Clinical Overview of Lupus/CTD (Connective Tissue Diseases)

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Clinical Overview of Lupus/CTD(Connective Tissue
Diseases)

• Rich Callahan MSPA, PA-C
• Fletcher Allen Health Care
• Dept. of Dermatology
• Burlington, VT

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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 CTDs. This is why
  dilated periungual capillary loops are commonly
  visible in patients with Lupus, Scleroderma and
  dermatomyositis.

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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.

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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.

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CTDs Some Examples

• Lupus Erythematosus
• Dermatomyositis
• Scleroderma
• Relapsing Polychondritis
• Reiters Disease
• Ankylosing Spondylitis

• Polyarteritis nodosa
• Kawasakis disease
• Psoriatic arthropathy
• Polymyositis
• Polymyalgia rheumatica
• Temporal arteritis
• Sjogrens Disease

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We will focus on the big three which will most
likely be seen in clinical practice Lupus,
Dermatomyositis and Scleroderma.
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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.
• Its important in dermatology because 85 of all
  Lupus cases have skin involvement.
• Its not rare, and its not common either
• About 40 cases/100,000 in North America

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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.

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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.)

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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
  femalesgtmales, age usually 30-40 years. More
  common in African-Americans

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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.

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Additional skin lesions/signs of SLE

• Arthritis
• Nephropathy
• Fever
• Neurologic involvement
• Raynauds
• Serositis
• Thrombocytopenia
• Oral Ulcers (shallow erosions on buccal mucosa,
  hard palate, lips)

• Thrombosis
• Discoid/SCLE lesions (more on this later)
• Myositis
• Hemolytic anemia

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Diagnosis of SLE

• Heres where it gets tricky no one diagnostic
  criteria or clinical characteristic will define
  the disease.
• Its more of a clinical big picture diagnosis,
  where a group of clinical signs/symptoms/diagnosti
  c test results meet the criteria for SLE.
• Lets 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.)

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American College of Rheumatology 1997 Revised
Criteria for Classification of SLE. (Presence of
4 or more compatible with SLE)

• 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

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Anti-Nuclear Antibody (ANA) is important
diagnostic test for Lupus and CTDs

• 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.

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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

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ANA

• A test that detects presence of antinuclear
  antibodies (ANAs) in human serum. ANAs are
  antibodies that target human DNA as antigen.
• It is a direct immunoflorescence (DIF) test in
  which patients serum is placed on a substrate of
  cultured human cells.
• If ANAs are present, they attach to nuclear
  components in the cells.
• Fluorescein-stained anti-human immunoglobulins
  are then applied which attach to the ANAs.

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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.

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It Gets a lot more complicated!Further Lupus
Evaluation

• Skin biopsy (shavegtpunch) 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.

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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.

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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 didnt link
  this episode to her skin rash.

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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

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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.

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Clinical Example cont

• Everything came back negative except for the ANA,
  which was quite elevated at a titer of 1160,
  with speckled and peripheral patterns. She was
  on BCPs 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 wasnt too
  impressive to look at.
• She seemed more anxious and now had bilateral
  cervical lymphadenopathy and well as sweats and
  continuing fatigue.

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Rheumatology to the rescue

• Although we still couldnt 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.

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Plaquenil Deficiency

• An old joke in dermatology circles.
• Reserved for a small, but real group of patients
  in whom LE is suspected, but cant 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!

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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 hasnt seen it much
  before could be in for a hard time.
• If the suspicion for SLE is there, but you cant
  prove it, refer to someone who has more
  experience with it.
• Always listen to the patient, because sometimes
  they will tell you whats 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.

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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.

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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-to-red 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
• FemalesgtMales.
• Incidence peak around age 40
• UV exposure and physical trauma can induce or
  worsen lesions.

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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.

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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.

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Other symptoms of SCLE

• Arthritis
• Arthralgias
• Renal disease
• Serositis
• CNS symptoms
• Never as severe as in SLE

• Photosensitivity
• Periungual telangiectasias
• Vasculitis

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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

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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.

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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.

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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.

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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
  5-10 cases/million adults.

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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.
• Gottrons papules eruption of fixed, firm,
  red-to-violaceous flat-topped papules on
  backs/sides of fingers, may or may not spare
  knuckles.

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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.

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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 havent 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.

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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 legsgtarms.
  Slowly develops over weeks to months.
• DTRs remain normal.

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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

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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 patients serum CK.
• Methotrexate, azathioprine, cyclophosphamide
  all potent immunosuppressants with many potential
  side effects.

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Scleroderma(Sometimes referred to as Systemic
Sclerosis)

• A rare autoimmune disease which is highly
  disfiguring and potentially fatal.
• Affects women 3 x gt 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.

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Scleroderma Clinical Presentation

• Presentation often preceded by history of
  Raynauds 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 Raynauds (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)

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Scleroderma Clinical Presentation

• Unusual disease in that patients 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.

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Joe Monroe (SDPA founder) uses the word CREST as
a way to remember clinical criteria for
Scleroderma

• Calcinosis especially in fingers
• Raynauds present in gt90 of scleroderma cases
• Esophageal dysmotility leading to reflux
• Sclerodactyly hardening of skin, tapering of
  distal digits
• Telangiectasias on face, chest, mouth, even
  internally.

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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.

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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

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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.