Systemic connective tissue
diseases:
systemic
lupus erythematosus (SLE) systemic sclerosis (SS)
Systemic
lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown
cause which can affect the skin, joints, kidneys, lungs, nervous system, serous
membranes and/or other organs of the body. Distinct immunologic abnormalities,
especially the production of a number of antinuclear antibodies, are another
prominent feature of the disease. The clinical course of SLE is characterized
by periods of remissions and chronic or acute relapses. Women, especially in
their 20s and 30s, are affected more frequently than men. Treatment is based on
preventive measures, reversal of inflammation, prevention of organ impairment,
and alleviation of symptoms.
History
The term ‘lupus’
was first used during the
Middle Ages to describe erosive skin lesions evocative of a
‘wolf’s bite’. In 1846 the Viennese physician Ferdinand von Hebra (1816–1880)
introduced the butterfly metaphor to describe the malar rash. He also used the term ‘lupus erythematosus’ and published
the first illustrations in his Atlas of Skin Diseases in 1856. Lupus was
first recognised as asystemic disease with visceral manifestations by Moriz
Kaposi (1837–1902). Th e systemic form was further established by Osler in
Epidemiology
International statistics
The highest rates of prevalence have been
reported in
The Lupus Foundation of American estimates
prevalence to be up to 1.5 million cases, which likely reflects
inclusion of milder forms of this disease. The frequency of SLE varies by race
and ethnicity, with higher rates reported in blacks and Hispanics. The
incidence of SLE in black women is approximately 4 times higher than that in
white women. SLE is also more frequent in Asian women than in white women.
Race-, sex-, and age-related
demographics
Worldwide, the prevalence of SLE appears to
vary by race. However, there are different prevalence rates for people of the
same race in different areas of the world. The contrast between low reported
rates of SLE in black women in Africa and high rates in black women in the
Female-to-male ratio
More than 90% of cases of SLE occur in
women, frequently starting at childbearing age. The use of exogenous
hormones has been associated with lupus onset and flares, suggesting a role for
hormonal factors in the pathogenesis of the disease. The risk of SLE
development in men is similar to that in prepubertal or postmenopausal women.
Interestingly, in men, SLE is more common in those with Klinefelter syndrome (ie,
genotype XXY), further supporting a hormonal hypothesis. In fact, a study by
Dillon et al found that men with Klinefelter syndrome had a more severe course
of SLE than women but a less severe course than other men.
The female-to-male ratio peaks at 11:1
during the childbearing years. A correlation between age and
incidence of SLE mirrors peak years of female sex hormone production. Onset of
SLE is usually after puberty, typically in the 20s and 30s, with 20% of all
cases diagnosed during the first 2 decades of life. The prevalence of SLE is highest in women
aged 14 to 64 years. SLE does not have an age predilection in males, although
it should be noted that in older adults, the female-to-male ratio falls.
This effect is likely due to loss of the estrogen effect in older females.
Etiology
Although the specific cause of SLE is
unknown, multiple genetic predispositions and gene-environment interactions
have been identified (see the chart in the image below). This complex situation
perhaps explains the variable clinical manifestations in persons with SLE.
HLA
= human leukocyte antigen; UV = ultraviolet light.
In systemic lupus erythematosus (SLE), many
genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab) responses,
B-cell and T-cell interactions, and immune clearance processes interact to
generate and perpetuate autoimmunity.
SLE has a modest recurrence rate in
families: 8% of affected patients have at least one first-degree family member
(parents, siblings, and children) with SLE; this is in contrast to 0.08% of the
general population. In addition, SLE occurs in both twins in 24% of
identical twins and 2% of nonidentical twins, which may be due to a combination
of genetic and environmental factors. Some studies have synthesized what is
known about the mechanisms of SLE disease and genetic associations. At
least 35 genes are known to increase the risk of SLE. A genetic predisposition is supported by 40%
concordance in monozygotic twins; if a mother has SLE, her daughter's risk of
developing the disease has been estimated to be 1:40, and her son's risk,
1:250.
HLA-A1, HLA-B8, and HLA-DR3 are more common
in persons with SLE than in the general population. The presence of the null
complement alleles and congenital deficiencies of complement (especially C4,
C2, and other early components) are also associated with an increased risk of
SLE.
Patients with SLE have higher titers of
antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral
loads, and make antibodies to retroviruses, including antibodies to protein
regions homologous to nuclear antigens. In patients with SLE and EBV infection,
the B cells are not primarily defective; rather, the SLE/EBV phenomenon is due
to a T-cell abnormality, which causes failure in normal immunoregulation of the
B-cell response. Viruses
may stimulate specific cells in the immune network. Chronic infections may induce
anti-DNA antibodies or even lupuslike symptoms, and acute lupus flares often
follow bacterial infections.
POTENTIAL ETIOLOGIC FACTORS
•
Viruses (EBV)
•
Hormones (estrogen)
•
Genetic predisposition (HLA B8)
•
Drugs (e.g., procainamide)
↓
Loss of tolerance
↓
Polyclonal  cell hyper-reactivity
↓
AUTOANTIBODY PRODUCTION
(anti-double-stranded DNA, etc.)
↓
Immune complex formation in circulation and tissues
↓
TISSUE INJURY
•
Glomerulonephritis
•
Vasculitis
•
Serositis
•
Arthritis
Environmental and exposure-related causes
of SLE are less clear. They potentially include the following:
·
Silica dust and cigarette
smoking may increase the risk of developing SLE
·
Administration of estrogen to
postmenopausal women appears to increase the risk of developing SLE.
·
Breastfeeding is associated
with a decreased risk of developing SLE
·
Photosensitivity is clearly a
precipitant of skin disease
·
Ultraviolet light stimulates
keratinocytes, which leads not only to overexpression of nuclear ribonucleoproteins
(snRNPs) on their cell surfaces but also to the secretion of cytokines that
simulate increased autoantibody production.
Patogenesis
The pathogenesis of
lupus remains unclear although the concept of apoptosis goes some way to
explaining how the immune system may recognise predominantly intracellular
antigens. Autoantigens are released by necrotic as well as apoptotic cells.
Defects in the clearance of apoptotic cells have been described in SLE which
may lead to aberrant uptake by macrophages which then present the previously intracellular antigens
to T and B cells thus driving the autoimmune process. Recent work has expanded
these concepts and dissected out possible defects in clearance of apoptotic
bodies including complement deficiencies, defects in macrophage handling
and presentation of these antigens to
the immune system. The most striking recent studies have demonstrated the
development of autoantibodies years
before the onset of clinical features of SLE and the antiphospholipid
syndrome (APS). Antinuclear antibodies occurre earlier than antiDNA antibodies
and a significant number of these patients had a rise in the anti-DNA titres
just prior to diagnosis. Interestingly, anti-Sm and anti-RNP antibodies
appeared shortly before diagnosis suggesting a crescendo of autoimmunity
resulting in clinical illness. This data also suggests that autoantibodies
alone do not necessarily result in clinical disease and that other factors
possibly genetic and environmental may be important. It may be possible in the
future to predict the onset of clinical features of lupus by clinical
assessment and monitoring the development of various lupus autoantibodies.
Classification
The nature of the disease
ü
acute
ü
subacute
ü
chronic:
Ø
recurrent arthritis,
Ø
discoid lupus,
Ø
Raynaud's syndrome,
Ø
thrombocytopenic purpura syndrome,
Ø
Sjogren syndrome
Stage of activity
ü
Active
Ø
high
Ø
moderate
Ø
minimal
ü
Moderate
ü
Severe
CLINICAL MANIFESTATIONS
Musculoskeletal involvement
Joints
Arthralgia occurs in
about 90% of all patients with SLE. Characteristically, it is polyarticular,
symmetrical, episodic and flitting in nature. The patients’ symptoms often
exceed the objective clinical findings and usually there is no clinically overt
arthritis. Synovial effusions are uncommon and of small volume when they do
occur. However, approximately 10% of SLE patients do have a deforming Jaccoud’s
arthritis. In contrast to patients with rheumatoid arthritis, the deformities
are not usually associated with synovial hypertrophy or bony erosions. In fact,
tenosynovitis is more common than
erosive synovitis
and is the cause of the “swan-neck” deformities and ulnar deviation seen in the
Jaccoud’s arthritis of lupus. Examination of the synovial fluid usually reveals
a white cell count of less than 3000/mm3, predominantly mononuclear cells. The
fluid is often positive for rheumatoid factor and anti-nuclear antibody
Muscles
Clinically obvious
muscle involvement has been reported in 30-50% of SLE patients. However,
myalgia, muscle weakness and tenderness, may be due to a variety of other
complications. Thus both corticosteroid and rarely chloroquine therapy may
cause a myopathy. In addition, myalgia may be induced by an adjacent
arthralgia, although only 5% of lupus patients have met the ACR criteria for
both SLE and polymyositis.
Dermatological involvement
Cutaneous lesions
may occur in up to 85% of SLE patients. The butterfly rash is erythematous,
often blotchy, and found mainly over the malar bones and across the bridge of the nose.
.
Although it is the
best known skin lesion, it is merely one of numerous ways in which lupus manifests cutaneously. Lesions such as maculopapular and discoid
lesions, splinter haemorrhages, dilated capillaries at the nail base, bullous
lesions, angioneurotic oedema, livedo
reticularis and buccal, genital
and nasal ulceration have also been described.
http://drugline.org/ail/pathography/3141/
Vasculitic skin lesions
are usually found at the nailfolds and finger tips or on the extensor surface of the forearm. When they occur around the malleoli,
they may lead to tender, deep, leg ulcers which can take months to heal.
Many SLE rashes are
exacerbated by ultraviolet light and indeed generalized lupus flares may follow exposure to direct sunlight with
inadequate protection. A particularly
photosensitive rash is
subacute cutaneous lupus erythematosus
(SCLE) which is often associated with anti-Ro antibodies.
http://mizzouderm.com/autoimmune.html
Babies born to
mothers with anti-Ro and/or anti-La antibodies are at risk of neonatal lupus
syndrome.
http://youritablets.com/systemic-lupus-erythematosus-symptoms-and-treatment/
The deposition of
immunoglobulins at the dermal-epidermal junction in skin biopsies from patients
with lupus was first reported over 40 years ago. These immunoglobulins are
usually of the IgG or IgM isotype.
Approximately, 90% of biopsies from lupus skin lesions have such immunoglobulin deposits which usually appear as
a band along the dermal-epidermal junction, giving rise to the name the “lupus band test”. In
patients with SLE, deposition of immunoglobulin and complement may be found in clinically normal
skin and is thus a useful adjunct to diagnosis since no such deposition is found in patients with
discoid lupus or control subjects.
Lupus nephritis
More than 70% of
patients with SLE have renal involvement at some stage of their disease.
These descriptions allow better
communication between pathologists translating static images from histology
slides into meaningful descriptions of the huge variety of biopsy appearances
for clinicians. Of the different pathological classes, diffuse proliferative
glomerulonephritis (Class IV) has the worst
prognosis,
resulting in 11-48% of patients with end stage renal disease at 5 years.
http://www.med.niigata-u.ac.jp/npa/Lectures/Lupus.htm
International Society of Nephrology/Renal Pathology
Society 2003 classification of lupus nephritis
Class I
Minimal
mesangial lupus nephritis
Normal glomeruli by
light microscopy, but mesangial immune deposits by immunofluorescence
Class II
Mesangial
proliferative lupus nephritis.
Purely mesangial
hyper-cellularity of any degree or mesangial matrix expansion by light microscopy,
with mesangial immune deposits. May be a few isolated sub-epithelial or
sub-endothelial deposits visible by immunofluorescence or electron
microscopy, but not
by light microscopy
Class III
Focal
lupus nephritisa
Active or inactive focal,
segmental or global endo- or extra-capillary glomerulonephritis involving
<50% of all glomeruli, typically with focal sub-endothelial immune deposits,
with or without mesangial alterations
Class III (A)
Active lesions:
focal proliferative lupus nephritis
Class III (A/C)
Active and chronic
lesions: focal proliferative and sclerosing lupus nephritis
Class III (C)
Chronic inactive
lesions with glomerular scars: focal sclerosing lupus nephritis
Class IV
Diffuse
lupus nephritis
Active or inactive
diffuse, segmental or global endo- or extra-capillary glomerulonephritis
involving 50% of all glomeruli, typically with diffuse sub-endothelial immune
deposits, with or without mesangial alterations. This class is divided into
diffuse segmental(IV-S) lupus nephritis when 50% of the involved glomeruli have
segmental lesions,
and diffuse global (IV-G) lupus nephritis when 50% of the involved glomeruli
have global lesions. Segmental is defined as a glomerular lesion that involves
less than half of the glomerular tuft. This class
includes cases with
diffuse wire loop deposits but with little or no glomerular proliferation
Class IV-S (A)
Active lesions:
diffuse segmental proliferative lupus nephritis
Class IV-G (A)
Active lesions:
diffuse global proliferative lupus nephritis
Class IV-S (A/C)
Active and chronic
lesions: diffuse segmental proliferative and sclerosing lupus nephritis
Active and chronic
lesions: diffuse global proliferative and sclerosing lupus nephritis
Class IV-S (C)
Chronic inactive
lesions with scars: diffuse segmental sclerosing lupus nephritis
Class IV-G (C)
Chronic inactive
lesions with scars: diffuse global sclerosing lupus nephritis
Class V
Membranous
lupus nephritis
Global or segmental
sub-epithelial immune deposits or their morphologic sequelae by light
microscopy and by
immunofluorescence
or electron microscopy, with or without mesangial alterations
Class V lupus
nephritis may occur in combination with class III or IV in which case both will
be diagnosed
Class V lupus
nephritis show advanced sclerosis
Class VI
Advanced
sclerosis lupus nephritis
90% of glomeruli
globally sclerosed without residual activity
A Indicate the
proportion of glomeruli with active and with sclerotic lesions.
B Indicate the
proportion of glomeruli with fibrinoid necrosis and/or cellular crescents.
Indicate and grade
(mild, moderate, severe) tubular atrophy, interstitial inflammation and
fibrosis, severity of
arteriosclerosis or
other vascular lesions.
Lungs
The immunosuppressive
therapy required by many SLE patients predisposes them to concurrent infection.
The lungs are a frequent target for this “secondary” infection and bacteria
(including tubercule bacilli), viruses and fungi may all cause pneumonia in
lupus patients.Parenchymal alterations, attributable to SLE itself, have been
described in 18% of patients. These patients had interstitial fibrosis,
pulmonary vasculitis and interstitial pneumonitis. However, many non-specific
pulmonary lesions previously attributed to SLE, such as alveolar haemorrhage
alveolar wall necrosis, oedema and hyaline membranes, are probably secondary to
factors such as intercurrent infection, congestive heart failure, renal failure
and oxygen toxicity.In the relatively few cases studied, immune complex
deposition has been closely correlated with histological evidence of
inflammatory lesions in the pleural (and pericardial) membrane.
Abnormal pulmonary
function tests, notably diminished total lung capacity and flow rates, in
clinically mild patients with dyspnoea, poor diaphragmatic movement, basal
crepitations and occasionally cyanosis and clubbing, are found in up to 50% of
SLE patients. A similar proportion of SLE patients may have an acute lupus
pneumonitis with a mononuclear cell infiltrate detectable in the alveolar
septae. These patients frequently complain of dyspnoea, pleuritic chest pain
and coughs. Haemoptysis is less common and true pulmonary haemorrhage from
necrotizing alveolar capillaritis is rare. Pleural effusions may be found in
about half of these patients (and in other SLE patients especially during
generalized disease flares). The effusions are normally small to moderate in
size and are usually exudates (i.e. protein content >3 g/100 ml). They are
rarely haemorrhagic and usually have a glucose concentration double that found
in rheumatoid effusions (normally, 20 mg/100 ml or less).
Heart
Pericardium
Abnormalities of
the electrocardiogram, notably of the T wave, are the most frequent
manifestation. A
pericardial rub may be more common than a significant pericardial effusion.
Histological abnormalities vary from occasional foci of fibrinoid degeneration
and inflammatory cell infiltrates to far more extensive lesions. Adhesive
chronic pericarditis and very large effusions causing tamponade are very rare.
Myocardium
Whilst true
myocardial involvement is less frequent than pericardial disease, prolongation
of the PR interval (approximately 10%), fibrinoid degeneration, myocardial
infarction and coronary stenosis due to arteritis are occasionally seen. New
imaging techniques such as cardiac MRI suggest that myocardial involvement may
be more common than previously thought.There is increasing evidence that
premature accelerated atherosclerosis considerably increases the risk of cardiovascular
events in patients with SLE and this is described in a separate module of this
course.
Valves
Systolic murmurs
are frequently heard in around 30% of SLE patients. However, they probably
reflect the hyperdynamic circulation consequent upon the anaemia often found in
these individuals. In contrast, diastolic murmurs are uncommon. Libman-Sacks
endocarditis has long been described as a feature of SLE. Although found in up
to 50% of autopsied
cases, it rarely causes clinically significant lesions. Histologically, the
lesions are small (1-
Central nervous system lupus
The ACR
classification criteria for central nervous system (CNS) lupus has changed
considerably from
seizures and psychosis. The ACR nomenclature now includes 19 different
syndromes that are classifiable . An emerging concept is the distinction
between CNS manifestations due to lupus and those due to the APS. A wide
variety of neuropsychiatric manifestations attributable to APS have been
described including strokes, seizures, movement disorders, transverse
myelopathy, demyelination syndromes, transient ischaemic attacks, cognitive
dysfunction, visual loss and headaches including migraine.
Neuropsychiatric syndromes observed in SLE.
Central nervous system:
ü
Aseptic
meningitis
ü
Cerebrovascular disease
ü
Demyelinating syndrome
ü
Headache (including migraine and
benign intracranial hypertension)
ü
Movement disorder (chorea)
ü
Myelopathy
ü
Seizure disorders
ü
Acute confusional state
ü
Anxiety disorder
ü
Cognitive dysfunction
ü
Mood disorder
ü
Psychosis
Peripheral nervous system:
ü
Acute inflammatory
demyelinating polyradiculoneuropathy (Guillain-Barré syndrome)
ü
Autonomic disorder
ü
Mononeuropathy, single/multiplex
ü
Myasthenia gravis
ü
Neuropathy, cranial
ü
Plexopathy
ü
Polyneuropath
Laboratory diagnosis
of CNS lupus can be difficult. Abnormal electroencephalograms occur in about
70% of patients with neurologic complaints and usually show diffuse slowing or
focal abnormalities. Cerebrospinal fluid (CSF) shows elevated protein levels in
50% and increased mononuclear cells in 30% of patients; oligoclonal bands and
increased Ig synthesis may be found. Lumbar puncture is recommended when the
diagnosis of CNS lupus is in doubt or when infection is a possible cause of
symptoms. Magnetic resonance imaging (MRI) with contrast is the most sensitive
radiographic technique to detect acute and chronic lesions of SLE; changes are
often nonspecific. Patients with focal neurologic lesions are more likely to
have positive MRI scans than those with diffuse manifestations. Computed
tomography (CT) scans are useful to rule out bleeding or mass lesions, if
indicated. Angiograms can detect vasculitis and vascular occlusions or emboli;
they cannot visualize vessels smaller than 50 um; lupus vasculitis usually
involves smaller vessels. Laboratory measures of disease activity often do not
correlate with neurologic manifestations. Neurologic problems (with the
exception of deficits resulting from large infarcts) usually improve with
immunosuppressive therapy and/or time; recurrences are seen in approximately
one-third of patients.
Gastrointestinal System
Common
gastrointestinal (GI) symptoms include nausea, diarrhea, and vague discomfort.
Symptoms may result from lupus peritonitis and may herald a flare of SLE.
Vasculitis of the intestine is the most dangerous manifestation, presenting
with acute crampy abdominal pain, vomiting, and diarrhea. Intestinal
perforation can occur and usually requires immediate surgery. Patients with
pseudoobstruction have abdominal pain; x-rays show dilated loops of small bowel
which may be edematous; surgery should be avoided unless frank obstruction is
present. Glucocorticoid therapy is useful for all these GI syndromes. Some
patients have GI motility disorders similar to those in scleroderma; they are
not benefited by steroids. Acute pancreatitis occurs and can be severe,
resulting from active SLE or from therapy with glucocorticoids or azathioprine.
Elevated amylase levels may reflect pancreatitis, salivary gland inflammation,
or macroamylasemia. Elevated serum transaminase levels are common in patients
with active SLE but are not associated with significant hepatic damage; they
return to normal as the disease is treated.
Ocular Manifestation
Retinal vasculitis
is a serious manifestation; blindness can develop over a few days, and
aggressive immunosuppression should be instituted. Examination shows areas of
sheathed, narrow retinal arterioles and cytoid bodies (white exudates) adjacent
to vessels. Other ocular abnormalities include conjunctivitis, episcleritis,
optic neuritis, and the sicca syndrome.
Esophagus
Lupus patients occasionally complain of
dysphagia or odynophagia. This can be multifactorial from hypomotility, from
reflux disease, or from candidiasis from immunosuppression. If the symptoms are
severe, they deserve a regular dysphagia evaluation with motility studies,
x-rays, and maybe an endoscopy. Although treatment is directed at the cause,
motility drugs are no longer favored due to their arrythmogenic potential.
Antireflux medications or antifungals are used when appropriate.
Abdomen
Abdominal pain is a diagnostic challenge in
SLE and is probably one of the most clinically threatening GI manifestation to
be aware of. Min and colleagues looked at causes of acute abdominal pain in SLE
patients in emergency departments (EDs). They documented that 59.1% of visits
to the ED by SLE patients were from pain due to ischemic bowel disease. The
other causes were splenic infarcts, renal venous thrombosis, pancreatitis,
serositis, upper GI bleeds, pelvic inflammatory disease, and ectopic pregnancy.
Peptic ulcer disease with perforation also manifested as an acute abdomen in a
small number of patients with SLE and concomitant NSAID use. Treatment
of acute abdominal pain is directed at the cause, with appropriate medical or
surgical management of the presenting manifestation.
Intestines
In the bowel, SLE can manifest with
vasculitis, malabsorption, or dysmotility. Mesenteric vasculitis in
lupus can manifest as an acute abdomen with fever, nausea, vomiting, diarrhea,
and rectal bleeding or with the characteristic mesenteric ischemic pain related
to meals. The mesenteric involvement can be attributed to either a lupus flare
or antiphospholipid antibodies. Suspicion based on a clinical, angiographic, or
CT examination of mesenteric vasculitis without bowel perforation warrants an
evaluation by a rheumatologist and a possible aggressive therapeutic approach
with intravenous steroids with or without other cytotoxic agents, besides the
routine treatments with nothing by mouth, IV fluids, cultures, and
broad-spectrum antibiotics. If there is intestinal perforation
from vasculitis, surgery is the first option followed by cautious start of
steroids and cytotoxic agents in the postoperative period. Malabsorption in the
form of a protein-losing enteropathy in lupus is uncommon and manifests with
diarrhea, abdominal pain, and anasarca. The enteropathy might respond to
steroids with or without cytotoxic drugs.
Pancreas
Pancreatitis in lupus is uncommon and could
occur in a setting of high SLEDAI scores, antiphospholipid antibody syndrome,
and probable steroid use. The more likely causes, as in any other
setting, are gallstones, alcohol, and hypertriglyceridemia. Treatment is the
same as for pancreatitis from any other cause and includes nothing by mouth, IV
fluids, withholding causal drugs, and, rarely, use of steroids if the cause is
established by exclusion.
Liver
Drugs, viruses, fatty infiltration, or
congestion have been implicated as more common causes of liver enzyme
abnormalities in SLE patients. Hepatitis from lupus (lupus
hepatitis), although uncommon, manifests as a mild elevation in liver enzymes
(aspartate transaminase [AST], alanine transaminase [ALT)], lactate
dehydrogenase [LDH], alkaline phosphatase), usually in a setting of active
lupus. Such biochemical liver abnormalities from an SLE flare have a tendency
to reverse with steroids. Lupoid hepatitis is a separate entity and is considered
a subset of chronic active autoimmune hepatitis, where the liver is the main
organ of involvement. Patients with lupus hepatitis and lupoid hepatitis can
have arthralgias, hypergammaglobulinemia, and positive ANAs. Serologic
differentiation may be possible at times and in general involves the presence
of anti–ribosomal P and dsDNA autoantibodies in lupus hepatitis versus
anti–smooth muscle and auto–liver-kidney-mitochondrial (LKM) antibodies in
lupoid hepatitis. Definite differentiation is only possible on histology, which
shows a lobular involvement in lupus hepatitis versus rosetting of liver cells
and dense lymphoid infiltrate in lupoid hepatitis.
Haematological abnormalities
Red blood cells
A normochromic,
normocytic anaemia is frequently found in SLE patients, with concomitant low
levels of both the serum iron and iron binding capacity. This abnormality
appears to be related, as in other diseases, to chronic inflammation and
shunting of elemental iron from erythroblasts to macrophages.Iron-deficiency
anaemia may be induced by non-steroidal anti-inflammatory drugs, which can
cause gastrointestinal haemorrhage. Excessive blood loss from menorrhagia,
sometimes related to severe thrombocytopenia, may have the same effect.
Haemolytic anaemia as detected by the Coombs’ test is another rare feature of
SLE. Autoimmune thrombocytopenia occasionally manifests simultaneously with
haemolytic anaemia: this
condition is known
as Evan’s syndrome.
Platelets
Two forms of
thrombocytopenia (platelet count < 100 x 109/l) are found in SLE. Firstly,
it may be encountered in a chronic form, generally associated with mild
disease. Secondly, it may occur in an acute form, similar to idiopathic
autoimmune thrombocytopenic purpura. This latter association is with disease carrying
a greater morbidity and mortality. Platelet destruction appears to be mediated
by anti-platelet antibodies and aPL are also associated with thrombocytopenia
as well as with thrombosis.
White blood cells
Persistent
leucopenia (< 4.0 x 109/l) is one of the ACR criteria for the classification
of SLE. It probably results from a combination of destruction of white cells by
autoantibodies, decreased marrow production, increased or marginal splenic
pooling, and complement activation. It should also be noted that the
immunosuppressive drugs used in the treatment of SLE may cause a marked
leucopenia.
Serological abnormalities
The serum from SLE
patients may bind to an extensive array of molecules including nucleic acids
(antinuclear antibodies) and phospholipid binding proteins (lupus
anticoagulant, anticardiolipin antibodies, β2 glycoprotein 1 antibodies).
Antibodies may also be detected against diverse cells including leukocytes,
erythrocytes, platelets and neurones. In addition to these autoantibodies, numerous
other abnormalities are evident, including the LE cell phenomenon,
hypocomplementaemia, elevated levels of acute phase proteins, gamma globulins
and circulating immune complexes.
Non-specific features
Fever,
lymphadenopathy, hair loss and Raynaud’s phenomenon are all commonly found in
SLE patients. Fever in lupus patients may be striking and often requires
extensive investigation to exclude concurrent infection, although a normal CRP
in this context usually suggests a low likelihood of sepsis.
Lymphadenopathy may also be dramatic in SLE, to such an extent that
lymph node biopsy may have to be performed to exclude malignancy. Some patients
seem more prone to this feature than others and in this group the degree of
lymphadenopathy may reflect general disease activity.
Splenomegaly occurs in about 10% of patients.
The clinical
diagnosis of SLE hinges on careful and very thorough assessment of the
presenting clinical
features, examination of all the organ systems and selected investigations.
Clinical symptoms
Symptoms often
occur intermittently and cumulatively over many months and years. Oral ulcers,
arthralgia, hair fall, Raynaud’s phenomenon, photosensitive rashes, pleuritic
chest pains, headaches, fatigue, fevers and lymphadenopathy are just a few of
the many non-specific presenting features of this disease.
There are no
diagnostic criteria for lupus and the ACR classification criteria are often
misused in this context and can result in missed diagnosis/under-treatment. For
example a patient may present with arthritis, Raynaud’s phenomenon, malaise,
fevers, lymphadenopathy, oral ulcers and a positive ANA. This patient clearly
may have SLE but does not fulfil the 4 criteria needed for classification by
the ACR criteria but investigation and treatment should not be delayed until
these criteria are fulfilled. The ACR criteria were specifically designed to be
highly specific for research studies to enable consistency between studies and
have been updated to include antiphospholipid
antibodies in the
criteria.
The objective
assessment of lupus has depended on a number of disease activity scoring
systems which usually give a single numeric value.
Diagnostic criteria
|
The 1982 Criteria for
Classification of Systemic Lupus Erythematosus, Updated 1997 |
||
|
1. Malar rash |
Fixed erythema, flat or
raised, over the malar eminences |
|
|
2. Discoid rash |
Erythematous raised patches
with adherent keratotic scaling and follicular plugging; atrophic scarring
may occur
Discoid plaques of the hand |
|
|
3. Photosensitivity |
Exposure to UV light causes
rash |
|
|
4. Oral ulcers |
Includes oral and
nasopharyngeal, observed by physician
|
|
|
5. Arthritis |
Nonerosive arthritis
involving two or more peripheral joints, characterized by tenderness,
swelling, or effusion |
|
|
6. Serositis |
Pleuritis or pericarditis
documented by ECG or rub or evidence of pericardial effusion
|
|
|
7. Renal disorder |
Proteinuria > 0.5 g/d or
> 3+, or cellular casts |
|
|
8. Neurologic disorder |
Seizures without other cause
or psychosis without other cause |
|
|
9. Hematologic disorder |
Hemolytic anemia or
leukopenia (< 4000/mL) or lymphopenia (< 1500/mL) or thrombocytopenia
(< 100,000/mL) in the absence of offending drugs |
|
|
10. Immunologic disorder |
Anti-dsDNA, anti-Sm, and/or
anti-phospholipid |
|
|
11. Antinuclear antibodies |
An abnormal titer of ANAs by
immunofluorescence or an equivalent assay at any point in time in the absence
of drugs known to induce ANAs |
|
|
If four of these criteria
are present at any time during the course of disease, a diagnosis of systemic
lupus can be made with 98% specificity and 97% sensitivity. |
||
Laboratory and instrumental investigations
Clinical examination
of all organ systems including routine urinalysis and blood pressure
measurement is mandatory. Simple investigations may yield useful information.
For example, a grossly elevated erythrocyte sedimentation rate (ESR) with a
normal C-reactive protein (CRP) is a strong pointer to lupus and related
connective tissue diseases. Blood count abnormalities such as anaemia,
neutropenia, lymphopenia and thrombocytopenia are also common. Serologically can be
found:
|
Autoantibodies in Patients with SLE |
|
|||
|
|
Incidence, % |
Antigen Detected |
Clinical Importance |
|
|
Antinuclear antibodies |
98 |
Multiple nuclear |
Human cell substrates are more sensitive than
murine. Repeatedly negative tests make SLE unlikely. |
|
|
Anti-DNA |
70 |
DNA (ds) |
Anti-dsDNA is relatively disease-specific;
anti-ssDNA is not. High titers are associated with nephritis and clinical
activity in some patients.
The fluorescent antinuclear antibody test:
specificities of systemic lupus erythematosus. B, Nuclear rim pattern of anti-DNA antibodies. |
|
|
Anti-Sm |
30 |
Protein complexed to 6 species of small
nuclear RNA |
Specific for SLE.
The fluorescent antinuclear antibody test:
specificities of systemic lupus erythematosus. A, Speckled nuclear pattern
of anti-Sm antibodies. |
|
|
Anti-RNP |
40 |
Protein complexed to U1RNA |
High titer in syndromes with features of
polymyositis, lupus, scleroderma, and mixed connective tissue disease.
If present in SLE without anti-DNA,
risk for nephritis is low. |
|
|
Anti-Ro (SS-A) |
30 |
Protein complexed to y1-y5
RNA |
Associated with Sjogren's syndrome, subacute
cutaneous lupus, inherited C¢ deficiencies, ANA-negative lupus, lupus in
the elderly, neonatal lupus, congenital heart block. Can cause nephritis. |
|
|
Anti-La (SS-B) |
10 |
Phosphoprotein |
Always associated with anti-Ro. Risk for
nephritis is low if present. Associated with Sjogren's syndrome. |
|
|
Antihistone |
70 |
Histones |
More frequent in drug-induced LE (95%) than in
spontaneous SLE. |
|
|
Antiphospholipid |
50 |
Phospholipids |
Three types (lupus anticoagulant (LA),
anticardiolipin (aCL), and false-positive test for syphilis (BFP). The LA and
aCL (particular high-titer IgG) are associated with clotting, fetal loss,
thrombocytopenia, and valvular heart disease. Antibodies to b2-glycoprotein
I are part of this group. |
|
|
Antierythrocyte |
60 |
Erythrocyte |
A small proportion of these patients develop
overt hemolysis. |
|
|
Antiplatelet |
30 |
Platelet surface + cytoplasm |
Associated with thrombocytopenia in 15% of
patients. |
|
|
Antilymphocyte |
70 |
Lymphocyte surface |
Probably associated with leukopenia and
abnormal T cell function. |
|
|
Antineuronal |
60 |
Neuronal and lymphocyte surface |
In some series, high titers of IgG correlate
with diffuse CNS lupus. |
|
|
Antiribosomal P |
20 |
Ribosomal P protein |
In some series, antibody in serum correlates
with psychosis or depression due to CNS SLE. |
|
Antinuclear antibodies
are highly sensitive but not specific and anti-dsDNA antibodies are specific
but not sensitive and it is important to recognise that a negative result for
anti-dsDNA antibodies does not exclude a diagnosis of lupus.
This table is not a standardized guideline,
and tests can vary in different clinical settings. The clinical assessment and
tests must be combined to make an appropriate diagnosis of SLE.
Diagnostic Tests for Systemic
Lupus Erythematosus
|
Test |
Possible Abnormalities |
Mechanism |
Significance and Use |
|
CBC plus differential |
Anemia, thrombocytopenia, |
Autoantibodies to |
Disease activity markers for SLE and |
|
Basic metabolic panel |
Elevated BUN/Cr ratio |
Immune complex |
Diagnosis |
|
ESR and CRP |
Elevated |
Inflammatory markers |
Disease activity marker for follow-up if |
|
Complements (C3, C4) |
Low |
Immune complex |
Disease activity marker |
|
Urine chemistry |
Proteinuria, hematuria, |
Glomerulonephritis or |
SLE nephritis and/or nephrotic syndrome |
|
LFTs |
Elevated transaminases |
Unknown |
Lupus hepatitis, nephrotic syndrome (low |
|
ANA (IFA + EIA) |
Useful as a screening test |
|
ANA-negative lupus is rare (manifests |
|
ENA panel |
Anti-Sm, anti-RNP, |
Antibodies to specific |
Anti-Sm: Highly specific for SLE |
|
dsDNA antibody |
Positive |
Antibodies to the |
Diagnostic of SLE |
|
APLAs |
Lupus anticoagulant panel, |
Antibodies to |
Moderate to high titers of IgG and IgM in |
APLA, antiphospholipid antibody; BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; Cr, creatinine; CREST, calcinosis, Raynaud's syndrome, esophageal involvement, sclerodactyly, telangiectasia; CRP, C-reactive protein; CTD, connective tissue disease; dsDNA, double-stranded DNA; EIA, enzyme immunoassay; ENA, extractable nuclear antigens; ESR, erythrocyte sedimentation rate; IFA, immunofluorescent antibody; Ig, immunoglobulin; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; MCTD, mixed connective tissue disease; NSAID, nonsteroidal anti-inflammatory drug; RA, rheumatoid arthritis; RBC, red blood cell count; RNP, ribonuclear protein; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome
TREATMENT
Patient Education
In order to obtain optimal
results from drug therapy, patient education plays a vital role and must be
paid due attention. Every newly diagnosed patient needs to be educated about
the disease. In this regard, pamphlets especially written for patients can be
very helpful. For illiterate patients, the treating physician or a specialist
nurse will have to spend the necessary time on education. It is often useful to
offer a new patient the opportunity to interact with other previously diagnosed
lupus patients who are identified by the specialist as having a positive
outlook of the disease and the enthusiasm to function as a counsellors. In many
advanced centres (outside
General approach to the drug
therapy of SLE
Since there is a range of
severity of disease manifestations, proper categorization based on clinical and
laboratory features is the first therapeutic step. The following scheme is
recommended:
Category I (Mild SLE)
Characterised
by arthritis, arthralgia, myalgia, fatigue, mild mucocutaneous involvement,
low-grade fever, mild serositis, lupus headache, musculoskeletal complaints are the commonest features of SLE. For mild
symptoms, NSAIDs and analgesics may suffice. NSAIDs can occasionally cause
adverse effects which may resemble those produced by the disease itself such as
proteinuria, edema, renal failure and aseptic meningitis. In some patients, the
above symptoms may not be alleviated with NSAIDs alone, and they should be
prescribed antimalarials (chloroquine, hydroxychloroquine). These drugs are particularly
useful for cutaneous manifestations of SLE. These agents have multiple
properties: immunosuppressive anti-inflammatory and sun-blocking. They are also
reported to possess anti-platelet and cholesterol lowering effects. The drug of
choice is hydroxychloroquine (200 mg BD for 3 months and then 200 mg
daily). The maintenance dose must not exceed 6 mg/kg/day. Although the
incidence of retinal toxicity is very low, annual monitoring of vision with perimetery
using a red object is recommended (for chloroquine, 6-monthly monitoring is
desirable). The drug must be discontinued if a central scotoma is detected at
any stage. Other significant side effects include nausea, pruritus,
hyperpigmentation, myopathy and rarely psychosis. Use of hydroxychloroquine
during pregnancy is controversial. When antimalarials are withdrawn after
prolonged administration, some patients may develop a relapse of lupus
activity. In refractory cases, quinacrine may be combined with
hydroxychloroquine. Alternatives include dapsone and thalidomide. Quinacrine
and thalidomide are, however, not available in
Category II (Moderate SLE)
Characterised by high-grade
fever, toxaemia, severe mucocutaneous manifestations, marked photosensitivity,
moderate to severe serositis, lupus pneumonitis, mild to moderate myocarditis,
mesangioproliferative or minimal change lupus nephritis, haemolytic anaemia and
thrombocytopenia For moderate and severe manifestations, prednisolone 1 mg/kg
orally per day is the drug of choice. Antimalarials may be administered
concomitantly. High dose of steroid must be continued till disease activity is
well controlled that usually takes up to 6 weeks when it should be tapered off
slowly over 6 to12 months. In a toxic appearing patient, the administration of
intravenous pulse methylprednisolone (15 mg/kg, max.
Category III (Severe SLE)
Characterised by
organ/life-threatening features such as focal/diffuse proliferative
glomerulonephritis with or without azotaemia/hypertension, lupus cerebritis
with recurrent seizures, acute confusional state, coma; systemic necrotizing
vasculitis such as one causing peripheral gangrene, GI bleeding or mononeuritis
multiplex. A combination therapy consisting of high-dose daily oral prednisolone
(40-60 mg/day) and intravenous cyclophosphamide pulses (0.75 gm/m2,
maximum of
Category IV (SLE with
miscellaneous features)
Characterised by
antiphospholipid syndrome (recurrent DVT, CVAs, recurrent foetal loss etc.),
pure membranous lupus nephritis, chronic sclerosing lupus nephritis, seizures
without other evidence of lupus activity, behavioural disorders without other
serious manifestations, resistant thrombocytopenia or haemolytic anaemia
Immunosuppressive therapy does not play any significant role in these
conditions. Treatment of antiphospholipid syndrome is described in appendix. If
seizures or psychosis occur as isolated events with no evidence of lupus
activity elsewhere in the body, only symptomatic treatment is recommended.
Steroids are not indicated. Pure membranous glomerulonephritis (WHO Class V)
may be treated initially with prednisolone 1 mg/kg/day. If there is no
response after 6 weeks (85-90% of cases), steroids may be quickly tapered off
because they are not likely to help. There is no proven role of cytotoxic drugs
in the treatment of this condition in SLE. Renal failure occurs but is less
frequent as compared with proliferative glomerulonephritis. Chronic sclerosing
glomerulonephritis is best treated with conservative therapy, dialysis and
transplantation. Immunosuppressive therapy is not beneficial. At least, 3
months of dialysis is recommended before considering renal transplant as the
outcome of the transplant is better in patients whose lupus disease activity
remains clinically stable on dialysis for at least 3 months. For refractory
thrombocytopenia, danazol may be useful. Colchicine and vincristine are
sometimes useful to improve the platelet count. Splenectomy may be indicated in
some cases where platelet count tends to be less than 50,000/ cu mm and
maintenance requirement for steroids is high. Such patients should receive
pneumococcal vaccine. Plasmapheresis may be employed in refractory cases where
steroid and cyclophosph-amide pulses do not produce satisfactory results.
Intravenous immunoglobulin has also been used in similar situations. A few instances
of successful remission of refractory lupus following stem cell transplant are
reported.
Other specific entities:
Transverse myelitis : Requires aggressive treatment with prednisolone orally 1.5 mg/kg/day and
IV cyclophsophamide bolus. If there is no improvement, plasmapheresis should be
considered.
Seizures: For generalized seizure, phenytoin and barbiturates are used and for
focal, carbamazepine, valproate or gabapentin is used.
Headaches: Most patients respond to NSAIDs.
In intractable cases steroid may be used. Chorea: No specific therapy is
required.
Cranial /autonomic and
peripheral neuropathy: Oral prednisolone in a dose of 1mg/kg/day is useful.
Cognitive dysfunction: Consider reducing the dose of prednisolone. If associated with APS,
anticoagulate.
Principles of treatment of
lupus nephritis
General measures: It is
advisable to restrict salt if hypertension is present, fat if hyperlipidemia or
nephrotic syndrome is present, protein should be restricted if azotaemia is
present and calcium should be supplemented with steroid therapy. Meticulous
control of hypertension is desirable. Pregnancy should be avoided during active
lupus nephritis with suitable contraception (vide infra). NSAIDs should be
avoided in the presence of impaired renal function. Immunosuppressive therapy:
This is generally guided by the WHO Class of lupus nephritis.
1. Class I: Immunosuppressive therapy is not indicated.
2. Class IIa: Immunosuppressive therapy is not indicated.
3. Class IIb: If proteinura is > 1 gram/24 hours, antidsDNA is high and C3 is low,
prednisolone should be administered at a dose of 20 mg daily for 6-12 weeks,
followed by tapering over next 3 months.
4.Class III & IV: Protocol for this group is already described above (See Category III
under management).
5. Class V: Described under management above (Category IV). A high chronicity index
correlates with poor renal outcome with progression to end stage renal disease
despite treatment. High activity Index is also associated with poor outcome if
not treated aggressively with appropriate immunosuppressive therapy. Patients
with high chronicity index and serum creatinine more than 3 mg/dL should not be
treated aggressively unless activity index is also high. If serum creatinine is
chronically high and more than 5 mg/dL, aggressive immunosuppressive therapy is
harmful. Such patients will be better managed with dialysis and transplantation
in due course.
Treatment of APS This can be considered under the following heads:
1. Deep venous thrombosis: The
main purpose of treatment here is to prevent pulmonary embolism. Standard
measures include bed-rest, elevation of the affected limb to allow the oedema
and tenderness to subside and anticoagulant therapy. Heparin and warfarin
should be started simultaneously so as to allow an overlap of about 5 days. INR
should be adjusted between 3 and 4 on long-term warfarin therapy. The duration
of warfarin therapy is life-long in patients with recurrent venous thrombosis.
Thrombolytics such as streptokinase, urokinase and tPA can be used but they are
not more effective in preventing pulmonary embolism. Thromboendarterectomy and
percutaneous insertion of IVC filter may be considered in special
circumstances.
2. Acute arterial thrombosis:
In a patient with APS this usually means a TIA or stroke, with MI and digital
gangrene being less common. In some patients with acute stroke (< 3 hours
duration), thrombolytics can be used but the standard of care is usually
heparin followed by warfarin. Low-dose aspirin is strongly recommended in
patients who continue having thrombotic events despite full anticoagulation.
APS patients with acute MI can be treated with thrombolytics, angioplasty or
coronary stents. Peripheral arterial thrombosis can be treated with
thrombolytics or heparin or angioplasty.
3. Catastrophic APS: These
patients develop thrombosis in multiple organs and the features mimic DIC and
TTP. Oral contraceptives and other drugs, pregnancy, infection and surgical
procedures have been identified as predisposing factors.
Crises of SLE
Treatment of the autoimmune crisis
High dose of
glucocorticoids including pulses therapy
A.
combination "pulses" therapy - 1000 mg of methylprednisolone + 1000 mg of
cyclophosphamide at the first day and then at the second and third day – only
1000 mg of methylprednisolone
B.
-combination of high doses of glucocoticoids and cyclosporine A (5 mg/kg per
day in the course of 6 weeks)
- plasmapheresis
Treatment of the cerebral
crisis
-
combination "pulses" therapy - 1000 mg of methylprednisolone + 1000 mg of
cyclophosphamide at the first day and then at the second and third day – only
1000 mg of methylprednisolone
-
cyclophosphanum (cyclophosphamide) intravenous
-
plasmapheresis
- immune
globulin 0,4 g/kg intravenous in the course of 5 days
Treatment of the hematologic
crisis
- high dose
of glucocorticoids including pulses therapy
-
combination of high doses of glucocoticoids and cyclosporine A (5 mg/kg per day
in the course of 6 weeks)
- immune
globulin 0,4 g/kg intravenous in the course of 5 days
SYSTEMIC SCLEROSIS
Systemic sclerosis (SSc) is a chronic multisystem disorder of unknown etiology characterized
clinically by thickening of the skin caused by accumulation of connective
tissue and by involvement of visceral organs, including the gastrointestinal
tract, lungs, heart, and kidneys.
Epidemiology
SSc has a worldwide
distribution and affects all races. The onset of disease is unusual in
childhood and young men. The incidence increases with age, peaking in the third
to fifth decade. Women overall are affected approximately three times as often
as men and even more often during the late childbearing years (8:1).
Etiology
Immunologic mechanisms and heredity (certain HLA
subtypes) play a role in etiology. SSc-like syndromes can result from exposure
to vinyl chloride, bleomycin, pentazocine, aromatic hydrocarbons,
contaminated rapeseed oil, or l-tryptophan.
Pathogenesis
IMMUNOLOGIC ABNORMALITIES: Patients with scleroderma
exhibit abnormalities of the humoral and cellular immune systems. The number of
circulating  lymphocytes is
normal, but there is evidence of hyperactivity, as manifested by
hypergammaglobulinemia and cryoglobulinemia. Antinuclear antibodies are common
but are usually in a lower titer than in SLE. Antibodies virtually specific for
scleroderma include nucleolar
autoantibodies, antibodies to ScL-
Cellular immune derangements in
progressive systemic sclerosis include a decrease in the number of circulating
T cells, a decrease in helper T cells, and an increase in suppressor T cells.
Although functional lymphocyte studies are inconclusive, lymphocytes from patients with this disease are sensitized to skin
extracts or collagen. They respond to these substances by proliferating and by
producing lymphokines, which may cause chemotaxis and enhanced collagen
synthesis by fibroblasts.
Other disorders associated with autoimmune
phenomena, such as thyroiditis and primary biliary cirrhosis, are increased in
incidence in patients with scleroderma.
http://www.sciencedirect.com/science/article/pii/S0049017207001771
FIBROSIS: Progressive
systemic sclerosis is characterized by excessive collagen deposition in many
tissues. Although the cause remains obscure, it is thought that this fibrosis
may be due to an abnormality in fibroblast function. Fibroblasts from patients
with this disorder show increased collagen
synthesis in tissue culture, possibly because T cells sensitized to
collagen produce lymphokines.
CHROMOSOMAL CHANGES: Almost all (96%) of patients with scleroderma have chromosomal
abnormalities, such as chromatid breaks, translocations, and deletions. These
abnormalities are acquired rather than inherited and are associated with a
"serum breaking factor." The significance of these chromosomal
abnormalities is unclear.
PATHOLOGY
The skin in scleroderma displays
early edema and then induration, with the latter characterized by the
following:
•
A striking increase in collagen fibers in the
reticular dermis
•
Thinning of the epidermis with loss of rete pegs
•
Atrophy of dermal appendages
•
Hyalinization and obliteration of arterioles
•
Variable mononuclear infiltrates, consisting primarily
of T cells
The stage of induration may progress
to atrophy or revert to normal. Similar histologic
alterations occur in the synovium, lungs, gastrointestinal tract, heart,
and kidneys.
Classification
|
Classification of
Scleroderma |
|
Localized
Scleroderma (Localized cutaneous fibrosis) |
|
·
Limited
or generalized morphea: Circumscribed patches of sclerosis ·
Linear
scleroderma: Linear lesions seen in childhood ·
En
coup de sabre: Linear lesions of the scalp or face |
|
Systemic
Scleroderma (Cutaneous and noncutaneous involvement) |
|
·
Limited cutaneous systemic sclerosis (lcSSc), formerly called CREST syndrome (calcinosis of the digits, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) ·
Diffuse
cutaneous systemic sclerosis (dcSSc): Sclerosis of proximal extremities, trunk,
and face ·
Systemic
sclerosis sine scleroderma (ssSSc): Organ fibrosis on; no skin thickening |
CLINICAL MANIFESTATIONS
Skin
In the skin,
a thin epidermis overlies compact bundles of collagen that lie parallel to the epidermis.
Fingerlike projections of collagen extend from the dermis into the subcutaneous
tissue and bind the skin to the underlying tissue. Dermal appendages are
atrophied, and rete pegs are lost. In early stages of disease, a mononuclear
cell infiltrate of predominantly T cells surrounds small dermal blood vessels.
Increased numbers of T cells, monocytes, plasma cells, and mast cells are
found, particularly in the lower dermis of involved skin.
Gastrointestinal Tract
In the lower
two-thirds of the esophagus, the histologic findings consist of a thin mucosa
and increased collagen in the lamina propria, submucosa, and serosa. The degree
of fibrosis is less than in the skin. Atrophy of the muscularis in the
esophagus and throughout the involved portions of the gastrointestinal tract is
more prominent than the amount of fibrotic replacement of muscle. Ulceration of
the mucosa is often present and may be due to either SSc or superimposed peptic
esophagitis. Chronic esophageal reflux can lead to metaplasia of the lower
esophagus (Barrett's esophagus), which is a premalignant lesion. Striated
muscles in the upper third of the esophagus are relatively spared. Similar
changes may be found throughout the gastrointestinal tract, especially in the
second and third portions of the duodenum, in the jejunum, and in the large
intestine. Atrophy of the muscularis of the large intestine may lead to the
development of large-mouth diverticula. In the later stages of the disease, the
involved portions of the gastrointestinal tract become dilated. Infiltration of
lymphocytes and plasma cells in the lamina propria is also present.
Lung
With pulmonary involvement, diffuse
interstitial fibrosis, thickening of the alveolar membrane, and peribronchial
and pleural fibrosis are observed. Bronchiolar epithelial proliferation
accompanies the pulmonary fibrosis. Rupture of septa produces small cysts and
areas of bullous emphysema. Small pulmonary arteries and arterioles show
intimal thickening, fragmentation of the elastica, and muscular hypertrophy;
this may occur without interstitial pulmonary fibrosis and produce pulmonary
hypertension, particularly in a subset of patients with limited cutaneous SSc.
Musculoskeletal System
The synovium
in patients with arthritis is similar to that seen in early rheumatoid
arthritis and shows edema with infiltration of lymphocytes and plasma cells. A
characteristic finding is a thick layer of fibrin overlying and within the
synovium. Later in the disease the synovium may become fibrotic. Fibrinous deposits
appear on the surfaces of tendon sheaths and in the overlying fascia and may
lead to audible creaking over moving tendons.
Histologic
features of primary myopathy consist of interstitial and perivascular
lymphocytic infiltrations, degeneration of muscle fibers, and interstitial
fibrosis. Arterioles may be thickened, and capillaries may be decreased in
number. Pathologic and electrophysiologic findings of polymyositis in proximal
muscles are present in the few patients who are considered to have the overlap
syndrome of SSc and polymyositis.
Heart
Cardiac
involvement consists of degeneration of myocardial fibers and irregular areas
of interstitial fibrosis that are most prominent around blood vessels.
Intermittent spasm of blood vessels may result in contraction band necrosis,
similar to change observed in myocardial infarction in patients with
atherosclerotic coronary artery disease. Fibrosis also involves the conduction
system, leading to atrioventricular conduction defects and arrhythmias. The
wall of smaller coronary arteries may be thickened. Fibrinous pericarditis and
pericardial effusions are found in some patients.
Kidney
Renal
involvement is found in over half the patients and consists of intimal
hyperplasia of the interlobular arteries; fibrinoid necrosis of the afferent
arterioles, including the glomerular tuft; and thickening of the glomerular
basement membrane. Small cortical infarctions and glomerulosclerosis may be
present. The renal pathologic change is often indistinguishable from that observed
in malignant hypertension. Renal vascular lesions, however, may be present in
the absence of hypertension. Immunofluorescence studies of kidney have shown
IgM, complement components, and fibrinogen in the walls of affected vessels.
Angiographic renal studies in patients with SSc may show constriction of the
intralobular arteries, a finding that simulates the vasospasm of the digital
arteries observed in Raynaud's phenomenon. Cold-induced Raynaud's phenomenon
has been shown to decrease renal blood flow.
Other Organs
Primary
liver involvement is not common. Primary biliary cirrhosis occurs in some
patients, particularly in those with the limited cutaneous form of SSc.
Fibrosis of the thyroid gland may develop in the presence or absence of
autoimmune thyroiditis.
Thickening
of the periodontal membrane with replacement of the lamina dura is demonstrated
radiographically as widening of the periodontal space and may cause gingivitis
and loosening of the teeth. The decreased oral aperture and mucosal dryness
make eating and oral hygiene difficult.
CLINICAL MANIFESTATIONS
|
Clinical Features of Systemic Sclerosis |
|
||
|
|
Percent of Patients with Clinical Feature during Course of Disease |
||
|
Clinical Feature |
Limited |
Diffuse |
|
|
Raynaud's phenomenon |
95-100 |
90-95 |
|
|
Skin thickening |
98b |
100 |
|
|
Subcutaneous calcinosis |
50 |
10 |
|
|
Telangiectasia |
85 |
40 |
|
|
Arthralgias/arthritis |
40 |
70 |
|
|
Myopathy |
5 |
50 |
|
|
Esophageal dysmotility |
80 |
80 |
|
|
Pulmonary fibrosis |
35 |
40 |
|
|
Isolated pulmonary arterial
hypertension |
<10 |
<1 |
|
|
Congestive heart failure |
<1 |
30 |
|
|
Renal crisis |
<1 |
15 |
|
|
a Limited cutaneous and
diffuse cutaneous subsets of SSc. |
|
||
|
b 2% or fewer of patients
have SSc sine scleroderma. |
|
||
There are two major
forms of scleroderma, localized scleroderma and systemic scleroderma
(sclerosis). Diffuse (dcSSc) and limited (lcSSc) scleroderma are the two main types
of systemic sclerosis.
Scleroderma limited
to the skin only can be subdivided into morphea and linear scleroderma.
The clinical spectrum of
scleroderma. In literature the concept of scleroderma is synonymous with all
subgroups presented above.
Localized
Scleroderma
The more
common form of the disease, localized scleroderma, only affects the skin
without any internal organ involvement. It often appears in the form of waxy
patches (morphea) or streaks on the skin (linear scleroderma).
Vascular abnormalities,
especially of the microvasculature are a prominent feature of SSc. The degree
and rate of skin and internal organ involvement vary among patients. Two
subsets, however, can be identified, even though there is some overlap.
|
Subsets of Systemic Sclerosis |
|||
|
|
Diffuse |
Limiteda |
|
|
Skin involvement |
Distal and proximal
extremities, face, trunk |
Distal to elbows, face |
|
|
Raynaud's phenomenon |
Onset within 1 year or at
time of skin changes |
May precede skin disease by
years |
|
|
Organ involvement |
Pulmonary (interstitial fibrosis);
renal (renovascular hypertensive crisis); gastrointestinal; cardiac |
Gastrointestinal; pulmonary
arterial hypertension after 10-15 years of disease in <10% of patients;
biliary cirrhosis |
|
|
Nail fold capillaries |
Dilatation and dropout |
Dilatation without significant
dropout |
|
|
Antinuclear antibodies |
Antitopoisomerase 1 |
Anticentromere |
|
One subset
is referred to as diffuse cutaneous
scleroderma and is characterized by the rapid development of symmetric skin
thickening of proximal and distal extremities,
These
criteria are not, however, applicable to clinical practice as many patients
have SSc who do not meet these criteria. Scleroderma can also occur in a
localized form limited to the skin, subcutaneous tissue, and muscle and without
systemic involvement. Localized scleroderma occurs most often in children and
young women but can affect any age group. The two localized forms are morphea,
which occurs as single or multiple plaques of skin induration, and linear
scleroderma, which involves an extremity or face. Linear scleroderma of one
side of the forehead and scalp produces a disfiguration referred to as en coup
de sabre because it resembles a wound from a sword. It may be associated with
hemiatrophy of the same side of the face.
SSc also
occurs in association with features of other connective tissue diseases. The
term overlap syndrome has been used to describe such patients. Undifferentiated
connective tissue disease has been suggested as a designation for patients who
do not have diagnostic criteria for any one connective tissue disease.
Clinical
manifestations of scleroderma. A, Generalized morphea. B, Diffuse edema of
hands. C, Firm, thickened skin. D, Flexion contractures of fingers. E,
Raynaud's phenomenon (pallor phase).
It is not
uncommon for this less severe form of scleroderma to regress or stop
progressing without treatment.
On these
photo: Ischemic digital ulcer, telangectasias on the face, dorsum of the hand mucosa, calcinosis cutis.
Systemic Scleroderma
Systemic scleroderma always leads
to some internal organ involvement. It is further divided into two subsets of
disease, limited or diffuse. According to LeRoy and colleagues, limited or
diffuse disease is based on the extent of skin tightening. In limited disease (formerly called CREST)
CREST syndrome
[calcinosis, Raynaud's
phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias]
syndrome), skin tightening is confined to the fingers, hands, and forearms
distal to the elbows, with or without tightening of skin of the feet and of the
legs distal to the knees. Proximal extremities and the trunk are not involved.
In diffuse disease or diffuse cutaneous systemic sclerosis (dcSSc), the skin of
the proximal extremities and trunk is also involved. Both dcSSc and lcSSc are
associated with internal organ involvement; however, patients with dcSSc are at
greater risk for clinically significant major organ dysfunction. Systemic
sclerosis sine scleroderma (ssSSc) is a rare disorder in which patients develop
vascular and fibrotic damage to internal organs (phenotypically similar to that
in limited scleroderma), in the absence of cutaneous sclerosis.
|
Subsets of Systemic Sclerosis |
|
Diffuse Cutaneous Systemic Sclerosis (dcSSc) |
|
·
Onset of Raynaud's within 1
year of onset of skin changes (puffy or hidebound) ·
Truncal and acral skin involvement
·
Presence of tendon friction
rubs ·
Early and significant
incidence of interstitial lung disease, oliguric renal failure, diffuse
gastrointestinal disease, and myocardial involvement ·
Absence of anticentromere
antibodies ·
Nailfold capillary dilation
and capillary destruction ·
Antitopoisomerase antibodies
(30% of patients) |
|
Limited Cutaneous Systemic Sclerosis (LcSSc) |
|
·
Raynaud's phenomenon for
years (occasionally decades) ·
Skin involvement limited to hands,
face, feet, and forearms (acral) or absent ·
A significant late incidence
of pulmonary hypertension, with or without interstitial lung disease,
trigeminal neuralgia, skin calcifications, telangiectasias ·
A high incidence of
anticentromere antibodies (70%-80%) ·
Dilated nailfold capillary
loops, usually without capillary dropout |
Raynaud's Phenomenon SSc usually begins insidiously; the first
symptoms are frequently Raynaud's phenomenon and puffy fingers. Some 95% of patients
will experience Raynaud's phenomenon, which is defined as episodic
vasoconstriction of small arteries and arterioles of fingers, toes, and
sometimes the tip of the nose and earlobes. Episodes are brought on by cold
exposure, vibration, or emotional stress. Patients experience pallor and/or
cyanosis followed by rubor on rewarming. Pallor and/or cyanosis are usually
associated with coldness and numbness of fingers and/or toes, and rubor with
pain and tingling. Not all patients appreciate the three color phases. A
history of digit pallor appears to be the most reliable symptom for the
presence of Raynaud's phenomenon. Raynaud's phenomenon may precede skin changes
by several months or even years in those patients who subsequently develop the
limited cutaneous form of SSc. In diffuse cutaneous SSc, skin changes are seen
typically within a year of the onset of Raynaud's phenomenon. After 2 or more
years of Raynaud's phenomenon, few patients who have this as their only symptom
will subsequently develop SSc.
Raynaud's phenomenon
is characterized by blood vessel spasms in the fingers, toes, ears or nose,
usually brought on by exposure to cold. Raynaud's phenomenon and Raynaud's
disease, a similar disorder, may occur on their own or they may be associated with
autoimmune disorders such as rheumatoid arthritis, systemic lupus
erythematosus, and most frequent in scleroderma.
Skin Features
In early
disease, fingers and hands are swollen. Swelling may also involve forearms,
feet, lower legs, and face. However, lower extremities are relatively spared.
This edematous phase may last for a few weeks, months, or even longer. The
edema may be pitting or nonpitting and accompanied by erythema. The skin
changes begin distally in the extremities and advance proximally. The skin
gradually becomes firm, thickened, and eventually tightly bound to underlying
subcutaneous tissue (indurative phase). In patients with diffuse cutaneous
scleroderma, skin changes will become generalized, involving initially the
extremities, followed by the face and trunk over a period of time, varying from
months to a few years. In some patients, the skin changes may develop gradually
over several years. Rapid progression of these changes over a 1- to 3-year
period is associated with a greater risk of visceral disease, particularly of
the lungs, heart, or kidneys. Also in diffuse cutaneous SSc, the skin changes
usually peak in 3 to 5 years and then slowly improve. On the other hand,
patients with limited cutaneous scleroderma will usually have a more gradual
progression of skin changes, which are restricted to fingers or distal
extremity and face and may continue to worsen. In both subsets of SSc, skin
thickening is usually greater in the distal extremity. After many years of
disease, the skin may soften and return to normal thickness or become thin and
atrophic.
Case report: female 20 years of age. Early stage scleroderma shows facial skin
involvement resulting in a total change of the facial expression due to loss of
the contours of the skin.
Case report: Female 34 years of age. Aggressive form of scleroderma with widespread skin
involvement. Total elimination of the facial expression, numerous
telengiectasia in plaque form, pointy nose, microstomia with a deviation due to
TMJ resorption.
Pronounced retrognat profile and typical shiny facial skin. Loss of
mandibular ramus shows clinically. The eye gives a sunk in expression.
The Hands of a Young Woman after Several Months of Rapidly Progressive
Scleroderma. The skin is taut and indurated, and there is limitation of both
fist closure and finger extension.
The Face of a Young Woman with Several Months of Rapidly Progressive
Scleroderma. The facial skin is taut with an immobile facies and limitation of
the oral aperture.
The face of a woman with long-standing diffuse scleroderma exhibiting
multiple telangiectasias and exaggerated radial furrowing
Shiny and thickened skin with effacement of normal
markings secondary to tautness, called sclerodactyly, is seen in this image.
Advanced Changes of Scleroderma in the Hand of a Woman with Long-Standing
Disease. The skin is taut and thickened, with irregular pigmentary change and
palmar telangiectasias. Ulcerations are present over bony prominences and the
fingers reveal extensive trophic abnormalities.
Multiple ischemic digital tip ulcerations and a single digit with sharply
demarcated dry gangrene in the hands of a woman with long-standing limited
scleroderma.
Scleroderma, which
is often known as systemic sclerosis, is a progressive and chronic connective tissue
disorder, and is often classified as a rheumatic disease. Some unknown factor
triggers the over-production of collagen (body protein) causing thickening,
hardening and scarring of the skin and other organs. Normally collagen keeps
the skin soft, but the overproduction makes the affected tissue thick and hard.
This, in turn, affects the amount of blood the small vessels carry to many
parts of the body.
In the
extremities, the taut skin over fingers gradually limits full extension, and
flexion contractures develop. Ulcers may appear on the volar pads of the
fingertips and over bony prominences such as elbows, malleoli, and the extensor
surface of the proximal interphalangeal joints of the hands. These ulcers may
become secondarily infected. The volar pads of the fingertips develop pitting
scars and lose soft tissue. In some instances, resorption of the terminal
phalanges occurs. Skin over the extremities, face, and trunk may become darkly
pigmented, even without exposure to the sun. Hyperpigmentation of the skin may
occur over superficial blood vessels and tendons. Areas of hypopigmentation may
also develop, similar to vitiligo, involving the eyebrows, scalp, and trunk.
The sparing of pigment around hair follicles gives the skin a "salt-and-pepper"
appearance. Other patients may develop a diffuse tanning of the skin. The skin
loses hair, oil, and sweat glands and so becomes dry and coarse. Vaginal
dryness occurs and may cause dyspareunia.
In some patients,
particularly those with the limited cutaneous form of disease, calcific
deposits develop in intracutaneous and subcutaneous tissue. The sites commonly
involved are periarticular tissue, digital pads, olecranon and prepatellar
bursae, and skin along the extensor surface of the forearms.
|
|
|
Linear Scleroderma of the Face (Coup de Sabre) in a 13-Year-Old Boy with
8 Years of Disease. Atrophy of the subcutaneum and of the mandible are apparent,
as is an isolated depression of bone over the forehead. Progressive facial
distortion has occurred along with the ongoing asymmetric growth. Reconstructive surgery is
planned for early adulthood. |
|
Linear Scleroderma of the Left Leg in an 11-year-Old Girl. Diffuse muscle
atrophy is apparent. As this patient enters puberty, progressive leg length
discrepancy is expected. |
|
|
|
|
|
|
|
|
|
The Arm of a 59-Year-Old Woman with 4 Months of Eosinophilic Fasciitis.
The superficial skin is not thickened but is irregularly tethered to deeper
tissues that have a woody induration. There is a coarse, orange peel
appearance and patchy erythema. The exaggerated furrow over the course of
superficial veins in the volar forearm is pathognomonic of idiopathic
eosinophilic fasciitis and of the fasciitis secondary to the
eosinophilia-myalgia syndrome. |
The overlying
skin may break down, with drainage of calcific material. Involvement of the
face results in thinning of the lips, loss of skin wrinkles and facial
expression, as well as microstomia, which may make eating and dental hygiene
difficult. The nose takes on a pinched or beaklike appearance. Wrinkles appear
around the mouth perpendicular to the lips. Small telangiectatic mats may
appear on the fingers, face, lips, tongue, and buccal mucosa after several
years. They are seen more frequently in patients with limited cutaneous SSc but
are also observed in patients with long-standing diffuse cutaneous SSc. The
capillary beds of nail folds of the fingers may show enlargement of capillaries
with little or no capillary loss, usually indicative of limited cutaneous
scleroderma. In diffuse cutaneous scleroderma, there is disorganization of the
capillary beds with dilated capillaries interspersed with areas where
capillaries have disappeared. These capillary changes, which are observed by
wide-angle microscopy or with an ophthalmoscope used as a magnifier, are not
found in patients who have only Raynaud's phenomenon.
Musculoskeletal Features
More than
half the patients with SSc complain of pain, swelling, and stiffness of the
fingers and knees. A symmetric polyarthritis resembling rheumatoid arthritis
may be seen. In more advanced stages of the disease, leathery crepitation can
be palpated over moving joints, especially the knee. Extensive fibrotic
thickening of the tendon sheaths in the wrist can produce a carpal tunnel
syndrome. Muscle weakness is usually present in patients with severe skin
involvement and, in most cases, is due to disuse atrophy. There is a
distinctive histologic myopathy that accompanies SSc that is not associated
with muscle enzyme abnormalities. A few patients develop a myositis
characterized by proximal muscle weakness and muscle enzyme elevations that are
identical to polymyositis (overlap syndrome). In addition to terminal
phalanges, resorption of bone may involve ribs, clavicle, and angle of
mandible.
|
|
|
Scleroderma. This posterioranterior radiograph demonstrates flexion of
the fingers, loss of the tufts of the index finger and middle finger distal
phalanges and calcification including finger tip calcification. |
|
|
|
The radiograph shows almost complete osteolysis of the carpal bones with
focal osteolytic changes in several digits and bony fusion of the third
distal interphalangeal joint. |
|
Roentgenogram of the fingers revealing resorption and dissolution of the
phalangeal tufts and multiple areas of punctate subcutaneous calcinosis. |
The majority
of patients from both subsets of SSc have gastrointestinal involvement.
Symptoms attributable to esophageal involvement are present in >50% of patients
and include epigastric fullness, burning pain in the epigastric or retrosternal
regions, and regurgitation of gastric contents. These symptoms, most noticeable
when the patient is lying flat or bending over, are due to the reduced tone of
the gastroesophageal sphincter and to dilatation of the distal esophagus.
Peptic esophagitis frequently occurs and may lead to strictures and narrowing
of the lower esophagus. However, it seldom results in bleeding. Barrett's
metaplasia may develop, but transition to adenocarcinoma is uncommon.
Dysphagia, particularly of solid foods, may occur independent of other
esophageal symptoms and is caused by loss of esophageal motility due to
neuromuscular dysfunction. Manometry or cineradiography reveals decreased amplitude
or disappearance of peristaltic waves in the lower two-thirds of the esophagus.
Raynaud's phenomenon in the absence of a connective tissue disease is also
associated with esophageal dysmotility. Later in the course of the illness,
dilatation and atony of the lower portion of the esophagus as well as reflux
are seen. With gastric involvement, barium studies show dilatation, atony, and
delayed gastric emptying. Patients may complain of early satiety. Gastric
outlet obstruction can also occur.
Hypomotility
of the small intestine produces symptoms of bloating and abdominal pain and may
suggest an intestinal obstruction or paralytic ileus (pseudoobstruction).
Malabsorption syndrome with weight loss, diarrhea, and anemia is due to
bacterial overgrowth in the atonic intestine or possibly to obliteration of
lymphatics by fibrosis. Roentgenographic features of the second and third
portions of the duodenum and of the jejunum include dilatation, loss of the
usual feathery pattern, and delayed disappearance of barium. Pneumatosis
intestinalis occasionally occurs and appears as radiolucent cysts or linear
streaks within the wall of the small intestine. Benign pneumoperitoneum may
result from the rupture of these cysts. Involvement of the large intestine may
cause chronic constipation and fecal impaction with episodes of bowel
obstruction. A segment of atonic bowel may act as a fulcrum for intussuception
to occur. Barium studies of the large intestine may show dilatation, atony, and
large-mouth diverticula. Laxity of the anal sphincter may cause incontinence or
rarely anal prolapse. Some patients may have gastrointestinal features of SSc
with little or no cutaneous or other organ involvement, referred to as SSc sine
scleroderma. Vascular ectasia may develop in the stomach and intestine and can
be the source of gastrointestinal bleeding. These dilated submucosal
capillaries in the stomach appear on endoscopy as broad stripes¾hence the term
"watermelon stomach."
Pulmonary
Features Pulmonary involvement occurs in at least two-thirds
of SSc patients and is now the leading cause of death in SSc, replacing renal
disease, which can usually be treated effectively. The most common symptom is
exertional dyspnea, often accompanied by a dry, nonproductive cough. Bilateral
basilar rales may be present. In the majority of patients, symptoms usually
correlate with radiologic evidence of pulmonary fibrosis and with restrictive
lung disease on pulmonary function tests.
Pulmonary
function tests are frequently abnormal and show a reduction in vital capacity
and decreased lung compliance. Impairment of gas exchange is reflected by a low
diffusing capacity and low PO2 with exercise. These abnormalities may be
present even when the chest radiograph is normal. Chest film may show a pattern
of linear densities, mottling, and honeycombing involving most prominently the
lower two-thirds of the lung. Early interstitial pulmonary disease can be
detected by high-resolution computed tomography (HRCT) and bronchoalveolar
lavage (BAL).
Active
inflammatory alveolitis gives a "ground glass" appearance on HRCT.
The recovery by BAL of increased numbers of cells, mostly alveolar macrophages
accompanied by neutrophils or eosinophils, is evidence for alveolitis. Both interstitial fibrosis and
vascular lesions are found in the lungs of patients with SSc.
http://www.learningradiology.com/caseofweek/caseoftheweekpix2009-340/cow357-1arr.jpg
Interstitial
pulmonary fibrosis may be the predominant lesion in patients with diffuse or
limited cutaneous SSc. Patients with diffuse cutaneous involvement who have
antitopoisomerase 1 antibodies are particularly at risk of developing severe
pulmonary fibrosis. In the absence of significant interstitial fibrosis, a
severe form of pulmonary arterial hypertension may develop after many years of
disease in a subset of patients with limited cutaneous SSc. Fewer than 10% of
patients will develop this complication, which is caused by narrowing and
obliteration of pulmonary arteries and arterioles by intimal fibrosis and
medial hypertrophy. Pulmonary hypertension is manifested initially by
exertional dyspnea and eventually by the appearance of right-sided heart
failure. Pulmonary artery pressure can be measured noninvasively by
two-dimensional echocardiography. The prognosis is extremely poor with the
development of pulmonary hypertension; the mean duration of survival is
approximately 2 years.
A less
common pulmonary problem is aspiration pneumonia resulting from gastric reflux
due to lower esophageal atony. Restriction of chest movement caused by
extensive fibrotic skin involvement of the thorax rarely occurs. Superimposed
bacterial or viral infection can be a serious complication in patients with
pulmonary fibrosis. An increased frequency of alveolar cell and bronchogenic
carcinoma is seen in patients with pulmonary fibrosis.
Cardiac Features
Primary
cardiac involvement in SSc includes pericarditis with or without effusions,
heart failure, and varying degrees of heart block or arrhythmias. The majority
of patients with diffuse cutaneous SSc have cardiac abnormalities.
Cardiomyopathy attributable to myocardial fibrosis appears in <10% of
patients and involves primarily those patients with diffuse cutaneous
scleroderma. Radionuclide studies have shown abnormalities of left ventricular
function due to myocardial fibrosis. Cold-induced vasospasm of the hands
produces defects in myocardial thallium perfusion. The characteristic pathologic
feature of contraction band necrosis results from cardiac muscle damage caused
by intermittent vasospasm of coronary vessels. Patients may experience angina
pectoris even though coronary angiograms are normal. Patients can also develop
left ventricular failure secondary to systemic hypertension or cor pulmonale
secondary to pulmonary arterial hypertension.
Renal Features
Renal
failure was the leading cause of death in SSc until the advent of effective treatment.
Significant renal disease occurs mostly in those patients with diffuse
cutaneous scleroderma. A high risk of renal crisis is present in those patients
who have rapidly progressive widespread skin thickening in their first 2 to 3
years of disease. Renal crisis is characterized by malignant hypertension,
which can progress rapidly to renal failure. These patients manifest
hypertensive encephalopathy, severe headache, retinopathy, seizures, and left
ventricular failure. Hematuria and proteinuria are followed by oliguria and
renal failure. The mechanism for the hypertensive crisis is activation of the
renin-angiotensin system. Before the advent of effective antihypertensive
drugs, the majority of these patients died within 6 months. A small number of patients
may develop renal crises in the absence of hypertension. Renal failure can also
develop insidiously later in the course of disease in the setting of mild to
moderate hypertension and proteinuria. In these patients or those with
clinically unrecognized renal disease, reduction of renal plasma flow secondary
to heart failure or volume depletion resulting from overdiuresis may
precipitate renal crisis. An indicator of impending renal failure is
microangiopathic anemia, which may occur in a normotensive patient. The
presence of a large chronic pericardial effusion may also herald subsequent
renal failure.
Other Features
Symptoms of dry eyes and/or dry mouth are frequently present in patients
with SSc. Lip biopsy may show lymphocytic infiltration of minor salivary glands
characteristic of Sjogren's syndrome or intraglandular or periglandular
fibrosis secondary to SSc. Antibodies to SS-A (Ro) and/or SS-B (La) are found
in those patients with lip biopsies consistent with Sjogren's syndrome (overlap
syndrome-SSc and Sjogren's syndrome) and not in those with salivary gland
fibrosis.
Hypothyroidism
occurs in a significant number of patients and may be associated with high
levels of antithyroid antibodies. Fibrosis of the thyroid gland may be present
but also occurs in the absence of autoimmune thyroiditis. Other manifestations
of SSc include trigeminal neuralgia and male impotence secondary to decreased
penile tumescence. These men have normal serum levels of testosterone and
gonadotropins. Pathogenesis of this abnormality has been considered to be
caused by vascular and/or autonomic nervous system abnormalities. Biliary
cirrhosis is occasionally observed in patients with limited cutaneous SSc.
The 1980 Criteria for systemic sclerosis (ACR)
Major criterion:
Proximal
scleroderma: symmetric thickening, tightening, and induration of the skin of
the fingers and/or the skin proximal to the metacarpophalangeal or
metatarsophalangeal joints. The changes may affect the entire extremity, face,
neck, and trunk (thorax and abdomen).
Minor criteria:
1.
Sclerodactyly: preceding skin changes limited to the finger.
2. Digital
pitting scars or loss of substance from the finger pad: depressed areas at tips
of fingers or loss of digital pad tissue as a result of ischemia.
3. Bibasilar
pulmonary fibrosis: bilateral reticular pattern of linear or lineonodular
densities most pronounced in basilar portions of the lungs on standard chest
roentgenogram; may assume appearance of diffuse mottlng or “honeycomb lung”.
These changes should not be attributable to primary lung disease.
*The patient should fulfi
ll the major criterion or two of the three minor criteria.
LABORATORY FINDINGS
The
erythrocyte sedimentation rate may be elevated. Hypoproliferative anemia
related to chronic inflammation is the most common cause of anemia in SSc.
Anemia may also be caused by iron deficiency secondary to gastrointestinal
bleeding. Bacterial overgrowth due to atony of the small bowel may lead to
vitamin B12 and/or folic acid-deficiency anemia. Microangiopathic hemolytic
anemia is most often associated with renal involvement and is caused by the
presence of intravascular fibrin in renal arterioles. Polyclonal
hypergammaglobulinemia, consisting mostly of IgG, is found in approximately
half the patients. Rheumatoid factor, in low titer, is present in 25% of
patients. Cryoglobulins may be present in the serum. Antinuclear antibodies
detected by using a cultured human laryngeal carcinoma cell line (HEp-2)
substrate are present in 95% of patients (Table 7).
|
Table 7. Autoantibodies in Systemic Sclerosis |
|||
|
Autoantibody |
Clinical Association |
Percent |
|
|
Antitopoisomerase 1 |
Diffuse cutaneous SSc |
40 |
|
|
Anticentromere |
Limited cutaneous SSc |
60-80 |
|
|
Anti-RNA polymerase I, II, III |
Diffuse cutaneous SSc |
5-40 |
|
|
Anti-Th RNP |
Limited cutaneous SSc |
14 |
|
|
Anti-U1 RNP |
Limited cutaneous SSc Mixed connective tissue
disease |
5-10 95-100 |
|
|
Anti-PM/Scl |
Overlap (SSc, polymyositis) |
25 |
|
|
|
|||
Antinuclear antibodies that
have a high specificity for SSc are antitopoisomerase 1 (Scl-70),
antinucleolar, and anticentromere. Antitopoisomerase 1, originally called
anti-Scl-70, recognizes the nuclear enzyme DNA topoisomerase
Laboratory Studies
The following findings may be found with laboratory
studies:
·
Increased erythrocyte sedimentation rate
·
Thrombocytopenia
·
Hypergammaglobulinemia
·
Microangiopathic hemolytic anemia
·
Increased creatine phosphokinase levels in patients
with muscle involvement
·
Increased urea and creatinine levels in patients with
kidney involvement
·
C-reactive protein: The nonspecific inflammatory
marker C-reactive protein was found elevated in about one quarter of patients
with systemic sclerosis, especially early disease, in whom it correlated with
disease activity, severity, poor pulmonary function, and shorter survival.
Imaging Studies
Chest radiographs may show normal findings in 5-10% of
the patients, even when the patients have respiratory tract symptoms. In
approximately 30-60% of patients, fibrosis of the basal parts of the lungs is
observed. Occasionally, pictures of diffuse ground-glass and honeycomb lung
patterns are observed. In patients with honeycomb lung patterns, changes are
irreversible. These changes can be an important feature of patient's response
to treatment.
Bone radiography reveals generalized osteopenia, which
most commonly affects the hands. Intra-articular calcifications often are
observed.
High-resolution computed tomography (HRCT) and
scintigraphy reveal thickening of the alveolar walls and intestinal tissue and
honeycomb-appearing lungs.
http://www.learningradiology.com/caseofweek/caseoftheweekpix2009-340/cpw357-2arr.jpg
Gastrointestinal tract changes may be depicted.
Scintigraphy of the esophagus may reveal a disturbance
of the esophageal passage.
Manometric esophageal changes may be observed during
invasive examination.
Cardiac and pulmonary vascular involvement in systemic
sclerosis should be evaluated. Cardiac abnormalities may be assessed by Doppler
echocardiography. Left- and right-sided heart diseases were found to
be common in persons with systemic sclerosis. A few patients had a restrictive
mitral flow pattern, possibly due to primary cardiac involvement of systemic
sclerosis.
Because cardiac involvement is one of the major
problems in systemic sclerosis, evaluation of ventricular function using
echocardiographic strain imaging should be considered, because it appears to be
useful to detect subclinical cardiac involvement in systemic sclerosis patients
with normal standard echocardiographic and tissue Doppler velocity findings.
With bronchoalveolar
lavage (BAL), abnormal numbers of granulocytes, particularly neutrophils
and eosinophils are present in BAL fluid. In addition, the concentration of
vascular endothelial growth factor may be low.
Lung function tests reveal ventilation-perfusion
changes, including the following:
·
Reduced carbon monoxide diffusion capacity
·
A reduced partial pressure of oxygen, with a normal or
low partial pressure of carbon dioxide
·
Restrictive ventilatory defect, with reductions in
pulmonary compliance, vital capacity, and total lung capacity
·
Decreased diffusion capacity of carbon monoxide
transfer factor (DLCO) levels, which is a measure of diffusion capacity
The gas transfer measurement (KCO), adjusted for
alveolar volume, is also reduced.
Heart changes, including myocardial disease,
pericardial problems, conduction system disease, and arrhythmias, can be
observed with the following tests:
·
Electrocardiography (ECG)
·
Holter 24-hour monitoring
·
Doppler ultrasonography (US)
Exophthalmos, macroglossia, and/or gigantism may be
present, with increased polyphasic potentials of normal or decreased amplitude.
Antihistone
antibodies can be observed in the course of systemic sclerosis,
but they are not characteristic. The following antinuclear antibodies (ANAs) are characteristic of scleroderma:
·
Antibodies
against topoisomerase I DNA (Scl 70) are
detected in the serum of patients with systemic sclerosis. The antibodies are
detected in two thirds of patients with dSSc and interstitial lung fibrosis.
·
Anticentromere
antibodies (ACAs) are most commonly detected in patients with lSSc; in
these patients, changes in the heart, kidneys, and lungs (without fibrosis) are
observed less frequently than in other patients.
ANAs can be detected in the course of systemic
sclerosis. ANAs include antibodies against fibrillarin, a 34-kd protein of
ribonucleoprotein U3 RNP; antibodies against the ribonucleoprotein nucleolar
7-2 RNA protein particle Th RNP; and antibodies to 20-110-kd proteins related to
preribosomes (PM-Scl). Anti-PM/Scl antibodies are seen in roughly 24% of
patients with polymyositis/systemic sclerosis overlap syndrome. They are also
found in 3-10% of systemic sclerosis patients. The spectrum of
systemic sclerosis-associated ANA differs in patients with and without
cutaneous involvement.
Elevated high-sensitivity C-reactive protein appears
related to the occurrence of antimitochondrial antibody in these patients.
With capillary
microscopy, enlarged capillaries are observed in all 3 portions of the
capillary nail fold–arterial, apical, and venous– and especially at the edge of
the nail fold. Adjacent areas are avascular.
Spirometry
demonstrates functional lung disturbances. In approximately 70% of patients,
the DLCO is decreased.
Histologic Findings
In the active indurative phase, a loss of rete ridges
occurs, epidermal skin appendages atrophy, and collagen fibers in the reticular
dermis appear broad and hyalinized. A loss of space between collagen bundles is
noted. Mononuclear cells, mostly T cells, form a variable perivascular
infiltrate in the deep dermis and subcutis. Later, sclerotic changes
predominate. The number of adnexal structures is reduced, and a loss of
periadnexal fat is noted.
The amount of hyalinized collagen, myofibroblasts,
mean epidermal thickness, the mononuclear cellular infiltration, and the
frequency of focal exocytosis varied significantly between those with and those
without local clinical skin involvement.
TREATMENT
EULAR
recommendations:
I.
SSc-related digital vasculopathy (Raynaud’s phenomenon, digital ulcers).
1.
Nifedipine and intravenous iloprost reduce the
frequency and severity of SSc-related Raynaud’s phenomenon (SSc-RP) attacks.
Dihydropiridine-type calcium antagonists, usually oral nifedipine, should be
considered for first-line therapy for SSc-RP, and intravenous iloprost, or
other available intravenous prostanoids, should be considered for severe
SSc-RP. Intravenous
prostanoids (in particular iloprost) should be considered in the treatment of
active digital ulcers in patients with SSc. Intravenous iloprost (0.5–2 ng/kg
per minute for 3–5 consecutive days) significantly reduced the number of
digital ulcers in comparison with placebo in one small RCT.
2.
Bosentan should be considered in diffuse SSc with
multiple digital ulcers, after failure of calcium antagonists and, usually,
prostanoid therapy.
II. SSc-PAH
Two high-quality RCT indicate that
bosentan improves exercise capacity, functional class and some haemodynamic
measures in pulmonary arterial hypertension (PAH). Bosentan should be strongly
considered to treat SSc-PAH. Sildenafil (a selective type 5 phosphodiesterase
inhibitor), may be considered to treat SSc-PAH (orally at a
dose of 20 mg, 40 mg or 80 mg three times a day).
III. SSc-related skin involvement
Methotrexate may be considered for
treatment of skin manifestations of early diffuse SSc.
IV. Scleroderma interstitial lung disease
In view of the results from two high-quality RCT and despite its known
toxicity, cyclophosphamide should be considered for the treatment of
SSc-related interstitial lung disease (SSc-ILD). The efficacy and safety of
cyclophosphamide in the treatment of SSc-ILD was evaluated in two high. The
first trial, involving 158 SSc patients with active alveolitis, demonstrated
that cyclophosphamide given orally at
a dose of 1–2 mg/kg per day improved
lung function tests, dyspnoea score and quality of life over 12 months
compared.
V. Scleroderma renal crisis
Despite the lack of RCT, experts
believe that angiotensinconverting enzyme (ACE) inhibitors should be used in
the treatment of scleroderma renal crisis (SRC).
RCT evaluating the efficacy of ACE
inhibitors in the treatment of SRC are lacking. Since the first report
demonstrating a beneficial effect of ACE inhibitors in two patients with SRC,64
numerous case reports and uncontrolled studies have reported on ACE inhibitors
in SRC. A prospective analysis of 108 patients with SRC has suggested that
patients on ACE inhibitors (captopril in 47 and enalapril in eight) had a
significantly better survival rate at 1 year (76%) and 5 years (66%) compared
with patients not on ACE inhibitors (15% at 1 year and 10% at 5 years,
respectively). Treatment with ACE inhibitors was significantly associated with
better survival in
SRC, after adjustment for age and
blood pressure (p,0.001).
VI. SSc-related gastrointestinal
disease
Despite the lack of specific RCT, experts believe that proton pump inhibitors
(PPI) should be used for the prevention of SScrelated gastro-oesophageal reflux
disease (GORD), oesophageal ulcers and strictures. Specific RCT for the
efficacy of PPI in patients with SSc are lacking. The efficacy of PPI in the
treatment of GORD in a general population is well documented in meta-analyses
of RCT.
Despite the lack of specific RCT, experts believe that prokinetic drugs
should be used for the management of SScrelated symptomatic motility
disturbances (dysphagia, GORD, early response in satiety, bloating,
pseudo-obstruction, etc).
Despite the lack of specific RCT, experts
believe that, when malabsorption is caused by bacterial overgrowth, rotating
antibiotics may be useful in SSc. No RCT regarding the efficacy of antibiotics
in the treatment of SSc-related bacterial overgrowth or malabsorption were
found. In general, current treatment of small intestinal bacterial overgrowth
is based on empirical courses of broad-spectrum antibiotics such as quinolones
or amoxicillin-clavulanic acid.
References
A -
1.
Davidson’s Principles and
practice of medicine (21st revised ed.) / by Colledge N.R., Walker
B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.
2.
3.
The Merck Manual of Diagnosis
and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and
others. – published by Merck Research Laboratories, 2011.
4.
Web -sites:
A.
http://intranet.tdmu.edu.ua/data/kafedra/internal/index.php?&path=vnutrmed2/classes_stud
D.
http://emedicine.medscape.com/
E.
http://meded.ucsd.edu/clinicalmed/introduction.htm
B - Additional:
1.
Scleroderma: From Pathogenesis
to Comprehensive Management [Hardcover]/John Varga.; Christopher P.
Denton.; Fredrick M. Wigley/ Springer.- 2011.- 709 p.
2.
Systemic
Lupus Erythematosus / Smolen, Josef S.; Zielinski, Christoph C.;
Geyer, G. -2012. - 200 p.
3.
Clinical Rheumatology (The
Clinical Medicine Series) 12 edition/ Pacific Primary Care Software PC/ M.D.,
C. G. Weber.- 2011.- 526 p.
4.
Kelley's Textbook of
Rheumatology, 9th Revised edition / Firestein, Gary S.; Budd, Ralph C.;
Gabriel, Sherine E.; O'Dell, James R.; McInnes, Iain B.-2012.-
2292 p.