Clinical Overview of Lupus/CTD
(Connective Tissue Diseases)
Rich Callahan MSPA, PA-C
Fletcher Allen Health Care
Dept. of Dermatology
Burlington, VT
CTD formerly known as CVD
• Formerly known as “collagen vascular diseases,” now used
interchangeably with CTD.
• The term “vascular” was included because it was
recognized early on that the vascular system has a higher
sensitivity to the autoimmune process that drives these
diseases.
• Vasculitis, or inflammation of the blood vessels, plays a
role in many of the CTD’s. This is why dilated periungual
capillary loops are commonly visible in patients with
Lupus, Scleroderma and dermatomyositis.
What are connective tissue
diseases? (CTD)
• A group of diseases of unknown etiology affecting
multiple systems within the body.
• All share a common characteristic: The presence
of antibodies in the serum of ill patients.
• These autoantibodies are more than likely
responsible for the diseases, although they can be
elusive at times, making CTD a clinical, rather
than laboratory diagnosis.
Diagnosis of CTD is tricky
• Almost always difficult to diagnose because CTD
has no specific onset, duration or set of clinical
characteristics.
• There are no “gold standard” tests for the
diagnosis of CTD.
• For this reason, diagnosis is based on sets of
clinical criteria, rather than any one diagnostic
procedure.
CTD’s – Some Examples
• Lupus
Erythematosus
• Dermatomyositis
• Scleroderma
• Relapsing
Polychondritis
• Reiter’s Disease
• Ankylosing
Spondylitis
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Polyarteritis nodosa
Kawasaki’s disease
Psoriatic arthropathy
Polymyositis
Polymyalgia
rheumatica
• Temporal arteritis
• Sjogren’s Disease
We will focus on the “big three”
which will most likely be seen in
clinical practice: Lupus,
Dermatomyositis and
Scleroderma.
Of the Big 3, we will focus on Lupus as it has the
most dermatologic manifestations.
• What is Lupus?
• An autoimmune disease of unknown origin in
which autoantibodies attract to specific types of
connective tissue and cause damage resulting in
clinical signs, symptoms and abnormalities.
• It’s important in dermatology because 85% of all
Lupus cases have skin involvement.
• It’s not rare, and it’s not common either:
About 40 cases/100,000 in North America
Why is diagnosing Lupus important?
• Because a subtype of Lupus known as SLE (systemic
lupus erythematosus) can have serious multisystem
involvement resulting in significant morbidity/mortality if
not recognized/treated.
• Affects multiple systems within the body including
immune, hematologic, neurologic, renal, cardiovascular,
rhematologic and dermatologic.
• Patients who present with skin lesions
suggestive/diagnostic for Lupus need a full work-up to
exclude SLE.
Lupus Subtypes
• SLE: Systemic Lupus Erythematosus - Presents with a
wide range of skin lesions and always has some level of
multisystem involvement.
• CCLE: Chronic Cutaneous LE (or discoid lupus) Defined by its characteristic “discoid” skin lesion. Has the
least potential for systemic involvement.
• SCLE: Subacute Cutaneous LE – Also has wide range of
skin lesions. Often some systemic involvement, but
usually has a benign course.
• (These are the 3 common subtypes – the two others,
Neonatal LE and drug-induced LE – are quite rare.)
Clinical Presentation - SLE
• Rash occurs in 85% of patients with SLE: Erythematous
patches and plaques primarily on sun exposed surfaces of
head, trunk and upper extremities:
• Face
• Upper chest
• Shoulders/extensor arms
• Dorsal hands/fingers (spares the knuckles)
• Lesions may/may not be scaly and never itch.
• Butterfly rash occurs in 30-60% of patients with SLE
• Photosensitivity in 50% of patients. Tends to be
females>males, age usually 30-40 years. More common in
African-Americans
Butterfly Rash
• Also known as bi-malar rash. Often a butterfly-shaped,
erythematous patch covering malar (cheek) and nasal
areas. Spares nasolabial folds.
• Often triggered by recent sun exposure.
• Presents in many different ways:
– Scale/No scale
– Vesicular
– Atrophy/No atrophy
– Just erythema w/o textural changes.
Additional skin lesions/signs of SLE
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Arthritis
Nephropathy
Fever
Neurologic involvement
Raynaud’s
Serositis
Thrombocytopenia
Oral Ulcers (shallow
erosions on buccal
mucosa, hard palate, lips)
• Thrombosis
• Discoid/SCLE lesions
(more on this later)
• Myositis
• Hemolytic anemia
Diagnosis of SLE
• Here’s where it gets tricky – no one diagnostic criteria or
clinical characteristic will define the disease.
• It’s more of a clinical “big picture” diagnosis, where a
group of clinical signs/symptoms/diagnostic test results
meet the criteria for SLE.
• Let’s not forget, these patients are usually sick. They will
complain of many other symptoms in addition to skin
lesions: Joint pain, fever, lymphadenopathy, psychosis,
bruising, etc.)
American College of Rheumatology: 1997 Revised
Criteria for Classification of SLE.
(Presence of 4 or more compatible with SLE)
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Butterfly Rash
Discoid Rash
Photosensitivity
Oral ulcers
Arthritis
Serositis (Pleuritis or
pericarditis)
• Renal disorder
(Proteinuria or cellular
casts.)
• Neurologic disorder
(seizures/psychosis)
• Hematologic disorder
(deficiencies of all cell
types)
• Immunologic disorder
(presence of
autoantibodies in serum)
• Positive ANA
Anti-Nuclear Antibody (ANA) is important
diagnostic test for Lupus and CTD’s
• The only serum antibody test we will discuss in
detail as it is common to all CTD and is the first
test ordered when you suspect it.
• It is sensitive for CTD, but not specific: 95% of
patients with CTD will have a positive ANA, but
there are many other diseases which will have it as
well.
• It is worth noting that approximately 5% of
otherwise normal blood donors will have positive
ANA.
Role of ANA titer in diagnosis of Lupus
• Other causes of positive ANA include neoplasms,
liver disease, active chronic infections and use of
birth control pills.
• A positive ANA alone will not diagnose Lupus,
but will be strongly suggestive of the diagnosis if
other criteria exist.
• A negative ANA strongly suggests against the
diagnosis of Lupus, but does not rule it out if
several other signs/symptoms of Lupus are present
ANA
• A test that detects presence of antinuclear antibodies
(ANA’s) in human serum. ANA’s are antibodies that
target human DNA as antigen.
• It is a direct immunoflorescence (DIF) test in which
patient’s serum is placed on a substrate of cultured human
cells.
• If ANA’s are present, they attach to nuclear components in
the cells.
• Fluorescein-stained anti-human immunoglobulins are then
applied which attach to the ANA’s.
ANA
• The prepared specimen is then viewed under fluorescent
microscopy, and different patterns of fluorescence will
emerge: Homogenous, speckled, peripheral and nucleolar.
• Sometimes the pattern seen will help suggest towards a
certain diagnosis, sometimes not.
• The important lesson to learn is that a positive ANA
accompanied by other signs of Lupus is strongly
suggestive of the diagnosis needs further work-up to assess
for presence of internal disease.
• The PCP at this stage would refer to rheumatology or
dermatology for further evaluation if possible.
It Gets a lot more complicated!
Further Lupus Evaluation
• Skin biopsy (shave>punch) of lesional skin for
histopathology and perilesional skin for DIF (need to have
special DIF bottle on hand.)
• Complete review of systems
• Additional antibody testing: nDNA, Ro, La, Sm, nRNP
• Urinalysis
• CBC, ESR, C3, C4
• Unless your supervising doc really knows Lupus, best to
have rheumatology or dermatology pursue additional
work-up.
Clinical Example
• Nicole was a 28 y/o Caucasian female patient currently
under treatment for acne when she developed an
asymptomatic “photosensitive” eruption on bilateral
forearms.
• Although described as initially being pink and somewhat
scaly by the patient, by the time I saw it a week later in had
changed to a faint rash of small, slightly scaly purple
papules.
• At the same time she described a recent bout of fatigue,
“fevers,” headaches and loss of appetite.
It is worth noting at this point that she had an
unexplained esophageal stricture about 6 months
prior
• I was treating her for acne at the time. ENT
treated her with prednisone, which seemed to help,
and eventually performed a procedure to relieve
her esophageal stricture.
• Her symptoms stopped after the procedure.
• Because her condition improved, ENT did not
look any further, and called the esophageal
stricture idiopathic.
• At the time of first presentation, I didn’t link this
episode to her skin rash.
First presentation of rash – a diagnostic
procedure was performed
• A 4mm punch biopsy was done centered on one of
the papules on her forearm, and sent for routine
histopathology.
• Specimen was read as prurigo nodularis, an
eczematous condition of thickened, lichenified
skin from chronic rubbing and scratching.
• This biopsy resulted suggested against a diagnosis
of LE
What made everything more interesting was that she
was convinced the whole time that she had Lupus
• Claimed to have a strong family history of Lupus, and said
this was “exactly what happened” to her aunt who had it.
• (Text books cite an incidence of positive family history in
about 5% of cases.)
• Continued to complain of “fevers,” fatigue and loss of
appetite. No objective signs of fever in our office.
• I had a negative biopsy, but we ordered a battery of tests
anyway including a slew of antibodies, urinalysis, CBC,
ESR, etc.
Clinical Example con’t
• Everything came back negative except for the ANA, which
was quite elevated at a titer of 1:160, with speckled and
peripheral patterns. She was on BCP’s at the time, which
can falsely elevate ANA, but not usually this high.
• She came back a week later with a new photosensitive rash
on her upper chest. It was blotchy, pink, poorly-defined
and faint. It was not in the slightest bit scaly, and wasn’t
too impressive to look at.
• She seemed more anxious and now had bilateral cervical
lymphadenopathy and well as sweats and continuing
fatigue.
Rheumatology to the rescue
• Although we still couldn’t prove a diagnosis or the
presence of internal involvement related to Lupus, it was
still strongly suspected.
• In addition, the patient seemed sick and was convinced she
had Lupus.
• She was referred to rheumatology, who promptly
diagnosed her with Lupus on clinical grounds and initiated
treatment with Plaquenil.
• I called the patient a week later, who seemed to be feeling
much better after a week of treatment.
“Plaquenil Deficiency”
• An old joke in dermatology circles.
• Reserved for a small, but real group of patients in
whom LE is suspected, but can’t be proven
definitively with diagnostic testing.
• When you treat them empirically with an LE drug
(like plaquenil) and they get better on it, they have
been diagnosed with plaquenil deficiency!
The Moral of the Story?
• SLE can be a tricky diagnosis at times, in that it can be
present despite multiple negative diagnostic tests.
• It is ultimately a clinical diagnosis, which means that a
practitioner who hasn’t seen it much before could be in for
a hard time.
• If the suspicion for SLE is there, but you can’t prove it,
refer to someone who has more experience with it.
• Always listen to the patient, because sometimes they will
tell you what’s wrong with them.
• When in doubt, refer to rheumatology. Better to let them
rule out LE than miss a patient who could progress to
systemic involvement.
Treatment of SLE
• Oral Steroids - prednisone, prednisolone, etc.
These drugs are effective anti-inflammatory
treatment for various forms of internal organ
involvement.
• Antimalarials – hydroxychloroquine (Plaquenil)
Effective treatment for all skin lesions of LE.
Generally safe for long-term treatment.
• Dapsone – a seldom-used antibiotic which shows
some efficacy in treating skin lesions of LE.
CCLE – Clinical Presentation
(Chronic Cutaneous LE, sometime referred to
as Discoid LE or DLE)
• Classic lesion is “discoid,” or circular in shape. Usually
presents as asymmetrically scattered, raised, violaceous-tored flat-topped plaques of 1-3cm diameter. Firmly
adherent scale which has a “carpet tack” texture on its
underside. (Because scaling penetrates the hair follicles.)
• Usually appear on face, scalp and neck
• Females>Males.
• Incidence peak around age 40
• UV exposure and physical trauma can induce or worsen
lesions.
CCLE Lesions
• Epidermal/dermal atrophy over time leads to
smooth, whitish plaques, which are essentially
hypopigmented.
• This hypopigmentation is permanent and present a
greater problem for darker-skinned patients.
• Chronic lesions in the scalp can be scarring, which
obliterates follicular structures and ultimately
results in permanent alopecia.
• Lesions can last from months to years.
Clinical Presentation of SCLE
(Subacute Cutaneous LE)
• Lesions present in 2 distinct morphologic groupings
• Papulosquamous pattern SCLE: Faded to brightly
erythematous scaling papules and large plaques.
• Annular-polycyclic pattern SCLE: Eruption of annular
plaques, brightly erythematous with clearly-defined, raised
scaly border. Lesions often have central clearing.
• In both cases, lesions spare lateral trunk, axillae, inner
arms and knuckles.
• Lesions resolve with hypopigmentation and telangiectasia
formation.
Other symptoms of SCLE
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Arthritis
Arthralgias
Renal disease
Serositis
CNS symptoms
Never as severe as in
SLE
• Photosensitivity
• Periungual
telangiectasias
• Vasculitis
Diagnosis of CCLE/SCLE
• As any patient with LE
can progress to SLE, a full
work-up is mandatory at
baseline, even in patients
who only present with
skin lesions:
• H&P
• Lesional biopsy for
histopathology.
Perilesional biopsy for
DIF.
• CBC, ESR, platelets
• ANA
• Other antibodies: nDNA,
anti-RNP, Ro, La, Sm
• Urinalysis
• BUN/Creatinine
Treatment of CCLE/SCLE
• First line of defense is photoprotection, as Lupus
is by nature a photosensitive disease.
• Avoid direct sun exposure between 10am-3pm.
• Use broad-spectrum sunscreens (SPF 30 or higher;
zinc oxide or titanium dioxide.)
• Sun-protective hats and clothing will help.
Treatment of CCLE/SCLE
• Topical Steroids (Classes I-V)
• Intralesional steroids - mostly triamcinolone acetonide
(Kenalog)
• Oral antimalarials – hydroxycholoquine (Plaquenil)
• Dapsone
• Others that have been tried with varying degrees of success
include: Azathioprine (Imuran,) methotrexate,
thalidomide, acitretin and isotretinoin.
Treatment of CCLE/SCLE
• Primarily cutaneous, sub-acute LE can
progress to SLE with multisystem
involvement without warning, at any time.
• CCLE/SCLE patients need to be followed
periodically with laboratory testing/office
visits to monitor for this potential
development of SLE.
Dermatomyositis (DM)
• An autoimmune inflammatory disease of the
muscles often diagnosed by characteristic skin
findings. When skin findings absent, is called
polymyositis.
• Can occur in children, but more often in adults
over 40. Often associated with underlying
malignancy in adults.
• Proximal muscle weakness is most common
presenting symptom.
• Male = female. All age groups. Approximately 510 cases/million adults.
Clinical Presentation of DM – Has 6 Classic
Characteristics
• Heliotrope rash – violaceous hue that
surrounds eyes, accompanied by periorbital
and facial edema. Can also affect face,
shoulders, chest. Can look/feel “like a
sunburn.”
• Gottron’s papules – eruption of fixed,
firm, red-to-violaceous flat-topped papules
on backs/sides of fingers, may or may not
spare knuckles.
Clinical Presentation of DM
• Violaceous Scaling Patches – Erythema with a
purple hue distributed symmetrically in patches
over knees, elbows and backs of hands. Unlike
the hand rash of SLE, the knuckles are not spared.
• Periungual telangiectasias – proximal nails folds
are thickened, rough and erythematous.
Numerous superficial telangiectasias are visible
with opthalmoscope on red 3 or with a
dermatoscope.
Clinical Presentation of DM
• Symmetrical proximal muscle weakness - Usually
precedes dermatologic manifestations of DM so need to
assess by Get-up-and-go-test.
• If you haven’t heard of it, you will during your geriatric
practicum in the winter.
• Test administered to older patients to assess muscle
strength: Patient is seated upright in a chair with armrests
and asked to push off the armrests and lift themselves into
a standing position.
• The patient is timed and assessed for difficulty in
performing the task.
Clinical Presentation of DM
• Get-up-and-go-test is a good assessment for
proximal muscle weakness, and must be
given to all patients presenting with skin
findings suggestive of dermatomyositis.
• Weakness tends to symmetrically affect
legs>arms. Slowly develops over weeks to
months.
• DTR’s remain normal.
Diagnosis of DM
• Skin biopsy for
histopathology and DIF
• Biopsy of weak muscles
• Muscle enzymes – CK,
AST, ALT, LDH
• 24 hour urine for
creatinine an even more
sensitive measure of
muscle damage.
• ANA
• Serum antibodies – Ro,
La, Sm, nRNP, Jo-1
• Significant association
with occult malignancy in
adults presenting w/DM.
• Do pelvic, breast exams
and mammogram. CXR,
DRE, colonoscopy, PE
Treatment of DM
• DM can occur in an acute setting, or be chronic/recurrent
over periods of years. Early diagnosis and treatment
greatly improves patient outcomes.
• Oral steroids – first line treatment and often used
chronically over long periods of time in tapering doses
until remission or adequate control. (usually prednisone.)
Dose can be adjusted based on improvement as indicated
by periodic checks of patient’s serum CK.
• Methotrexate, azathioprine, cyclophosphamide – all potent
immunosuppressants with many potential side effects.
Scleroderma
(Sometimes referred to as Systemic Sclerosis)
• A rare autoimmune disease which is highly disfiguring and
potentially fatal.
• Affects women 3 x > men
• Characterized by sclerotic, vascular and inflammatory
changes to various tissues including skin and internal
organs, often with multi-system involvement.
• Often affects lungs, heart and GI tract.
• Usual onset ages 30-50 years.
• Etiology is unknown.
Scleroderma Clinical Presentation
• Presentation often preceded by history of Raynaud’s
phenomenon, migrating arthritis, dysphagia and heartburn.
Also GI symptoms such as diarrhea and constipation.
• Skin disease runs characteristic course of edema to
sclerosis to atrophy in affected areas of skin.
• Hands usually start with Raynaud’s (for months to years)
then progress to edema, then sclerosis with ulcerations at
fingertips and sclerodactyly(hard fingers). Skin becomes
tight and leathery with obliteration of sweat glands and
hair.
• Often seen in CREST presentation (more later)
Scleroderma Clinical Presentation
• Unusual disease in that patient’s can look much younger
than actual age.
• Facial skin becomes shiny and extremely taut. Lips are
thinned and nose starts to look like a beak. Many
prominent telangiectasias.
• In other areas (trunk/proximal extremities) skin becomes
hardened and waxy, no longer able to wrinkle or fold.
• Calcinosis Cutis – Hard, white nodules around fingertips
and knuckles as a result of cutaneous calcification.
Joe Monroe (SDPA founder) uses the word CREST
as a way to remember clinical criteria for
Scleroderma
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Calcinosis: especially in fingers
Raynaud’s: present in >90% of scleroderma cases
Esophageal dysmotility: leading to reflux
Sclerodactyly: hardening of skin, tapering of
distal digits
• Telangiectasias: on face, chest, mouth, even
internally.
Scleroderma Clinical Presentation
• Signs of internal involvement can include:
• GI: Dysphagia, constipation, diarrhea, bloating,
malabsorption.
• Respiratory: Pulmonary fibrosis.
• Cardiac: Conduction defects, HF, pericarditis.
• Renal: Uremia, malignant hypertension.
(Leading cause of death.)
• Musculoskeletal: CTS, weakness.
Diagnosis of Scleroderma
• Usually a straightforward clinical diagnosis with
characteristic findings.
• Punch biopsy of lesional skin usually diagnostic.
• Do ROS with goal of finding internal involvement if
present.
• PE of periungual regions with opthalmoscope on red 3 or
with dermatoscope (dermlite)
• ANA
• Other antibodies: Ro, La, Sm, nRNP, Scl-70
Treatment of Scleroderma
• Treating scleroderma with internal involvement is still
difficult and only partially effective. Numerous agents
have been tried: Penicillamine, methotrexate, prednisone,
relaxin, interferons and cyclosporine.
• Cutaneous disease is managed primarily by watching for
signs of secondary infection, which can opportunize on
compromised skin barrier (usual culprit is staph.)
• PT becomes important in advanced disease to maintain
ROM over joints.