Mixed Connective Tissue
Disease
Dan Mandel, MD
Mixed Connective Tissue Disease
• Autoimmune Disease
• Features of:
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SLE
Scleroderma
Inflammatory Myositis (Polymyositis)
Rheumatoid Arthritis
• Serology: positive anti U1-RNP Ab
• Abreviated as MCTD
Terminology
• Mixed Connective Tissue disease
• Patient meets criteria for MCTD generally with antibody
positivity (RNP Ab)
• Undifferentiated Connective Tissue disease
• Patient does not meet criteria for any given
autoimmune disease but has features suggesting the
early features of an autoimmune disease.
• Overlap Syndrome
• One dominant autoimmune disease with overlap
featueres of another.
UCTD vs Overlap vs MCTD
Undifferentiated Connective
Tissue Disease
Polymyositis-Scleroderma
Overlap
Mixed Connective Tissue
Disease
Epidemiology of MCTD
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Prevalence 3-4 per 100,000 population
Female to Male Ratio is 3:1
Present in all races
Peak age of Onset: 15-25
Sensitivity of ANA in Rheumatology
RNP Antibody – Sensitivity is 100% in Mixed Connective Tissue Disease
Specific Antibodies in Rheumatology
Immunology of MCTD
• Extractable Nuclear antigens:
• Ribonucleoproteins extractable from nucleus
• SSA, SSB, smith, RNP, Jo-1, Scl-70, others
• U1-RNP Antibody
– Antigen: complex of series of small
ribonucleoproteins containing (U1-snRNP)
• 3 polypeptides (70 kd, A, C)
• Linked to U1 RNA
Immunology of MCTD
U1-snRNP
usmle287.wordpress.com
U1 RNA
http://en.wikipedia.org/wiki/U1_spliceosomal_RNA
Gene Splicing
www.biology.arizona.edu
genome.wellcome.ac.uk
70KD protein is dominant
antigen
U1RNA is another antigen
Anti-RNP Ab
• Generally the IgG anti-U1 RNP Ab is checked
• IgG form is generally more associated with
MCTD, while IgM form may often occur in
Lupus.
• When found in isolation suggests MCTD
Immunology of MCTD
Immunogenicity
Innate
Adaptive
Immunology of MCTD
Elevated IL-1
and IL-6
production
MCTD as separate entity
Clinical Features of MCTD
• Early Features
• Arthritis – can be erosive or non-erosive
• Raynaud’s
• Puffy Hands/sausage digits
• Later features
• Can develop skin thickening typical of Scleroderma
• Can develop lupus manifestations
• Can develop organ involvement: lungs, kidneys, muscle.
Raynauds in Rheumatology
Exam Findings In MCTD
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Scleroderma Features
SLE (Lupus) Features
Inflammatory Myositis Features
Rheumatoid Arthritis
Systemic Sclerosis (Scleroderma)
• Limited Scleroderma
• Skin thickening is distal to elbows and knees, not involving
trunk
• Can involve perioral skin thickening (pursing of lips)
• Less organ involvement
• Seen in CREST syndrome
• Isolated pulmonary hypertension can occur
• Diffuse Scleroderma
• Skin thickening proximal to elbows and knees, involving the
trunk
• More likely to have organ involvement
• Pulmonary fibrosis and Renal Crisis are more common.
Scleroderma Features
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Calcinosis
Raynaud’s
Esophageal Dysmotility
Sclerodactyly (skin thickening of digits)
Telangiectases
CREST Features
ACR and Mayo Foundation
Calcinosis on x-ray
Gupta E., et al. Malaysian Family
Physician. 2008;3(3):xx-xx
ACR
ACR
Scleroderma Skin Manifestations
Sclero.org
International
Scleroderma Network
Kahaleh B. Rheum Dis Clin N Amer 2008:57-71
Nailfold Capillaroscopy
SLE (Lupus) Features
• Lupus: (MD SOAP N HAIR)
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Malar Rash
Discoid Lesions
Serositis
Oral Ulcers
Arthritis
Photosensitivity
Neurologic (seizures, neuropsychiatric)
Hair Loss, Hematologic (cytopenias)
ANA Positivity
Immunologic (ds-DNA, Smith, RNP, anti-SSA, APLA)
Raynauds, Renal
Malar Rash
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Often mildly scaly
Typically involves bridge of nose
Spares Nasolabial fold
Generally non-pruritic but can be
American College of Rheumatology Slide Collection
Discoid Skin Lesions
• Early: well demarkated, erythematous, indurated scaly plaques.
• Late: atrophic, well demarkated scars.
• Often occurs in people without Systemic Lupus Erythematosus
American College of Rheumatology Slide Collection
Serositis
Pleural effusions
www.learningradiology.com
Pericarditis
www.bukisa.com
• Chest Pain
• Acute Abdomen
reference.medscape.com
Peritonitis
reference.medscape.com
Other Features of Lupus
Arthritis/Arthralgias
Oral Ulcers
Photosensitivity
Neurologic Manifestations of Lupus
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Seizures (rare in MCTD)
Neuropsychiatric Lupus/Psychosis (rare in MCTD)
Strokes related to aniphospholipid syndrome.
Trigeminal Neuropathy (occurs in MCTD but less
commonly in SLE).
Other Lupus Manifestations
Specific
Antibodies
Anti-RNP
Anti-ds-DNA
Anti-Smith
Anti-SSA
Antiphospholipid
Hair loss / Alopecia
www.dermhairclinic.com
ANA Positive
en.wikipedia.org
Immunologic
Raynaud’s Syndrome
Inflammatory Myositis Features
• Symptoms
• Proximal Muscle weakness
» Difficulty getting out of chairs or getting up from
crouching
» Difficulty lifting objects overhead
• Generally is painless, though may have mild pain
• Generally without significant muscle tenderness
• Laboratory Tests:
• Elevated muscle enzymes (CK, AST>ALT, Aldolase,
Myoglobin)
• Normal inflammatory markers: ESR and CRP
Inflammatory Myositis Exam
www.clinicalrehabspecialists.com
meded.ucsd.edu
at.uwa.edu
Inflammatory Myositis
Manifestations & Workup
•
http://www.iomonitoring.pro/emg.htm
Inflammatory Myositis
Manifestations & Workup
Olsen NJ, et al. Rheum Dis Clin N. Amer 1996;22(4):783-796
http://www.rayur.com/muscle-biopsy.html
Inflammatory Myositis
Manifestations & Workup
Arq. Neuro-Psiquiatr. vol.62 no.4 São Paulo Dec. 2004
• Biopsy helps to confirm disease
Classification Criteria for MCTD
MCTD Manifestations and frequency
Serologies in MCTD
Features of Diseases
Feature
MCTD
SLE
Scleroderma
Polymyositis
Renal Involvment
Less Common
Common
Renal Crisis may
occur
Rare
Pulmonary
PAH/ILD
Less common
PAH/ILD
ILD may occur
Esophageal
Dysmotility
Common
Rare
Common
Uncommon, but
dysphagia
Antiphospholipid
Syndrome
Less common
Common
Less common
Less common
Cytopenias
Can Occur
Common
Rare
Rare
Sclerodactyly
Common
Rare
Common
Rare
Neurological
Less Common,
(trigeminal)
More Common
Rare
Rare
Treatment of MCTD
• Arthritis
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Prednisone
Hydroxychloroquine
Methotrexate
Biologics (Rituxan, Orencia, anti-TNF) – generally with
erosive disease and/or RF/CCP positive.
Treatment of MCTD
• Raynaud’s
• Nifedipine or amlodipine
• Sildenafil
• Nitroglycerine (not used as much – had been used as
patch or ointment – cannot use with sildenafil)
• Digital Ischemia – acute
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Hospitalization with IV prostoglandins
Anticoagulation with heparin
Search for hypercoagulability (Antiphospholipid Ab)
Evaluation for vasculitis / arterial obstruction
Treatment of MCTD
• Scleroderma Skin
• Often no treatment for limited disease
• Methotrexate
• Mycophenolate
Treatment of MCTD
• Inflammatory Myositis
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Prednisone
Methotrexate
Azathioprine
Rituximab
mycophenolate
IVIG
Treatment of MCTD
• Pulmonary Involvement
– Interstitial Lung Disease
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Prednisone
Mycophenolate
Cyclophosphamide
Rituximab
Azathioprine maintenence
– Pulmonary Hypertension
• Vasodilators (Ca chanel blockers, sildenafil,
prostoglandin)
Treatment of MCTD
• Lupus Type Manifestations
– Depends on manifestations
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Prednisone
Hydroxychloroquine
Mycophenolate
Azathioprine
Methotrexate
Belimumab (Benlysta)
Rituximab
IVIG
Treatment of MCTD
• Lupus Arthritis
• Prednisone
• Hydroxychloroquine
• Methotrexate
• Oral Ulcers
• Hydroxychloroquine
• Topical steroids
• Raynaud’s
• Vasodilators
Treatment of MCTD
• Malar Rash
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Prednisone
Hydroxychloroquine
Mycophenolate
Azathioprine
• Thrombocytopenia
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Prednisone
IVIG
Rituximab
Plaquenil
Treatment of MCTD
• Leukocytopenia
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Often no treatment required
Prednisone
Hydroxychloroquine
Mycophenolate
• Antiphospholipid Syndrome
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Anticoagulation
IVIG
Rituximab
Plaquenil
Avoid estrogen (avoid OCP’s with estrogen)
Treatment of MCTD
• Lupus Nephritis
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Prednisone
Mycophenolate
Cyclophosphamide
Azathioprine
• Pericarditis/Pleuritis
• NSAIDs
• Prednisone
Prognosis in MCTD
• Survival Rates
• 5 yrs: 98%
• 10 yrs: 96%
• 15 yrs: 88%
• Major causes of death
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Pulmonary hypertension: 9/280 patients
Cardiovascular events: 7/280
TTP: 3/280
Infections 3/280
J Rheumatol. 2013 Jul;40(7):1134-42
MCTD Phenotypes
Antiphospholipid
Myositis/ILD
RA/Scleroderma
Survival of Phenotypes
Myositis/ILD
RA/Scleroderma
Antiphospholipid
Case 1
• A 47 year old female with Raynaud’s symptoms and puffy hands, hand
pain,who presents with difficulty lifting objects overhead and leg
weakness.
• Exam
• Fluctuating pallor/cyanosis of few digts of hands
• Lungs are clear
• No sclerodactyly, oral ulcers, malar rash, alopecia
• Strength significantly reduced in proximal upper and lower
extremities; normal distally; neck strenght intact.
• Labs
• ANA positive, RNP Ab positive, ESR 10, CRP 0.5
• CK level 5000, Aldolase elevated
• Antiphospholipid Ab’s negative, C3 & C4 normal, UA normal; antiSmith/SSA/SSB/Jo-1/ds-DNA negative
• What is the next step, diagnosis and treatment.
Case 1
• Next steps:
• Obtain MRI of weakest thigh or proximal arm
• Obtain muscle biopsy
• CXR baseline is normal
• Diagnosis
• Mixed Connective Tissue Disease with primary features of
Polymyositis
• Treatment
• Start Prednisone
• Start methotrexate or azathioprine
• Course:
• Over a period of months strength gradually improves and CK level
declines; there is decrease in puffy hands and hand pain with
treatment.
Case 2
• A 60 year old female with history of Mixed Connective tissue disease with
positive RNP antibody, sclerodactyly, Raynaud’s, past inflammatory
myositis presents with left lower extremity DVT; lab tests are performed at
the time.
• Exam
• Sclerodactyly to MCP joints in both hands
• Lungs are clear
• No oral ulcers, malar rash, alopecia
• Strength intact.
• Labs
• ANA positive, RNP Ab positive, ESR 30, CRP 1.0, CK normal
• C3 & C4 normal, UA normal; anti-Smith/SSA/SSB/Jo-1 negative
• Anticardiolipin Ab 80, Lupus anticoagulant positive, B2 GP Ab
negative.
• What is the treatment, diagnosis, possible complication.
Case 2
• Treatment/Next Step
• Anticoagulation with Lovenox bridge to coumadin
• Repeat antiphospholipid antibodies in 12 weeks; if still
present, patient will require indefinite anticoagulation.
• Diagnosis
• Mixed Connective Tissue disease with scleroderma and
myositis components with secondary antiphospholipid
syndrome.
• Potential Complication
• Pulmonary hypertension with antiphospholipid
antibodies
Case 3
• A 22 year old female previously healthy develops Raynauds, malar rash,
and oral ulcers in the past 3 months. She has had fatigue and joint pain
without swelling involving the hands. She denies dry eyes or dry mouth.
LMP 1 week ago.
• Exam
• Malar rash sparing nasolabial fold and oral ulcers noted, mild
fluctuating cyanosis of several digits noted during visit, puffy
hands.
• Lungs are clear, oral mucosa moist.
• No sclerodactyly or alopecia noted.
• Strength intact.
• Labs
• ANA positive, RNP Ab positive, anti-SSA positive ESR 90, CRP 1.2,
CK normal, low C3 and C4.
• UA normal; anti-Smith/SSB/Jo-1/ds-DNA negative
• Antiphospholipid antibodies negative, urine pregnancy test neg.
• What is the diagnosis, treatment, important counseling information.
Case 3
• Diagnosis:
• Mixed Connective Tissue Disease with primary features of Lupus
(SLE)
• Treatment
• Start Prednisone
• Start hydroxychloroquine (Plaquenil)
• May need to consider Azathioprine or mycophenolate if steroid
sparing agent is needed to decrease steroids.
• Counseling information:
• Due to lupus and positive she would need high risk OB when she
would like to become pregnant.
• With positive anti-SSA Ab there is 1-3% risk of neonatal lupus with
heart block but this can be monitored and potentially treated.
• Would be best to wait until disease is better to control to plan for
pregnancy
References
• Up to Date
• Medscape
• Ortega-Hernandez OD, et al; Best Practice & Research Clinical
Rheumatology 26 (2012) 61–72
• Hoffman RW; Clinical Immunology 2008 (128); 8-17
• Cappelli S, et al; j.semarthrit.2011.07.010
• Szodoray P, et al; Lupus 2012 (21); 1412-1422
• Keith MP; et al; Autoimmunity Reviews 6 (2007) 232–236
• Faye N; et al; Clin Chest Med 31 (2010) 433–449
• Schur PH; The Rheumatologist, February 2009
• Hajas A; J Rheum 2013 (40; 7) 1134-1142
• Prete M, et al; Autoimmunity Reviews xxx (2014) xxx–xxx