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pathogenesis is extremely variable, ranging from
cases that do not require treatment to severe, lifethreatening cases. Anti-double-stranded DNA
antibodies and anti-Sm antibodies are diseasespecic antibodies, and complications of renal
lesions affect the prognosis.
2.1.2 Pathophysiology
The basis of the pathogenesis of SLE is an autoimmune phenomenon centered on B cell hyperactivation. Inammation and tissue damage are
caused by the persistent activation of lymphocytes
due to the acquisition of tolerance of T cells and B
cells that recognize self-antigens and the dysfunction of regulatory T cells. Activated B cells produce an excessive amount of autoantibodies, such
as anti-DNA antibodies, and the immune complexes formed by binding with self- antigens are
deposited in tissues, activating the complement
system and causing persistent inammation.
2.1.3 Epidemiology
The age of onset is 20 to 40years, with those in
their 20s accounting for 40% of all cases. The
male-to-female ratio is approximately 1:20, with
females being overwhelmingly affected. The
prevalence in Japan is estimated to be about 100
per 100,000 people.
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Fig. 15.7 Buttery rash of systemic lupus
erythematosus
2.1.4 Symptoms
1. Mucocutaneous manifestations: The most
characteristic eruption in SLE is erythema of
the cheeks, which is also called buttery rush
because of the shape of the eruption. This
edematous erythema often appears as the rst
symptom of SLE and is found almost symmetrically on both cheeks, centered on the
dorsum of nose, with healthy skin remaining
inside the nasolabial sulcus (Fig. 15.7). The
other specic eruption is erythema with keratotic scales, which is called discoid erythema,
and is found on the exposed areas of the head,
face, auricles, and dorsum of the ngers.
Raynaud’s phenomenon, in which the ngers
and toes show a triphasic color change of
white, purple, and red, and alopecia may also
occur. Oral ulcers are also frequently seen, but
they are characterized by being painless and
located on the hard palate (Fig.15.8).
Fig. 15.8 Oral ulceration in systemic lupus
erythematosus
2. Bone and joint symptoms: Arthritis with
joint swelling, heat sensation, and pain may
occur. Joint deformity may occur with laxity
of periarticular tissues, but unlike arthritis of
rheumatoid arthritis (RA), it is nondestructive
and can generally be temporarily corrected by
passive reposition (Jaccoud’s arthropathy).
Aseptic necrosis of bone may occur in patients
with SLE treated with corticosteroids, and the
femur head is the most common site of
necrosis.
3. Respiratory and cardiovascular symptoms:
Aseptic pleurisy and pericarditis may occur,
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accompanied by chest pain, dyspnea, and
fever. When myocarditis occurs, nonspecic
ST-T changes and arrhythmias appear on the
electrocardiogram. In the pulmonary parenchyma, interstitial pneumonia and alveolar
hemorrhage may appear during the active
phase of the disease. Pulmonary arterial hypertension (PAH) may also occur, and is an
important factor in determining the prognosis.
4. Renal manifestations: The nephropathy
associated with SLE is known as lupus nephritis and is present in about half of all patients
with SLE.Proteinuria, erythrocyturia, leukocyturia, and cylindruria occur early in the
course of the disease, leading to nephrotic
syndrome and renal failure as the disease progresses. In some cases, dialysis may eventually be required.
5. Neuropsychiatric symptoms:
Neuropsychiatric lupus (NPSLE) is a disorder
of the nervous and mental systems associated
with SLE. Neuropathy is diverse and can
manifest as central, peripheral, or autonomic
symptoms.
6. Gastrointestinal symptoms: Peritonitis may
occur, resulting in abdominal pain and ascites.
Vasculitis of the mesenteric artery causes
intestinal ischemia, which may lead to infarction, ulceration, and hemorrhage of the intestine. It may also cause intestinal obstruction
(lupus enteritis).
2.1.5 Clinical Examination
1. Inammation reaction: In the active stage of
SLE, the erythrocyte sedimentation rate and
serum gammaglobulin are increased, but there
is usually no signicant increase in CRP. If
CRP is strongly positive, the presence of
arthritis, serositis, vasculitis, or infection
should be suspected.
2. Hematologic test: In the active phase of SLE,
all three blood cell systems (white blood cells,
red blood cells, and platelets) may be
decreased. Among the white blood cells, lymphocytes are mainly decreased. Autoimmune
hemolytic anemia associated with the production of autoantibodies against red blood cells
results in a marked decrease in red blood cells,
a decrease in haptoglobin levels, an increase
in indirect bilirubin, and a positive Coombs
test. The decrease in platelets is often due to
decreased platelet production or platelet
destruction in the periphery by antiplatelet
antibodies, and thrombocytopenia may also
occur in patients with anti-phospholipid antibody syndrome.
3. Immunological test: Anti-nuclear antibodies
(ANA) are positive in almost 100% of patients
with SLE. Anti-double-stranded DNA antibodies and anti-Sm antibodies are known as
disease-specic antibodies, and anti-doublestranded DNA antibodies are also used as an
indicator of disease activity. In some cases,
serum immune complexes increase and serum
complement titers decrease during the active
phase of SLE.Antibodies against cardiolipin
and lupus anticoagulant are also positive in
SLE, which tends to cause (1) arteriovenous
thrombosis, (2) habitual abortion, and (3)
thrombocytopenia, which is called antiphospholipid antibody syndrome.
4. Renal function tests and urinalysis: In
patients with lupus nephritis, urine protein is
persistently positive, and erythrocyte and leukocyte columns are seen in the active stage of
nephritis. As renal damage progresses, serum
creatinine and BUN increase, leading to renal
failure.
2.1.6 Treatment
The mainstay of treatment for SLE is corticosteroid therapy. The dosage of corticosteroids is
determined based on the following factors: (1)
disease activity, type and severity of the affected
organ, and (2) complications. Small doses of corticosteroids (<20mg/day of prednisolone equivalent) are used for mild cases such as arthritis and
rash, moderate doses (30–40mg/day of prednisolone equivalent) are used for moderate cases such
as pleurisy, pericarditis, and some thrombocytopenia, and high doses (about 60mg/day of prednisolone equivalent) are used for severe cases
such as refractory lupus nephritis, alveolar hemorrhage, and marked hemolytic anemia. In cases
where it is difcult to reduce the dose of adrenal
corticosteroids, immunosuppressive drugs should
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be used in combination. The effectiveness of
immunosuppressive drugs has been established
in the treatment of refractory lupus nephritis, and
active concomitant use of corticosteroids and
immunosuppressive drugs is considered.
2.1.7 Prognosis
The short-term prognosis of SLE is good except
in some patients with refractory disease such as
alveolar hemorrhage, but the long-term prognosis
is still poor. In order to improve the long-term
prognosis, it is necessary to establish treatment
aimed at remission of lupus nephritis and to avoid
deaths due to infectious diseases such as sepsis
resulting from immunosuppressive therapy.
2.2 Systemic Sclerosis (SSc)
2.2.1 Disease Overview
It is a connective tissue disease characterized by
brotic lesions of the skin and visceral organs
such as the esophagus, intestines, and lungs, and
peripheral circulatory disturbances such as
Raynaud’s phenomenon and digital ulcers.
2.2.2 Pathophysiology
The etiology is unknown, whereas it is considered to be an autoimmune disease because specic antibodies are detected. In patients with
SSc, activation of immunocompetent cells such
as broblasts and T cells, vascular endothelial
cell damage, and subsequent repair mechanisms
are observed in the lesions. These cells are closely
related to each other to form pathological conditions such as skin sclerosis and peripheral circulatory disorders.
SSc (lcSSc), in which the cutaneous sclerosis is
distal to the knee and elbow, and diffuse cutaneous SSc (dcSSc), in which the cutaneous sclerosis extends proximally to the knee and elbow.
The prognosis of lcSSc is generally better than
that of dcSSc, but attention should be paid to
complications of pulmonary arterial hypertension (PAH).
2.2.5 Symptoms
1. Peripheral vascular lesions: Raynaud’s phe-
nomenon is the most common initial symptom of SSc. This phenomenon is caused by
transient constriction of arteries induced by
cold exposure or mental tension, resulting in
pallor (ischemia), followed by purple (cyanosis), and ushing (recanalization) during
recovery (Fig.15.9). In cases of severe periph-
eral circulatory disturbance, intractable skin
ulceration or necrosis of the tips of the ngers
or toes may occur.
2. Skin lesions: In the early edematous stage,
the ngers become swollen rather than sclerotic (sausage-like ngers). The skin becomes
hard and shiny as the disease progresses, and
telangiectasia and pigmentation may also
occur. In dcSSc, skin sclerosis extends to the
entire body (sclerosis phase). After reaching
its peak, skin sclerosis slowly improves (atrophy phase), and in some cases it disappears
completely.
3. Joint and muscle lesions: Complications of
arthritis are observed in approximately 20%
2.2.3 Epidemiology
The number of patients in Japan is estimated to
be more than 20,000, and the male-to-female
ratio is 1:12, with the overwhelming majority
being women, and the preferred age group is 30
to 50years old.
2.2.4 Classication
SSc is classied into two types based on the
extent of cutaneous sclerosis. Limited cutaneous
Fig. 15.9 Raynaud’s phenomenon
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of patients. Inammation and brosis of the
neighboring tissue to the tendon cause
impaired tendon mobility, and joint contracture and muscle atrophy occur with the progression of skin sclerosis.
4. Oral lesions: In patients with signicant
facial skin sclerosis, sclerosis of the skin
around the mouth and impaired range of
motion of the temporomandibular joint cause
opening difculties. In addition, tongue
movement is restricted due to shortening and
thickening of the lingual frenum. Atrophy of
the oral mucosa and telangiectasia are also
observed.
5. Gastrointestinal lesions: Dysphagia,
heartburn, and nausea may occur due to
decreased peristalsis associated with sclerosis of the lower esophagus. Similar lesions
may also be seen in the small and large
intestines, and in some cases, abnormal
overgrowth of intestinal bacterium due to
decreased peristalsis in the small intestine
may result in malabsorption syndrome. In
rare cases, intestinal gas may ow into the
wall of the thinning colon or into the
abdominal cavity, causing pneumatosis cystoides intestinalis.
6. Respiratory lesions: Interstitial pulmonary
lesions are seen in about 60% of patients
with SSc, and when they progress to pulmonary brosis, they are an important prognostic complication. The initial symptoms are
dry cough and dyspnea on exertion, and progressive brosis leads to respiratory failure.
About 10% of patients with SSc have PAH,
which is also an important prognostic
complication.
7. Cardiac lesions: Not only complications of
secondary heart failure associated with pulmonary brosis and PAH, but also conduction defect and myocardial damage may
occur due to peripheral angiostenosis of
coronary arteries and brosis of myocardium itself.
8. Renal lesions: Sudden constriction of the
renal arteries causes a marked decrease in
renal blood ow and progressive renal dysfunction, called scleroderma renal crisis,
which often occurs in patients who are positive for anti-RNA polymerase III antibodies.
2.2.6 Clinical Examination
1. Blood tests: ANA is detected by immunose-
rological tests in 50% to 90% of cases.
Disease- specic antibodies such as Scl-70,
anti-centromere and anti-U1-RNP antibodies
may be found. Scl-70 antibodies are associated with dcSSc, anti-centromere and antiU1- RNP antibodies with lcSSc.
2. X-ray examination: In SSc, bone X-ray nd-
ings may include resorption of the distal phalanges of the ngers and subcutaneous
calcication. Gastrointestinal contrast radiography shows decreased peristalsis and dilatation of the lower esophagus, and plain chest
radiography shows linear and reticular shadows suggestive of interstitial lung disease.
2.2.7 Treatment
Although there is no radical treatment, symptomatic therapy is the basic treatment, and it is important to protect the ngertips from cold and to
encourage smoking cessation. For Raynaud’s
phenomenon and skin ulcers, peripheral vasodilators (calcium channel blockers, prostanoids)
are used, and for gastroesophageal reux disease
due to decreased esophageal peristalsis, antacids
(proton pump inhibitors) and prokinetic agents
(mosapride) are used. For PAH, pulmonary artery
dilators (veraprost, phosphodiesterase 5 inhibitors, endothelin receptor inhibitors) are used, and
angiotensin-converting enzyme inhibitors are
used for scleroderma renal crisis. Bosentan, an
endothelin receptor inhibitor, is used to prevent
the development of hand ulcers.
2.2.8 Prognosis
In dcSSc, skin sclerosis progresses rapidly during
the rst 3 to 5years after the onset of the disease,
but improves slowly after the peak in most cases.
In contrast, in lcSS, skin sclerosis is mild and
unchanging over a long period of time. The most
common cause of death is the progression of
interstitial lung lesions, followed by PAH, and
these lung lesions account for about half of all
deaths.
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2.3 Polymyositis/
Dermatomyositis: PM/DM
2.3.1 Disease Overview
PM is a chronic inammatory muscle disease
that causes widespread damage to striated muscle. The symptoms are muscle weakness of the
trunk, proximal muscles of the extremities, cervical muscles, and pharyngeal muscles. It is called
DM when it is accompanied by characteristic
cutaneous symptoms, such as heliotrope eruption
and Gottron’s sign, in addition to myositis symptoms. Patients with dermatomyositis, especially
the elderly, should be monitored for malignancy.
2.3.2 Pathophysiology
Although the etiology is unknown, myopathology shows inltration of mononuclear cells, such
as T cells, B cells, and macrophages, around unnecrotic myobers, and degeneration, necrosis,
and regeneration of myobers in cases with myositis. Clinically, there are two types of DM:
myositis- only PM and dermatitis-only DM.It is
considered to be an autoimmune inammatory
myopathy that develops myositis and dermatitis
at the severity of each case.
purplish- red edema or papules with hyperkeratosis and skin atrophy on the dorsal of nger
joints is called Gottron’s sign. A skin rash
resembling Gottron’s sign appearing on the
extensor surfaces of the elbows and knees is
also a characteristic skin nding of DM.
3. Respiratory symptoms: Interstitial lung
lesions are a common complication in patients
with PM/DM. The subjective symptoms are
dry cough and dyspnea on exertion, but respiratory failure occurs in some patients.
Particularly in patients with DM who have
few myositis symptoms, interstitial pneumonia progresses rapidly and can be fatal.
4. Joint symptoms: Although polyarthritis may
occur, unlike in RA, bone erosion does not
occur and, in principle, joint deformity due to
bone destruction does not occur.
5. Others: Although subjective symptoms are
rare, arrhythmias, conduction disturbances,
and abnormalities in cardiac wall motion
associated with myocarditis may be observed.
Carcinoma of the digestive organs, lungs,
mammary glands, or reproductive organs may
develop within 2 years before or after the
diagnosis of PM/DM.
2.3.3 Epidemiology
The estimated total number of patients with PM/
DM in Japan is about 17,000, and the number of
patients with PM and DM is about the same. The
ratio of males to females is 1:3, and the onset of
PM/DM peaks in the age groups of 5 to 9years
and 50years.
2.3.4 Symptoms
1. Muscular symptoms: The muscle weakness
of the trunk, proximal muscles of the extremities, neck muscles, and pharyngeal muscles
progresses slowly and symmetrically, and the
patient has difculty climbing stairs, squatting, lifting heavy objects, and raise the head
in the supine position. When the pharyngolaryngeal muscles are severely damaged, dysphagia and dysarthria appear.
2. Cutaneous manifestations: Erythema with
purplish-red edema on the eyelids is called
heliotrope eruption, and erythema with
2.3.5 Clinical Examination
1. Blood tests: The myogenic enzymes CK,
aldolase, AST, ALT, LDH, and myoglobin are
elevated in myositis. In addition, CK-MB and
cardiac troponin are elevated in the presence
of myocardial damage. Leukocytosis and elevation of C-reactive protein (CRP) may also
be observed, reecting inammation. ANA is
detected by immunoserological tests in about
80% of cases. Anti-aminoacyl-tRNA synthetase antibodies, such as anti-Jo-1 antibody, are
known as disease-specic antibodies, but their
detection rate is low (10–20%). Anti-MDA-5
antibodies are also disease-specic antibodies, and are positive in 20 to 30% of cases, and
are closely associated with rapidly progressive interstitial pneumonia, which is fatal due
to rapid progression of respiratory failure.
2. Electromyography: The appearance of resting activity such as ber-spontaneous potentials and positive sharp waves with a regular
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cycle is characteristic of muscles affected by
myositis. During contraction at any time, socalled myogenic changes, which are lowamplitude, short-duration motor unit
potentials, can be seen and are useful for
diagnosis.
3. Magnetic resonance imaging (MRI): It can
be used for qualitative diagnosis of muscle tissue, such as edema caused by inammatory
changes in muscle tissue, brosis and steatosis. MRI, which is a non-invasive examination, is useful for diagnosis and evaluation of
therapeutic effect.
4. Muscle biopsy: In muscle affected by myosi-
tis, inammatory cell inltration, degeneration and necrosis of myobers, and uneven
size of myobers can be seen, which is important for denitive diagnosis.
2.3.6 Treatment
If the symptoms are only the skin, the main
treatment is to avoid skin exposure and topical
corticosteroids should be used. For muscle
symptoms, rest is necessary during the acute
phase of the disease, but after the disease has
stabilized, rehabilitation should be performed
aggressively to restore muscle strength. For
drug therapy, high- dose corticosteroids (60mg/
day of prednisolone equivalent) are initially
administered, and the dose is gradually
decreased as the disease progresses. In cases in
which corticosteroids alone are ineffective or in
which it is difcult to reduce the dose of corticosteroids, immunosuppressive drugs should be
used in combination. High-dose gamma globulin therapy may be used for refractory myositis.
Patients with rapidly progressive interstitial
pneumonia are also treated initially with highdose corticosteroids and, in some cases, with
steroid pulse therapy using higher doses of corticosteroids administered intravenously. AntiMDA-5 antibody-positive patients are especially
susceptible to fatal interstitial pneumonia, and
should be treated with immunosuppressive
drugs.
2.3.7 Prognosis
Patients with rapidly progressive interstitial
pneumonia or malignancy have a poor prognosis.
The 5-year survival rate for all patients is about
80%, but treatment methods are improving, and
further improvement is expected in the future.
2.4 Sjögren’s Syndrome (SS)
2.4.1 Disease Overview
Chronic inammation and destruction of glandular tissue occur mainly in the lacrimal and salivary glands due to inammatory cell inltration,
and the main symptoms are dry eye due to
decreased lacrimal uid secretion and xerostomia
due to decreased salivary secretion.
2.4.2 Pathophysiology
Although the etiology is still unknown, it is
thought to be an autoimmune disease because of
the appearance of various autoantibodies, such as
anti-SS-A, anti-SS-B, and rheumatoid factor, and
hypergammaglobulinemia. Pathologically, there
is a marked mononuclear cell inltration, mainly
lymphocytes, around the conduits of salivary
glands and lacrimal gland, atrophy and disappearance of acinar tissues, and stenosis of the
lumen of the duct. This causes decreased lacrimal
and salivary secretion.
2.4.3 Epidemiology
The estimated total number of patients with SS in
Japan is about 70,000. The male to female ratio is
1:17.4, and the peak age of onset is in the 50s
and 60s.
2.4.4 Classication
SS can be divided into primary, uncomplicated by
other autoimmune diseases, and secondary, complicated by autoimmune diseases such as RA and
SLE. Primary SS can be divided into glandular
type, in which the lesions are conned to the lacrimal and salivary glands, and extraglandular type,
in which the active lesions extend to other organs.
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Fig. 15.10 Flat tongue
2.4.5 Symptoms
1. Xerostomia: The oral cavity becomes dry due
to decreased salivary secretion, and the tongue
becomes smooth due to atrophy of the tongue
papillae (Fig. 15.10). In addition, since oral
cleansing effect of saliva is reduced, tooth caries frequently occurs.
2. Ocular dryness: Decreased lacrimal uid
secretion causes dry keratoconjunctivitis,
which leads to foreign body sensation, burning sensation, and redness of the eyes.
3. Extraglandular symptoms.
(a) Arthritis: Primary SS may be complicated
by polyarthritis. However, it is rarely
accompanied by joint destruction as in RA.
(b) Lymphatic malignancies: The frequency
of malignant lymphoma is clearly higher
in SS than in normal subjects. The frequency of mucosa-associated lymphoid
tissue extranodal follicular marginal zone
lymphoma (MALT lymphoma) is also
high, especially in the salivary glands.
(c) Skin lesions: Erythema annulare,
Raynaud’s phenomenon, and purpura
associated with hypergammaglobulinemia
and cryoglobulinemia may be seen.
(d) Organ lesions: SS is often associated with
autoimmune thyroid diseases such as
chronic thyroiditis (Hashimoto’s disease)
and Graves’ disease. Although infrequent,
interstitial pneumonia may complicate
the disease, and symptoms such as cough
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and dyspnea may be observed. As a renal
lesion, tubular acidosis due to interstitial
nephritis may be a complication of renal
disease. Primary biliary cholangitis may
also occur, although it is rare. Peripheral
neuropathy is associated with sensory
disturbance and numbness.
2.4.6 Clinical Examination
1. Blood tests: High incidence of hypergamma-
globulinemia, mainly IgG, accompanied by
increased blood sedimentation, but elevated
CRP is rare. Antinuclear antibodies are
detected in 80% to 90% of patients, and antiSS- A and anti-SS-B antibodies are also often
positive, although anti-SS-B antibodies are
more specic for SS than anti-SS-A
antibodies.
2. Ophthalmologic examination: Decreased
lacrimal secretion is assessed by Schirmer’s
test (positive when tears wet the lter paper
less than 5mm in 5min), and dry keratoconjunctivitis is assessed by Rose Bengal or uorescein staining.
3. Salivary gland function tests: Decreased
salivary secretion is determined by the gum
test (chewing gum for 10min and measuring
saliva volume: positive when the volume is
less than 10mL) or the Saxon test (chewing
gauze for 2min and measuring weight gain:
positive when the weight is less than 2g). In
the past, salivary gland contrast was used to
observe structural changes in salivary
glands, but this has been discontinued
recently because of problems such as pain
and infection. Salivary gland scintigram
99m
using
TcO4 is useful for objective evaluation of salivary gland function. The accumulation in the parotid and submandibular
glands decreases reecting a decrease in
salivary gland function, and in severe salivary gland disorders, accumulation is rarely
seen.
4. Minor salivary gland biopsy and lacrimal
gland biopsy: Biopsy of the lower lip where
minor salivary glands are distributed and lacrimal gland shows lymphocytic inltration
and disruption of glandular structures around
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the conduits of salivary glands and lacrimal
gland.
2.4.7 Treatment
In the absence of serious extraglandular lesions,
symptomatic treatment is the mainstay of therapy. Although M3-type muscarinic acetylcholine
receptor stimulants are often effective in stimulating salivary secretion, they are associated with
a high incidence of hyperhidrosis and should be
started in small doses. Steroids may be used for
organ lesions such as interstitial pneumonia and
interstitial nephritis.
2.4.8 Prognosis
The prognosis is good, with few life-threatening
complications except for severe extraglandular
lesions such as severe interstitial pneumonia or
malignant lymphoma.
2.5 Mikulicz’ Disease
Mikulicz’ disease is a persistent swelling associated with inammation of the salivary and
lacrimal glands. The swollen glandular tissue
is markedly inltrated with mononuclear cells,
and it was previously thought to be a subtype
of SS.However, while typical SS is more common in women, Mikulicz disease is more common in men. Furthermore, Mikulicz’ disease
differs from SS in that the dryness is milder
and the response to corticosteroid therapy is
better, despite the marked adenopathy. Since
serum IgG4 is often elevated, and IgG4producing plasma cells are found in the lacrimal gland and salivary gland, Mikulicz’ disease
is now included in IgG4-related disease. The
organs and tissues affected by IgG4-related
diseases are shown in Table15.2.
Table 15.2 Organ/tissue lesions included in IgG4related diseases
Organ and tissue Diseases
Pancreas Autoimmune pancreatitis
Lacrimal gland/
ophthalmology
Salivary gland Sialadenitis (Mikulicz’ disease),
Arteries Inammatory aortic aneurysm,
Renal/
retroperitoneal
Prostate Prostatitis
Dural/pituitary/
thyroid
Lung/mediastinum IgG4-related lung disease,
Liver and biliary
system
Lymph nodes IgG4-related lymphadenopathy
Dacryoadenitis (Mikulicz’
disease), orbital inammation
(IgG4-related eye disease)
Küttner tumor
periaortitis, arteritis
Tubulointerstitial nephritis,
retroperitoneal brosis
Hypertrophic Pachymeningitis,
autoimmune hypophysitis,
Riedel’s thyroiditis
inammatory pseudotumor,
mediastinal brosis
Sclerosing cholangitis, IgG4related liver disease
toms are recurrent oral aphthous ulcers, cutaneous manifestations, uveitis, recurrent genital
ulcers, and repeated acute inammatory attacks.
Among the main symptoms, visual disorder
caused by uveitis is the most problematic, but
special lesions such as gastrointestinal, vascular,
and neurological lesions can cause organ
derangement.
2.6.2 Pathophysiology
Although the etiology of the disease is still
unknown, the strong correlation with HLA-B51
suggests that some environmental factors may be
added to the genetic predisposition, leading to the
onset of the disease. It is assumed that trace
chemical substances and indigenous oral bacteria
are involved as environmental factors. The basic
pathogenesis of this disease is thought to be an
increase in neutrophil function based on a hypersensitivity reaction of T cells.
2.6 Behçet’s Disease (BD)
2.6.1 Disease Overview
BD is an intractable multiorgan invasive disease
proposed by Behçet in Turkey. The main symp-
2.6.3 Epidemiology
Patients are accumulating along the former Silk
Road, the estimated number of patients in Japan
is 20,000, and the peak age of onset is in the 30s,
with a male to female ratio of 1:1.
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2.6.4 Symptoms
1. Recurrent aphthous ulcers of the oral
mucosa: Almost always present and often the
rst symptom. The buccal mucosa, malar
mucosa, gingival mucosa, and tongue are covered with shallow, painful, round ulcers with
well-dened margins. They heal without scarring in about a week, but recurrence is
common.
2. Skin manifestations: Erythema nodosum- like
rash, a painful subcutaneous nodule, and supercial thrombophlebitis, a painful funicular, are
most common on the lower legs. Acneiform
eruption and folliculitis-like eruptions are
found on the face, neck, and back. Severe redness of the skin at the site of shaving in men,
blood sampling, or injection reects the
increased irritability of the skin and is detected
on examination as a needle reaction.
3. Ocular lesions: Paroxysmal iridocyclitis
(anterior segment ocular type) and retinal
uveitis (ocular fundus type) are repeated.
During the anterior segment ocular type
attacks, photophobia, conjunctival injection,
and eye pain are seen, and in typical cases,
hypopyon iritis occurs. During ocular fundus
type attacks, patients have blurred vision and
decreased visual acuity, which may affect the
prognosis of vision.
4. Genital ulceration: Painful, well- demarcated,
punched ulcers, most commonly on the scrotum and penis in males and on the labia majora
and minora in females, which may leave scars
after healing.
5. Arthritis: Redness, pain, and swelling appear
transiently in large joints of the extremities
such as the knee, elbow, and shoulder, and
disappear within a few weeks.
6. Epididymitis: Transient and recurrent swelling
and pain in the testicles. The frequency of occurrence is low, but it is highly specic to BD.
7. Gastrointestinal lesions: In intestinal
Behçet’s disease, punched-out ulcerations are
seen in the gastrointestinal tract. The lesions
can occur anywhere from the esophagus to the
rectubem, and the ileocecal region is the most
common site; abdominal pain, bloody stool,
and diarrhea are the main symptoms.
8. Vascular lesions: Angio-Behçet disease can
cause vasculitis in both arteries and veins
regardless of the size of the vessel, but venous
lesions such as deep vein thrombosis of the
lower extremities are more common.
Depending on the location of the lesion, aortic
aneurysm, brain circulatory disturbances,
superior vena cava syndrome, Budd-Chiari
syndrome, and many other conditions may
occur.
9. Central nervous system disorders: Neuro-
Behçet disease can be divided into acute and
chronic progressive forms. The acute form
develops as meningitis or brainstem encephalitis. The chronic progressive type is more
intractable, and in addition to neurological
symptoms such as leukomalacia, necrosis of
white matter, hemiplegia due to demyelination, cerebellar symptoms, dysarthria, and
dysphagia, gradually progressive personality
changes and dementia are problems.
2.6.5 Clinical Examination
1. Blood tests: In the active stage, elevated
erythrocyte sedimentation rate, elevated CRP
value, and leukocytosis are observed. No
disease- specic antibodies have been found to
conrm the diagnosis, but HLA-B51 and A26
may be helpful.
2. Other examinations: Intestinal and skin
lesions are often biopsied for pathologic evaluation. CT and MRI are also useful to examine vascular lesions and central nervous
system lesions.
2.6.6 Treatment
For oral aphthous ulcers, genital ulcers, and skin
lesions, local treatment centered on external corticosteroids is used. Nonsteroidal antiinammatory drugs are used to treat arthritis and
epididymitis. On the other hand, ocular lesions
that can cause severe visual disorder and specic
types (intestinal, vascular, and neuro-Behçet’s
disease) that affect the prognosis of life require
aggressive treatment, including systemic administration of steroids and immunosuppressive
drugs. In recent years, anti-TNF-α antibody biologics have been used to treat refractory uveitis
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and intestinal, vascular, and neuro-Behçet’s disease, and are expected to improve the prognosis.
2.6.7 Prognosis
Although symptoms appear chronically and
repeatedly, the prognosis is not bad except for
ocular lesions and specic lesions such as intestinal, vascular, and neuro-Behçet’s disease. As
mentioned above, the use of anti-TNF-α antibody
biologics is expected to improve the prognosis of
ocular lesions and specic lesions.
2.7 Notes fromDentistry
Perspective
MasayukiAzuma,KeikoAota
The problems in dental treatment of patients with
collagen disease can be roughly divided into two
categories: problems caused by the oral symptoms
of collagen disease itself and problems caused by
the drugs used to treat collagen disease.
2.7.1 Dental Treatment Problems
Caused by Collagen Disease Itself
Systemic Lupus Erythematosus (SLE)
Erythema and ulcers of the oral mucosa are
among the many organ lesions that may occur. It
is generally painless, appears in the acute phase,
and disappears in response to treatment. In SLE,
the incidence of secondary Sjögren’s syndrome
has been reported to be 13%, and xerostomia
should also be noted [14].
Systemic Scleroderma
Oral manifestations include ankyloglossia (44%)
due to brosis of the lingual frenum and trismus
(26%) due to sclerosis of the skin around the lips
[15].
Sjögren’s Syndrome
Oral symptoms include signicant xerostomia.
With decreased salivary secretion, various oral
symptoms such as oral candidiasis, dental caries,
taste disorder, dysphagia, halitosis, glossalgia,
and denture incompatibility may occur.
2.7.2 Dental Treatment Problems
Caused by Collagen Disease
Drugs
Adrenocortical steroids are frequently used in the
treatment of collagen diseases to control chronic
inammation and immune abnormalities. Because
steroids have a wide range of physiological effects,
attention should be paid to various side effects.
When steroids are used, drugs for osteoporosis are
also used to prevent secondary osteoporosis. In
addition, immunosuppressive agents, biological
agents, and antithrombotic agents are used in the
treatment of collagen diseases (Table15.3).
Table 15.3 Drugs most commonly used by patients with collagen diseases
Type Main effect Side effects to be especially careful about
Adrenocorticosteroid Anti-inammatory action,
Immunosuppressant (drug) Immunosuppressive action Induction of infections, severe disease
Biological drug Regulatory action of molecular
Antithrombotic agents
(anticoagulants, antiplatelet
agents)
Osteoporosis drugs
(bisphosphonates)
immunosuppressive action
targeted therapy target molecules
Antithrombotic Bleeding
Decreased bone formation Osteomyelitis, osteonecrosis of the jaw
1. Inducement of infectious diseases and serious
illness
2. Osteoporosis
3. Atherosclerotic lesions (myocardial infarction,
cerebral infarction, aneurysm, thrombosis)
4. Induction and exacerbation of diabetes mellitus
5. Gastrointestinal disorders
6. Adrenal insufciency, steroid withdrawal
syndrome
7. Mental disorder
Induction of infections, severe disease
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