Professor Graham R V Hughes MD FRCP

Clinician’s Manual on Lupus
Clinician’s Manual on Lupus
Editor
Professor Graham R V Hughes MD FRCP
Head of The London Lupus Centre,
London Bridge Hospital
Dr Shirish Sangle MD
Associate Consultant, Lupus Unit,
St Thomas’ Hospital, London
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Contents
Author biographies ix
PART ONE The growth of lupus

1 Lupus: An introduction 1
Distribution of lupus 1
Is lupus on the increase? 2
What has changed in lupus? 2
2 What is lupus? 5
Who gets lupus? 6
Clinical features 7
PART TWO Lupus organ by organ

3 Skin 11
Livedo reticularis 13
Subacute cutaneous lupus erythematosus 13
Discoid lupus 15
Lupus profundus 16
Alopecia 16
4 Tendons and joints 19

Tendons 19
Joints 19
Muscles 21
5 Kidney 23
Pathology 23
Clinical features 24
Vascular lesions 25
Treatment 25
6 The brain 27
Mechanisms 27
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Stroke 28
Headache 29
Memory loss 29
Seizures 29
Myelopathy 30
Neuropsychiatric features 30
Peripheral neuropathy 30
Treatment 31
7 Heart and blood vessels 33

Heart 33
Atheroma 35
Vasculitis 36
8 Liver and gastrointestinal tract 39

Liver 39
Gastrointestinal tract 39
9 Blood 41
White blood cells 42
Red cells 42
Platelets 42
PART THREE Diagnosis and treatment

10 Diagnosing lupus 45
Clinical clues 46
Diagnostic criteria 46
Laboratory tests 48
Antiphospholipid antibodies 50
Full blood count 51
Complement levels 51
C-reactive protein 51
Urinalysis and electrolytes 51
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11 Treatment 53
General management 53
Drug therapy 54
PART FOUR Lupus-like disorders

12 Sjögren’s syndrome 63
Pathology 64
Eye 66
Mouth and gastrointestinal tract 66
Vagina and bladder 67
Kidney 67
Nervous system 67
Blood 67
Purpura 68
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Malignancy 69
Diagnosis 69
Schirmer’s tear test 69
Immunology 70
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Etiology 72
Treatment 72
13 Hughes syndrome
(the antiphospholipid syndrome) 73
Introduction 74
Blood 74
Pregnancy 74
Brain 76
Heart 76
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Treatment 79
The future 80
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14 Mixed connective tissue disease

(and overlap syndromes) 81
Immunology 83
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15 Vasculitis 85
Classification 85
Wegener’s granulomatosis 85
Polyarteritis nodosa 91
Takayasu’s arteritis 92
PART FIVE Lupus-related topics

16 Lupus-related topics 97
Lupus and pregnancy 97
Lupus in children 97
Lupus and late arterial disease 98
Lupus and malignancy 98
Drug-induced lupus 99
Lupus: soil versus seed 100
Author biographies
Professor Graham Hughes is often referred to as “the father of lupus”
in the UK. Trained at the London Hospital, he went on to spend two
years in New York under the leadership of Dr Charles Christian, where
he worked on the introduction of the DNA-binding test.
In 1971, he opened the lupus clinic at Hammersmith Hospital before
moving to St Thomas’ Hospital where he set up the Louise Coote Lupus
Unit, a specialist unit dealing uniquely with lupus and related diseases.
In 1983, he described the antiphospholipid syndrome, now known as
Hughes Syndrome, and in 1991 was awarded the International League
of Associations for Rheumatology (ILAR) prize for this work. He also
instituted an annual postgraduate meeting “Ten Topics in Rheumatology”,
now in its 25th year, with satellite “Ten Topics” meetings in six countries.
Professor Hughes is founder and editor of the international journal
LUPUS.
Other honors include Master of the American College of Rheumatology
and doctor honoris causa degrees from the University of Marseille and
University of Barcelona.
Professor Hughes is best known for his work with patients and is Life
President of the patients’ charity Lupus UK.
Shirish Sangle is an associate consultant at the Louise Coote Lupus

Unit, St Thomas’ Hospital, London. He has been working with Professor
Hughes since 2000. His main fields of research include livedo reticularis,
non-traumatic bone fractures, and arterial stenosis in Hughes syndrome.
IX
PART ONE
The growth of lupus

Chapter 1
Lupus: An introduction
Forty years ago lupus (systemic lupus erythematosus) was widely regarded
as a rare, largely untreatable disease: at best, requiring high dose ster-
oids; at worst, ending in renal failure. However, lupus is now recognized
as an important and relatively common disease affecting up to 1 in 800
women; it is more common than multiple sclerosis or leukemia. In many
countries, lupus is now seen by every primary care practitioner. It is
very treatable, and most patients diagnosed early can expect a normal
lifespan. It is predominantly a disease of young women (most commonly
affecting women between the ages of 15–45) but can affect men as well.
Pregnancy, once contraindicated in lupus, is now largely successful.
Distribution of lupus
Possibly due to the photosensitivity seen in many patients, lupus is more
common in sunny countries. For example, there are higher rates of lupus
in Spain and Italy than in England or Scotland.
In some countries in East Asia — notably Singapore, the Philippines,
Indonesia and China — lupus appears particularly common, overtaking
rheumatoid arthritis in prevalence (Figure 1.1).
There are also ethnic differences, with lupus being more common (and
more severe) in Asian and African patients than in Northern Europeans.
Lupus is especially common in the African-American and Afro-Caribbean
communities, although strangely, it is considered rare in Africa itself.
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Global distribution of lupus
Figure 1.1 Global distribution of lupus. Global incidence of lupus is estimated to be between
1 to 10 cases per 100,000. Prevalence is highest among Asian, African-American, Afro-Caribbean
and Hispanic-American populations. Dots indicate areas of higher incidence of lupus.
Is lupus on the increase?

Yes, very much so. One of the questions commonly asked is if lupus is
becoming more common. It is certainly true that disease rates can fluctu-
ate; for instance, in the UK, rheumatoid arthritis appears to be waning.
The likely answer is that with greater awareness, many more cases of
lupus are now being diagnosed.
Another theory for the possible rise in lupus is the ‘hygiene theory.’
Today infants and children are exposed to far fewer infections and
those who develop infections are treated with antibiotics. Thus the
immune system does not fully develop protective infection-fighting
immune responses.
What has changed in lupus?

Recently, there have been major changes in understanding and
managing lupus. One of the most important changes has been increased
awareness. Lupus was once relegated to the ‘rare diseases’ section of
medical textbooks. Doctors received little in the way of exposure to or
-6 1 6 4 " / * / 5 3 0 % 6 $ 5 * 0 / t
education about lupus and the general public were largely unaware of
it. Today, media pieces on lupus regularly appear in magazines and on
the internet, radio and television. A number of cases of lupus in well-
known showbusiness personalities have also raised its profile. And most
importantly, patients’ self-help groups have sprung up all over the world,
providing patients with information about their diagnosis and disease
management advice.
As a result of increased awareness and testing advances, earlier
diagnosis is now possible using extremely sensitive tests, such as double
stranded DNA (dsDNA)-antibody testing, reducing the time to diagnosis
and treatment in a large proportion of patients. Finally, more effective
treatments are now available, allowing patients to live longer, healthier
lives. These treatments will be discussed in detail in Chapter 11.
Chapter 2
What is lupus?
Lupus is a condition in which the immune system, for some currently

unexplained reason, becomes overactive. In lupus, the body produces
antibodies (which can appear years before the disease itself; Figure 2.1)
and these in turn can damage sensitive organs and tissues, notably the
small blood vessels (vasculitis; Figure 2.2) and the kidney.
Other functions of the immune system can also become faulty, includ-
ing immune protection (T cell function) and apoptosis, the removal of
tissue waste from cell breakdown (Figure 2.3).
Appearance of lupus antibodies prior to diagnosis
Anti La
Antibody
Anti Ro Diagnosis of lupus
dsDNA
0 5 10 15 20
Years
Figure 2.1 Appearance of lupus antibodies prior to diagnosis. Lupus antibodies (eg,
extractable nuclear antigen [ENA], double-stranded DNA [dsDNA], anti-La, anti-Ro) can appear up
to 15 years before the clinical manifestation of lupus.
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Vasculitis
Blood vessel
Endothelial cell
Immune complexes
Vessel lumen
Inflammation
Blood vessel
Figure 2.2 Vasculitis. Vasculitis occurs when immune complexes deposited in the blood vessels
lead to inflammation.
Defective apoptosis in lupus
Normal apoptosis Abnormal apoptosis in lupus
Impaired phagocytosis
by apoptotic cell
Necrotic cell
Phagocytosis T
Immune reaction
Figure 2.3 Defective apoptosis in lupus. Defective disposal of apoptotic (dead) cells triggers
an immune reaction. Autoimmunity in lupus is thought to involve improper disposal of apoptotic
cells, which acts as a trigger for the production of characteristic auto-antibodies.
Who gets lupus?

Lupus mainly affects young women of childbearing age (15–45 years of
age), with nine times as many cases in women than men. It is unusual
for new cases of lupus to develop after menopause. Lupus can sometimes
run in families, especially when other autoimmune conditions such as
thyroid disease, rheumatoid arthritis, or Hughes syndrome are prominent
(Figure 2.4).
8 ) "5 * 4 -6 1 6 4 t
Autoimmune disease in relatives
Patient with lupus
Carrier for lupus
Not affected
Figure 2.4 Autoimmune disease in relatives. While there is a genetic basis for the development
of lupus, it is often triggered by a mixture of environmental and genetic factors. There is an
increased concordance in identical twins and non-identical siblings.
Clinical features
Common early symptoms are non specific and include fatigue, flu-like
features such as aches and pains, and low-grade fever. There may be
hair loss, skin rashes and chest discomfort from pleurisy. The hands
may show digital blisters and Raynaud’s phenomenon. Urine testing
may show proteinuria.
Sometimes, however, the onset may be more dramatic, with peri-
carditis, widespread ‘pain all over’, or neurological features including
headaches and seizures.
A common presenting scenario is of a woman between 20 and 30 years
of age with ongoing fatigue, faint skin rashes (commonly on the V-neck,
eyebrows and cheeks), aches and pains but no joint swelling, and some
hair loss. There may have been a past history of headaches or migraine,
growing pains, or a prolonged episode of glandular fever.
Because lupus can have a rather slow onset, diagnosis can sometimes
be delayed. Fortunately, the main blood test for lupus (anti-dsDNA anti-
body) is very specific for the disease. Indeed it is now known that positive
antibody tests (such as an anti-dsDNA) may antedate clinical diagnosis
by months or even years.
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One of the characteristic features of lupus is its tendency to wax and

wane. The onset may be dramatic, with nephritis, widespread vasculitis,
pericarditis, and hemolytic anemia, followed by a period of minimal
symptoms. However, even in dramatic ‘new’ cases such as this, there is
often a preceding history of months of fatigue, arthralgias (joint pain),
and hair loss.
Three clinical points should be addressed: sometimes new cases of
lupus appear in the months after delivery of a baby and this is occasion-
ally misdiagnosed as puerperal depression. Secondly, lupus can and does
sometimes present with predominantly (and even exclusively) neuropsy-
chiatric features, ranging from agoraphobia through to frank psychosis.
Thirdly, family history is very important. There may well be a history of
other autoimmune diseases, including lupus, in other family members.
PART TWO
Lupus organ by organ

Chapter 3
Skin
A variety of skin rashes is seen in lupus. The most well known is the clas-
sical ‘butterfly’ rash on the cheeks and the bridge of the nose (Figure 3.1).
However, this rash is seen in less than half of all patients.
The most common rash is a widespread flat pink rash, that is promi-
nent on the V-neck, face (including eyebrows), hands, and lower limbs
(Figure 3.2).
These rashes are often sun-provoked, coming on after a holiday, for
example (Figure 3.3). It should be noted, however, that sun-sensitivity
is not a universal feature.
Butterfly rash in lupus
Figure 3.1 Butterfly rash in lupus. A classic malar ‘butterfly rash’ affecting the cheeks and nose.
Patient also has scarring on the left cheek, suggesting additional discoid lesion.
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Flat pink rash on neck and arms
Figure 3.2 Flat pink rash on neck and arms. The most common rash associated with lupus,
typically distributed across the face, arms, hands, and V-neck area of the anterior chest.
Sun-provoked rash on back
Figure 3.3 Sun-provoked rash on back. Rashes associated with lupus are often photosensitive
and are aggravated by sun exposure. These rashes tend to appear on the face, arms, hands, chest,
and back.
Other skin features seen in lupus include finger and toe chilblains
(Figure 3.4; more common in children), subungual splinter hemorrhages,
mouth ulcers, and cutaneous vasculitis (lesions commonly seen on the
elbows and tips of fingers and toes).
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Hand chilblains
Figure 3.4 Hand chilblains. Discoloration caused by chilblains, a type of vasculitis triggered by
exposure to cold temperatures. It can also be exacerbated by smoking.
A number of skin-related features deserve separate comment:

Livedo reticularis
Subacute cutaneous lupus erythematosus (SCLE)
Discoid lupus
Lupus profundus
Alopecia
Livedo reticularis
A peculiar lattice-like condition (known by some patients as ‘corned beef
skin’; Figure 3.5) is seen in a number of conditions including vasculitis
and cryoglobulinemia. It is seen in lupus, but is especially prominent
in patients with Hughes syndrome (see Chapter 13). It is a particularly
important symptom because of its association with increased risk of
headache and stroke.
Subacute cutaneous lupus erythematosus

Subacute cutaneous lupus erythematosus (SCLE) is an easily recognized
skin lesion, often circular or doughnut shaped, that develops especially
on the upper chest (Figure 3.6) and is sometimes mistaken for a fungal
lesion. It is clinically associated with anti-Ro/La antibodies. SCLE is often very
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Livedo reticularis
Figure 3.5 Livedo reticularis. A lattice-like discoloration of the skin (‘corned beef skin’) caused
by poor circulation. Livedo reticularis is found in patients with lupus, but is more often seen in
Hughes syndrome and vasculitis.
Subacute cutaneous lupus erythematosus (SCLE)
Figure 3.6 Subacute cutaneous lupus erythematosus (SCLE). Well defined erythematous
discoid skin lesions shown on the chest and neck are typical of SCLE. This non-scarring rash is
linked to photosensitivity and is associated with anti-Ro and anti-La antibodies.
4 , * / t
photosensitive, is occasionally associated with Sjögren’s syndrome (see

Chapter 12) and tends to have a good prognosis. In pregnancy, maternal
anti-Ro antibodies can cross to the intrauterine fetus, leading to a similar
rash in the newborn (neonatal lupus) which is usually benign. Less benign
is the association of anti-Ro antibodies with rare infant congenital heart
block (see Chapter 16).
Discoid lupus
Although discoid lupus generally has a better prognosis than systemic
lupus erythematosus, it can nevertheless be widespread and disfigur-
ing. Discoid lupus causes skin to become scaly, patchy, and raised and
commonly affects the scalp (Figure 3.7), the face, and the limbs (often
in small patches resembling psoriasis). Blood tests for systemic lupus are
usually negative/normal for lupus antibodies and most patients (although
not all) respond well to antimalarial treatment.
Discoid lupus lesions on the scalp
Figure 3.7 Discoid lupus lesions on the scalp. Discoid lupus affecting the scalp may cause hair
loss due to permanent scarring. Distribution can be anywhere on the skin, but it is most commonly
seen on areas of the body exposed to the sun (eg, cheeks, ears, and scalp).
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Lupus profundus
Rarely, patients with lupus can develop a lumpy deep subcutaneous pan-
niculitis. This condition often presents with numerous, slightly tender
subcutaneous lumps, with puckering of the overlying skin. Lesions com-
monly affect the limbs and trunk, but occasionally cause disfiguring
lesions on the face.
Alopecia
Hair loss is a common and important feature of lupus and is an early indi-
cation of a flare of the disease. Occasionally, it can be acute and severe.
Fortunately, in almost all cases, total regrowth of the hair occurs once
the disease is brought under control. The occasional exception is the
patient with discoid lupus where inadequately treated disease can lead to
permanent (and usually patchy) scalp scaring and baldness (Figure 3.8).
Alopecia in lupus
Figure 3.8 Alopecia in lupus. Alopecia and sever scarring in discold lupus.
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Diagnosis of cutaneous lupus is generally straightforward, given the

background history and findings. In the past, skin biopsy with histology
was widely used. Immunofluoresence of the biopsy characteristically
showed a band of immunofluorescence (immune complexes and
complement) at the dermo-epidermal junction (Figure 3.9), and was
called the ‘lupus band test’. However, this test is now rarely used as
other non-invasive tests are available.
Lupus immunofluorescence band test on skin biopsy
Figure 3.9 Lupus immunofluorescence band test on skin biopsy. An immunofluorescence

staining to identify a band of immune complexes and complement at the dermo-epidermal
junction.
Chapter 4
Tendons and joints
Possibly the most common symptom in lupus is aches and pains. These
can be severe, often with ‘pain all over’. The symptoms fluctuate and
with clinical remission can disappear completely. Unlike rheumatoid
arthritis, chronic joint swelling is rare and joint erosion is very unusual.
The symptom of widespread pain can result from a mix of muscle, joint
and tendon inflammation.
Tendons
Tendon involvement is an important feature of lupus. Patients often com-
plain of stiffness in the fingers, with difficulty in straightening the fingers
fully. There may be tendon crepitus or even triggering. Occasionally,
larger tendons such as the Achilles may be involved and tendon rupture
is an occasional complication.
An extreme (although unusual) manifestation of tendon involvement
in lupus is the development of severe deformities in the fingers (and
sometimes the toes) due to ongoing tendon contractures, a condition
known as Jaccoud’s arthritis (Figure 4.1A and B).
Joints
While the joints themselves largely escape erosive damage in lupus, one
major problem in some patients is avascular necrosis, or cellular bone
death, usually as a result of high dosage steroids and most commonly
leading to necrosis of the head of the femur.
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Jaccoud’s arthopathy
Figure 4.1A and B Jaccoud’s arthopathy. Hand showing deformity caused by Jaccoud’s
arthopathy. It is characterized by non-erosive joint deformation and is thought to be caused by
tendon inflammation and contracture.
The earliest signs of avascular necrosis of the femur head are groin
discomfort and limitation of hip rotation. MRI may show characteristic
changes (Figure 4.2A) long before X-ray changes appear (Figure 4.2B).
Management of early avascular necrosis generally requires avoidance
of weight-bearing. Occasionally, surgical decompression is helpful.
Ultimately, total hip replacement is the treatment of choice.
While active widespread synovitis is unusual in lupus, it is less unusual
in mixed connective tissue disease (MCTD; see Chapter 14). Some MCTD
patients suffer troublesome symmetric small joint pain and swelling often
resembling early rheumatoid arthritis.
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MRI showing avascular necrosis of the hip
Figure 4.2A MRI showing avascular necrosis of both hip joints.
X-ray showing avascular necrosis of hip
Figure 4.2B X-ray showing avascular necrosis of the hip. Avascular necrosis of the hip is
also observed in lupus patients, especially those receiving corticosteroids. Arrow shows area of
necrosis of the head of the femur.
Muscles
While aches and pains are a feature of lupus, true inflammatory myositis
is rare. (Raised muscle enzymes are sometimes seen in patients on statins).
On the contrary, in MCTD, myositis can be troublesome and on occasion
severe, requiring combinations of steroid and immunosuppressive
treatments (particulary methotrexate).
Chapter 5
Kidney
One of the most feared complications of lupus is nephritis (inflammation

in the kidney), which can develop insidiously and, in undiagnosed or
untreated patients, may potentially lead to renal failure. However, with
greater awareness and early treatment, the prognosis of lupus nephri-
tis has improved markedly and the majority of cases can be brought
into remission.
Pathology
The pathology of the glomerular injury in lupus is classified into six
classes (in accordance with International Society of Nephrology [ISN]
and Renal Pathology Society [RPS]).
Class I Minimal glomerular disease (Figure 5.1A).

Class II Mesangial proliferative lupus nephritis (Figure 5.1B).
Class III Focal proliferative glomerulonephritis (Figure 5.1C).
Class IV Diffuse segmental proliferative glomerulonephritis
(necrosis, cellular crescents, variable sclerosis; Figure 5.1D).
Class V Membranous (Figure 5.1E).
Class VI Sclerosing nephropathy (fibrosis, hyalinised glomeruli,
“tombstones”) (Figure 5.1F).
Immunofluorescence may reveal deposits containing immunoglobulin.
23
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Renal pathology of lupus nephritis (Class I-VI)
A Class I B Class II C Class III
D Class IV E Class V F Class VI
Figure 5.1A–F Renal pathology of lupus nephritis (Class I-VI). A, Class I: Minimal mesangial
lupus nephritis (no treatment necessary); B, Class II: Mesangial proliferative lupus nephritis;
C, Class III: Focal segmental glomerulonephritis (<50% glomeruli are affected); D, Class IV: Diffuse
lupus nephritis (>50% of glomeruli are affected); E, Class V: Membranous lupus nephritis; F, Class
VI: Advanced sclerosing lupus nephritis (beyond treatment with immunosuppressive therapy).
Because the histological picture is critical to the choice of treatment

(for example, there is little point in prescribing strong immunosuppres-
sives for a kidney with essentially ‘dead’ glomeruli), renal biopsy is widely
considered vital in the early clinical assessment of a patient with lupus
in whom proteinuria or other renal sequelae are present. Modern renal
biopsy under radiological guidance with a fine needle is now regarded as
very safe (though not sufficiently risk-free to be considered in a patient
with a solitary kidney).
Clinical features
The most common early manifestation of nephritis is proteinuria; as such,
it is our policy to teach patients with lupus to self-test the urine monthly
in cases of suspected active nephritis. Regular urinalysis is a vital part of
lupus assessment, checking for proteinuria and active urinary sediment
or casts. More severe renal involvement can lead to nephrotic syndrome,
hypertension, or even renal failure.
, * % / & : t
Vascular lesions
Patients with lupus who test positive for antiphospholipid (aPL) antibodies
and those patients with primary antiphospholipid syndrome (APS or
Hughes syndrome) are more prone to intraglomerular thrombosis
(Figure 5.2), a feature which can add significantly to renal impairment
if not treated. Thrombosis in larger vessels such as the renal artery and
renal vein can also occur in Hughes syndrome. Interestingly, patients
with Hughes syndrome can develop focal stenotic lesions in the renal
artery, leading to hypertension.
Treatment
The use of drugs such as cyclophosphamide, azathioprine, rituximab,
belimumab, and mycophenolate mofetil have vastly improved the outlook
for renal lupus, with a move away from prolonged high-dose steroids.
For those patients developing renal failure in lupus, dialysis and trans-
plant are usually successful. In fact, it is unusual for lupus to flare after
a renal transplant.
Renal pathology in Hughes syndrome: thrombotic microangiopathy
Figure 5.2 Renal pathology in Hughes syndrome: thrombotic microangiopathy. Micro-infarcts

in the renal blood vessels. Thrombotic microangiopathy may lead to chronic renal impairment.
Chapter 6
The brain
Lupus has been described as “a predominantly neurological disease in

which other organs may also be involved.” However, the percentage of
patients with lupus with neurological involvement varies, depending largely
on definition and inclusion criteria. Nevertheless, it is now recognized
that brain features of lupus are more common than previously thought,
especially when more sensitive neurocognitive impairment is fully included.
Mechanisms
There are three main mechanisms by which brain dysfunction is thought
to arise: direct antibody attack (a number of antineuronal antibodies are
now recognized), inflammatory vasculitis, and thrombosis (Figure 6.1).
Until recently, most clinical neurological features in lupus were
attributed to ‘central nervous system vasculitis’. Not so today, as true
inflammatory vasculitis is rare. Possibly the most important mechanism
is cerebral blood flow impairment which can cause thrombosis and blood
‘sludging’, leading to ischemia (the latter is linked to Hughes syndrome;
see Chapter 13).
Indeed the overlap between aPL-associated neurological features and
lupus-associated neurological features is so great that a major rethink
concerning the relative contributions of the two disorders is under-
way. This is not entirely academic as decisions regarding treatment,
such as whether to prescribe anti-inflammatory corticosteroids versus
anticoagulants, are dependent on widely differing etiologies.
27
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Brain injury in lupus
B
1 Inflammation
(Antibody-mediated attack)
2 Vasculitis 3 Clot formation
Blood vessel
Figure 6.1A and B Brain injury in lupus. A, CT scan showing brain injury; B, Brain injury in
lupus can be caused by: 1, Antibody - mediated attack; 2, Cerebral vasculitis; 3, Blood sludging
and thrombosis (often seen in Hughes syndrome).
Stroke
One of the most feared complications of lupus is stroke. Stroke is strongly
associated with aPL antibodies and Hughes syndrome. This topic is further
discussed in Chapter 13 (Figure 6.2).
5 ) & # 3 " * / t
Major stroke in a patient with lupus
Figure 6.2 Major stroke in a patient with lupus. Brain CT scan image showing a major stroke.
Patients with lupus are at greater risk of ischemic stroke due to higher likelihood of vasculitis,
thrombosis, and Libman-Sacks endocarditis..
Headache
One of the most common features of lupus is headache, which is often
frequent and migrainous. Sometimes patients with headache respond
to steroids but more commonly react to anti-aggregants or anticoagu-
lants. In patients with Hughes syndrome, headaches can be a precursor
to transient ischemic attacks.
Memory loss
This can be mild and a nonspecific feature of chronic inflammatory
illness. In Hughes syndrome, memory loss may be severe and give rise
to fears of Alzheimer’s disease.
Seizures
During the early, severe phase of lupus, seizures are not uncommon
(Figure 6.3). As lupus responds to treatment, these become uncommon.
Seizures (ranging from grand mal to temporal lobe epilepsy) are more
common in patients that are aPL-positive (see Chapter 13).
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Seizures in lupus
Figure 6.3 Seizures in lupus. Electroencephalograph (EEG) showing a seizure in a patient with lupus.
Arrow shows abnormal wave pattern in a seizure.
Myelopathy
A rare but serious manifestation of lupus is transverse myelitis (Figure 6.4).
Usually acute, it will respond to speedy treatment, which is typically
a combination of steroids, immunosuppressives, and (increasingly)
anticoagulants.
Neuropsychiatric features
Active lupus can lead to a wide range of neuropsychiatric manifestations.
Depression is common, as are phobias. Psychosis can be a prominent
presentation. Generally responsive to a combination of antipsychotic
and lupus medication, lupus-related psychosis rarely leads to long-term
neuropsychiatric sequelae.
Peripheral neuropathy
As distinct from vasculitis, peripheral neuropathy is uncommon in
lupus. Other problems encountered in lupus include balance disorders,
atypical multiple sclerosis, movement disorders, balance difficulties,
5 ) & # 3 " * / t
Transverse myelitis in lupus
Figure 6.4 Transverse myelitis in lupus. Pale areas in the spinal cord are indicated by arrows. In
lupus, this condition is typically caused by inflammation of the spinal cord (shown as pale spots)
due to vasculitis and/or the presence of antiphospholipid antibodies.
myasthenia, ocular involvement (including optic neuritis and ischemic

lesions). Patients with Hughes syndrome or aPL antibodies are at a greater
risk of transient ischemic attacks and stroke.
Treatment
Over the years, aggressive immunosuppressive therapy (eg, pulse cyclo-
phosphamide regimes) and steroids have been used to treat the effects
of lupus on the brain, mirroring the practice in lupus nephritis.
More and more, recognition of the role of blood clotting (or ‘sludging’)
in the pathogenesis of lupus with neurological features has lead to the
increased use of aspirin, heparin, and warfarin in the management of
complex cases.
Chapter 7
Heart and blood vessels
All three layers of the heart can be affected by lupus. Blood vessel
involvement is a central feature of the pathology of lupus, causing not
just inflammatory small vessel vasculitis, but also thrombosis in the veins
and arteries, and later in the course of the disease, accelerated atheroma
in a significant number of patients.
Heart
The most common cardiac manifestation is pericarditis (Figure 7.1),
usually presenting with sharp central chest pain during a flare of the
disease. Inflammation of the pericardium may be accompanied by
Chest CT showing pericardial and pleural effusion
Figure 7.1 Chest CT showing pericardial and pleural effusion. 0GUFOSFMBUFEUPJOGMBNNBUJPO

It is estimated that 20–50% of patients with lupus develop pleuritis and/or pericarditis.
33
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pleurisy and, less commonly, by peritonism. The pericarditis occasionally

leads to pericardial effusions, although cases of constrictive pericarditis
are unusual.
The inflammation of the pericardium generally responds to steroid
treatment, with fairly high doses (30–40 mg of prednisolone daily)
required to ease the pain. It is said that flares of lupus often follow a
similar pattern in an individual and recurrent pericarditis is a feature in
some patients. By contrast, inflammatory cardiomyopathy is an unusual
feature of lupus. Even in MCTD, where myositis can be prominent, inflam-
mation of the cardiac muscle is unusual.
Historically, one of the earliest known cardiac manifestations of
lupus is the thrombotic/vegetative valve lesion known as Libman-Sacks
endocarditis (Figure 7.2). This lesion, now recognized as being more of
a feature of in Hughes syndrome than of lupus, initially leads to cardiac
murmurs and mild echocardiographic changes, but in extreme cases can
lead to valve failure. This increases the risk of cerebral emboli and may
require treatment with intensive anticoagulation and valve replacement.
Interestingly, valve involvement is much more a feature of Hughes
syndrome than of any other prothrombotic disorder and thus echocar-
diography is an essential part of the investigation of any patient with
antiphospholipid antibodies.
Libman-Sacks endocarditis
Figure 7.2 Libman-Sacks endocarditis. Libman-Sacks endocarditis is a cardiac manifestation of

lupus that causes mulberry-shaped clusters on the ventricular surface of the heart valves.
) & " 3 5 " / % # -0 0 % 7 & 4 4 & - 4 t
Atheroma
Coronary artery disease and cardiac ischemia are also recognized as
complications of lupus. There are two main causes: aPL antibodies and
late atheroma. Patients with aPL antibodies — both those with primary
Hughes syndrome and patients with lupus that test positive for aPL anti-
bodies — have been known to have an increased risk of coronary artery
thrombosis. For example, testing aPL-positive may increase the risk of
heart attack in young women by up to 22 times. Occasionally, myocardial
infarction can be acute and fatal.
More subtle arterial thrombotic lesions in Hughes syndrome and
patients with lupus that are aPL-positive can lead to cardiac arrhythmias
and cardiomyopathy (Figure 7.3). These cases highlight the need in lupus
to check aPL status and consider anticoagulant therapy alongside the
more routine lupus drugs.
In the long-term patient with lupus, clinicians must be alert to the
possible complications of accelerated arterial disease.
Cardiac myoview scan showing cardiac ischemia
Figure 7.3 Cardiac myoview scan showing cardiac ischemia. Results of a cardiac myoview
stress test showing cardiac ischemia (as shown in white box). Accelerated atherosclerosis is a
feature of lupus and affected patients are at a higher risk of developing ischemic heart disease.
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Vasculitis
Vasculitis is a feature of active lupus. The inflammation mainly affects
small blood vessels and classical clinical features include small ischemic
lesions on the tips of the hands and feet (Figure 7.4 and Figure 7.5). An
important diagnostic clue to vasculitis is the presence of small-to-medium
sized (1–2 mm) lesions on the elbows.
Other sites where vasculitis may be seen are the nail beds, in the eye
on ophthalmoscopic examination (Figure 7.6), and in larger skin ulcers.
The other vascular pathology ranges from livedo reticularis (seen espe-
cially on the upper arms, wrists, and knees), ischemic lesions that can lead
to skin ulcers (Figure 7.7), and in extreme cases, digital limb gangrene.
Thrombosis of larger vessels can include renal artery thrombosis,
stroke, myocardial infarction, and occasionally even affect the largest
vessels such as the aorta. In lupus, these major arterial lesions are
mainly seen in patients that are aPL-positive. A peculiar lesion seen in
aPL-positive patients with lupus and in Hughes syndrome is localized
stenosis, including renal artery stenosis and celiac artery stenosis (see
Chapter 13; Figures 13.6 and 13.7).
Digital vasculitis
Figure 7.4 Digital vasculitis. Vasculitis of the hands in a patient with lupus, with visible lesions
and discoloration.
) & " 3 5 " / % # -0 0 % 7 & 4 4 & - 4 t
Vasculitis-associated foot lesions
Figure 7.5 Vasculitis-associated foot lesions. Lesions on the foot in a patient with vasculitis. In
some patients, lesions may develop into ulcers if left untreated.
Vasculitis of the eye
Figure 7.6 Vasculitis of the eye. Vasculitis of the eye causes inflammation in the small blood
vessels of the retina. This may lead to sporadic visual blurring and loss of vision.
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Skin ulcers caused by ischemic lesions
Figure 7.7 Skin ulcers in lupus. Ulcers can result from inflammatory vasculitis
and thromboses.
Chapter 8
Liver and gastrointestinal tract
Liver
One of the odd facts about lupus it that the liver is rarely a primary
target organ, although the term ‘lupoid hepatitis’ is used for some forms
of autoimmune hepatitis. Thus abnormal liver function tests in a patient
with lupus should raise three main alternative diagnoses:
1. Hughes syndrome (with hepatic thrombosis)
2. Drug side-effects (eg, azathiaprine)
3. A secondary diagnosis (eg, infection)
Gastrointestinal tract
Involvement of the gastrointestinal (GI) tract in lupus seems to vary
in frequency from continent to continent. For example, this complica-
tion is common in South East Asia, but unusual in Western Europe.
The three main pathological processes leading to GI involvement are:
inflammation (eg, peritonitis), thrombosis (eg, bowel infarction, celiac
artery stenosis), or iatrogenic in nature (eg, high-dose steroids, non-
steroidal anti-inflammatory drugs).
Abdominal pain is often seen during a lupus flare. Most commonly
due to lupus peritonitis, the pain is rarely chronic and usually settles
with steroid therapy. Other causes of abdominal pain are bowel ischemia,
chronic pancreatitis, and vasculitis. However, an iatrogenic cause, notably
due to nonsteroidal anti-inflammatories, is not uncommon.
39
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For patients with Raynaud’s phenomenon, esophageal problems,

spasms, dysphagia, and reflux esophagitis can be prominent. Sjögren’s
syndrome, with severe mouth dryness, can also result in dysphagia. As
lupus predominately affects a relatively younger age group, gallbladder
disease is unusual.
Chapter 9
Blood
Routine blood analysis in lupus can turn up a number of abnormalities

including leukopenia (low white blood cell count) (Figure 9.1), anemia,
thrombocytopenia, raised erythrocyte sedimentation rate (usually with
a normal C-reactive protein level), raised gamma globulin levels, abnor-
mal renal function tests and low vitamin D levels, not to mention the
plethora of raised levels of antibodies seen in this disease.
Thrombocytopenia and leukopenia in lupus
Figure 9.1 Thrombocytopenia and leukopenia in lupus. Blood film showing a lymphocyte but
no platelets or other white blood cells.
41
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White blood cells

Leukopenia is common and white blood cell (WBC) counts of 2.0–3.0
x 109/L are seen regularly and counts as low as 1.5 or 1.0 x 109/L are
often seen in otherwise seemingly healthy patients with lupus. The most
common cause is neutropenia (though lymphopenia is also frequently
seen, especially in patients treated with steroids). Interestingly, despite
low WBCs, major infections in these patients are uncommon, presumably
because the WBCs which are present function normally.
The clinical difficulty arises in neutropenic patients with lupus on
immunosuppressive therapy. Bone marrow examination may be needed
to make a correct diagnosis. However, it is an interesting fact that in
many neutropenic patients with lupus, WBCs increase when treatment
is stepped up (even with immunosuppressive therapy).
Red cells
Anemia in lupus is most commonly either iron-deficient (often due to
nonsteroidal medication) or due to chronic inflammation (normochromic
normocytic).
Hemolytic anemia (often Coombs’-positive) is less common, but can
be a presenting manifestation of the disease. A combination of hemolytic
anemia and thrombocytopenic purpura (Evans syndrome) is sometimes
seen in both lupus and Hughes syndrome.
Platelets
Thrombocytopenia is a well known feature of lupus, sometimes antedating
the diagnosis of lupus by years. Although very low platelet counts (below
10 x 109/L) can be seen, mild thrombocytopenia (90–100 x 109/L) is
more common.
As with some of the other features of lupus (such as many of the
neurological features), thrombocytopenia is now recognized as being
more strongly associated with Hughes syndrome and the presence of
circulating aPL antibodies.
PART THREE
Diagnosis and treatment

Chapter 10
Diagnosing lupus
Lupus is a condition where a single test is almost diagnostic; high titres

of double stranded anti-DNA antibodies (dsDNA) are rarely, if ever, seen
in any other condition. The only other condition which sometimes gives
diagnostic difficulty is Sjögren’s syndrome (see Chapter 12), where high
titers of anti-nuclear antibodies can lead (usually for technical reasons)
to ‘borderline’ positive anti dsDNA titers.
Statistically, lupus primarily affects young woman (9:1 female: male
ratio), thus it is vanishingly rare to see a new case of lupus in a fifty year
old male, for example (Figure 10.1).
An unusual case: a male patient with lupus
Figure 10.1 An unusual case: a male patient with lupus. Lupus does affect males but accounts for
less than 10% of total cases. The disease does not appear to differ in presentation or severity.
45
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Clinical clues
Skin
The ‘classical’ butterfly rash on the cheeks and bridge of the nose is, in
fact, seen in less than half of all patients. Skin rashes, while common, can
present in many forms and on different parts of the body. Examination
should always include inspecting the elbows for small red spots or
blisters, as the elbows are a favored site of vasculitis but uncommon in
other diseases with rashes. Other important rash sites are the eyebrows,
the V-neck, the scalp (alopecia is a major diagnostic clue), palms, and
soles of feet.
Malaise
Lupus often presents gradually and can result in delayed diagnosis.
Fatigue is the most common symptom, with flu-like aches and pains (but
no swelling) being prominent. Chest discomfort (usually from pleurisy)
is common, as is weight loss, fever, and lymphadenopathy.
Neuropsychiatric features
Neuropsychiatric features including headache, depression, and phobias can
be prominent, especially in the early stages of the disease. Occasionally,
the onset can be dramatic, with seizures (especially in those patients with
aPL antibodies) and psychosis. It is important to remember that lupus
can flare or present for the first time in the early puerperium.
Diagnostic criteria
In order to regularise research publications, especially those assessing
new treatments, the American College of Rheumatology (ACR) drew
up a set of 11 criteria for the classification of lupus (Table 10.1). If four
or more of these criteria are present, the patient could be classified as
having lupus for the purpose of inclusion in a study. Sadly this useful
and worthy goal has been widely, and wrongly, used for diagnosis. For
example, a person with only three criteria may be excluded from lupus
diagnosis. The ACR criteria have also been taken up by patient groups
and appears in general literature.
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1997 update of the 1982 American College of Rheumatology revised

criteria for classification of systemic lupus erythematosus
Criterion Definition
1. Malar rash Fixed erythema, (flat or raised), over the malar eminences, tending to
spare the nasolabial folds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or
physician observation
4. 0SBMVMDFST 0SBMPSOBTPQIBSZOHFBMVMDFSBUJPO VTVBMMZQBJOMFTT PCTFSWFECZ
physician
5. Nonerosive Involving 2 or more peripheral joints, characterized by tenderness,
arthritis swelling, or effusion
6. Pleuritis or a. Pleuritis: convincing history of pleuritic pain or rubbing heard by
Pericarditis a physician or evidence of pleural effusion OR
b. Pericarditis: documented by electrocardigram or rub or evidence of
pericardial effusion
7. Renal disorder a. Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation
not performed OR
b. Cellular casts: may be red cell, hemoglobin, granular, tubular,
or mixed
8. Neurologic a. Seizures: in the absence of offending drugs or known metabolic
disorder derangements; (eg, uremia, ketoacidosis, or electrolyte imbalance) OR
b. Psychosis: in the absence of offending drugs or known metabolic
derangements, (eg, uremia, ketoacidosis, or electrolyte imbalance)
9. Hematologic a. Hemolytic anemia-with reticulocytosis OR
disorder b. Leukopenia: < 4,000/mm3 on ≥ 2 occasions OR
c. Lyphopenia: < 1,500/ mm3 on ≥ 2 occasions OR
d. Thrombocytopenia: <100,000/ mm3 in the absence of offending drugs
10. Immunology a. Anti-DNA: antibody to native DNA in abnormal titer OR
b. Anti-Sm: presence of antibody to Sm nuclear antigen OR
c. Positive finding of antiphospholipid antibodies on:
1. an abnormal serum level of IgG or IgM anticardiolipin antibodies
2. a positive test result for lupus anticoagulant using a standard
method
3. a false-positive test result for at least 6 months confirmed by
Treponema pallidum immobilization or fluorescent treponemal
antibody absorption test
11. Positive An abnormal titer of antinuclear antibody by immunofluorescence or
antinuclear an equivalent assay at any point in time and in the absence of drugs
antibody
Table 10.1 1997 update of the 1982 American College of Rheumatology revised criteria for
classification of systemic lupus erythematosus. Disease criteria used for lupus classification.
If a patient has 4 or more of 11 criteria, it is considered likely that the patient has lupus.
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Clearly, for the physician considering a possible diagnosis of lupus,

these criteria are extremely restrictive, as one could correctly diagnose
lupus in a patient with a butterfly rash, seizures, hair loss, and nephritis,
but would potentially misdiagnose dozens of patients that display less
‘classical’ symptoms.
Some years ago, our group drew up a list of criteria which might
prove useful as pointers towards a diagnosis of lupus (Table 10.2). While
many of the features on this ‘alternative criteria’ list are not specific,
collectively two or three positive in a young woman with ongoing malaise
could be suggestive of possible lupus.
Laboratory tests
There are several key tests in a patient with suspected lupus: anti-dsDNA,
full blood count, erythrocyte sedimentation rate (ESR), C-reactive protein
(CRP), electrolytes, and urinalysis in particular.
Anti-DNA and other antibodies

The hallmark of lupus is the frequency and breadth of non-organ specific
antibodies such as anti-DNA, anti-Smith (Sm), anti-Ro, and anti-RNP.
Organ-specific antibodies such as thyroid and celiac antibodies (more
common in Sjögren’s syndrome) are rather unusual.
The ‘screening’ test for lupus is the anti-nuclear antibody (ANA) test.
This test potentially picks up a variety of non organ–specific antibodies
(Figure 10.2A and B). Over 90% of patients with lupus are ANA-positive,
usually in titers higher than 1 in 80. Other diseases, notably Sjögren’s
syndrome, rheumatoid arthritis, and other autoimmune conditions, can
show ANA positivity. Rarely, drug reactions can show lupus-like features
and cause a patient to test ANA-positive (drug-induced lupus).
Since their discovery some 40 years ago, anti-DNA antibody tests
have turned out to be one of the most specific in the whole of medicine.
It is extremely rare for false positives to occur for any other disease.
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St Thomas’ alternative criteria for lupus diagnosis

1. Teenage “Growing pains” in the UK is a label widely used for joint pains in teenagers and
“growing pains” seems to cover a spectrum of rheumatology from arthritis through to lupus
2. Teenage Headache, cluster headache, and migraine can be encountered and a
migraine strong history of teenage migraine may be of lupus significance, either at
the time or subsequently
3. Teenage Prolonged teenage ‘glandular fever’ is a diagnosis often wrongly
‘glandular applied and prolonged periods off school in many patients with lupus is
fever‘ a recurrent issue
4. Severe A common feature in many patients with lupus. Not only are they
reaction to susceptible to insect bites but often reactions are severe and prolonged, as
insect bites the skin is a major organ affected by lupus
5. Recurrent Lupus itself does not seem to be a cause of recurrent miscarriage but when
miscarriages the antiphospholipid syndrome is present, recurrent spontaneous fetal loss
can occur
6. Premenstrual Although difficult to quantify, it is believed that significant premenstrual
tension syndrome flare is sufficiently prominent in lupus to be included in this list. All
rheumatic diseases are clinically influenced by the menstrual cycle
7. Septrin allergy Adverse reactions to septrin are quite common in lupus and the clinical
onset of the disease may coincide with their use
8. Agoraphobia Agoraphobia/claustrophobia are often present at a time when lupus disease is
active. A history of these conditions (including panic attacks), can be protracted,
lasting for months or even years. In many cases, the history is not volunteered
or the episodes are in the interim and considered unrelated to lupus
9. Finger flexor Arthralgia and tenosynovitis are common features in lupus and although
tendonitis not specific, the finding of mild to moderate ten-finger flexor synovitis
is a useful pointer in the presence of other lupus features. It is subtly yet
significantly different in pattern to other arthritic diseases
10. Family As the genetics and statistics of the various autoimmune diseases become
history of better defined, the strength of a particular family history will become
autoimmune more precise. The family history is important, as lupus can be genetically
disease determined
11. Dry Schirmer’s A “bone dry” Schirmer’s test (testing levels of eye moisture) points
test towards Sjögren’s syndrome and in the patient with vague or nonspecific
symptoms, it is a very useful test
12. Borderline C4 Genetic complement deficiencies have been known to be associated with
lupus for over three decades and in the diagnostically difficult patient,
especially where a family history is present, borderline C4 levels can be
significant indicators
13. Normal CRP A very low CRP in an otherwise inflammatory situation is strongly
with raised ESR supportive of lupus or primary Sjögren’s syndrome
14. Lymphopenia In the patient with nonspecific complaints and unremarkable blood tests,
a borderline or low lymph count can be overlooked. It can be common
in lupus and is certainly worth inclusion among minor criteria to assist in
making a diagnosis
Table 10.2 St Thomas’ alternative criteria for lupus diagnosis. Ten clinical and four
investigative criteria based on clinical experience. CRP, C-reactive protein; ESR, erythrocyte
sedimentation rate.
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Homogenous antinuclear antibodies
A Homogenous B Speckled pattern
Figure 10.2 A and B Homogenous antinuclear antibodies. Antinuclear antibodies (ANA)

are observed in over 90% of patients with lupus. The test screens for auto-antibodies in the
bloodstream, and the pattern and titer of the results are then used to determine the origin. They
are also seen in other related conditions such as Sjögren’s and scleroderma.
Other antibodies
Extractable nuclear antibodies is the name given to a collection of anti-
nuclear and anti-cytoplasmic antibodies identified in lupus. Some of the
more important in lupus are:
Anti-Sm: Fairly specific for lupus, but less diagnostically
useful than anti-DNA. (Named after a patient called Smith).
Anti-RNP: Seen in mixed connective tissue disease (see Chapter 14)
and lupus. Strongly associated with Raynaud’s phenomenon.
Anti-Ro and Anti-La: Associated with Sjögren’s, with
photosensitivity and cutaneous rashes, notably SCLE (see
Chapter 3). Also associated with rare fetal problems of neonatal
lupus rash and congenital heart block.
Anti-C1q: Not in widespread use, but said to be a useful marker for
renal disease in lupus.
Antiphospholipid antibodies
Antiphospholipid (aPL) antibodies are generally measured by two tests:
anticardiolipin antibodies and the so-called ‘lupus anticoagulant’. Both
tests are required, as some sera only demonstrate positivity in one of
the two tests (Table 10.3). In recent years, a third serum test (anti-beta
2 glycoprotein 1) has been added, but is not yet in widespread use.
% * "( / 0 4 * / ( -6 1 6 4 t
Laboratory results from a patient with aPL-positive Hughes syndrome

Antibody aPL result
LA Positive
aCL (IgM/IgG) Medium to high titer
B2 GPI (IgM/IgG) Medium to high titer
Table 10.3 Laboratory results from a patient with aPL-positive Hughes syndrome. Positive
lupus anticoagulant (LA) or anticardiolipin (aCL) antibodies and/or B2 glycoprotein I (B2GPI)
in medium to high titers at least twice (twelve weeks apart) are included in criteria for Hughes
syndrome. aPL, antiphospholipid.
Testing for aPL antibodies is one of the single most important diagnostic
procedures in lupus, as it pinpoints patients with lupus that are more
prone to arterial and venous thrombosis.
Full blood count

Leukopenia, anemia, and (occasionally) thrombocytopenia are features
of lupus (see Figure 9.1). In the commonly faced differential diagnosis of
lupus versus infection, the WBC count can be a helpful diagnostic tool,
as WBC count is low in lupus but high in infections.
Complement levels
During flares of lupus, it is common for complement levels (usually C3
and C4 are measured) to fall. However, an interpretation of this can be
flawed, as a number of patients with lupus have various genetic comple-
ment deficiencies that can lead, for example, to a permanently low C4 level.
C-reactive protein
CRP levels are generally low in lupus but rise when an infection is
present. In the management of febrile patients with lupus, the CRP test
is an extremely valuable guide to distinguishing between a lupus flare
or an infection.
Urinalysis and electrolytes

The routine monitoring of any patient with lupus must include assess-
ment of renal function by measuring urea, creatinine, and electrolytes.
In addition, measuring serum albumin will give a guide to the degree
of proteinuria, if present. Proteinuria is the most common early marker
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of lupus renal involvement, with active urine sediment suggesting more

active renal disease. Thus, a routine part of any lupus consultation
is urinalysis.
Other investigations
X-rays, echocardiography, doppler, dual-emission X-ray absorptiom-
etry (DEXA), MRI, and angiography are all part of the diagnostic
armamentarium in lupus.
Chapter 11
Treatment
One of the major advances in the management of lupus has been the move
towards more conservative treatment. Gone is long-term use of high-
dose steroids for all, with a graded and more individualised approach
now recommended instead.
General management
As many patients with lupus are photosensitive, avoidance of excessive
ultraviolet (UV) light is advisable (Figure 11.1). The most harmful UV
light to a patient with lupus is that given out during the midday hours.
Sunscreens are moderately effective but not totally preventative to
sensitive lupus skin.
Consequences of excessive ultraviolet light on a patient with lupus
Discoid rash
Ultraviolet rays
Mouth ulcers Butterfly rash
(sunlight)
Arthritis Fatigue
Figure 11.1 Consequences of excessive ultraviolet light on a patient with lupus. Ultraviolet
light (especially around midday) can cause a flare in lupus symptoms.
53
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Vitamin D
Is it well understood that Vitamin D, a hormone, is important for bone
strength. However, it is now known to have an important role in immune
protection (Figure 11.2). Increasingly, Vitamin D supplementation is
being advocated in lupus. Vitamin D levels can be measured using a
simple blood test and will likely become a standard investigation in lupus.
Diet
There is not currently a specific diet recommended for patients with
lupus, although many have been advocated.
Middle-aged patients with lupus have been found to have a higher ten-
dency towards atheroma. The reasons for this are still being investigated
and suspects include steroids, inflammation, and aPL antibodies, among
others. Thus, in terms of practical therapeutics, lipid/cholesterol checks and
dietary measures are important. Statins are increasingly used at an early
stage in patients with lupus who have marginally raised cholesterol levels.
Drug therapy
Plaquenil
Quinine, derived from the cinchona tree of South America, has long
been known for its therapeutic properties, especially in the manage-
ment of fever, joint pains and fatigue. Just over a century ago, Dr Payne
of St Thomas’ Hospital in London suggested that chloroquine, a quinine
derivative now famous for its use in malaria, was potentially useful in
systemic lupus.
Hydroxychloroquine (Plaquenil), an analogue of chloroquine, now
plays a central role in the management of lupus, so much so that the
drug has become regarded as maintenance therapy. The commonly used
dose is 200 mg daily. Some advocate a higher dose but in a percentage
of patients, 400 mg daily can lead to gastrointestinal side effects (eg,
‘gassy stomach’). The drug’s effects on fatigue and skin rashes are strik-
ing and in many patients, this is the only medication required for lupus
management. Plaquenil is safe in pregnancy and, at a low dose, is not
toxic to the retina. However, patients should be informed that smoking
reduces the drug’s therapeutic effect.
5 3 & "5 . & / 5 t
Metabolism of vitamin D
UV-B
Provitamin D3
Liver
25-hydroxycholecalciferol
< 0)
%3]
Kidney
EJIZESPYZDIPMFDBMDJGFSPM< 0)
2D3]
Active vitamin D-calcitriol
Increased intestinal Bone Improved Decreased

absorption health immunity tumour activity
Figure 11.2 Metabolism of vitamin D. A pictorial representation of the metabolism of vitamin

D (cholecalciferol). Low vitamin D levels may cause T lymphocyte dysfunction, which can lead to
immune disorders.
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Steroids
Prednisolone can be life-saving in severe lupus and is the drug of choice
for acute flares causing complications such as pericarditis. For severe
flares, ‘pulse’ methyl prednisolone is widely used (500 mg intravenously
given on three successive days). Doses of oral prednisolone over 30 mg
daily are less frequently used and a dose of 20 mg, gradually lowering
to 7.5 mg or 5 mg daily, is the aim.
Failure to respond to the lower doses is an indication to add a steroid-
sparing agent such as plaquenil, azathioprine, or mycophenolate mofetil.
Azathioprine
Azathioprine (Imuran) has been used to treat lupus for half a century and
is still widely used. One in ten patients (usually those with a deficiency
of the enzyme TMPT) cannot tolerate the drug and experience nausea
or more severe side effects such as neutropenia. Azathioprine’s continu-
ing advantage in the face of newer drugs is that it is safe in pregnancy.
Mycophenolate mofetil
Mycophenolate mofetil (MMF, Cellcept) has proved to be effective as
an immunosuppressive and is rapidly taking over from azathioprine as
a first-line immunosuppressive agent. Side effects include diarrhea and
chest infections but for the majority of patients, the drug is well tolerated.
Studies have shown that MMF is successful in inducing remission and
in maintaining stability in lupus nephritis (Figure 11.3).
Cyclophosphamide
Doctors at the National Institutes of Health (NIH) in the US have made
an enormous contribution to the treatment of lupus nephritis. Their
careful studies introduced the ‘NIH regime’ of regular pulses of intrave-
nous cyclophosphamide. This has had a profound effect on survival in
lupus nephritis but had a high incidence of infections (including shingles)
and a high incidence of ovarian failure, a disaster in a disease affect-
ing young women. Over the past two decades, the low dose ‘St Thomas’
Hospital regime’ showed lower doses (eg, 500 mg cyclophosphamide
every two weeks for six pulses) was equally effective but with far fewer
5 3 & "5 . & / 5 t
Response to mycophenolate mofetil in lupus nephritis
5
Disease activity
4
3
2
1
0
3 months 6 months 2 years 5 years
Induction Maintenance
Figure 11.3 Response to mycophenolate mofetil in lupus nephritis. Mycophenate mofetil

is an immunosuppressive agent used to induce remission and provide long term (>5 years)
maintenance in active lupus nephritis.
side effects. This low dose regime is now being taken up all over Europe
and is known as the ‘Euro-Lupus’ regime (Figure 11.4).
Anti B cell agents

This is the era of the monoclonal antibodies, which are immunosup-
pressive agents that allow a more focused attack on the mediators of
the disease, such as the B cell (Figure 11.5).
For example, rituximab, an anti-B cell agent, is already in wide usage
for severe lupus. Initial experience is very positive both in efficiency and
tolerance. Belimumab (Benlysta® ), an agent focused on a B cell marker
looks equally promising and has recently overcome most of the hurdles
‘Low dose’ cyclophosphamide regimen (St Thomas’ regime,

Euro-lupus regime)
Three pulses methyl

prednisolone
AZA/MMF
0 2 4 6 8 10 Weeks
Six pulses cyclophosphamide, 500 mg
Figure 11.4 ‘Low dose’ cyclophosphamide regimen (St Thomas’ regime), (Euro-lupus
regime). Low dose cyclophosphamide has few side effects and does not appear to cause infections
or infertility. It is as effective as higher doses (eg, NIH regime).
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Anti-B-cell agents
Belimumab
Soluble BLyS
BLyS receptor
Reduced BLyS
receptor signalling
B cell B cell
apoptosis
CD-20 receptor
Reduced CD-20
receptor signalling
Rituximab
Figure 11.5 Anti-B-cell agents. A reduction in BLyS or CD-20 signalling in B cells promotes
apoptosis and reduces inflammation. Belimumab blocks binding of soluble BLyS to its receptors.
BLyS, B lymphocyte stimulator.
to become a recognized drug prescribed specifically for the treatment of

lupus. So far, this is the only drug which has been approved by the Food
and Drug Administration in the US and European Medicines Agency in
Europe for the treatment of lupus. Preliminary results are very promis-
ing as a specific therapy targeting antibody proliferation, and in clinical
trials, levels of anticardiolipin antibodies were also reduced. This drug
has opened a new chapter for patients who were previously bombarded
with corticosteroids and nonspecific immunosuppressive drugs. At long
last a number of new agents (abatacept, atacicept, and epratuzumab to
name a few) are on the horizon for lupus treatment.
Intravenous immunoglobulin
It seems unlikely that such a ‘blunderbuss’ therapy as pooled intravenous
immunoglobulin (IVIG) that comes from a large numbers of donors could
be successfully used in lupus. And yet it has been a success, particularly
in patients with comorbidities and severe forms of the disease in whom
infection limits the scope for immunosuppressives.
Unfortunately, for most health centres, IVIG is expensive, and avail-
ability is limited. Furthermore, the normal IVIG treatment consists of
five days of intravenous infusions that must take place within a hospital,
which is a major consideration. Perhaps an alternative treatment will
5 3 & "5 . & / 5 t
come from the splitting off of the active components for use against
specific antibody-mediated diseases.
Plasma exchange
In 1973, we published a study in The Lancet describing the first study
of plasmapheresis in lupus. It was not a particularly good study and
unfortunately, there have been few good studies since. In theory,
plasmapheresis (the spinning down of blood allowing the removal of ‘bad’
antibodies) has huge potential. It is still used, but mainly in intensive care
units, and appears in anecdotal data in cases such as catastrophic Hughes
syndrome. Results are encouraging but further investigation is needed.
PART FOUR
Lupus-like disorders
Chapter 12
Sjögren’s syndrome
In 1905, Henrik Sjögren, a Swedish ophthalmologist, described a triad of

clinical features consisting of dry eyes, dry mouth and aches and pains.
In the past 40 years or so, the syndrome has come to be recognized as
not only as a common and important condition, but a syndrome occupy-
ing a central pivotal place amongst autoimmune diseases (Figure 12.1).
Associations with Sjögren’s syndrome
Lupus
Mixed
connective Hughes
tissue disease syndrome
Sjögren’s
syndrome
Lymphoma Thyroid
disease
0UIFS
Rheumatoid
autoimmune
arthritis
diseases
Figure 12.1 Associations with Sjögren’s syndrome. Diseases and conditions associated
with Sjögren’s syndrome. The syndrome tends to be associated with other autoimmune and
connective tissue diseases.
63
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In many ways, Sjögren’s is considered the ‘older first cousin’ of lupus,

as there is a similar proliferation of auto-antibodies (in particular ANA),
the clinical features of fatigue, aches, pains, and occasional sun sensitivity.
The main differences between the diseases are that Sjögren’s affects
an older age group, generally has fewer life-threatening features, and
patients with Sjögren’s have a tendency to produce both organ specific
antibodies (eg, thyroid) as well as non-organ specific antibodies (eg, ANA).
It is now customary to classify Sjögren’s syndrome as ‘primary’ but
when accompanied by other clear cut diagnoses such as rheumatoid
arthritis, it is classified as ‘secondary’ (Figure 12.2).
Pathology
The main pathological finding in Sjögren’s syndrome is a lymphoid infil-
trate in the exocrine glands, notably the salivary and lachrymal glands,
but also extending elsewhere. The initial stage is of a focal infiltration,
but in later stages the lymphoid infiltrate can become overwhelming,
leading to atrophy of the exocrine structures of the gland, with resultant
dryness of the mouth and eyes.
Other organs affected by the infiltrate and atrophy are vaginal and
bladder walls, esophagus, and the upper respiratory tract.
Primary and secondary Sjögren’s syndrome
Rheumatoid arthritis
Primary Sjögren’s syndrome

Secondary
Sjögren’s syndrome
Figure 12.2 Primary and secondary Sjögren’s syndrome. Sjögren’s syndrome is considered
primary when it occurs alone; when associated with another disease (eg, rheumatoid arthritis),
it is termed secondary.
4 + ½ ( 3 & / 4 4 : / % 3 0 . & t
Clinical features
General
The most common age of onset is generally later than that of lupus,
usually in the 4th or 5th decade. As well as dry eyes and mouth, there
may be considerable fatigue. Myalgia and arthritis are frequent, though
commonly occur without joint swelling. There may be morning stiffness
and, in some patients, a history of photosensitivity. Lymphadenopathy,
particularly in the neck, is intermittent. In some patients, splenomegaly
(a tippable spleen) is noted.
It is important to remember the clinical features of the conditions asso-
ciated with Sjögren’s, including Hughes syndrome (headache, migraine,
balance disturbance, and transient ischemic attack) and hypothyroidism
(constipation, cold sensitivity, skin changes, weight gain and sluggish
reflexes) (Figure 12.3).
Allergies (including food allergy) are also a strong feature of the con-
dition. For example, in the years when gold salts were used in the treat-
ment of rheumatoid arthritis, allergic reactions were twice as common in
rheumatoid athritis patients with associated Sjögren’s as in those without.
One common feature is an allergy to Septrin, a sulphur-containing
antibiotic now rarely used. Septrin allergy was such a regular feature
in the past history of Sjögren’s patients that it became something of a
diagnostic criterion.
Eye
Although dryness of the eyes is one of the pivotal features of the syn-
drome, many patients do not notice or complain of it. A more common
complaint is of irritation or scratchiness, which is often put down to
allergy or hay fever. In others, there may be a history of ‘stickiness’ of
the eyes in the morning, photophobia, or difficulty with contact lenses.
Later stages can include corneal ulceration.
Mouth and gastrointestinal tract

A dry mouth is possibly the most common complaint in Sjögren’s, with
many patients having to take a jug of water to bed with them. Both the
quantity as well as the quality of the saliva produced by the infiltrated
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Features of Sjögren’s syndrome
Dry eye
Dry mouth
Swollen salivary glands
Thrombosis
Pain in joints
Gynecological and
urological symptoms
Purpura
Figure 12.3 Features of Sjögren’s syndrome. Symptoms of Sjögren’s disease include dry
eyes, dry mouth, swollen salivary glands, vasculitis, pulmonary symptoms, joint pain, and
gynecological/urological problems. Sjögren’s syndrome is a chronic autoimmune disorder in
which tear and saliva production is impaired.
salivary glands is poor. In the early stages of Sjögren’s, the parotid and
submandibular glands can become swollen, either intermittently, or
chronically, and in some cases significant parotid gland swelling can
lead to a characteristic ‘hamster’ or ‘marmoset’ facies.
Poor saliva leads to poor dental hygiene, and gum and dental problems
are common in Sjögren’s and require vigilant dental care.
If the mouth dryness extends into the esophagus, swallowing dry
foods is made even more difficult. It is possible that poor mucus protec-
tion in the stomach mucosa might render Sjögren’s patients more at risk
from anti-inflammatory drug-induced gastritis.
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Vagina and bladder

Vaginitis sicca is a problem in many patients, leading to dyspareunia,
thrush, and other vaginal problems. Somewhat underestimated has been
the problem of recurrent cystitis in Sjögren’s – in some cases urethral
symptoms; in others, more serious interstitial cystitis.
Kidney
Renal tubular acidosis, and occasionally other renal tubular defects,
have long been recognized as a complication of Sjögren’s, notably those
patients with very high globulin levels. Occasionally, the renal involvement
is that of interstitial nephritis (Figure 12.4). Glomerular nephritis has
been reported but is rare.
Nervous system
Trigeminal neuralgia, a neuropathic disorder that causes short, stab-
bing bursts of facial pain, is commonly seen in Sjögren’s. It is also a
feature of Hughes syndrome but the exact inter-relationships of these
two syndromes and trigeminal neuralgia are not yet certain. Other
cranial neuropathies, as well as peripheral neuropathy, are sometimes
seen. Central nervous system involvement is reported, but the compli-
cations described (stroke and atypical multiple sclerosis, for example),
may be more strongly associated with Hughes syndrome rather than
to Sjögren’s per se.
The same may be true for the balance problems sometimes seen in
Sjögren’s, some of which may be secondary to the associated conditions
of hypothyroidism or Hughes syndrome.
Blood
As with lupus, borderline neutropenia is a common feature of
Sjögren’s. In some cases, persistent moderately severe neutropenia
(eg, 1.0–2.0 x 109 WBC/L) is seen with little in the way of infections
(see Figure 9.1). Thrombocytopenia and hemolytic anemia are well
reported but unusual.
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Interstitial nephritis in Sjögren’s disease
Figure 12.4 Interstitial nephritis in Sjögren’s disease. A renal biopsy specimen showing
tubular damage in a kidney of a patient with Sjögren’s syndrome. Interstitial nephritis is a kidney
disorder involving inflammation of kidney tubules, which can affect the kidney function and
inhibit waste filtration.
Many Sjögren’s patients run a persistently raised ESR (eg, over

40mm/hour); indeed Sjögren’s is one of the more prominent causes of
prolonged unexplained raised ESR. Interestingly, as in the case of lupus,
the CRP may remain low even in the face of a raised ESR.
Purpura
A small number of Sjögren’s patients notice intermittent purpuric
lesions on the lower legs. These often appear after unusual exercise or
long-haul flights. In some patients, the frequency and severity of the
purpura can lead to chronic discolouration of the legs (usually below
the knees). In extreme cases, peripheral neuropathy can result from the
purpura-induced ischemia.
Other autoimmune diseases

Other autoimmune diseases, notably Hashimoto’s thyroiditis, idiopathic
hypothyroidism and Addison’s disease, are known to be associated with
Sjögren’s. Others include pernicious anemia, celiac disease, rheumatoid
arthritis and multiple sclerosis. Somewhat surprisingly, the strengths
of some of these associations are not fully elucidated and some may be
underestimated. For example, routine Schirmer tear testing for Sjögren’s
is probably not practised in many cases of multiple sclerosis.
4 + ½ ( 3 & / 4 4 : / % 3 0 . & t
Malignancy
Non-Hodgkin’s lymphoma (NHL) is increased in frequency in all autoim-
mune conditions, but particularly in primary Sjögren’s (Figure 12.5); there
is a 44-fold increase compared with the general population, especially in
cases with persistently enlarged parotids and chronic lymphadenopathy.
However, the tendency to NHL may not be a feature of the mild version
of Sjögren’s that is usually associated with rheumatoid arthritis.
CT scan of lymphoma
Hepatosplenomegaly Abdominal lymphadenopathy
Liver
Spleen
Figure 12.5 CT scan of lymphoma. A CT scan of patient with lymphoma showing enlarged
liver, spleen and abdominal lymph nodes (arrowed). A small number of Ro-positive patients with
Sjögren’s develop Non Hodgkin’s lymphoma.
Diagnosis
Table 12.1 lists the main diagnostic features of Sjögren’s syndrome.
Schirmer’s tear test

The Schirmer’s tear test, although somewhat simple, is a surprisingly
useful clinical aide (Figure 12.6).
A sterile, standardised strip of blotting paper (Schirmer paper) is
hooked over the lower eyelid and left for 5 minutes. In normal eyes, the
irritation caused by the paper soaks the blotter in seconds. In Sjögren’s, it
is often totally dry. Conventionally, wetting of under 15mm is considered
an abnormal (“dry”) Schirmer’s test. The major benefit of the test is that
it generally gives a clear answer, especially as, somewhat surprisingly,
diuretics, antihistamines and older age have little drying effect on a
Schirmer’s test.
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The main diagnostic features of Sjögren’s syndrome

Routine tests
Raised ESR/normal CRP
WBC normal or low
Hyperglobulinemia (polyclonal)
Immunology
Positive ANA 60–80%
Positive anti-Ro and anti-La 50–60%
Negative anti dsDNA
Positive rheumatoid factor 50–60%
Negative anti-CCP (unless RA present)
Eye tests
Dry Schirmer’s tests
Positive fluorescent dye tests
Histology
Minor salivary glands: Lymphocyte infiltration
Table 12.1 The main diagnostic features of Sjögren’s syndrome. A list of diagnostic features
in Sjögren’s syndrome. ANA, antinuclear antibodies; anti- CCP, anti- citrullinated peptides;
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
The test is crude (by ophthalmological standards) and formal oph-

thalmological assessment, including a dry eye test such as Rose bengal
staining, is also advised. Rose bengal is a dye which, when dropped
on to the cornea, stains devitalised or damaged epithelium in the con-
junctiva (Figure 12.7). Examination shows the roughened or punctate
pattern of keratitis.
Immunology
The infiltration of salivary glands is predominantly lymphocytic, and
involves CD4+ T-helper/memory cells. Early on, the infiltrate is around
the ducts, and later replaces the functional tissue.
Although a variety of auto-antibodies – ANA, anti-thyroid, celiac
antibodies, rheumatoid factors – are produced, the predominant and
most specific antibodies are those directed against Ro and La antibodies.
Ro (also known as SSA) is primarily localised in the cytoplasm and
thus, in some cases, conventional anti-nuclear staining may remain
negative. Anti-Ro antibodies are found more frequently in patients with
4 + ½ ( 3 & / 4 4 : / % 3 0 . & t
earlier disease onset, longer duration, prominent parotid enlargement,

and more intense infiltration of the salivary glands.
Furthermore, anti-Ro and anti-La antibodies correlate with other
disease manifestations such as purpura, leukopenia, and polyclonal
gammopathy. The association of anti-Ro antibodies with neonatal lupus
and congenital heart block is discussed in Chapter 16.
Other diagnostic tests

Lip biopsy
Biopsy of a minor salivary gland (pinhead sized glands in the lip) gives,
in most cases, a mirror image of the pathology taking place in the larger
Dry Schirmer’s test
Figure 12.6 Dry Schirmer’s test. The Schirmer’s test is a method of measuring aqueous tear
production and involves placing small strips of filter paper under the lower eyelid. Sicca syndrome
in Sjögren’s syndrome can be easily assessed by this test.
Rose bengal test for eyes
Figure 12.7 Rose bengal test for eyes. The rose bengal staining test is used patients suspected of
having Sjögren’s syndrome to determine the presence of keratoconjunctivitis sicca (dry eye syndrome).
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glands such as the parotid. The biopsy, a small incision in the lower lip,
can cause discomfort and is not routinely used.
Scintigraphy
Isotope scanning using technetium-99 measures the rate of secretion
from the salivary glands into the mouth. In Sjögren’s, the secretion of
labelled saliva is delayed.
Etiology
As with lupus, there is evidence for genetic, environmental and hormonal
factors in the pathogenesis of Sjögren’s syndrome. There is a marked
female preponderance, though the age of onset is much later than that of
most lupus cases. Clinical evidence for genetic contributions comes from
the many large family cohorts, including those with related autoimmune
features such as celiac, thyroid and rheumatoid diseases.
Although no clear-cut environmental causes have been proven,
two viruses have been implicated. Firstly, hepatitis C virus, endemic
in certain countries such as Egypt, can cause a Sjögren’s-like illness.
Secondly, many patients with Sjögren’s have a past history of glandular
fever caused by the Epstein-Barr (E-B) virus, that is often severe and
lasting many months. While the E-B virus is thus under suspicion as a
cause of Sjögren’s, more evidence is needed.
Treatment
The antimalarial drug hydroxychloroquine (Plaquenil) is the mainstay
of treatment for Sjögren’s. In doses ranging from 200–400 mg daily, it
is particularly effective in improving the fatigue associated with the
condition. For acute flares, short courses of steroids (5–10 mg prednisolone
daily for 1–2 weeks) can be very effective. For those with more extensive
or resistant disease, azathioprine (and more recently mycophenolate
mofetil) is widely used.
Many patients with Sjögren’s syndrome suffer features of Hughes
syndrome (sometimes even in the absence of positive aPL tests) and in
such cases, the addition of low dose aspirin is helpful.
Chapter 13
Hughes syndrome
(the antiphospholipid syndrome)
An increasingly important link between aPL antibodies and a clinical

syndrome is becoming recognized worldwide. This syndrome, known
as the antiphospholipid syndrome (APS) or Hughes syndrome, is a
prothrombotic disorder leading to both arterial and venous thrombosis
and, in pregnancy, recurrent abortion and pregnancy loss (Figure 13.1).
Features of Hughes syndrome
Venous
thrombosis
Recurrent Arterial
Hughes syndrome
miscarriages thrombosis
Antiphospholipid Neurological
antibodies features
Figure 13.1 Features of Hughes syndrome. A diagram detailing the major features of Hughes
syndrome, including thrombosis, presence of antiphospholipid antibodies and recurrent miscarriage.
73
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Introduction
The Wassermann reaction (WR), an early test for syphilis, is essentially
the forerunner of the modern aPL test. For over half a century, it was
recognized that a “false-positive WR” could be found in some patients
with lupus.
In 1983, we described the clinical details of a syndrome characterised
by recurrent thrombosis, neurological disease, occasional thrombocyto-
penia, and recurrent pregnancy loss. Critically, the thromboses involved
arteries (eg, stroke and heart attack) as well as veins.
We identified the link with aPL antibodies and set up sensitive assays
for their detection. We also recognized that the syndrome could exist
outside of lupus and called the syndrome the antiphospholipid syndrome
(APS). Technically, the antibodies aren’t specifically directed to phospho-
lipids, but protein co-factors such as prothrombin and beta 2 glycoprotein
1 are required for the pathological clotting process to go ahead. For this
reason, the alternative, simpler title “Hughes syndrome” was proposed
by the international APS congress in 1992. The main clinical criteria for
Hughes syndrome are listed in Table 13.1.
Blood
Because of the tendency toward thrombosis formation, Hughes syndrome
is often referred to as ‘sticky blood syndrome.’ Venous thrombosis (eg,
deep vein thrombosis) can be the first presentation and result in life-
threatening pulmonary embolism. Internal organ venous thromboses
can include adrenal glands (Addison’s; Figure 13.2), kidneys (eg, renal
vein thrombosis), and the liver (eg, Budd-Chiari syndrome).
Arterial thrombosis can involve the limbs, as well as critical internal
organs such as the brain, kidney, heart, and gastrointestinal tract.
Perhaps surprisingly, thrombocytopenia is an occasional feature and
sometimes can be severe and acute, with platelet counts of 10 x 109/L or
less but more commonly with borderline counts of 100 x 109 to 120 x 109/L.
Pregnancy
There is an increased risk of miscarriage and fetal death that is pre-
dominantly due to placental ischemia. In fact, Hughes syndrome is now
) 6 ( ) & 4 4 : / % 3 0 . & ŷ 5 ) & " / 5 * 1 ) 0 4 1 ) 0 - * 1 * % 4 : / % 3 0 . & Ÿ t
Main criteria for Hughes syndrome

1. Venous thrombosis
t Deep vein thrombosis (DVT)
t Pulmonary embolism
t Renal vein thrombosis
t Saggital sinus thrombosis
2. Arterial thrombosis
t Stroke
t Renal artery thrombosis
t Myocardial infarction
t Bowel ischemia
0SHBOT
t Brain
t Eye
t Kidney
t Liver
t Adrenal glands
3. Pregnancy loss
t Multiple miscarriages
t Late fetal loss
t Intra uterine growth retardation
t Infertility ( some cases)
4. Wide variety of neurological features
t Epilepsy
t Memory loss
t Movement disorder
5. Occasional thrombocytopenia
Table 13.1 Main criteria for Hughes syndrome. A list of the main criteria used to diagnose
Hughes syndrome.
Adrenal infarction in Hughes syndrome
Figure 13.2 Adrenal infarction in Hughes syndrome. Adrenal infarction (arrowed) due to
thrombosis in the adrenal glands. Infarction is more common in patients with Hughes syndrome.
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recognized as the most common treatable cause of recurrent miscarriage

and some women can suffer a dozen or more miscarriages without treat-
ment. Late pregnancy loss, as well as other late pregnancy complications,
is common. However, treatment has revolutionised the outcome for these
women and is one of the success stories of modern medicine.
Brain
Brain involvement is a prominent feature and signs and symptoms cover
the whole spectrum of neurology. The brain is peculiarly sensitive to the
hypoxia associated with the ‘blood sludging’ effect of Hughes syndrome.
The two most common features are migraine (often going back to child-
hood) and memory loss, causing patients to frequently express concern
about Alzheimer’s disease. Strokes in patients with Hughes syndrome
account for up to one in five young strokes (aged under 45) and can
recur if untreated.
Other neurological presentations include epilepsy (up to one in five of
idiopathic teenage epilepsy cases tested aPL-positive), visual disturbance,
balance problems and transverse myelopathy. Some cases have proved
to be indistinguishable from multiple sclerosis. Chorea and movement
disorders are also seen.
Heart
Heart valve thrombosis and damage (eg, Libman-Sacks endocarditis) are
well documented (Figure 13.3). Myocardial ischemia and heart attack
are also seen. Recent studies have suggested that Hughes syndrome
might prove to be a significant cause of heart attack in younger patients.
Other organs
Skin ischemia and skin ulceration is often seen. A very common feature
is livedo reticularis (see Chapter 3), a clinical finding which appears to
be a very significant pointer towards thrombosis in Hughes syndrome.
Lung involvement can range from acute (pulmonary embolism;
Figure 13.4) to insidious (pulmonary hypertension).
In the kidney, small vessel thrombosis can be a significant factor in
the pathology in patients with lupus who are aPL-positive.
) 6 ( ) & 4 4 : / % 3 0 . & ŷ 5 ) & " / 5 * 1 ) 0 4 1 ) 0 - * 1 * % 4 : / % 3 0 . & Ÿ t
Cardiac valve deformity in Hughes syndrome
Figure 13.3 Cardiac valve deformity in Hughes syndrome. An estimated 30% of patients with
Hughes syndrome have valvular lesions.
Pulmonary embolism in Hughes syndrome
Figure 13.4 Pulmonary embolism in Hughes syndrome. Mismatched ventilation perfusion

scan showing pulmonary embolism in Hughes syndrome.
Renal artery thrombosis results from a focal narrowing of an other-

wise healthy looking renal artery, leading to hypertension (Figure 13.5).
Similar focal occlusions are seen in other arteries such as the carotid
and the celiac (Figure 13.6) and mesenteric arteries (the latter leading
to mesenteric angina).
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Angiogram showing renal artery stenosis in Hughes syndrome
Right renal
arterty stenosis
Aorta
Figure 13.5 Angiogram showing renal artery stenosis in Hughes syndrome. 0GUFOQSFTFOUT
as uncontrolled hypertension in Hughes syndrome. Stenosis can restrict blood flow to the kidney,
impairing function.
Celiac artery thrombosis in Hughes syndrome
Figure 13.6 Celiac artery thrombosis in Hughes syndrome. Thrombosis is clearly visible on the
celiac trunk (see arrow).
In the locomotor system, focal ischemia can lead to bone fracture

(especially in the metatarsals; Figure 13.7) and joint ischemia (eg, avas-
cular necrosis of the head of the femur).
) 6 ( ) & 4 4 : / % 3 0 . & ŷ 5 ) & " / 5 * 1 ) 0 4 1 ) 0 - * 1 * % 4 : / % 3 0 . & Ÿ t
Non-traumatic metatarsal fractures in Hughes syndrome
Figure 13.7 Non-traumatic metatarsal fractures in Hughes syndrome. Patients with Hughes
syndrome are at greater risk of stress fractures, which may be caused by micro-infarcts in the
metatarsal bones. Left figure shows callus formation; Right figure shows a recent fracture.
As an autoimmune disease, it is not unusual for patients with Hughes

syndrome to have a family history of other related conditions – notably
Sjögren’s syndrome, lupus and thyroid disease.
Treatment
At present, Hughes syndrome treatment is largely limited to anticoagulant
drugs such as aspirin, heparin and warfarin.
Aspirin or clopidogrel is used for those with histories of migraine,
and as prophylaxis in those found to be aPL-positive (for example lupus
and Sjögren’s patients with positive aPL, as well as in aPL-positive
pregnancies).
Low molecular weight heparin is used in pregnancy in patients with
previous thrombosis or poor pregnancy histories. It is also sometimes
used in clinical trials in aPL-positive patients with, for example, increas-
ingly severe migraine, before considering the use of warfarin. Warfarin is
vital in those patients with a major thrombosis, or with ischemic lesions
on brain MRI, and in most cases is used for life.
A high international normalized ratio (INR) (eg, 3.5) is often required
for clinical control, and for this reason, self-testing INR by the patient,
in collaboration with his or her anticoagulant clinic, is advised.
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The future
Newer anticoagulants, such as dabigatran (Pradaxa) will certainly be a
welcome addition to the therapeutic armoury. So too will newer selec-
tive immunosuppressives such as the anti-B cell agents rituximab and
belimumab. Anecdotally, these agents are already being tried in some
more severe and resistant cases.
The description of Hughes syndrome has linked many specialities,
and added a new line of diagnoses and treatment to a wide variety of
common clinical conditions, ranging through balance problems, to
miscarriages, to epilepsy, to migraine, to heart attack. With so many
disciplines involved, spreading the word to busy clinicians is a priority.
Chapter 14
Mixed connective tissue disease

(and overlap syndromes)
In 1966, Dr Gordon Sharp described a condition characterised by

Raynaud’s, joint problems, ‘overlapping’ features of lupus and scleroderma
and defined by the presence of a specific antibody: anti-ribonucleoprotein
(anti-RNP). Although initially criticized as a concept, the condition he
described, mixed connective tissue disease (MCTD), has been accepted
by the medical community and is often referred to as Sharp’s disease.
Indeed with its link to a single antibody that is often in high titer, it is
one of the most intriguing of the connective tissue diseases.
Clinical features
Raynaud’s phenomenon
With the possible exception of scleroderma, no other condition displays
such severe Raynaud’s syndrome. The classic triad of white, blue and
red skin discoloration can affect both toes and fingers, even sometimes
bizarrely just a single digit. The ischemia can be severe, leading to
ulceration and even loss of one or more digits (Figure 14.1).
Joints and tendons

A common and notable feature is of ‘sausage-like’ swelling of fingers.
Due to a combination of tendonitis and subcutaneous swelling, this
often leads to marked stiffness and puffiness of the fingers. There may
81
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Raynaud’s phenomenon
Figure 14.1 Raynaud’s phenomenon. Discoloration of the digits due to restricted blood supply.
Raynaud’s phenomeron can also cause numbness and pain.
be tendon crepitus and other tendons in the shoulder or lower limbs, for
example, can be affected.
Joint swelling in most cases is mild, though a sub-group of patients
do develop rheumatoid-like disease, reinforcing the concept of ‘mixed’
connective tissue disease.
Muscles
In some cases, a true inflammatory myopathy occurs, with muscle
weakness, raised creatine phosphokinase and abnormal electromyogram.
Indeed myositis can be the predominant and presenting feature
(Figure 14.2A and B). Anti-RNP measurement is an important part of
the workup of cases of myositis.
Myositis shown on longitudinal MRI scan
A B
Figure 14.2A and B Myositis shown on transverse MRI scan. A Longitudinal MRI scan. B
Transverse MRI scan. Bright areas indicate inflamed muscles, usually associated with elevated
creatine kinase.
. * 9 & % $0 / / & $ 5 * 7 & 5 * 4 46 & % * 4 & " 4 & ŷ " / % 0 7 & 3 - " 1 4 : / % 3 0 . & 4Ÿ t
Other organs
As with other causes of Raynaud’s, esophageal problems can be severe.
These include dysphagia, reflux, and even stenosis. Systemic features
can mimic lupus, with photosensitivity, pleurisy, and pericarditis. Severe
renal involvement in MCTD is rare.
Immunology
One of the interesting features of MCTD is its immunological profile.
Unlike lupus, which is characterised by a veritable rainbow of antibod-
ies (over 100 have been described), MCTD is essentially characterised
by one antibody: anti-RNP. In ANA testing, this shows up as a ‘speckled’
pattern that is often present in high titers, even at a dilution of over one
in a million.
As well as this extraordinarily high titer of anti-RNP in some patients,
other fairly nonspecific signs of immunological over-activity include raised
gammaglobulin levels and (occasionally) a positive rheumatoid factor test.
Outcome
MCTD has been almost universally regarded as an overlap of Sjörgren’s
syndrome, scleroderma, Raynaud’s, myositis and rheumatoid arthritis
but generally with a more benign outcome (Figure 14.3). While this may
be true for overall prognosis, in clinical practice, MCTD is often more
Mixed connective tissue disease: clinical associations
Scleroderma
Sjögren’s
Raynaud’s
syndrome
MCTD
Myositis Arthritis
Figure 14.3 Mixed connective tissue disease: clinical associations. An overlap of scleroderma,
myositis, Sjögren’s syndrome, arthritis, and Raynaud’s phenomenon.
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troublesome and more resistant to management than any of its better

known relatives.
In many patients moderately high steroid doses (eg, 20 mg daily)
are needed to control symptoms, while in others, particularly those
with prominent muscle or joint involvement, are given steroid sparing
agents such as methotrexate or anti-tumor necrosis factor (TNF) agents.
Chapter 15
Vasculitis
Although much of the pathology of lupus is in fact small vessel vasculi-

tis, it is customary to separate the group of disorders grouped under the
‘primary’ vasculitis label.
The group differs from lupus in a number of ways including the rela-
tively few immunological markers (anti-neutrophil cytoplasmic antibodies
being an exception), and the high inflammatory markers such as ESR,
CRP, leukocyte count and (often) high platelet counts.
Classification
There have been many attempts to classify this heterogeneous group
of diseases. By far the simplest and most practical for the clinician is
by vessel size (Figure 15.1). Thus Takayasu’s arteritis affects large (and
very large) arteries such as the aorta; polyarteritis nodosa and Wegener’s
granulomatosis affects smaller arteries; a variety of inflammatory arte-
ritides (eg, allergic vasculitis) affect the smallest vessels.
For the clinician, these diseases are generally clearly distinguishable
from lupus. A few of the major vasculitides are discussed briefly here.
Wegener’s granulomatosis
This once uniformly fatal disease is now largely treatable with
cyclophosphamide.
85
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Classification of vasculitis
Small-vessel vasculitis
(eg, microscopic polyangiitis, Wegener’s granulomatosis)
Medium-sized-vessel vasculitis
(eg, polyarteritis nodosa, Kawasaki’s disease)
Large-vessel vasculitis
(eg, giant-cell arteritis, Takayasu’s arteritis) Goodpasture’s syndrome
Henoch-Schölein purpura and

cryogobulinemic vasculitis
Microscopic polyangiitis, Wegener’s granulomatosis,

and Churg-Strauss syndrome
Figure 15.1 Classification of vasculitis. Vasculitis indicates inflammation of blood vessels.

Classification is primarily based on blood vessel size.
The condition consists of two features: granulomatous necrosis, affect-

ing sinuses and lungs, and more widespread inflammatory vasculitis,
affecting the arteries of limbs as well as internal organs.
The classical picture is development of chronic sinusitis, leading
to blood-stained and necrotic nasal discharge. CT scans of the sinuses
show filling of the sinuses and (later) erosion of bone (Figure 15.2).
Granulomatous lesions can fill the eye socket leading to exophthalmos
(Figure 15.3). The lungs are commonly involved, with almost the full
spectrum of pulmonary presentations ranging from pleural effusions to
‘cannonball’ lung pictures (Figure 15.4). Features of Wegener’s granulo-
matosis also include peripheral neuropathy (including mononeuritis mul-
tiplex), vasculitic skin lesions (Figure 15.5), liver and kidney involvement
(Figure 15.6) and myocardial infarction.
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Wegener’s granulomatosis – CT scan of sinus showing collapsed

nasal bridge
Figure 15.2 Wegener’s granulomatosis – CT scan of sinus showing collapsed nasal septum.
Wegener’s granulomatosis can cause bony erosions, destruction and mucosal thickening.
Intra-orbital mass in Wegener’s granulomatosis
Figure 15.3 Intra-orbital mass in Wegener’s granulomatosis. An intra-orbital granuloma

(arrowed) in Wegener’s granulomatosis can affect vision and, in severe cases, destroy the orbit.
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Wegener’s granulomatosis – lung involvement
Figure 15.4 Wegener’s granulomatosis – lung involvement. Lung nodules and cavity
formation in the lungs may present as hemoptysis.
Wegener’s granulomatosis – skin ulcers
Figure 15.5 Wegener’s granulomatosis – skin ulcers. Severe cutaneous ulcers in a patient with
Wegener’s granulomatosis.
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Renal involvement in Wegener’s granulomatosis
Figure 15.6 Renal involvement in Wegener’s granulomatosis. Necrotising glomerulonephritis,

showing necrotic glomerulus scarring and inflammatory infiltrate.
Diagnosis
The clinical picture of vasculitis is usually well defined and diagnosis is
generally straightforward.
Inflammatory features include a raised CRP (often very high), raised
WBC (sometimes over 20 x 109/L and high platelets (often over 400 x 109/L).
CT scans of sinuses and chest X-rays may show the characteristic
pictures. The ultimate proof of the diagnosis comes from tissue biopsy
(eg, bronchoscopy), though obtaining clear histological proof in a newly
sick patient with Wegener’s granulomatosis is the exception rather than
the rule.
The one immunologically useful test is anti-neutrophil cytoplasmic
antibody (ANCA). It was found some years ago that most patients with
Wegener’s granulomatosis had a circulating antibody directed against a
constituent of cytoplasm. Two main antigens have since been recognized:
myeloperoxidase, now known to be responsible for the P-ANCA antibodies.
C-ANCA (an easy memo is ‘C for classical’ as in classical Wegener’s) is the
specific test for Wegener’s granulomatosis (Figure 15.7A). P-ANCA, by
contrast, is seen in a number of inflammatory diseases (Figure 15.7B).
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C-ANCA
Figure 15.7A C-ANCA. Anti cytoplasmic antibodies (PR3) are seen in more than 70% of patients
with Wegener’s granulomatosis. ANCA, antineutrophil cystoplasmic antibodies.
P-ANCA
Figure 15.7B P-ANCA. Anti cytoplasmic antibodies (myeloperoxidase) are seen in various types
of vasculitis including Wegener’s granulomatosis, Churg-Strauss syndrome and polyarteritis nodosa.
ANCA, antineutrophil cytoplasmic antibodies.
Treatment
The use of pulse cyclophosphamide has revolutionised the treatment
of Wegener’s granulomatosis. Eye swelling, sinus obstruction, and lung
shadows often melt dramatically following even the first IV pulse of the
drug. Thus, speedy diagnosis is vital.
Most Wegener’s granulomatosis patients treated with IV
cyclophosphamide attain remission, though life-long observation is
mandatory, as the disease can frequently flare.
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Polyarteritis nodosa
Polyarteritis nodosa (PAN) is a rarely seen extreme form of vasculitis,
often presenting dramatically, with a high early fatality rate. The patho-
logical picture is one of inflammation affecting mainly medium-sized
arteries that is often so intense that it casues weaknesses in the vessel wall
and secondary aneurysm formation, resulting in the knotted (‘nodosa’)
formation which gives the disease its name.
The clinical picture is one of extreme and acute inflammatory disease,
including nephritis, hypertension, lung lesions, myocardial infarction, gut
necrosis (Figure 15.8), testicular infarction (Figure 15.9) and mononeu-
ritis multiplex, a nervous system disorder that involves pathognomonic
‘picking off’ of peripheral nerves, often in a seemingly random pattern.
Peripheral white blood counts can exceed 30 x 109/L, and C-reactive
protein values are usually over 100.
In 1970, an association between PAN and hepatitis B was identified.
Subsequent series of PAN cases included many cases of drug addiction
and hepatitis B infection, and serological studies demonstrated circulating
immune complexes of hepatitis B virus and antibody.
As with Wegener’s granulomatosis, PAN treatment is initially with
a combination of steroids and immunosuppressives. Unlike Wegener’s
granulomatosis however, the illness is usually a ‘one shot’ condition:
life-threatening at first but, if controlled, usually remains dormant
thereafter.
Mesenteric involvement in polyarteritis nodusa
Figure 15.8 Mesenteric involvement in polyarteritis nodusa. Micro-aneurysms on mesenteric

blood vessels in polyarteritis nodusa.
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Testicular infarction in polyarteritis nodusa
Figure 15.9 Testicular infarction in polyarteritis nodusa. An ultrasound image showing

testicular infarction (dark area; arrowed) in a patient with polyarteritis nodusa. Infarction can
occur if polyarteritis nodusa is severe enough to affect blood supply and cause necrosis.
Takayasu’s arteritis
This acute onset vasculitis affects the aortic arch and its main branches
(Figure 15.10), classically resulting in absent arm pulses (but with normal
leg pulses). Cerebral and ocular circulation can be affected. The etiology
is unknown but the illness is often biphasic, starting with generalised
flu-like symptoms, with the arteries becoming clinically involved some
weeks later. If caught early, treatment is with steroids and immunosuppres-
sives, though the later occlusive sequelae may require vascular surgery.
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Takayasu’s arteritis
Figure 15.10 Takayasu’s arteritis. Complete occlusion of right subclavian and left common
carotid arties due to Takayasu’s arteritis. This condition generally involves large blood vessels.
PART FIVE
Lupus-related topics
Chapter 16
Lupus-related topics
Lupus and pregnancy

Lupus used to be regarded as a contraindication to pregnancy. Sadly, many
patients with lupus were strongly advised against becoming pregnant.
Times have changed and indeed many lupus centres now run busy preg-
nancy clinics. We now recognise that lupus itself generally has no major
impact on pregnancy outcome (those with marked renal impairment or
hypertension excepted).
The major risk in lupus is related to aPL antibodies. As with the
Hughes syndrome, patients with lupus who are aPL-positive have an
increased chance not only of repeated pregnancy loss, but also of other
pregnancy related conditions, notably intrauterine growth retardation.
Thus, aPL-positive patients with lupus need to be considered for aspirin
and/or heparin treatment during pregnancy.
Patients with lupus carrying anti-Ro antibodies are at risk of giving
birth to an infant with congenital heart block, a rare development which
occurs in 1 in 500 births (Figure 16.1). There is a very low risk, but the
risk increases to 1 in 20 in pregnancies following a first child born with
a congenital heart block.
Lupus in children
Although lupus normally affects individuals in their teens and upwards
(in girls after the start of menstruation), lupus can and does affect children
(and even toddlers).
97
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An ECG showing complete heart block
Figure 16.1 An ECG showing complete heart block. An ECG showing P Wave (arrows) and
QRS complexes occuring independently. Congenital heart block is a rare complication seen in
newborns due to transplacental transfer of Ro antibodies from the mother.
The clinical patterns in children are similar to those in adults, and in

general, treatment options are the same. Provided the diagnosis is made
quickly and treatment is started immediately, the prognosis is no worse
than that in adults. In our practice, we have dozens of patients in whom
lupus first presented under the age of 12 but are now in remission and
no longer taking strong medicines.
Lupus and late arterial disease

In recent years, it has been recognized that patients with lupus have an
increased risk of atheromatous disease later in life (in the 40s, 50s and
60s), including coronary disease and stroke; so much so that lupus has
been labelled by some ‘the new diabetes’. The cause(s) of this phenom-
enon are not yet clear, but possible contributors include steroids, chronic
inflammation, and renal disease.
Lupus and malignancy

Despite many patients with lupus receiving immune-altering drugs,
coming in and out of hospitals and presumably coming into contact with
a multitude of viruses, malignancy in lupus is strikingly uncommon.
However, one clinical association may have influenced publications
in the past: Non-Hodgkin’s lymphoma (NHL) has an increased preva-
lence in Sjögren’s patients, notably those patients with enlarged parotids
and other glands. This group of patients is older than the average lupus
age (often in their 60s) and immunologically different (for instance,
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anti-dsDNA negative). However, it is possible that some previous studies

claiming a higher NHL risk in lupus may well have included patients
from the Sjögren’s group, as the average age in some reported series
strongly suggests this.
A second caveat concerns cervical cancer. Many years ago it was
reported that many patients with lupus had abnormal cervical smears.
We wondered whether either the vaginal dryness or perhaps the medica-
tion they were prescribed was the underlying reason. Almost universally,
these abnormal smears turned out to be benign and cervical cancer has
not been an increased problem in our patients.
Drug-induced lupus
Other factors reported as triggering lupus are drugs, including hydrala-
zine (a blood pressure drug), Septrin, (an older sulphur-contain-
ing antibiotic), and anti-TNF drugs (used for rheumatoid arthritis)
(Figure 16.2).
In some of these examples, the condition usually known as drug-
induced lupus, rarely progresses to kidney disease and usually (with
the exception of Septrin) disappears on stopping the offending drug.
One notable cause of drug-induced lupus is minocycline, an antibiotic
that has been widely used for the treatment of acne in teenagers. In a
small number, the recipient developed joint pains and other features of
Drugs that have been shown to cause drug-induced lupus
Hydralazine Isoniazid
Procainamide Drug induced lupus Minocycline
Anti -TNF antibodies Propylthiouracil
Figure 16.2 Drugs that have been shown to cause drug-induced lupus. A number of drugs
may produce a lupus-like syndrome. The adverse effects generally clear up upon stopping the
offending treatment.
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lupus. Perhaps, not surprisingly, the connection in some cases was not
made and the drug-induced lupus became severe.
Flares of lupus have also been occasionally reported after vaccina-
tion and immunization, and suggestions have been made that some
solvents or adjuvants used in vaccines may have had a triggering effect.
However, one of the most common triggers of lupus appears to be stress.
The mechanisms are probably complex. There is plenty of evidence,
for example, that stress has measurable effects on the immune system.
Clinically, some cases dramatically highlight the link. For example, one
of our patients suffered two family bereavements in a year and in both
cases, these events were followed by a severe drop in platelet counts.
Coincidence perhaps, but there are numerous such cases in any large
lupus practice.
Lupus: soil versus seed

Clearly, lupus has something of a genetic basis, as there are many families
with more than one lupus sufferer. Twin studies show an increased lupus
risk in the twin sibling of a patient with lupus. Furthermore, relatives
of lupus patients have an increased propensity to other auto-immune
conditions such as thyroid disease, Sjögren’s and rheumatoid arthritis.
Studies by genetic departments are, not surprisingly, confirming these
observations and in time, it may be possible to find a genetic ‘fingerprint’
for lupus (see Figure 2.4). As well as genetic factors, it is increasingly
accepted that environmental factors can either trigger or exacerbate lupus
flares. The most well known is sunlight, or more specifically ultraviolet
light. UV light is known to alter the DNA in the cells of the skin, rendering
it more allergic or immunogenic. Thus, it is not uncommon for a lupus
flare to seemingly start after a sunny holiday or honeymoon.

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Clinician’s Manual on Lupus

Clinician’s Manual on Lupus

© 2012 Springer Healthcare, a part of Springer Science+Business Media.

British Library Cataloguing-in-Publication Data.

Commissioning editor: Dinah Alam

PART ONE The growth of lupus

PART TWO Lupus organ by organ

4 Tendons and joints 19

7 Heart and blood vessels 33

8 Liver and gastrointestinal tract 39

PART THREE Diagnosis and treatment

PART FOUR Lupus-like disorders

14 Mixed connective tissue disease

PART FIVE Lupus-related topics

Shirish Sangle is an associate consultant at the Louise Coote Lupus

The growth of lupus

Global distribution of lupus

Is lupus on the increase?

What has changed in lupus?

Lupus is a condition in which the immune system, for some currently

Appearance of lupus antibodies prior to diagnosis

Anti Ro Diagnosis of lupus

Defective apoptosis in lupus

Normal apoptosis Abnormal apoptosis in lupus

Who gets lupus?

Autoimmune disease in relatives

Patient with lupus

Carrier for lupus

One of the characteristic features of lupus is its tendency to wax and

Lupus organ by organ

Butterfly rash in lupus

Flat pink rash on neck and arms

Sun-provoked rash on back

A number of skin-related features deserve separate comment:

Subacute cutaneous lupus erythematosus

Subacute cutaneous lupus erythematosus (SCLE)

photosensitive, is occasionally associated with Sjögren’s syndrome (see

Discoid lupus lesions on the scalp

Diagnosis of cutaneous lupus is generally straightforward, given the

Lupus immunofluorescence band test on skin biopsy

Figure 3.9 Lupus immunofluorescence band test on skin biopsy. An immunofluorescence

Tendons and joints

MRI showing avascular necrosis of the hip

Figure 4.2A MRI showing avascular necrosis of both hip joints.

X-ray showing avascular necrosis of hip

One of the most feared complications of lupus is nephritis (inflammation

Class I Minimal glomerular disease (Figure 5.1A).

Immunofluorescence may reveal deposits containing immunoglobulin.

Renal pathology of lupus nephritis (Class I-VI)

A Class I B Class II C Class III

D Class IV E Class V F Class VI

Because the histological picture is critical to the choice of treatment

Renal pathology in Hughes syndrome: thrombotic microangiopathy

Figure 5.2 Renal pathology in Hughes syndrome: thrombotic microangiopathy. Micro-infarcts

Lupus has been described as “a predominantly neurological disease in

Brain injury in lupus

2 Vasculitis 3 Clot formation

Major stroke in a patient with lupus

Transverse myelitis in lupus

Figure 7.1 Chest CT showing pericardial and pleural effusion. 0GUFOSFMBUFEUPJOGMBNNBUJPO