Connective Tissue Diseases SLE, Polymyositis, Scleroderma

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Connective Tissue DiseasesSLE, Polymyositis,
Scleroderma

• Janet Pope
• University of Western Ontario, London, ON

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Frequency of CTD

• RA 1
• SLE 0.1
• Scleroderma 0.01
• Polymyositis 0.001

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Case

• 22 year old college student
• New onset of red cheeks, hives in the sun,
  fatigue, Raynauds, weight loss, hair loss and
  stiff hands in the morning
• Her cousin has JRA

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What is the most likely diagnosis?

• Why

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Criteria for SLE

• Duration of gt 6 weeks and at least 4 of 11
  criteria

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SLE Criteria

• Malar rash
• Discoid or other rash
• Photosensitivity
• Oral ulcers
• Renal Glomerulernephritis or nephrotic syndrome
• Inflammatory Arthritis (non erosive)

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SLE criteria cont

• Pleuricy / Pericarditis / Serositis
• CBC leukopenia, hemolytic anemia,
  thrombocytopenia
• ANA
• double stranded DNA
• Other autoantibodies Smith, Ro, false VDRL
  (anticardiolipin antibody)

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NB

• Although Raynauds and alopecia are common, they
  are not part of the diagnostic criteria

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So what tests are you going to order?

• Tests for diagnosis
• Tests for prognosis
• Tests to be aware of in order to determine
  appropriate treatment (What organ involvement is
  occurring?)

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Labs

• CBC,diff, ESR
• Creatinine, urinalysis
• ANA
• Maybe ENA
• Dont order antiDNA unless if ANA is positive

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ANA is a screening test

• gt 95 of SLE is ANA positive
• A double stranded DNA cannot occur with a
  negative ANA (outside labs may do single stranded
  DNA)
• ANA negative SLE is often anti Ro positive

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What is ANA

• Antinuclear antibody is an autoantibody against a
  part of the nucleus
• It never rules in disease
• It is a screening test for SLE so if negative,
  it makes SLE highly unlikely

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Frequent ANA patterns

• Speckled
• Homogeneous / Diffuse
• Nucleolar
• Rim / Peripheral
• Centromere

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Positive test

• Titres so with a stronger positive, the
  dilution is larger (higher denominator)
• Ex. 1/1280 is a strong positive
• Pattern can change depending on the dilution
• Ex. 1/80 speckled and homogenous and 1/640
  homogenous

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Is there utility in following the titre?

• No
• In general repeating the test is a waste of money
• A positive test in past or at any time can count
  in the diagnostic criteria for SLE

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The results of the college student

• WBC 2.8, Hbg 111, Plt 43
• Creatinine 80, urine neg for protein and blood
• ANA 1/320 speckled
• ENA for anti Smith (Sm)
• antiDNA negative

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Does she have SLE?

• ANA
• Low WBC and plt
• anti Sm
• Malar rash
• Photosensitivity
• Possible inflammatory arthritis
• She has at least 5 criteria

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SLE Epidemiology

• 1/1,000 prevalence
• 9 women to 1 man
• Esp young women, but can occur at any age
• Rarely it is drug induced often milder course,
  joints, skin and serositis
• In a SLE patient, there is a slightly increased
  risk of family members having other connective
  tissue disease, RA, JRA

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Pathophysiology

• B and T cell abnormalities
• Cutaneous anery High viral titres but negative
  skin tests
• HLA associations with DR2 and 3, some with
  complement deficiencies
• Genetic predisposition and environmental triggers

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When do I order anti DNA?

• Only order anti DNA in the presence of a positive
  ANA, when you are expecting SLE
• It is very specific for SLE but very insensitive
  (ie in most of SLE, it is negative)
• only in approximately 20 of SLE

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What is anti DNA?

• It is an auto-antibody directed against the DNA
  in a nucleus (thus if positive, ANA should
  immunoflouresce and be positive)
• Pitfalls Outside labs often use a kit that will
  also be positive for single stranded DNA, which
  is neither sensitive nor specific

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What does anti DNA correlate with?

• It is highly specific for SLE
• It correlates with renal SLE (but not 100)
• Thus, it can be a bad prognosticator and it is
  part of the diagnostic criteria

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SLE Treatment

• Depends on system involvement
• NSAIDs and analgesics for joints
• Antimalarials for joints and rash
• Nothing really helps the fatigue
• Immunosuppression and corticosteroids for major
  organ involvement
• Cyclophospamide and steroids for active GN
• Azathioprine, mycophenylate, methotrexate

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SLE prognosis

• Worse if major organ involvement
• Deaths from infection in immunosuppressed people
• Later, accelerated atherosclerosis with CAD and
  premature death (50 fold increase)
• Complications from steroids such as AVN and
  osteoporosis

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What is an ENA

• ENA is extractable nuclear antigens or
  extra-nuclear antigens
• The lab will do a screen to see if it is positive
  or negative
• If positive, more assays are done to determine
  which antibody is positive

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ENA usually contains

• Anti Ro,
• Anti La
• Anti Sm (Smith fairly sensitive for SLE)
• Anti RNP (goes with MCTD and SLE)
• Anti Scl 70 (Topoisomerase 1) goes with diffuse
  scleroderma esp with interstitial lung disease
• Other anti PM-Scl (dermatositis), anti
  Jo1(polymyositis with interstitial lung disease),
  anti RNA polymerase

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Ro and La

• Anti Ro
• is associated with cutaneous SLE features
  including rash and photosensitivity
• is often in ANA negative SLE
• can go with anti La in Sjogrens
• can increase the risk of congenital heart block
  in babies whose moms are

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Antiphospholipid antibody syndrome (APS)

• Half are associated with SLE
• Occurs in 10-20 of SLE patients
• Syndrome of arterial and or venous clotting (CVA,
  DVT, PE), recurrent abortions and often livedo
  reticularis, low platelets

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Antiphospholipid antibody syndrome (APS)

• Positive tests may include
• Lupus anticoagulant (false prolongation of PTT)
• Anticardiolipin antibody (aCL) or other
  antiphospholipid antibodies
• False positive VDRL
• Abnormal RVV time (Russel venon viper time)

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APS

• Treatment varies on symptoms and signs
• ASA or LMW heparin in pregnancy
• Warfarin if DVT
• ASA and possibly warfarin if CVA

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Sjogrens syndrome

• A connective tissue disease with lymphocytic
  infiltration of exocrine glands (parotid,
  salivary, etc)
• Characterized by dry eyes and mouth (sicca
  complex)
• Sometimes with Raynauds, leucocytoclastic
  vasculitis, arthritis, parotid swelling

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Tests to order

• CBC, ESR (ESR often quite high in Sjogrens)
• ANA, ENA, RF

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Positivity in Sjogrens

• 1/3 RF
• 1/3 ANA
• 1/3 Ro and La
• Often hypergammaglobulinemia (polyclonal increase
  in IgG)

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Conclusions

• SLE is 10 times more rare than RA, but in
  Ontario, many more ANA tests are ordered thus
  most will be false positives
• Order only if the pretest likelihood suggests it
  could change your diagnosis

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Scleroderma

• Nonsystemic
• Linear
• Morphea
• Systemic
• Also named systemic sclerosis, progressive
  systemic sclerosis

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This talk is limited to

• Systemic sclerosis Scleroderma

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Scleroderma

• Rare connective tissue disease that has
• Fibrosis
• Vascular instability (intimal proliferation and
  Raynauds)
• Autoimmunity

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Prevalence of Scleroderma-SW Ontario
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Prevalence in the Literature
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Prevalence of scleroderma

• 1/40,000 to 1/10,000

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Is it autoimmune?

• In some patients with scleroderma the ANA is
  positive
• Greater than 80 in limited scleroderma and 50
  in diffuse scleroderma

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Scleroderma

• Limited or CREST Syndrome skin involvement
  distal to the elbows and knees, excluding the
  neck and face
• Diffuse scleroderma proximal involvement on the
  upper arms, upper legs, and/or trunk

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CREST

• Old fashioned term but still used
• Calcinosis
• Raynauds
• Esophageal dysmotility
• Sclerodactyly
• Telangiectasia

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Limited vs Diffuse Scleroderma

• Limited
• Most positive ANA
• 80 anticentromere
• Rare renal, heart, lung involvement
• May develop PAH in long standing disease

• Diffuse
• 50 ANA positive usually nucleolar
• Scl 70 in 30, correlates with pulmonary fibrosis
• Renal crisis with RNA polymerase
• Higher mortality

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Sclerodactyly and pigmentation

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Raynauds

• Primary
• Not associated with any other disease
• Secondary
• Associated with connective tissue diseases such
  as SLE, scleroderma, RA, Sjogrens, Polymyositis
• Reversible color change of the digitals with
  pallor and then rubor and or cyanosis

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Raynauds

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Treatment Raynauds

• Calcium channel blockers
• Cold avoidance
• Smoking cessation
• Other drugs

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Proof of Treatment in Raynauds associated with
Scleroderma

• Calcium channel blockers, esp Nifedipine
• Small trials, cant prove effectiveness for
  healing of digital ulcers
• Meta-analysis Arthritis Rheum 2001 441841-7

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Treatment of RP in Scleroderma with CCBs
Frequency of Attacks
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Prostacyclins/ Prostaglandin analogues

• Iloprost
• Very effective in IV(5 trials), less effective po
  (1 trial)
• Effective in RP frequency and severity of attacks
  and at healing and preventing digital ulcers
• Cisaprost po not effective
• Beraprost - effective for recurrent digital
  ulcers
• J Rheumatol 1999, 262173-8

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Treatment GI Tract

• Proton pump inhibitors are very effective for
  GERD
• Anti-reflux maneuvers include not eating after
  supper, raising the head of the bed, pro-kinetic
  drugs (ie. Domperidone, Maxaran) to propel food
  through the stomach
• Small bowel overgrowth can be treated by
  antibiotics on an intermittent basis
• Some drugs (ie. erythromycin, somatostatin) can
  help the bowels contract

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• Incontinence can also occur secondary to
• Hypotonic bowel
• Poor anal sphincter tone
• Diverticulosis can also occur in the bowel

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Renal Involvement

• Renal crisis is a condition with high blood
  pressure (usually), hemolysis (intra-vascular),
  and worsening renal function
• Renal crisis is secondary to poor blood flow to
  the kidney, as well as kidney changes with
  scarring around the blood vessels

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Renal Involvement (contd)

• Treatment has improved the mortality from
  scleroderma renal crisis, particularly rapid
  control of the blood pressure using ACE
  inhibitors
• Some patients do go on to temporary or permanent
  dialysis

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Lung Involvement

• Two main types
• Interstitial lung disease (inflammation and
  scarring of the lung parenchyma)
• Pulmonary hypertension with high pressures in the
  arteries perfusing the lungs

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Interstitial Lung Disease

• There is a current treatment trial underway of
  cyclophosphamide to try to prevent scarring and
  improve lung function

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Scleroderma lung - ground glass

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Prevalence of PAH (Pulmonary Arterial HTN) in
Scleroderma
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Pulmonary HTN (PAH)
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Prevalence in Scleroderma Related PAH

• Pulmonary Hypertension (PAH) in scleroderma is
  either
• Primary (vascular defect)
• Secondary (Secondary to pulmonary fibrosis)
• Or both

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Treatment of PAH

• Same as that for Primary Pulmonary HTN (PPH)
• Vasodilators such as calcium channel blockers
• Endothelin receptor antagonist (Bosentan)
• Prostacyclin analogs Epoprostenol (Flolan),
  Iloprost
• Anticoagulation
• Treatment of CHF and dysrythmia
• Oxygen
• Nitric Oxide

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Bosentan

• Endothelin-1 is a potent vasoconstrictor and
  smooth muscle mitogen
• Bosentan (Tracleer) is an Endothelin-1 antagonist

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Heart Involvement

• Patients with scleroderma can develop a
  cardiomyopathy with thickening heart muscles and
  reduced blood flow to the heart
• This is manifest by shortness of breath, angina
  or congestive heart failure
• It is treated the same way as congestive heart
  failure from other causes

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Pleural and Pericardial Effusions

• These can occur in scleroderma, particularly in
  those with diffuse scleroderma
• Sometimes treated with prednisone

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Arthritis in Scleroderma

• Many patients with scleroderma have arthralgia
• Some have inflammatory arthritis with swollen
  joints
• 20 on x-ray can have joint destruction
• This is treated with anti-inflammatories,
  physiotherapy, and sometimes disease-modifying
  drugs

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Calcinosis

• Calcium deposits are under the skin in pressure
  areas
• They can break open and ooze white, chalky
  material
• They are often painful

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Digital Tuft Resorption

• Patients with scleroderma can lose mass at their
  fingertips making them painful and appearing
  tapered or shortened

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Digital Ulcers

• Digital ulcers occur in many patients with
  scleroderma
• They are painful
• May take a long time to heal sometimes resulting
  in gangrene or rarely necessitating amputation
• Treatment with analgesics, blood thinners, and
  new drugs (ie. Bosentan) are being studied for
  increased healing and a decrease in new ulcers

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Digital Ulcers
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Bosentan reduces number of patients with new
digital ulcers
ITT with baseline DU
ITT
100
100
90
90
80
80
70
70
60
60
Patients with n or more ulcers ()
Patients with n or more ulcers ()
50
50
40
40
30
30
20
20
10
10
0
0
?1
?4
?7
?10
?1
?4
?7
?10
Number of new ulcers (n)
Number of new ulcers (n)
Placebo
Bosentan
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Disease Modification in Scleroderma

• Many trials have not shown help in most patients
  with scleroderma, including
• D-penicillamine
• Methotrexate
• Relaxin
• Chlorambucil

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However, other treatments are underway, including

• Biologic drugs, such as antibodies to decrease
  TGF-beta (tumor growth factor beta), which is
  important in causing fibrosis in scleroderma
• Other biologic trials are being considered for
  patients, such as blocking cTGF, this is
  important in fibrosis and fibroblast production
  in scleroderma, and is also an important target

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Targeted Therapies

• Anti TGFbeta antibodies under development, 1st
  trial negative
• cTGF antibodies
• Targeting pathological pathways
• Stem cell transplant study

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Mortality in Canadian Scleroderma

• 309 French Canadians
• 66 died (21.3) over up to 15 year FU
• Mortality increased with age, diffuse skin,
  abnormal ECG,
• low DLCO, anemia, SCL 70

• Toronto cohort
• With PAH
• Median survival 12 months

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Scleroderma Mortality

• Similar to breast cancer (50 5 year survival)
• From
• Interstitial lung disease
• Cardiomyopathy
• Pulmonary Hypertension
• We have found that those with renal involvement
  still have a very high mortality and was the
  highest association of mortality in our cohort

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Survival Curves of Scleroderma Patients With
Pulmonary Hypertension, Lung Involvement, or No
Major Organ Involvement
Koh et al. Br J Rheumatol. 199635989-993.
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Ratio Of FVC To DLCO Influences Survival In
Systemic Sclerosis
1.0
FVC / DLCO lt1.8 n337
Probability of Survival
P .007
FVC / DLCO gt 1.8 n169
Duration of disease, years from onset
Disproportionate and/or isolated reduction in gas
exchange (diffusing capacity) is dominant
determinant of survival in all forms of SSc lung.

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The Future

• The future for scleroderma appears promising,
  where more is being understood at the basic
  science level (pathophysiology, etiology and
  genetics)
• Scleroderma clinical trial outcome measurements
  have been developed
• More trials are underway in scleroderma now than
  there have been in the past few decades.

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Conclusions

• Scleroderma is a rare connective tissue disease
• It is accompanied by a lot of morbidity and at
  times mortality
• There are good treatments for symptom control of
  various organ systems
• There are some good treatments for reversing the
  progression of the organ-specific disease, such
  as scleroderma renal crisis
• The future appears promising for direct targets
  that may help in the treatment of scleroderma

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Polymyositis
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Polymyositis

• Dermatomyositis
• Peaks in kids and older adults
• In elderly may be perineoplastic adenoca
  usually
• Rash, photosensitivity

• Polymyositis
• Any age
• No rash or photosensitivity
• Not perineoplastic usually
• Worse if interstitial lung disease (anti Jo1)

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Polymyositis

• Rare
• Diagnosis made by esp proximal muscle weakness,
  elevated CK
• Muscle biopsy shows degeneration and regeneration
  of m bundles or with dermatomyositis perivascular
  inflammation
• EMG spontaneous fibrillation potentials,
  abnormal action potentials

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Other features

• Heliotrope rash
• Gottrens sign/papules
• Photosensitivity
• Mechanics hand
• Livedo reticularis
• Some are overlaps with other connective tissues
  diseases

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Antibody and Lab profile

• Increased CK (or aldolase), normal CBC
• Occ increased ESR
• May have ANA, ENA such as PM/Scl or Jo1
• Jo1 correlates with interstial lung disease and
  has a bad prognosis and is very specifici
• PM/Scl- often with scleroderma polymyositis
  overlap

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Treatment

• High doses of steroids
• Steroid sparing drugs such as Imuran,
  Methotrexate, Cytoxan
• Treatment and prevention of complications such as
  steroid induced osteoporosis
• Biologics possibly (TNF inhibitors)
• Lung disease needs aggressive treatment

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Complications

• Esophageal involvement aspiration
• Cardiac involvment arrhythmia
• Cancer associated death
• Heterotopic muscular calcification
• Raynauds ulcers
• Sclerodactyly flexion contractures

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