connective-tissue disease or malignancy. elevated levels of aspartate aminotransferase (formerly called
Immunologic Diseases
serum glutamic-oxaloacetic transaminase), lactate dehydro-
genase, alanine aminotransferase (formerly called serum glu-
tamic-pyruvic transaminase), and creatine phosphokinase.
TREATMENT
An underlying carcinoma should be ruled out in all cases of DM
since it is present in 10 to 25% of patients. Initial therapy consists
of bed rest combined with high doses of systemic corticosteroids.
In resistant cases, plasmapheresis or immunosuppressive drugs
such as methotrexate or azathioprine have been helpful.68
ORAL FEATURES
Oral involvement is rarely a part of the disease process of
DM. The most common clinical manifestations in the head
and neck include weakness of the pharyngeal and palatal
muscles, which causes difficulty in swallowing (dysphagia)
and nasal speech (dystonia). The muscles of mastication
and the facial muscles may also be involved, causing diffi-
culty in chewing. Involvement of the oral mucosa has been
described, but the lesions are not diagnostic. These lesions
include shallow ulcers, erythematous patches, and telang-
iectasis. More characteristic are the facial skin lesions, which
may present as a “butterfly” rash (similar to the lesions of
SLE) or as a swelling of the eyelids, face, or lips. Lilac-colored
eyelids secondary to stasis of blood in multiple telangiec-
tasias is also a common finding. Calcinosis of the soft tissues
is seen, especially in children. These calcified nodules may
appear in the face and may show up on dental radographs,
leading to misinterpretation. The tongue may also become
rigid due to severe calcinosis.
DENTAL MANAGEMENT
The disease process of DM poses no significant challenge to the
dentist. The same precautions as are necessary for all patients
who are taking high-dose long-term steroids and antimetabo-
lites should be taken.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a disease characterized by
inflammation of the synovial membrane. Women are
approximately three times more likely to be affected than
men, and 80% of people with RA develop signs and symp-
toms of the disease at between 35 and 50 years of age.
Epidemiologic studies suggest that the incidence of the dis-
ease is declining in younger age groups because of unknown
environmental factors.69
Unlike degenerative joint disease (osteoarthritis), which is
localized to the joints in middle-aged and elderly individuals,
rheumatoid arthritis affects people of all age groups and affects
other organs, including muscles and the hematopoietic system.
Although this disease is called arthritis, there are frequent
extra-articular manifestations.
NOMENCLATURE (SUBTYPES)
Several variations of RA exist. Felty’s syndrome accounts for
less than 5% of the total cases. In addition to having the usual
495
manifestations of RA, patients with Felty’s syndrome also have
splenomegaly and leukopenia, with neutrophils showing the
greatest decrease. In severe cases, recurrent bacterial infection
is a common cause of death.
Another variant is juvenile RA (Still’s disease), which is
thought by some rheumatologists to be a separate disease and
not just a simple variation of adult RA.70 Systemic extra-artic-
ular symptoms are prominent, including fever, lym-
phadenopathy, hepatosplenomegaly, carditis, and rash. Visual
impairment secondary to iridocyclitis (inflammation of the
iris and ciliary body) may also occur. In 50% of patients,
growth and sexual maturation are delayed during active stages
of the disease.
ETIOLOGY AND PATHOGENESIS
The pathogenesis of RA is unknown, but it appears to be mul-
tifactorial, involving genetic, immune, and infectious etiologies.
Genetic Factors. Studies of identical twins demonstrate that
genetic factors play an important role in the pathogenesis of
RA. This is confirmed by the findings of the HLA-DR4 major
histocompatibility complex in up to 70% of RA patients.
Immune Factors. Most of research into the cause of RA
involves studies of the immune system. The inflammatory
response that causes joint and other injury is immune in
nature. RA is believed to be a T-lymphocyte-driven disease in
which a sudden influx of T cells into the affected joint(s) is fol-
lowed by an increased number of macrophages and fibro-
blasts. The initiating factor of this immune response is
unknown. The evidence of immune features in this disease
includes the following:
1. The presence of rheumatoid factors (antigammaglobu-
lin antibodies that form soluble complexes, measured in
the serum by coating latex particles with IgG and test-
ing the agglutinating properties of the patient’s serum)
in the serum and synovial fluid of affected patients
2. Extensive collections of plasma cells and lymphocytes
found on histologic examination of affected tissues
3. Decreased complement levels in the synovial fluid of
affected patients (suggests complement use during
hypersensitivity reactions)
4. The overlap of RA with SLE and other diseases sus-
pected of an immune pathogenesis.
Infectious Factors. Several infectious agents (including both
bacteria such as streptococci and Mycoplasma, as well as viruses
such as Epstein-Barr virus) have been suggested to cause the
initial T-cell influx.
CLINICAL MANIFESTATIONS
The initial symptom in a majority of patients with RA is non-
specific weakness and fatigue, which may precede joint symp-
toms by several months. This is followed by symmetric pol-
yarthritis characterized by a complaint of stiffness and a
finding of a spindle-shaped swelling of the involved joints.
496 Principles of Medicine

The proximal interphalangeal joints of the fingers and

metacarpophalangeal joints of the hands are most commonly
involved (Figure 18-13); the wrists, elbows, knees, and ankles
also are frequently affected (Figure 18-14). In some patients,
all joints may be involved, including the temporomandibular
joint and the cricoarytenoid joint of the larynx. The joints
that are affected with RA become red, swollen, and warm to the
touch. Muscle atrophy around the affected joint is common.
Extracapsular manifestations include subcutaneous nod-
ules (Figure 18-15) (especially over pressure points), which
occur in 20 to 25% of patients; enlargement of the lymph
nodes and spleen; chronic skin ulcers from a diffuse arteritis;
pleural effusion; and pulmonary fibrosis. Rheumatoid granu-
lomas may affect the heart, the eyes, or the brain.
Some patients may have a short course of nondisabling
disease whereas others have an unrelenting downhill course of
crippling and severe disability. A fluctuating course of remis-
sions and exacerbations is seen in many patients, and this FIGURE 18-14 Rheumatoid arthritis in the knees. (Courtesy of Dr.
unpredictable course makes the choice of therapeutic regi- George Ehrlich)
mens difficult.

DIAGNOSIS AND LABORATORY EVALUATION
In 1987, The American College of Rheumatology revised the
criteria for the diagnosis of RA. The diagnosis is based on sat-
isfying at least four of the following seven criteria: (1) morn-
ing stiffness, (2) arthritis of three or more joint areas, (3)
arthritis of the joints of the hand, (4) symmetric arthritis, (5)
rheumatoid nodules, (6) serum rheumatoid factor, and (7)
radiographic changes. The first four criteria must be present
for at least 6 weeks, and the second through fifth must be
observed by a physician.71
Autoantibodies (such as ANA and rheumatoid factor) are
respectively found in 30 to 60% and 72 to 85% of adult
patients. However, these autoantibodies are not specific to RA
and are found in patients who have a number of other condi-
tions, such as SLE and scleroderma. Rheumatoid factor, par-
ticularly in high titers, adds weight to the diagnosis of RA and
is associated with more destructive disease and a worse prog-
nosis (see Table 18-1).
Other associated laboratory findings include an elevated
erythrocyte sedimentation rate and normochromic normo-
cytic anemia. Some tests may be helpful in excluding RA by
indicating an alternative diagnosis. For example, antibodies to
DNA would indicate SLE whereas anti-Ro (SS-A) or anti-La

FIGURE 18-13 Characteristic involvement of the hands in a patient FIGURE 18-15 Subcutaneous nodules of the arm in a patient with
with rheumatoid arthritis. (Courtesy of Dr. George Ehrlich) rheumatoid arthritis. (Courtesy of Dr. George Ehrlich)
Immunologic Diseases
(SS-B) antibodies suggest Sjögren’s syndrome. Conversely, the
absence of such antibodies favors a diagnosis of RA.
ORAL SIGNS
The treatment of RA can cause oral manifestations. The long-
term use of methotrexate and other antirheumatic agents such
as D-penicillamine and NSAIDs can cause stomatitis.
Cyclosporine may cause gingival overgrowth.
Direct effects of the disease are also seen. Patients with
long-standing active RA have an increased incidence of peri-
odontal disease, including loss of alveolar bone and teeth.
Similarities in the host immune responses of RA and peri-
odontal disease, involving reduced cellular and enhanced
humoral activity, have been reported72 although the increased
dental and periodontal disease may be chiefly related to a
decreased ability to maintain proper oral hygiene. Sjögren’s
syndrome is a common complication of RA (see Chapter 9,
“Salivary Gland Disease”). RA of the temporomandibular joint
(Figure 18-16) was discussed earlier (see Chapter 10).
DENTAL MANAGEMENT
The most common complication that affects dental treatment
relates to the toxicity of the drugs used to treat RA. It is imper-
ative that the dentist knows the drugs the patient is currently
taking and their possible side effects and interactions with
other drugs. The most common adverse effects of NSAIDs
involve the gastrointestinal (GI) tract and the kidneys. In addi-
tion, many patients take aspirin at dosages approaching 5 g per
day or take an equivalent dosage of NSAIDs. These drugs affect
platelet function, causing a prolongation of the bleeding time
and possible hemorrhage after surgery.
FIGURE 18-16 Evidence of flattening of the condylar articular surface
with deepening radiolucency in a patient with rheumatoid arthritis. Note the
lack of depth of temporal bone fossa.
497
Intramuscular doses of gold salts are used for some patients
who are refractory to other forms of treatment. The side effects
of this therapy include stomatitis, blood dyscrasias, and
nephrotic syndrome. Other refractory patients respond to D-
penicillamine, a drug that may cause bone marrow depression
as well as renal toxicity, heptotoxicity, or drug-induced pem-
phigus. Therefore, any patient who is taking either of these
drugs should have a complete blood count and chemistry prior
to dental treatment. Corticosteroids and immunosuppressive
drugs are still used for some refractory patients; therefore,
appropriate measures should be taken with these patients prior
to dental care (see “Dental Considerations” under “Systemic
Lupus Erythematosus,” above).
Patients with severe RA who have had joints surgically
replaced with prosthetic joints may require prophylactic
antibiotic therapy before invasive dental procedures. No pro-
phylaxis is indicated for otherwise healthy patients 2 years
after placement of a prosthesis. However, patients should
receive prophylactic antibiotics after the 2 years if they are on
immunosuppressive agents or have had postoperative joint
infections. Antibiotic prophylaxis should be considered for
patients who will be undergoing dental procedures that are
associated with a higher incidence of bacteremia. Such proce-
dures include dental extractions, periodontal surgery, implant
placement, replacement of avulsed teeth, endodontic therapy
beyond the apex, intraligamentary local anesthetic injections,
placement of orthodontic bands, and any procedure in which
bleeding is anticipated73 (Table 18-3).
Patients with Sjögren’s syndrome may require additional
instruction in personal oral care, instruction on diet and
dietary modifications, home clinical fluoride therapy treat-
ment for xerostomia, more frequent recall visits and radiog-
raphy, and more conservative treatment plans.74
TABLE 18-3 Indications for Antibiotic Prophylaxis for Dental
Patients with Total Joint Replacements and Suggested Antibiotic
Regimens
Dental procedures for which antibiotic prophylaxis is indicated
Dental extractions
Periodontal procedures
Dental implant placement
Reimplantation of avulsed teeth
Endodontic instrumentation beyond apex, or endodontic surgery
Initial placement of orthodontic bands (not brackets)
Intraligamentary injections of local anesthetic
Prophylactic cleaning of teeth or implants when bleeding is anticipated
Suggested antibiotic prophylaxis regimens
Patient not allergic to penicillin: cephalexin, cephradrine, or amoxicillin, 2 g
PO 1 hour before dental procedure
Patient not allergic to penicillin and unable to take oral medications: cefazolin
(1 g) or ampicillin (2 g) IM or IV 1 hour before dental procedure
Patient allergic to penicillin: clindamycin, 600 mg PO 1 hour before dental
procedure
Patient allergic to penicillin and unable to take oral medications: clindamycin,
600 mg IV 1 hour before dental procedure
Adapted from Treister N, Glick M.74
IM = intramuscularly; IV = intravenously; PO = orally.
498
The dentist should determine if the RA patient has a form
of the disease that affects the bone marrow (such as Felty’s syn-
drome) since such patients have an increased risk of develop-
ing infection due to neutropenia and hemorrhage secondary
to thrombocytopenia.75
Mixed Connective-Tissue Disease
The term “mixed connective-tissue disease” (MCTD) was
coined in 1972 to denote a condition that has the combined
clinical features of SLE, PSS, and DM. Clinicians have sug-
gested a variety of terms to describe the clinical disease in
patients who exhibit the clinical features of multiple
rheumatologic diseases. Such descriptive phrases include
overlap syndrome, sclerodermatomyositis, rheumatoid
arthritis and systemic lupus erythematosus (RUPUS), mixed
collagenosis, and systemic lupus erythematosus and sclero-
derma (lupoderma).
The cause of MCTD, as with other rheumatologic diseases,
is unknown. The prevalence of MCTD is also unknown, but
MCTD is believed to occur more commonly than DM, less often
than SLE, and as frequently as PSS. Most MCTD patients are
women, and the average age at the time of diagnosis is 37 years.76
Common clinical features of MCTD include Raynaud’s
phenomenon, polyarthritis, sclerodactyly, and inflammatory
myositis. Generalized lymphadenopathy has been observed in
50% of patients with MCTD. Pericarditis, renal disease, and
pulmonary disease are also common.77
Using HLA type to predict the differentiation of MCTD,
some investigators have suggested that MCTD is an interme-
diate stage in a genetically determined progression to a recog-
nized connective-tissue disease and that those whose disease
remains undifferentiated might be considered a distinct sub-
set.78 Black suggested in 1992 that the concept of MCTD as a
distinct disease entity is better replaced by the term “undiffer-
entiated autoimmune rheumatic/connective-tissue disorder”
because the condition of many of these patients later converts
to PSS or SLE.79
A prerequisite for the diagnosis of MCTD is the presence
of high titers of autoantibodies against small nuclear ribonu-
cleoprotein (SnRNP) antigen. The characteristic laboratory
abnormalities in MCTD cases include high titers (> 1:1,000)
of speckled ANAs, high levels of antibody to ribonuclease
(RNase)-sensitive extractable nuclear antigen, and the presence
of snRNP antigen antibody.80
Little has been reported concerning the oral manifesta-
tions of MCTD. The oral manifestations of conditions such as
xerostomia and a decreased mandibular range of movement
are possible features although few reports are available.
▼ ALLERGY
The modern dentist uses a wide variety of drugs to treat
patients, including antibiotics, hypnotics, and anesthetics. All
practitioners who use these medications must know how to
manage reactions to them. In this section, acute allergic reac-
Principles of Medicine
tions and their management is discussed. Stomatitis associated
with allergy is discussed in Chapter 4.
Acute allergic reactions are caused by an immediate-type
hypersensitivity reaction. A good model for understanding
this mechanism is anaphylaxis. A patient previously exposed
to a drug or other antigen has antibody (primarily IgE) fixed
to basophils and mast cells. When the antigen (in the form of
a drug, food, or an airborne substance) is re-introduced into
the body, it will react with the fixed antibody, bind comple-
ment, and open mast cells, releasing active mediators such as
histamine and slow-reacting substance of anaphylaxis (SRS-
A). These substances cause vasodilation and increased capillary
permeability, which result in fluid and leukocytes leaving the
blood vessels and accumulating in the tissues and forming
areas of edema. Constriction of bronchial smooth muscle
results when IgE is bound in the pulmonary region. The ana-
phylactic reaction may be localized and lead to urticaria and
angioneurotic edema, or a generalized reaction may result,
causing anaphylactic shock (Figure 18-17).
Localized Anaphylaxis
A localized anaphylactic reaction involving superficial blood
vessels results in urticaria (hives). Urticaria begins with pru-
ritus in the area of the release of histamine and other active
substances. Wheals (welts) then appear on the skin as an area
of localized edema on an erythematous base. These lesions
can occur anywhere on the skin or mucous membranes.
Urticaria of the lips and the oral mucosa occurs most fre-
quently after food ingestion by an allergic individual.
Common food allergens include chocolate, nuts, shellfish,
and tomatoes. Drugs such as penicillin and aspirin may cause
urticaria, and cold, heat, or pressure may cause the reaction
in susceptible individuals.
Angioneurotic edema (angioedema) occurs when blood
vessels that are deeper in the subcutaneous tissues are affected,
producing a large diffuse area of subcutaneous swelling under
normal overlying skin. This reaction may be caused by contact
with an allergen, but a significant number of cases are idio-
pathic. A recurrent form is inherited as an autosomal dominant
trait. Hereditary angioneurotic edema is fatal in approximately
FIGURE 18-17 Urticaria resulting from use of a nonsteroidal anti-
inflammatory drug.
Immunologic Diseases
one-quarter of cases because of severe laryngeal edema. The
mechanism of the hereditary form of the disease is a deficiency
of a C1 esterase inhibitor, which normally acts as an inhibitor
of the first component of complement and kallikrein.
Angioedema commonly occurs on the lips and tongue and
around the eyes (Figure 18-18). It is temporarily disfiguring
but is not serious unless the posterior portion of the tongue or
larynx compromises respiration. The patient who is in respi-
ratory distress should be treated immediately with 0.5 mL of
epinephrine (1:1,000) subcutaneously or 0.2 mL of intra-
venous epinephrine, injected slowly. When the immediate dan-
ger has passed, 50 mg of diphenhydramine hydrochloride
(Benadryl [Pfizer, Parsippany, N.J.]) should be given four times
a day until the swelling diminishes.
Serum Sickness
Serum sickness is named for its frequent occurrence after the
administration of foreign serum, which was given for the treat-
ment of infectious diseases before the advent of antibiotics.
The reaction is presently less common but still occurs as a
result of the susceptible patient’s being given tetanus antitoxin,
rabies antiserum, or drugs that combine with body proteins to
form allergens. Penicillin, a drug commonly prescribed by
dentists, occasionally causes serum sickness.
The pathogenesis of serum sickness differs from that of
anaphylaxis. Antibodies form immunocomplexes in blood
vessels with administered antigens. The complexes fix com-
plement, which attracts leukocytes to the area, causing direct
tissue injury.
Serum sickness and vasculitis usually begin 7 to 10 days
after the administration of the allergen, but this period can
vary from 3 days to as long as 1 month. Unlike other allergic
diseases, serum sickness may occur during the initial admin-
istration of the drug.
A
499
Major symptoms consist of fever, swelling, lym-
phadenopathy, joint and muscle pains, and rash. Less common
manifestations include peripheral neuritis, kidney disease, and
myocardial ischemia. Serum sickness is usually self-limiting,
with spontaneous recovery in 1 to 3 weeks. Treatment is symp-
tomatic; aspirin is given for arthralgia, and antihistamines are
given for the skin rash. Severe cases should be treated with a
short course of systemic corticosteroids, which significantly
shortens the course of the disease. Although this reaction is
rare, the dentist who is prescribing penicillin should be aware
of the possibility of serum sickness occurring weeks after use
of the drug.
Generalized Anaphylaxis
Generalized anaphylaxis is an allergic emergency. The mech-
anism of generalized anaphylaxis is the reaction of IgE anti-
bodies to an allergen that causes the release of histamine,
bradykinin, and SRS-A. These chemical mediators cause the
contraction of smooth muscles of the respiratory and intesti-
nal tracts, as well as increased vascular permeability.
The following factors increase the patient’s risk for ana-
phylaxis:
1. History of allergy to other drugs or food
2. History of asthma
3. Family history of allergy
4. Parenteral administration of the drug
5. Administration of high-risk allergens such as penicillin
Anaphylactic reactions may occur within seconds of drug
administration or may occur 30 to 40 minutes later, compli-
cating the diagnosis. The symptoms of generalized anaphylaxis
should be known so that prompt treatment may be initiated.
For example, patients have been diagnosed as allergic to local
anesthetics when a psychic reaction to an injection or a reac-
FIGURE 18-18 A, Angioneurotic edema of an allergic
reaction to intramuscularly administered penicillin. B, Same
patient 48 hours later, after therapy with epinephrine and
antihistamine agents.
500
tion to epinephrine have occurred. Such an erroneous diag-
nosis will make future dental management difficult.
The generalized anaphylactic reaction may involve the skin,
the cardiovascular system, the intestines, and the respiratory
system. The first signs often occur on the skin and are similar to
those seen in localized anaphylaxis (eg, urticaria, angioedema,
erythema, and pruritus). Pulmonary symptoms include dysp-
nea, wheezing, and asthma. GI tract disease (eg, vomiting,
cramps, and diarrhea) often follows skin symptoms. If these are
untreated, symptoms of hypotension appear as the result of the
loss of intravascular fluid; if untreated, this leads to shock.
Patients with generalized anaphylactic reactions may die from
respiratory failure, hypotensive shock, or laryngeal edema.
The most important therapy for generalized anaphylaxis is
the administration of epinephrine. All clinicians who admin-
ister drugs should have a vial of aqueous epinephrine (at a
1:1,000 dilution) and a sterile syringe easily accessible. For
adults, 0.5 mL of epinephrine should be administered intra-
muscularly or subcutaneously; smaller doses of from 0.1 to 0.3
mL should be used for children, depending on their size. If the
allergen was administered in an extremity, a tourniquet should
be placed above the injection site to minimize further absorp-
tion into the blood. The absorption can be further reduced by
injecting 0.3 mL of epinephrine (1:1,000) directly into the injec-
tion site. The tourniquet should be removed every 10 minutes.
Epinephrine will usually reverse all severe signs of gener-
alized anaphylaxis. If improvement is not observed in 10 min-
utes, re-administer epinephrine. If the patient continues to
deteriorate, several steps can be taken, depending on whether
the patient is experiencing bronchospasm or edema. For bron-
chospasm, slowly inject 250 mg of aminophylline intra-
venously, over a period of 10 minutes. Too rapid an adminis-
tration can lead to fatal cardiac arrhythmias. Do not give
aminophylline if hypotensive shock is a part of the clinical
picture. Inhalation sympathomimetics may also be used to
treat bronchospasm, and oxygen should be given to prevent or
manage hypoxia. For the patient with laryngeal edema, estab-
lish an airway. This may necessitate endotracheal intubation;
in some cases, a cricothyroidotomy may be necessary.
Latex Allergy
The increased use of protective gloves has led to numerous
undesirable cutaneous and mucosal reactions. Unfortunately,
the number of objective methods for verifying immediate der-
mal and mucosal irritation is rather small. While studies repeat-
edly uncover high prevalence rates, the nonspecific nature of the
symptoms and the lack of knowledge about latex allergy result
in missed diagnoses in many sensitized persons who are at risk
for the progression of serious allergic reactions.81 Originally,
urticaria, rhinitis, and eyelid edema were identified as immedi-
ate manifestations of latex allergy. Severe systemic reactions
(such as asthma and anaphylaxis), which may result in perma-
nent disability or even death, have now been recognized.81
In the health care setting, the two major strategies for man-
agement are (1) the safe care of the latex allergic patient and
(2) the prevention and treatment of occupational latex allergy
Principles of Medicine
in employees. In managing a patient with latex sensitivity, the
distinction between an immediate hypersensitivity reaction
to latex and an allergic contact dermatitis due to other irritants
must be established. At initial evaluation, latex allergy status
should be established by the history and documented clearly
on the chart. Any history of an immediate hypersensitivity
reaction to latex necessitates a latex-free environment for that
person. The operatory should include nonlatex products;
“hypoallergenic” latex gloves or latex-containing products
(such as blood pressure cuffs and disposable tourniquets)
should not be worn or used in the vicinity of persons who are
allergic to latex. Premedication with antihistamines, steroids,
and histamine H2 blocking agents is sometimes carried out in
operating rooms, but anaphylactic reactions have occurred
despite such pretreatment.
Workers who are irritated by gloves should change the type
of gloves worn or change the type of soap used for scrubbing.
In addition, the use of cotton liners and emollients may effec-
tively prevent sensitivity reactions. In cases of true latex allergy,
the avoidance of all latex products is the only measure that can
avert a serious allergic reaction.
All persons with latex hypersensitivity should carry an epi-
nephrine autoinjection kit and wear MedicAlert identifica-
tion. Acute systemic reactions to latex should be treated in the
same manner as other anaphylactic reactions are treated (ie,
airway and circulation assessment, administration of oxygen,
and administration of epinephrine and steroids as needed). In
the course of resuscitation, all latex contact must be avoided.82
▼ REFERENCES
1. Fearon DT, Locksley RM. The instructive role of innate immu-
nity in the acquired immune response. Science 1996;272:50–3.
2. Alam R. A brief review of the immune system. Primary Care
1998;25:727–38.
3. Haynes BF, Fauci AS. Introduction to the immune system. In:
Wilson JD, Braunwald E, Isselbacker KJ, editors. Harrison’s
principles of internal medicine. 14th ed. New York: McGraw-
Hill; p. 1753–76.
4. Roitt IM. Primary immunodeficiency. In: Roitt IM, Brostoff J,
Male D, editors. Clinical immunology. 5th ed. London: Mosby,
1998. p. 285–92.
5. Heraszewsli RA, Webster ADB. Primary hypogammaglobu-
linemia: a survey of clinical manifestations and complications.
QJM 1993;86:31.
6. Harrison LF, Shearer WT. Evaluation and management of B
and T cell abnormalities. Allergy Proc 1991;12:25-30.
7. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression
of a B-cell cytoplasmic tyrosine kinase in human X-linked
agammaglobulinemia. Cell 1993;72:279–90.
8. Mohamed AJ, Nore BF, Christensson B, Smith CI. Signalling of
Bruton’s tyrosine kinase Btk. Scand J Immunol 1999;49:113-8.
9. Mamlock RJ. Primary immunodeficiency disorders. Primary
Care 1998:25:739–58.
10. Nononyama S. Recent advances in the diagnosis of X-linked
agammaglobulinemia. Intern Med 1999;38:687.
11. Liese JG, Wintergerst U, Tympner KD, Belohradsky BH. High-
vs low-dose immunoglobulin therapy in the treatment of X-
linked agammaglobulinemia. Am J Dis Child 1992;146:335-9.
Immunologic Diseases
12. Secondary immunodeficiency. In: Roitt IM, Brostoff J, Male D,
editors. Clinical immunology. 5th ed. London: Mosby, 1998.
p. 293.
13. Cunningham-Rundles C. Disorders of the IgA system. In:
Stiehm ER, editor. Immunologic disorders in infants and chil-
dren. 4th ed. Philadelphia: W.B. Saunders; 1996.
14. Burrows PD, Cooper MD. IgA deficiency. Adv Immunol
1997;65:245-76.
15. Hong R. The DiGeorge anomaly. Clin Rev Allergy Immunol
2001;20:43-60.
16. Hillebrand G, Siebert R, Simeoni E, Santer R. DiGeorge syn-
drome with discordant phenotype in monozygotic twins. J
Med Genet 2000;37:E23.
17. Weissman IL, Shizuru J. Immune reconstitution. N Engl J Med
1999;341:1227-9.
18. Rogers MH, Lwin R, Fairbanks L, et al. Cognitive and behav-
ioral abnormalities in adenosine deaminase deficient severe
combined immunodeficiency. J Pediatr 2001;139:44-50.
19. Siegfried EC, Prose NS, Friedman NJ, Paller AS. Cutaneous
granulomas in children with combined immunodeficiency. J
Am Acad Dermatol 1991;25:761-6.
20. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telang-
iectasia gene with a product similar to PI-3 kinase. Science
1995;268:1749-53.
21. Lavin MF. Radiosensitivity and oxidative signalling in ataxia
telangiectasia: an update. Radiother Oncol 1998;47:113–23.
22. Norhagen GE, Engstrom PE, Hammarstrom L, et al. Oral and
intestinal microflora in individuals with different immunoglob-
ulin deficiencies. Eur J Clin Microbiol Infect Dis 1990;9:631-3.
23. Greenberg MS. Oral herpes simplex infections in immuno-
suppressed patients. Compend Suppl 1988;9:S289–91.
24. Porter AR, Scully C. Orofacial manifestations in the primary
immunodeficiency disorders. Oral Surg Oral Med Oral Pathol
1994;78:4–13.
25. Spickett GP, Misbah SA, Chapel HM. Primary antibody defi-
ciency in adults. Lancet 1991;337:281-4.
26. Tolo K. Periodontal disease mechanisms in immunocompro-
mised patients. J Clin Periodontol 1991;18:431-5.
27. Porter AR, Scully C. Orofacial manifestations in primary
immunodeficiencies: IgA. J Oral Pathol Med 1993;22:117–9.
28. Porter AR, Scully C. Orofacial manifestations in primary
immunodeficiencies: common variable immunodeficiencies. J
Oral Pathol Med 1993; 22:157–8.
29. Buckley RH. Advances in the diagnosis and treatment of pri-
mary immunodeficiency diseases. Arch Intern Med
1986;146:377-84.
30. Huston DP, Kavanaugh AF, Rohane PW, Huston MM.
Immunoglobulin deficiency syndromes and therapy. J Allergy
Clin Immunol 1991;87:1-17.
31. Steihm ER. Appropriate therapeutic use of immunoglobulin.
Transfus Med Revi 1996;10:203.
32. Yu Z, Lennon VA. Mechanism of intravenous immune globu-
lin therapy in antibody mediated autoimmune diseases. N Engl
J Med 1999;340:227-8.
33. Heimdahl A, Nord CE. Oral infections in immunocompro-
mised patients. J Clin Periodontol 1990;17:501-3.
34. Greenberg MS, Cohen SG, McKitrick J, Cassileth P. The oral
flora as a source of septicemia in patients with leukemia. Oral
Surg Oral Med Oral Pathol 1982;53:32-4.
35. Joint Statement of the American Thoracic Society, the
European Respiratory Society, and the World Association of
501
Sarcoidosis and Other Granulomatous Disorders. Statement
on sarcoidosis. Am J Respir Crit Care Med. 1999;160:736–55.
36. Jones RE, Chatham WW. Update on sarcoidosis. Curr Opin
Rheumatol 1999;11:83-7.
37. Arkachaisri T, Lehman TJ. Systemic lupus erythematosus and
related disorders of childhood. Curr Opin Rheumatol
1999;11:384-92.
38. Rubin RL. Etiology and mechanisms of drug-induced lupus.
Curr Opin Rheumatol 1999;11:357–63.
39. McCurdy D. Genetic susceptibility to the connective tissue dis-
eases. Curr Opin in Rheumatol 1999;11:399-407.
40. Naparstek Y, Plotz PH. The role of autoantibodies in autoim-
mune disease. Ann Rev Immunol 1993;11:79–104.
41. Evans J. Antinuclear antibody testing in systemic autoimmune
disease. Clin Chest Med 1998;19:613–25.
42. Mojcik CF, Klippel JH. End stage renal disease and systemic
lupus erythematosus. Am J Med 1996;101:100–7.
43. De Rossi SS, Glick M. Lupus erythematosus: considerations for
dentistry. J Am Dent Assoc 1998;129:330-9.
44. Bluestein HG. The central nervous system in systemic lupus
erythematosus. In: Lahita RD, editor. Systemic lupus erythe-
matosus. New York: Churchill Livingstone; 1992. p. 639.
45. Monash S. Oral lesions of lupus erythematosus. Dent Cosmos
1931;73:511.
46. Rhodus NL, Johnson DK. The prevalence of oral manifesta-
tions of systemic lupus erythematosus. Quintessence Int
1990;21:461-5.
47. Sanchez R, Jonsson R, Ahlfors E, et al. Oral lesions of lupus ery-
thematosus patients in relation to other chronic inflamma-
tory oral diseases: an immunologic study. Scand Dent Res
1988;96:569-78.
48. Karjalainen TK, Tomich CE. A histopathologic study of oral
mucosal lupus erythematosus. Oral Surg Oral Med Oral Pathol
1989;67:547-54.
49. Andonopoulos AP, Skopouli FN, Dimou GS, Drosos AA.
Sjögren’s syndrome in systemic lupus erythematosus. J
Rheumatol 1990;17:201-4.
50. Glick M. Glucocorticosteroid replacement therapy: a litera-
ture review and suggested replacement therapy. Oral Surg Oral
Med Oral Pathol 1989;67:614–20.
51. De Rossi SS, Glick M. Dental considerations for the patient
with renal disease receiving hemodialysis. J Am Dent Assoc
1996;127:211–9.
52. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North
Am 1996; 22:751–64.
53. Laing TJ, Gillespie BW, Toth MB, et al. Racial differences in
scleroderma among Michigan women. Arthritis Rheum
1997;40(4):734-42.
54. Callen JP. Collagen vascular diseases. Med Clin North Am
1998;82:1217–37.
55. Jimenez SA, Hitraya E, Varga J. Pathogenesis of scleroderma:
collagen. Rheum Dis Clin North Am 1996;22:647–74.
56. Silver RM, Heyes MP, Maize JC, et al. Scleroderma, fasciitis and
eosinophilia associated with the ingestion of tryptophan. N
Engl J Med 1990;322:874-81.
57. Steen VD. Clinical manifestations of systemic sclerosis. Semin
Cutan Med Surg 1998;17:48–54.
58. Steen VD, Conte C, Owens GR, et al. Severe restrictive lung dis-
ease in systemic sclerosis. Arthritis Rheum 1994;37:1283–9.
59. Rademaker M, Meyric K, Thomas RH, et al. The anti-platelet
effect of nifedipine in patients with systemic sclerosis. Clin
Exp Rheumatol 1992;10:57.
502
60. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of sys-
temic sclerosis with extracorporeal photochemotherapy:
results of a multicenter trial. Arch Dermatol 1992;128:337-46.
61. Nagy G, Kovacs J, Zeher M, et al. Analysis of the oral manifes-
tations of systemic sclerosis. Oral Surg Oral Med Oral Pathol
1994;77:141–6.
62. Montesi A, Pesaresi A, Cavalli ML, et al. Oropharyngeal and
esophageal function in scleroderma.Dysphagia 1991;6:219-23.
63. Callen JP. Oral manifestations of collagen vascular disease.
Semin Cutan Med Surg 1997;16:323–7.
64. Rubin MM, San Filippo RJ. Resorption of the mandibular
angle in progressive systemic sclerosis: case report. J Oral
Maxillofac Surg 1992;50:75-7.
65. Wood KE, Lee P. Analysis of the oral manifestations of systemic
sclerosis. Oral Surg Oral Med Oral Pathol 1988;65:172.
66. Dalakas MC. Polymyositis, dermatomyositis, and inclusion
body myositis. N Engl J Med 1999;325:1487–98.
67. Kovacs SO, Kovacs SC. Dermatomyositis. J Am Acad Dermatol
1998;39:899–920.
68. Villalba L, Adams EM. Update on therapy for refractory der-
matomyositis and polymyositis. Curr Opin Rheumatol
1996;8:544–51.
69. Michet C. Update in the epidemiology of the rheumatic dis-
eases. Curr Opin Rheumatol 1998; 10:129–35.
70. Gallagher KT, Bernstein B. Juvenile rheumatoid arthritis. Curr
Opin Rheumatol 1999;11:372–6.
71. Arnett FC, Edworthy SM, Bloch DA, et al. The American
Rheumatism Association 1987 revised criteria for the classifi-
cation of rheumatoid arthritis. Arthritis Rheum 1988;31:315-
24.
72. Kaber UR, Gleissner C, Dehne F, et al. Risk for periodontal dis-
Principles of Medicine
ease in patient with longstanding rheumatoid arthritis.
Arthritis Rheum 1997;40:2248–51.
73. American Dental Association and American Academy of
Orthopedic Surgeons. Antibiotic prophylaxis for dental
patients with total joint replacements. J Am Dent Assoc
1997;128:1004–8.
74. Treister N, Glick M. Rheumatoid arthritis: a review and sug-
gested dental care considerations. J Am Dent Assoc 1999;
130:689–98.
75. Rosenstein ED, Kramer N. Felty’s and pseudo-Felty’s syn-
dromes. Semin Arthritis Rheum 1991;21:129–42.
76. Sharp GC, Singsen BH. Mixed connective tissue disease. In:
McCarty DJ, editor. Arthritis and allied conditions: a textbook
of rheumatology. 11th ed. Philadelphia: Lea and Febiger, 1989.
p. 1080–91.
77. Prakash UBS. Respiratory complications in mixed connective
tissue disease. Clin Chest Med 1998;19:733–46.
78. Gendi NS, Welsh KI, Van Venrooij WJ, et al. HLA type as a pre-
dictor of mixed connective tissue disease differentiation. Ten
year clinical and immunogenetic follow up of 46 patients.
Arthritis Rheum 1995;38:259–66.
79. Black C, Isenberg DA. Mixed connective tissue disease: good-
bye to all that. Br J Rheumatol 1992;31:695–700.
80. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term out-
come in mixed connective tissue disease: longitudinal clinical
and serologic findings. Arthritis Rheum 1999;42:899–909.
81. Kujala V. A review of current literature on epidemiology of
immediate glove irritation and latex allergy. Occup Med
1999;49:3–9.
82. Reddy S. Latex allergy. Am Fam Physician 1998;71:93–100.