Gout is the classic example of crystal-induced inflammation of synovial
joints. It is a common condition, presenting in 1–4% of
adult men. Deposition of monosodium urate crystals in the joint
space leads to episodes of severe acute joint pain and swelling
(particularly in the great toe, midfoot, ankle, and knee). These
episodes tend to resolve completely and spontaneously within a week
even in the absence of therapy. If not properly treated, however,
this acute, self-limited form of the disease can evolve over many
years into a chronic, destructive pattern resulting in more frequent
and sustained periods of pain and resultant joint deformity. Accumulations
of urate crystals elsewhere in the body can lead to subcutaneous
deposits called tophi.
The critical initiating factor in gout is the precipitation of monosodium
urate crystals in synovial joints. This occurs when body fluids
become supersaturated with uric acid (generally at serum levels
> 7 mg/dL). Indeed, the degree of hyperuricemia correlates
well with the development of gout, with annual incidence rates of
about 5% for serum uric acid levels > 9 mg/dL.
Increased levels of serum uric acid result either from underexcretion
(90% of patients) or overproduction (10%) of uric
acid. A decreased glomerular filtration rate is the most frequent
cause of decreased excretion of uric acid and may be due to numerous
causes (see Chapter 16). Diuretic administration
is also a frequent cause of decreased excretion of uric acid. Overproduction
defects can result from primary defects in the purine salvage pathway
(eg, hypoxanthine phosphoribosyl transferase deficiency), leading
to an increase in de novo purine synthesis and high flux through
the purine breakdown pathway. Diseases causing increased cell turnover
(eg, myeloproliferative disorders, psoriasis) and DNA degradation
(eg, tumor lysis syndrome) are secondary causes of hyperuricemia.
Although the concentration of monosodium urate in joint fluid
slowly equilibrates with that in the serum, formation of crystals
is markedly influenced by physical factors such as temperature and
blood flow. The propensity for gout to involve distal joints (eg,
great toes and ankles), which are cooler than other body parts,
probably reflects the presence of local physical conditions at these
sites remote from the body core that favor crystal formation.
Monosodium urate crystals are not biologically inert. Their highly
negatively charged surfaces function as efficient initiators of
the acute inflammatory response. The crystals are potent activators
of the classic complement pathway, generating complement cleavage
products (eg, C3a, C5a) that are strong chemoattractants for neutrophil
influx (Figure 24–2). The crystals
also activate the kinin system and in that way induce local vasodilation,
pain, and swelling. Phagocytosis of crystals by synovial macrophages
activates the inflammasome (a complex of proteins that sense certain
intracellular stressors and activate IL-1 maturation) and stimulates
the release of proinflammatory cytokines (eg, IL-1, TNF, IL-8, PGE2). These
products increase adhesion molecule expression on local vessel endothelium
to facilitate neutrophil adhesion and migration and are also potent
chemoattractants for neutrophils. Neutrophils also amplify their
own recruitment by releasing leukotriene LTB4 upon phagocytosis
of urate crystals (Figure 24–2).
Mechanisms in initiation and amplification of the acute
inflammatory response in gout involve both cytokines and humoral
The intense inflammatory response in gout typically resolves spontaneously
and completely over the course of several days, even without therapy.
This down-modulation of the inflammatory response is a typical feature
of acute inflammation, whereby the inflammatory response itself
successfully removes the proinflammatory stimulus (Table
24–1). Numerous mechanisms appear to be responsible:
(1) efficient phagocytosis of crystals, preventing activation of
newly recruited inflammatory cells; (2) increased heat and fluid
influx, altering local physical and chemical conditions to favor
crystal solubilization; (3) coating of crystals with serum proteins,
rendering the surface of the crystals less inflammatory; (4) secretion
of a variety of anti-inflammatory cytokines (eg, TGF-β)
by activated joint macrophages; and (5) phagocytosis of previously
activated apoptotic neutrophils by macrophages in the joint, altering
the balance of cytokines secreted by these macrophages in such a way
that secretion of proinflammatory cytokines is inhibited while anti-inflammatory
cytokine secretion is enhanced.
Table 24–1 Mechanisms Causing Down-Modulation
of the Inflammatory Response in Gout. |Favorite Table|Download (.pdf)
Table 24–1 Mechanisms Causing Down-Modulation
of the Inflammatory Response in Gout.
|Efficient phagocytosis of crystals|
|Increased heat and fluid influx, favoring solubilization|
|Coating of crystals with serum proteins, shielding their
|Secretion of anti-inflammatory cytokines (eg, TGF-β)
by activated joint macrophages|
|Phagocytosis of apoptotic neutrophils, enhancing anti-inflammatory effects|
Thus, gout represents an excellent example of an acute inflammatory
response initiated by a proinflammatory force. The response is acute,
highly focused, and self-limited rather than self-sustaining and
associated with little tissue destruction in the acute phase. Flares
of disease represent recurrence of crystals in a proinflammatory
form in the joints. Myelomonocytic cells and humoral factors (eg,
cytokines and the complement and kinin cascades) are critical mediators
of the acute syndrome.
Episodic Oligoarticular Arthritis
Podagra—severe inflammatory arthritis at the first metatarsophalangeal
joint—is the most frequent manifestation of gout. Patients
typically describe waking in the middle of the night with dramatic
pain, redness, swelling, and warmth of the area. Flares of gout
typically produce one of the most intense forms of inflammatory
arthritis. The toes and, to a lesser extent, the midfoot, ankles
and knees are the most common sites for gout flares. Gout flares
frequently occur in circumstances that increase serum uric acid
levels, such as metabolic stressors leading to increased DNA or
adenosine triphosphate (ATP) turnover (eg, sepsis or surgery) or
dehydration. Agents that reduce prostaglandin synthesis (eg, nonsteroidal
anti-inflammatory drugs), reduce neutrophil migration into the joints
(eg, colchicine), or decrease the activation of myelomonocytic cells
(eg, corticosteroids) reduce the duration of a gouty flare.
Gouty arthritis can be diagnosed by examination of synovial fluid
from an actively inflamed joint under a polarizing microscope. Monosodium
urate crystals can be seen as negatively birefringent needle-like
structures that extend across the diameter of and are engulfed by
Firm, irregular subcutaneous deposits of monosodium urate crystals
may occur in patients with chronic gout and are referred to as tophi.
Tophi most often form along tendinous tissues on the extensor surfaces
of joints and tendons as well as on the outer helix of the ear.
Such tophi may extrude chalky material, containing urate crystals,
onto the skin surface and can be viewed for diagnostic purposes
under polarized microscopy.
In some patients, the total body burden of uric acid increases greatly
over years; deposits of monosodium urate crystals occur at multiple
joint sites. This may result in a persistent but more indolent inflammatory
arthritis associated with remodeling of the thin synovial membrane
into a thickened inflammatory tissue. Destructive and irreversible
joint deformities resulting from bone and cartilage erosions often
develop in this circumstance. Renal tubular injury and nephrolithiasis can
also develop under these conditions.
Therapy for acute gouty arthritis consists of agents that decrease
inflammatory cell recruitment and activation to the involved joints.
In contrast, prevention or prophylaxis of recurrent attacks of gouty
arthritis requires chronic therapy to decrease serum uric acid levels
into the normal range, where dissolution of crystals is favored.
Several agents are available that can accomplish this purpose. These
include uricosuric agents (eg, probenecid), which enhance excretion
of uric acid into the urine, and allopurinol, which inhibits uric
acid synthesis by inhibition of xanthine oxidase (a critical enzyme
in the uric acid synthetic pathway). Xanthine oxidase inhibitors are
conceptually appropriate for treatment of uric acid overproducers
(10% of patients), and uricosuric agents for treating uric
acid underexcretors (90% of patients). However, agents that
decrease uric acid production can be used for therapy of hyperuricemia
irrespective of cause and are often more convenient in terms of
dosage regimens. Several newer recombinant molecule therapies, including
an enzyme called uricase that directly breaks down uric acid, and
a soluble IL-1 receptor antagonist, have shown promising early results
in the treatment of refractory gout.
- 4. What physical factors other than
uric acid concentration influence crystal formation in gout?
- 5. What are some proinflammatory products
released by synovial macrophages upon phagocytosis of urate crystals?
- 6. Suggest five reasons why the intense
acute inflammatory response in gout typically resolves spontaneously
over the course of several days even in the absence of therapy.
- 7. What are three metabolic conditions
that can precipitate a gout flare?
- 8. Name three chronic sequelae of recurrent
Immune complex vasculitis is an acute inflammatory disease of
small blood vessels that occurs in the setting of ongoing antigen
load and an established humoral (antibody) immune response. Tissues
affected include the skin (leukocytoclastic vasculitic rash), joints
(inflammatory arthritis of small and medium-sized synovial joints),
and kidney (immune complex–mediated glomerulonephritis).
Antigens are frequently derived from exogenous sources, including
infections (eg, streptococcal skin infections) and numerous drugs
(especially antibiotics). An intense inflammatory response to such
antigens accounts for one of the names (“hypersensitivity
vasculitis”) given to this disorder. Release of endogenous
antigens in the setting of an autoimmune response (eg, SLE; see
later discussion) may similarly initiate the vasculitic process.
Any antigen that elicits a humoral immune response may give rise
to circulating immune complexes if the antigen remains present in
abundant quantities once antibody is generated. Immune complexes
are efficiently cleared in most circumstances by the reticuloendothelial
system and are rarely pathogenic. Their pathogenic potential is
realized when circulating immune complexes are deposited in the
subendothelium, where they set in motion the complement cascade
and activate myelomonocytic cells. The propensity for immune complexes to
deposit is a function of the relative amounts of antigen and antibody
and of the intrinsic features of the complex (ie, composition, size,
and solubility). The solubility of immune complexes is not a fixed
property, because it is profoundly influenced by the relative concentrations
of antigen and antibody, which generally change as an immune response
evolves. For physicochemical reasons, soluble immune complexes formed
at slight antigen excess are not effectively cleared by the reticuloendothelial
system and are of a size that allows them to gain access to and
be deposited at subendothelial and extravascular sites (Figure 24–3). When antibody is present
in excess, immune complexes are rapidly cleared by the reticuloendothelial
system and deposition does not occur.
Immune complex formation. Impact of concentrations of
antigens and antibodies.
Thus, if foreign antigens (eg, drugs or infectious organisms) induce
an antibody response in the setting of antigen excess, significant
numbers of immune complexes of the appropriate size are formed and
they may then be deposited in small vessels in various target organs
(in skin, joints, kidney, blood vessel walls) where they activate
several effector pathways (eg, FcR receptor, classic complement
cascade) and where they may lead to the characteristic skin rashes
(eg, palpable purpura), arthritis, and glomerulonephritis, which
are the hallmarks of small-vessel vasculitis. As the immune response progresses
and titers of specific antibody rise, or as the offending agent
is removed, complexes are more effectively cleared, leading to resolution
of the vasculitis.
A classic example of the altered pathogenicity of immune complexes
at various antigen-antibody ratios is serum sickness. (Penicillin-induced
hypersensitivity vasculitis represents a similar example.) When
serum products from animals (eg, horses) are injected into humans
for a therapeutic purpose (eg, as once was used for passive immunization
against snake venom), the foreign serum proteins stimulate an immune response,
with antibodies first appearing approximately 1 week after injection.
Soon thereafter, immune complexes appear, followed by the development
of fever, arthritis, rash, and glomerulonephritis, consistent with
deposition of soluble immune complexes and myelomonocytic cell activation
at multiple tissue sites. As the antibody titers
rise, immune complexes are no longer formed at great antigen excess
but approach the zone of equivalence and then the zone of antibody
excess. The latter complexes are effectively cleared and thus lose
their pathogenicity as the immune response evolves. Provided that
antigen administration is not sustained, the inflammatory disease
will resolve spontaneously as those immune complexes that were deposited
early (during the soluble phase) are cleared. Such significant clinical
effects of immune complexes usually occur only when the initial
antigen load is great (eg, a large bacterial load or drug administration).
of Immune Complex Vasculitis
Affected tissues are all highly enriched in small blood vessels, which
are the target of injury in this syndrome.
Small-Vessel (Leukocytoclastic) Vasculitis
A common clinical presentation of immune complex–induced
vasculitis in the skin is palpable purpura, which appears as red
or violaceous papules. Cutaneous immune complex vasculitis seldom
causes severe pain or tissue breakdown and only rarely leads to
long-term injury (see Chapter 8).
The most common pattern of joint involvement with immune complex
disease is that of a severe, rapid-onset and self-limited symmetric
polyarthritis. As the immune complexes are phagocytosed and cleared,
the immune response remits unless further waves of immune complexes
Glomeruli are beds of small blood vessels in the kidney where immune
complexes are likely to be deposited. Acute immune complex glomerulonephritis
causes proteinuria, hematuria, and formation of red blood cell casts,
due to disruption of the glomerular basement membrane caused by
subendothelial complex deposition. In cases of extensive immune
complex–mediated injury, immune complex vasculitis can
cause oliguria and acute renal failure.
The most effective treatment for immune complex vasculitis is
elimination of the inciting antigen (eg, by discontinuation of an
offending drug). Medications that reduce the degree of activation
of myelomonocytic cells (eg, corticosteroids) are also helpful.
Immune Complex Vasculitis, Wegener’s Granulomatosis, & Polyarteritis
The vasculitides are a diverse group of inflammatory syndromes
characterized by inflammatory destruction of blood vessels. However,
not all forms of vasculitis are caused by immune complex deposition.
This fact is highlighted by the current classification system for
the systemic vasculitides, which segregates diseases on the basis
of the size of the blood vessel involved, by the presence of circulating
autoantibodies, and by the histologic presence or absence of immune
complexes (Table 24–2).
Table 24–2 Classification of Vasculitic Syndromes
Based on Vessel Size. |Favorite Table|Download (.pdf)
Table 24–2 Classification of Vasculitic Syndromes
Based on Vessel Size.
|Vessel Size||Examples||Epidemiology and Demographics|
|Small vessel||Immune complex mediated; Henoch-Schönlein purpura||Common, evanescent. Predominantly in children, relatively
common compared with other autoimmune conditions|
|Medium vessel||Polyarteritis nodosa||Rare; about 5 cases per million|
|Large vessel||Giant cell arteritis||Only in patients older than 50 years; about 100 cases per million|
It is useful to contrast the clinical and pathophysiologic features
of immune complex vasculitis (see prior discussion) with those of
the “pauci-immune” vasculitic processes, which include
Wegener’s granulomatosis and polyarteritis nodosa. The
clinical hallmarks of Wegener’s granulomatosis include granulomatous
inflammation of the upper airway (eg, sinusitis) and lower airway
and lungs, as well as a necrotizing vasculitis involving the kidneys
and many other organs. Although immune complex deposition is not
a prominent feature in the pathophysiology of Wegener’s
granulomatosis, a specific group of antibodies highly specific to
this disease may play an important propagating role. These “ANCA” antibodies [antineutrophil cytoplasmic antibodies],
directed against components situated within neutrophil cytoplasmic
granules, may bind to and activate neutrophils at the interface
of the plasma and vessel wall and cause them to degranulate and damage
the vascular wall at these sites.
In contrast, neither ANCA antibodies nor immune complex deposition
plays a central role in the pathogenesis of polyarteritis nodosa,
a vasculitis affecting medium-sized muscular arteries and arterioles.
In this condition, the pathologic hallmark is an intense and destructive
myelomonocytic cellular infiltrate in the blood vessel wall (called fibrinoid necrosis),
leading to vessel occlusion, marked luminal narrowing and obsolescence.
The dominant pathologic features of this disease, therefore, are
organ and tissue dysfunction related to decreased perfusion and
subsequent impaired oxygen delivery from severely damaged medium-sized
vessels. Common manifestations of this condition include infarction of
nerve trunks (eg, mononeuritis multiplex), bowel ischemia (eg, mesenteric
insufficiency causing abdominal angina), kidney ischemia (eg, renal
insufficiency), and deep cutaneous ulcerations. The different vasculitic
syndromes, therefore, express unique phenotypes, clinical symptoms
and signs, and pathologic features reflecting their distinct underlying
- 9. In what two immunologic settings
does immune complex vasculitis occur?
- 10. What are the three most prominent
organ systems affected by immune complex vasculitis? Describe the
typical manifestations in each.
- 11. What three physical properties determine
whether immune complexes will be deposited in vessel walls?
- 12. What happens once subendothelial
deposition has occurred?
- 13. Why does pathogenicity of immune
complexes generally decrease as antibody titers rise?
SLE is the prototypic systemic autoimmune rheumatic disease,
characterized by chronic inflammatory injury to, and subsequent
damage of, multiple organ systems. A key feature of this disease
is the unique adaptive immune response, driven by antigens contained
in self tissues, which is apparently responsible for much of the
widespread pathologic consequences of the disease. Clinically, SLE
is episodic in nature, with a course characterized by flares and
remissions. It is also highly variable in severity, ranging from
mild to life threatening. Tissues frequently affected include the
skin, joints, kidneys, blood cell lines, serosal surfaces, and brain.
The prevalence of SLE is approximately 30 cases per 100,000 in
the general population in the United States. It occurs about nine
times more frequently in women than in men and is most prevalent
in blacks. Prevalence estimates rise to approximately 1 in 250 young
African American women.
SLE is a complex disease because of an interplay between inherited
susceptibilities (more than 20 different genetic loci are implicated)
and poorly defined environmental factors. Genetic deficiencies of
the proximal components of the classic complement pathway (eg, C1q,
C1r, C1s, C4), although rare in most populations, are the strongest
known risk factors defined for the development of lupus. Studies
have demonstrated that the classic complement pathway is required
for the efficient noninflammatory clearance of apoptotic cells by
macrophages. The development of lupus in individuals with these deficiencies may relate
to impaired clearance of apoptotic cells in this setting, with proinflammatory
consequences (see later discussion). The mechanisms whereby environmental
factors (eg, drugs, viral infections) function to initiate or propagate SLE
are not yet well understood.
It is useful to view the pathogenesis of SLE in discrete phases even
though these phases are not clearly separable clinically. Indeed,
it is likely that events underlying initiation occur before the
onset of clinically defined disease, which requires chronic amplification
of the propagation phase to become clinically apparent.
The exuberant autoantibody response in lupus targets a highly specific
group of self-antigens (Table 24–3).
Although this group of autoantigens does not share common features
(eg, structure, distribution, or function) in healthy cells, these
molecules are unified during apoptotic cell death, when they become
clustered and structurally modified in apoptotic surface blebs (Figure 24–4). Indeed, studies suggest
that the initiating event in lupus is a unique form of apoptotic
cell death that occurs in a proimmune context (eg, viral infection).
Several environmental exposures have been persuasively associated
with disease initiation in SLE. These include sunlight exposure
(associated with both disease onset and flares), viral infection (Epstein-Barr
virus exposure is strongly associated with SLE in children), and
certain drugs. These are agents to which humans are commonly exposed,
suggesting that those individuals who develop SLE have underlying
abnormalities that render them particularly susceptible to disease
Table 24–3 Autoantigens in Systemic
Lupus Erythematosus. |Favorite Table|Download (.pdf)
Table 24–3 Autoantigens in Systemic
|Nuclear||Nucleosomes (dsDNA and histone core)|
|Ro (60 kDa)|
|Cytoplasmic||Ribosomal protein P|
|Ro (52 kDa)|
|Membrane associated||Anionic phospholipids or phospholipid-binding proteins|
Although sharing no features in healthy cells, autoantigens
become unified in apoptotic cells. Here, they become clustered at
the surface of the apoptotic cells, and this structure is modified.
A critical susceptibility defect for the development and propagation
of SLE appears to be impairment of normal clearance of apoptotic
cells in tissues. Thus, in normal individuals, the fate of most
apoptotic cells is rapid and efficient phagocytosis by macrophages,
and antigens ingested in this way are rapidly degraded. Furthermore,
phagocytosis of apoptotic cells inhibits secretion of proinflammatory
cytokines from macrophages and induces secretion of several anti-inflammatory
cytokines, contributing to the impaired ability of apoptotic cells
to initiate a primary immune response. Last, the avid phagocytosis
of apoptotic cells by normal macrophages prevents significant numbers
from accessing dendritic cell populations, which are highly efficient
initiators of primary immune responses. Together, these factors
ensure that normal individuals do not efficiently immunize themselves
with apoptotic material derived from their own tissues. In contrast, impaired
clearance of apoptotic cells is observed in a subgroup of patients
with SLE. Under conditions in which apoptotic material is not efficiently
cleared by macrophages (eg, in C1q deficiency), suprathreshold amounts
of this material may gain access to potent antigen-presenting cell
populations under proimmune conditions and initiate a response to
molecules whose structure has been modified during delayed apoptotic
Autoantibodies in lupus can cause tissue injury by a variety
The most common pathogenic mechanism is generation and
deposition of immune complexes, in which antigen is derived from
damaged and dying cells. When the concentration and size of the
relevant complexes favor subendothelial deposition, these markedly
proinflammatory complexes initiate inflammatory effector functions
that result in tissue damage (see prior discussion). Of particular
importance is the ability of immune complexes to ligate the Fcγ receptor, which
activates myelomonocytic cell effector functions. The deposition
of immune complexes in the kidney, joints, and skin underlies several
of the central clinical features of SLE.
Autoantibodies bind to extracellular molecules in the target
organs and activate inflammatory effector functions at that site,
with consequent tissue damage. Examples of this phenomenon include
autoimmune hemolytic anemia and thrombocytopenia as well as the
photosensitive skin disease of the neonatal lupus syndrome (see
Autoantibodies directly induce cell death by ligating cell surface
molecules or by penetrating into living cells and exerting functional
It is important to note that the intracellular antigens that drive
the immune response in SLE can be derived from damaged or apoptotic
cells. Such damage or apoptosis occurs commonly in the course of
immune effector pathways. Thus, these effector pathways can generate
additional antigen, further stimulating the immune system and generating
still more antigen. This autoamplification is a central feature
of the propagation phase of lupus.
Type I interferons have recently been shown to play a central role
in amplification pathways in SLE, with clear evidence of increased
type I interferon activity during active disease. Type I interferons
induce the differentiation of monocytes into potent antigen-presenting
dendritic cells. Additionally, type I interferons enhance signaling
through toll-like receptors (TLRs), specifically increasing the
pro-inflammatory signaling of SLE antigens containing nucleic acids
through TLR 3, 7, and 9. Additionally, type I interferons sensitize
target cells to death through various inflammatory effector pathways,
increasing the antigen load presented to the immune system.
One of the characteristic features of an immune response is the establishment
of immunologic memory, so that when the organism again encounters
the antigen the immune system responds more rapidly and vigorously
to lower concentrations than were required to elicit the primary
response. Flares in SLE appear to reflect immunologic memory, occurring
in response to rechallenge of the primed immune system with antigen.
Apoptosis not only occurs during cell development and homeostasis
(particularly of hematopoietic and epithelial cells) but also in many
disease states. Thus, numerous stimuli (eg, ultraviolet light exposure,
viral infection, endometrial and breast epithelial involution) may
conceivably provoke disease flares.
SLE is a multisystem autoimmune disease that affects predominantly
women during the childbearing years (mean age at diagnosis is 30
years). It is characterized clinically by periodicity, and the numerous
exacerbations that occur over the years are termed flares. The symptoms
are highly variable but tend to be stereotyped in a given individual
(ie, the prominent clinical features often remain constant over
years). Production of specific autoantibodies is a universal feature.
Several organ systems are frequently affected. Prominent among these
is the skin, in which photosensitivity and a variety of SLE-specific skin
rashes (including a rash over the malar region, discoid pigmentary
changes to the external ear, and erythema over the dorsum of fingers)
are common. Like those who have other immune complex–mediated
diseases, patients with SLE may manifest a nonerosive symmetric
polyarthritis. Renal disease, which takes the form of a spectrum
of glomerulonephritides, is a frequent major cause of morbidity
and mortality. Patients may manifest a variety of hematologic symptoms
(including hemolytic anemia, thrombocytopenia, and leukopenia),
inflammation of serosal surfaces (including pleuritic and pericarditic
chest pain), as well as several neurologic syndromes (eg, seizures,
organic brain syndrome).
An intriguing neonatal SLE syndrome occurs in the offspring of
mothers who have antibodies directed against the Ro, La, or U1-RNP
proteins. In this condition, passive transfer of maternal autoantibodies
across the placenta results in congenital heart block and photosensitivity
in the neonate as a result of antibody-associated destruction of
developing tissues such as cardiac conduction system and skin cells
that transiently express these antigens.
Sjögren’s syndrome is a prevalent and slowly
progressive autoimmune rheumatic disorder in which the exocrine
glands are the primary target tissue. Affected individuals frequently
manifest intense dryness of their eyes (xerophthalmia) and mouth (xerostomia),
giving rise to the alternate name keratoconjunctivitis sicca. Histologically,
an intense mononuclear inflammatory infiltrate is observed in affected
lacrimal and salivary glands. Like other autoimmune rheumatic diseases,
prominent polyclonal hypergammaglobulinemia and high-titer levels
of characteristic autoantibodies are frequent features of the syndrome.
Sjögren’s syndrome occurs in approximately
1–3% of the adult population. As with SLE, the
prevalence is about nine times more frequent in women than men.
The prototypic affected individual is a woman in the fourth or fifth
decade of life. Sjögren’s syndrome occurs as both
a primary disorder and as a secondary process, in the context of
another well-defined autoimmune rheumatic disorder (especially SLE
and rheumatoid arthritis).
Viruses have been implicated in the development of Sjögren’s syndrome
but conclusive data are lacking. Epithelial cells in salivary glands
can be infected by a number of viral pathogens (including Epstein-Barr
virus, cytomegalovirus, hepatitis C, HIV, and coxsackievirus). In
an autoimmune mouse model, CMV infection leads to initial infection
of salivary glands, followed later by autoimmune salivary gland
inflammation. Whether a similar process occurs during initiation
of the human disease is not yet known.
Although the cause of Sjögren’s syndrome remains
unclear, several pathways have been implicated in pathogenesis.
Central among these is autoimmunity to epithelial tissues, with
an immune response directed against several ubiquitously expressed
antigens (eg, Fodrin, Ro, and La) as well as to some antigens expressed
specifically in secretory epithelial cells (eg, type 3 muscarinic
acetylcholine receptors [M3R]). The antibodies
to M3R are believed to prevent stimulated secretion of saliva and
tears and may be important generators of the hyposecretion that
characterizes the disease. In addition, exocrine tissues are also
infiltrated with activated cytotoxic lymphocytes, which induce death
of duct and acinar epithelium, with progressive loss of functioning
salivary tissue. The enrichment of HLA-DR3 in patients with Sjögren’s
syndrome may reflect the enhanced ability of these molecules to
present peptides contained within the pathogenic autoantigens.
The most prominent presenting symptoms in Sjögren’s
syndrome are ocular and oral dryness. Intense xerophthalmia (ocular
dryness) may express itself as eye irritation, with a foreign body
sensation or with pain. Such impairment in tear production heightens
the risk for corneal ulcer or perforation.
Impaired production of saliva, at rest and with stimulation when
eating, contributes to the prominent symptom of xerostomia (dry
mouth). Affected persons often relate difficulty in swallowing dry
foods or in speaking at length. An altered sensation of taste or
of oral burning may occur. Characteristically, individuals affected
by Sjögren’s syndrome are susceptible to new-onset
and severe dental caries at the gum line in mid-adult life. This
reflects the loss of the essential antibacterial functions of saliva,
with consequent excessive concentration of bacteria at dental surfaces.
Other epithelial surfaces may be similarly affected by diminished
secretions and contribute to dryness. For example, patients may
complain of skin and vaginal dryness. Dryness in the respiratory
tract may give rise to hoarseness and recurrent bronchitis. (It
is noteworthy that when immune activation is severe, patients experience
systemic symptoms, including fatigue, arthralgia, myalgia, and low-grade
fever.) Other potentially affected organ systems include the kidneys, lungs,
joints, and liver (resulting in interstitial nephritis, interstitial
pneumonitis, nonerosive polyarthritis, and intrahepatic bile duct
inflammation). As many as half of the affected individuals experience
autoimmune thyroid disease. Those patients with particularly severe
disease are at increased risk for cutaneousvasculitis (including
palpable purpura and skin ulceration) and lymphoproliferative disorders.
Current therapy is aimed primarily at symptomatic improvement.
Available agents include artificial tears, which serve as topical
lubricants to aid with eye dryness. Maintaining oral hydration,
with access to a regular supply of beverages, is encouraged. Use
of sugar-free gum and lozenges may stimulate salivary flow. More
recently, new cholinergic agonists have come to market aimed at
improving oral hydration by stimulating increased salivary production,
via muscarinic receptors, in affected submandibular salivary glands.
Effective anti-inflammatory and immunosuppressive treatment for
Sjögren’s syndrome has not yet been found, indicating
that the components of the critical amplification loops have not
yet been discovered. For those affected by severe disease sequelae (including
systemic vasculitis and mononeuritis multiplex), administration
of systemic immunosuppression is necessary.
The inflammatory myopathies—polymyositis and dermatomyositis—are
characterized by the gradual development of progressive motor weakness
affecting the arms and legs, as well as the trunk, in association
with histologic evidence of muscle inflammation. While such inflammation
predominantly involves striated muscle, it is important to recognize that
smooth muscle and even cardiac muscle may similarly, though less
commonly, be affected. Often, the afflicted patient experiences
increasing difficulty when rising from a seated position, in getting
out of bed, or in ascending a flight of stairs. It may become increasingly
difficult to reach up and lift dishes from an upper shelf or to
even brush one’s hair.
At the most severe end of the disease spectrum, affected persons
may develop profound impairment in swallowing solid foods and in
full lung expansion, arising from pathologic involvement of visceral
muscle affecting the esophageal and diaphragmatic muscle tissues,
respectively. These disease manifestations may result in nasal regurgitation
of swallowed liquid beverages and in profound respiratory compromise.
There is also a predilection for extramuscular involvement to occur, including
of the lung parenchyma (interstitial pulmonary fibrosis) and peripheral
joints (inflammatory polyarthritis), and in those with dermatomyositis,
mild, moderate, or even severe inflammation of the integument. At
the same time, diplopia (double vision, resulting from a paretic
ocular muscle) is distinctly uncommon in these two myositis disorders.
The inflammatory myopathies are relatively rare disorders. Polymyositis
has been estimated to occur with an annual incidence rate of approximately
5 cases per million. Women are affected twice as often as men. Interestingly,
dermatomyositis has a bimodal distribution in terms of age at onset;
the first peak occurs in childhood, and the second peak occurs in
mid and late adult life. Of note, polymyositis may clearly occur
as a primary disorder in and of itself. However, the polymyositis phenotype
may also occur as a secondary process, but when present in the context
of another well-defined autoimmune rheumatic disorder, such as systemic
lupus erythematosus, it is otherwise clinically and histologically
Autoantibodies are present in approximately 60% of all
patients with an inflammatory myositis. Two best examples are both
anti Jo-1 antibodies (that target histidyl tRNA synthetase), which
are found in approximately 20% of all patients with myositis
and in approximately 70% of patients with a myositis/interstitial
lung disease overlap syndrome, and anti-Mi-2 antibodies (that target
CHD4, a DNA binding protein), which are specific to dermatomyositis.
Since both nuclear and cytoplasmic antigens are targeted for an
immune response in these diseases, both antinuclear antibodies (ANA)
and anticytoplasmic antibodies (ANCA) can be found.
Recent studies suggest that one source of these autoantigens is
the regenerating muscle cell itself, which expresses higher levels
of myositis autoantigens than its normal counterpart. Some tumor
cells also express these same antigens at high levels. An intriguing
pathophysiologic hypothesis is that the immune response that targets
similar antigens in both tumor and inflamed muscle cells might be
responsible for the link between inflammatory myositis and malignancy.
Polymyositis and dermatomyositis share several similar pathologic
features but possess distinct ones as well. These include patchy
involvement, presence of inflammatory infiltrates, and areas of
muscle damage and regeneration. In polymyositis, inflammation is
located around individual muscle fibers (“perimysial”),
and the infiltrate is T-cell (CD8+>CD4+) and macrophage
predominant. It has been suggested that the inflammation seen in
polymyositis is driven by autoantigens expressed in the muscle environment,
given the restricted T-cell repertoire in both circulating and muscle-infiltrating
lymphocytes. Proinflammatory cytokines may induce a striking upregulation
of MHC class I molecules seen on affected muscle cells but not adjacent
normal myocytes. This MHC class I upregulation may lead to muscle
damage through antigen-specific interactions with infiltrating CD8+ T
cells, or through indirect mechanisms, by triggering a cell-damaging unfolded
protein response (“UPR” or “ER stress”)
in the muscle itself. Further damage occurs when infiltrating T
cells degranulate and release perforin and proteolytic granzymes
at specific sites of contact within the affected muscle.
In dermatomyositis, the pathology looks quite different, although
the outcome—profound muscle weakness—is the same.
The major pathologic hallmarks of this condition include atrophy
at the periphery of muscle bundles (“perifascicular atrophy”),
and a predominantly B-cell and CD4+ T-cell infiltrate localized
to the perifascicular space and surrounding capillaries (which are
reduced in number). Activation of the complement cascade is seen
as well. Major involvement of the capillaries has led many experts
to suggest that the primary disorder in dermatomyositis is a small-vessel vasculitis,
with myositis occurring later as a result of tissue ischemia and
repair. The characteristic skin and nailfold capillary changes seen
in patients with dermatomyositis lend support to this notion.
The inflammatory myopathies characteristically begin over a number
of weeks to a few months. The hallmark symptom of both polymyositis
and dermatomyositis is weakness. This characteristically involves
the upper and lower extremities and is predominantly proximal rather
than distal in location. While muscle pain or myalgia may be present,
weakness is the predominant symptom. Routine daily activities that
one might otherwise take for granted can become quite a chore, or even
an impossible ordeal, to perform. Examples include standing up from
a chair or toilet seat. In addition, the cutaneous features of dermatomyositis
can be quite debilitating and include a painful, burning sensation
of affected skin, as well as skin cracking and even breakdown with
There are four characteristic criteria for the diagnosis of polymyositis,
which are: (1) weakness, (2) elevated laboratory parameters of muscle
tissue (eg, creatine phosphokinase or aldolase), (3) an irritable
electromyogram upon electrodiagnostic evaluation (producing sharp
waves, spontaneous discharges), and (4) an inflammatory infiltrate
upon histologic evaluation. In patients with dermatomyositis, a
fifth criterion is a characteristic skin rash. Erythematous and/or
violaceous discoloration may occur periorbitally or in a V-neck
distribution on the trunk. These prototypic skin changes are termed periorbital
heliotrope and shawl signs, respectively. Erythematous scaly eruptions
may also occur over the extensor surface of the metacarpophalangeal
(MCP) and proximal interphalangeal (PIP) joints and are termed Gottron’s
sign. Extensive sheets of muscle and soft tissue calcification may
occur in children beset with dermatomyositis. Though recent efforts
to modify the original diagnostic criteria, by integration of newer imaging
modalities, including magnetic resonance imaging, or use of newer
autoantibodies with specificities for the inflammatory myopathies
have been proposed, the original criteria remain the foundation
for these two muscle disorders.
An important additional clinical feature of the inflammatory
myopathies has been the finding of an association with cancer in
multiple demographic groups and among diverse populations. In adult
patients, the new diagnosis of an inflammatory myopathy not infrequently
heralds the co-occurrence or subsequent development within 1–5
years of a malignancy. The veracity of this observation has been
confirmed in several population-based studies that link the diagnoses
of dermatomyositis and polymyositis with cancer in cancer registries.
A diagnosis of dermatomyositis carries a 2-fold greater risk of incident
malignancy, particularly stomach, lung, breast, colon, and ovarian
Corticosteroids are the front-line therapy for the inflammatory
myopathies and are often required in high doses, for an extended
period of time, to bring the marked inflammation in affected muscle
tissues under control and to restore the patient’s full
functional capacity. Therefore, careful review of the clinical and
histologic evidence supporting the diagnosis of an inflammatory
myopathy is indicated in order to be confident that the potential
drug-associated toxicity to which the patient is being exposed is
warranted. In addition, the clinician also must recognize that a
subset of treatment-refractory patients with presumed polymyositis
may in fact be cases of a toxic myopathy (ie, related to the use
of colchicines or a statin) or be attributable to a different myopathy
(eg, inclusion body myositis). Second-line immunosuppressive agents
integrated into treatment algorithms for the inflammatory myopathies include
methotrexate, mycophenolate mofetil, intravenous immunoglobulin,
Rheumatoid arthritis is a chronic systemic inflammatory disease
characterized by persistent symmetric inflammation of multiple peripheral
joints. It is one of the most common inflammatory rheumatic diseases
and is characterized by the development of a chronic inflammatory
proliferation of the synovial linings of diarthrodial joints, which
leads to aggressive cartilage destruction and progressive bony erosions.
Untreated, rheumatoid arthritis often leads to progressive joint destruction,
disability, and premature death.
The prevalence of rheumatoid arthritis in the United States is approximately
1% in the general population; similar prevalence rates
have been observed worldwide. The disorder occurs approximately
three times more frequently in women than in men and has its peak
onset in the fifth to sixth decade of life.
Like SLE, rheumatoid arthritis is a systemic autoimmune disease
in which abnormal activation of B cells, T cells, and innate immune
effectors occurs. In contrast to SLE, the majority of inflammatory
activity in rheumatoid arthritis occurs in the joint synovium. Although
the cause of rheumatoid arthritis is unknown, a complex set of genetic
and environmental factors appears to contribute to disease susceptibility.
Because the incidence of rheumatoid arthritis has been observed
to be similar in many cultures and geographic regions across the
globe, it is assumed that the environmental exposures that provoke rheumatoid
arthritis must be widely distributed. Early rheumatoid arthritis
is closely mimicked by transient inflammatory arthritis provoked
by several microbial pathogens. Thus, although a role for infection
in the development of rheumatoid arthritis has long been postulated,
it is not yet satisfactorily proven. Specific class II MHCalleles
(HLA-DR4), sharing a consensus QKRAA motif in the peptide-binding
groove, have been highly related to disease susceptibility and to
greater severity of rheumatoid arthritis.
Much of the pathologic damage that characterizes rheumatoid arthritis
is centered around the synovial linings of joints. Normal synovium
is composed of a thin cellular lining (one to three cell layers
thick) and an underlying interstitium, which contains blood vessels
but few cells. The synovium normally provides nutrients and lubrication
to adjacent articular cartilage. Rheumatoid arthritis synovium,
in contrast, is markedly abnormal, with a greatly expanded lining
layer (8–10 cells thick) composed of activated cells and
a highly inflammatory interstitium replete with B cells, T cells,
and macrophages and vascular changes (including thrombosis and neovascularization).
At sites where synovium and articular cartilage are contiguous,
rheumatoid arthritis synovial tissue (called pannus) invades and
destroys adjacent cartilage and bone.
Although the causes of rheumatoid arthritis remain unclear, several
important components of pathogenesis have been identified. As discussed
previously, it is useful to separate the initiating and propagating
phases of the disease and to recognize that the established rheumatoid
arthritis phenotype reflects a self-sustaining and amplified inflammatory
Concordance rates in twins vary between 15% and 35%,
implicating genetic factors in the pathogenesis of rheumatoid arthritis.
The most striking of these genetic factors defined to date involves
a specific subset of MHC class II alleles whose presence appears
to predominantly determine disease severity (patients homozygous
for disease-associated alleles have the most severe disease). These
MHC molecules function as antigen-presenting scaffolds, which present
peptides to CD4 T cells. Disease-associated alleles (belonging to
HLA-DR4/DR1 serotypes) share a sequence along their antigen-presenting
groove, termed the “shared epitope.” It has been
postulated that these alleles present critical antigens to the T
cells, which play a role in initiating and driving progression of
this disease. However, no specific antigens have yet been identified.
Recent high-throughput genomewide genetic association studies have
identified several new genetic risk factors for the development
of RA. These genes (ie, PADI4, PTPN22, CTLA4, STAT4, and
others) are involved in generating and propagating inflammatory
responses and possibly autoantibody production as well.
Environmental and infectious factors—Although
numerous bacterial and viral pathogens have been investigated as
perhaps having a role in the initiation of rheumatoid arthritis,
scrutiny has failed to identify a role for any specific infectious
cause. It is conceivable that any of several different infectious
agents might be able to induce non-pathogen-specific changes in
the joint that are associated with disease initiation in susceptible
Autoimmunity—There is significant evidence
supporting a role for autoimmunity in generating the rheumatoid arthritis
phenotype, including the presence of antigen-driven autoantibodies
such as IgG rheumatoid factors and anti-cyclic citrullinated peptide
(anti-CCP) antibodies. Anti-CCP antibodies, in particular, are highly
specific for RA and, as with the autoantibodies seen in SLE, can
appear several years prior to the onset of disease. They appear
to be a marker of a more destructive and aggressive RA phenotype,
and their titers may be modulated by disease activity. The reasons
these citrullinated peptides are targeted in RA are unknown, but
potential explanations include an increase in a member of the peptidyl
arginine deiminase family of enzymes (PADI, the enzymes that mediate
the conversion of arginine to citrulline) activity in synovial tissue
or altered activity of these enzymes due to genetic polymorphisms.
Cytokine elaboration in rheumatoid arthritis is markedly TH1
biased. Although the cytokine profile in rheumatoid arthritis synovium
is highly complex, with numerous pro-inflammatory and anti-inflammatory
cytokines expressed simultaneously (eg, TNF, IL-1, IL-6, granulocyte-macrophage colony-stimulating
factor [GM-CSF]), studies have persuasively demonstrated
that TNF is an important upstream principle in the propagation of
the rheumatoid arthritis inflammatory lesion (see later). Thus,
when pathways downstream of TNF are inhibited with soluble TNF receptors
or monoclonal antibodies to TNF, a rapid and markedly beneficial
effect on the inflammatory synovitis and overall state of well-being
is noted in many patients. Interestingly, the effects of anti-TNF
therapy were limited to the duration of therapy, and symptoms and
signs of inflammation returned rapidly on discontinuation of therapy.
Recent data also implicate TH17 cells in the pathogenesis
Rheumatoid arthritis is most typically a persistent, progressive disease
presenting in women in the middle years of life. Fatigue and joint
inflammation, characterized by pain, swelling, warmth, and morning
stiffness, are hallmarks of the disease. Almost invariably, multiple
small and large synovial joints are affected on both the right and
left sides of the body in a symmetric distribution. Involvement
of the small joints of the hands, wrists, and feet as well as the
larger peripheral joints, including the hips, knees, shoulders,
and elbows, is typical. Involved joints are demineralized, and joint
cartilage and juxtaarticular bone are eroded by the synovial inflammation, inducing
joint deformities. Although the lower spine is spared, cervical
involvement can also occur, potentially leading to spinal instability.
In highly active cases, extraarticular manifestations can occur.
These include lung nodules, subcutaneous “rheumatoid” nodules
(typically present over extensor surfaces), ocular inflammation
(including scleritis), or small-vessel vasculitis.
Prompt and aggressive treatment to control inflammation in rheumatoid
arthritis can slow or even stop progressive joint erosion. A number
of immunomodulatory medications have shown benefit in treating rheumatoid
arthritis. The primary pathway through which methotrexate—the
drug most commonly used as single-agent therapy for rheumatoid arthritis—acts
to diminish joint inflammation is still debated. One hypothesis
suggests that methotrexate induces increased local release of adenosine,
a short-acting anti-inflammatory mediator.
Rheumatoid arthritis is one of the first conditions in which biologic
modifiers of defined pathogenic pathways such as anti-TNF therapy
have been used successfully to treat disease. Inhibitors of TNF
(etanercept, infliximab, and adalimumab) act by sequestering TNF,
either to a recombinant soluble form of the TNF receptor (etanercept)
or to monoclonal antibodies to TNF (infliximab, adalimumab). Although
these agents have a high likelihood of achieving benefit in patients
with rheumatoid arthritis, their use is still limited by their high cost
and the potential risks of drug-associated toxicity (including susceptibility
to life-threatening infections and induction of other autoimmune
syndromes). Furthermore, although they are among the most potent
agents yet described for the control of rheumatoid arthritis, there
remain patients who fail to experience disease remission when treated
only with TNF blockade. As a general principle of therapy in rheumatoid
arthritis, it appears that using multiple agents with (presumably)
different and complementary mechanisms of action can lead to additional
benefit. T-cell–B-cell–APC interactions clearly
play important roles in the propagation phase of RA, and it is therefore
not surprising that additional biological agents have also shown
efficacy in the treatment of RA, including agents that inhibit B
cells (eg, rituximab) and costimulation (eg, CTLA4-Ig).
- 14. What are the antigens against
which antibodies are directed in SLE?
- 15. How many different genetic loci
are believed to confer susceptibility to SLE? Which are the strongest
- 16. What is believed to be the relationship
of apoptosis to the initiation of SLE?
- 17. What prevents normal individuals
from being immunized to apoptotic cell debris, and why does this
host defense break down in patients with SLE?
- 18. What are three stimuli that typically
provoke SLE flares?
- 19. What are the most prominently affected
organ systems in SLE?
A 58-year-old man with a long
history of treated essential hypertension and mild renal insufficiency
presents to the urgent care clinic complaining of pain in the right
knee. His primary care provider saw him 1 week ago and added a thiazide diuretic
to improve his blood pressure control. He had been feeling well
until the night before the clinic visit, when he noted some redness
and slight swelling of his knee. He went to sleep and was awakened
early by significant swelling and pain. He was able to walk only
with assistance. He has no history of knee trauma.
examination confirmed the presence of a swollen right knee, which
was erythematous and warm. Joint aspiration recovered copious dark
yellow, cloudy synovial fluid. Microscopic analysis demonstrated
30,000 leukocytes/μL, a negative Gram
stain, and many needle-like, negatively birefringent crystals consistent
with acute gout.
A. What factors may have
precipitated this gout flare?
A. Gout flares are typically precipitated
by a combination of metabolic and physical stressors in the setting
of either urate underexcretion, seen in the vast majority of cases,
or urate overproduction. The mild renal insufficiency may be associated
with a decreased glomerular filtration rate and thus poor urate
excretion. The recent addition of a diuretic further exacerbated
this underlying impairment.
B. Describe the inflammatory
pathways involved in acute gout.
B. Multiple inflammatory pathways are
invoked by the negatively charged urate crystals. For example, they
activate the classic complement pathway whose cleavage products
serve as effective neutrophil chemoattractants. The kinin system
is stimulated by crystals as well, contributing to the inflammatory signs
seen on examination such as tenderness and erythema from local vasodilation.
In addition, macrophages phagocytose urate crystals, initiating
the release of proinflammatory cytokines (eg, IL-1 and TNF), which
activate the vascular endothelium, encouraging neutrophil adhesion
and migration. Neutrophils are able to simulate their own recruitment
by releasing leukotriene B4 in response to urate crystal phagocytosis.
C. What agents should the
urgent care physician consider in treating this gout flare? What
are their mechanisms of action?
C. Therapy for an acute gouty flare should
target the proinflammatory mediators described previously. NSAIDs
such as ibuprofen reduce prostaglandin synthesis, colchicine impairs the
migration of neutrophils into the joints, and corticosteroids deactivate
myelomonocytic cells responsible for crystal phagocytosis and subsequent
cytokine release. Because gouty flares are typically self-limited
events, treatment is offered to alleviate symptoms and reduce the
duration of the flare. On the other hand, uricosuric agents, such
as probenecid, and xanthine oxidase inhibitors, such as allopurinol,
are typically reserved for the prevention of future attacks.
A 24-year-old man presents
with a worsening rash. One week ago, he had been at an urgent care
center with a sore throat and was diagnosed with “strep
throat.” He was prescribed penicillin and had been getting
better. The day before presentation, he noted the development of
a pink rash on his trunk, and on the day of his evaluation, it spread
to his arms and legs. On examination, the patient has a symmetric
maculopapular rash covering his extremities and trunk. Some of the
lesions on his legs are palpable.
A. What is the likely cause
of this patient’s rash?
A. This patient likely has an immune
complex vasculitis. When it manifests itself in the skin, it is
also called cutaneous small vessel or leukocytoclastic vasculitis.
B. What is the underlying
pathophysiology in this case?
B. Immune complexes are generated by the
combination of an antigen and an antibody. In this case, the antigen
is the penicillin that the person has been taking regularly for
a week. The penicillin stimulated an antibody response, leading
to antibody production against, and then binding to, the penicillin. The
antigen-antibody complexes are soluble and they are deposited in
the subendothelial space, in this case, in the small vessels of
the skin. There, they trigger an inflammatory response, which causes
a rash. If the supply of new antigen is cut off (eg, by stopping
the medication), the immune complexes are cleared by the immune
system and the process resolves.
C. What other organs can
this disorder affect and why?
C. The same process can also affect the
joints and the kidneys, both areas rich in small blood vessels.
The specific organ(s) affected depend on the solubility of the specific
A 28-year-old nursery school
teacher developed a marked change in the color of her urine (“cola-colored”)
1 week after she contracted impetigo from one of her students. She
also complained of new onset of global headaches and retention of fluid
in her legs. Examination revealed a blood pressure of 158/92,
resolving honey-crusted pustules over her right face and neck, 1+ pitting
edema of her ankles, and no cardiac murmur. Urinalysis revealed
2+ protein and numerous red cells and red cell casts. Her
serum creatinine was elevated at 1.9 mg/dL. Serum complement
levels (CH50, C3, and C4) were low. She was diagnosed with poststreptococcal
A. What is the relationship
between her skin infection and the subsequent development of glomerulonephritis?
A. Poststreptococcal glomerulonephritis
results from a skin infection with a nephritogenic strain of group
A (β-hemolytic) streptococci such as type 12. The
abrupt onset of hematuria (“cola”-colored urine),
edema, and variable degrees of hypertension most commonly occur
7–14 days after streptococcal pharyngitis or impetigo and
can occur sporadically or in clusters. Significant glomerular damage
can lead to rapid progression to oliguria and acute renal failure.
B. Describe the pathogenesis
of this disorder.
B. Bacterial infections can cause glomerular
damage through the deposition of antibody-antigen complexes. Vasculitis
does not occur, however, in the setting of all infections. Rather,
subendothelial deposition of immune complexes is required to damage
highly vascularized nephrons by fixing complement (this explains
the serum levels measured) and by activating myelomonocytic cells.
Deposition of these complexes can only occur in the presence of
excess antigens to make the complexes soluble, permitting them access
to the subendothelial space and enabling them to cause injury.
C. What is the natural history
of this form of immune complex vasculitis?
C. This disorder is usually self-limited;
95% of individuals recover normal renal function within
2 months after onset. As antibody titers rise, immune complex formation
decreases, and soluble complexes are eventually cleared provided
that antigen administration is not sustained. Treatment of underlying
infectious substrates may hasten resolution of the glomerulonephritis.
A 22-year-old African-American
woman with a family history of SLE reports intermittent arthralgias
in her knees. She denies any facial rash, photosensitivity, chest
pain, or shortness of breath. She is convinced she has lupus and
requests confirmatory blood tests.
A. What additional history
may be helpful in supporting the diagnosis of lupus as the cause
of this patient’s arthralgias?
A. This patient’s suspicion
that her arthralgias may be explained by lupus is supported by a
high prevalence of SLE among African American women—approximately
1 in 250—as well as her family history of this disorder.
In fact, if a mother has SLE, her daughters’ risk of developing
the disease is 1 in 40, considerably higher than the risk in the
general population. However, to make the diagnosis with reasonable
certainty, 4 of 11 diagnostic criteria should be met, supported
by a strong clinical impression: (1) malar rash, (2) discoid rash, (3)
photosensitivity, (4) oral ulcers, (5) arthritis, (6) serositis, (7)
renal disease, (8) neurologic disease, (9) hematologic disorders
(eg, hemolytic anemia, thrombocytopenia), (10) immunologic abnormalities
(eg, antibodies to native DNA), and (11) positive anti-nuclear antibody
B. Why is it essential to
elicit a medication history when considering this diagnosis?
B. A number of drugs (eg, procainamide,
hydralazine, isoniazid) have been implicated in provoking a lupus-like
syndrome. A helpful clue in distinguishing the drug-induced form
from SLE is that withdrawal of the offending drug typically results
in improved clinical features and resolution of abnormal laboratory
C. Describe three possible
mechanisms of autoantibody-induced tissue injury in SLE.
C. These mechanisms include (1) subendothelial
deposition of immune complexes, in which antigens are derived from
damaged or dying cells; (2) autoantibody binding to extracellular molecules
in the target organs (eg, skin, joints, kidneys, blood elements),
which activates inflammatory effector functions and induces damage
at that site; and (3) induction of cell death by autoantibodies.
D. Describe the natural history
of the disease. Which stimuli have been implicated in the exacerbations
that punctuate its course?
D. The natural history of SLE is characterized
by a relapsing, remitting course. Flares reflect immunologic memory,
sparked by rechallenge of a primed immune system with antigen. Numerous
stimuli such as viral infections, ultraviolet light exposure, and
endometrial and breast epithelial involution may induce apoptosis,
which resupplies immune inciting antigens. Despite this course,
10-year survival rates commonly exceed 85%.
A 47-year-old woman presents
to the clinic with a four-week history of fatigue, bilateral hand
pain and stiffness, and hand and wrist joint swelling. About a month
before presentation, she noticed that her hands were stiffer in
the morning, but thought that it was due to too much typing. However,
the stiffness has worsened, and she now needs about an hour each
morning to “loosen up” her hands. As the day goes
on, the stiffness improves, although it does not go away entirely.
She has also noticed that her knuckles and wrists are swollen and
feel somewhat warm. Physical examination reveals warm, erythematous
wrists and metacarpal joints bilaterally. Hand x-ray films show
periarticular demineralization and erosions, and blood test results
are significant for a mild anemia, elevated sedimentation rate,
and a positive rheumatoid factor. The patient is diagnosed with
A. What is the basic pathogenic
process in rheumatoid arthritis?
A. The pathophysiology of rheumatoid
arthritis is centered around the synovial linings of joints. The
normal synovium is one to three cell layers thick. In rheumatoid
arthritis, the synovium is markedly thickened and contains inflammatory
cells in the interstitium, including T cells, B cells, and macrophages. This
inflammatory tissue can invade adjacent bone and cartilage, accounting
for the bony erosions and joint destruction.
B. Describe the interplay
between genetic and environmental factors that leads to the pathogenic
B. Rheumatoid arthritis is thought to
arise when an environmental factor (such as an infection) triggers
an autoimmune response to antigens present in the synovium and elsewhere
in the body. However, the specifics have not been identified. No definite
infectious agents have been identified as causal agents in rheumatoid
arthritis. The autoimmune mechanisms involved in the triggering
and maintenance of the rheumatoid inflammatory response have also
not been definitively identified, although tumor necrosis factor
(TNF) plays a central role. Genetic factors have been found, arising
from the observation that twins have a 15–35% concordance
rate of developing rheumatoid arthritis. A specific subset of MHC
class II alleles have been found that determine disease severity.
C. How are novel treatments
being used to treat this condition?
C. For many years, the mainstay of treatment
for rheumatoid arthritis involved nonspecific immunosuppressant
agents. With the recognition of the central role of TNF in the autoimmune
response in rheumatoid arthritis, TNF inhibitors have found widespread
use in its treatment. These inhibitors sequester TNF so that it
cannot maintain the inflammatory response. They either are soluble
TNF receptors or monoclonal antibodies that bind the free TNF and
clear it from the body.