1. Mixed Connective Tissue Disease
Dan Mandel, MD

2. Mixed Connective Tissue Disease
Autoimmune Disease
Features of:
SLE
Scleroderma
Inflammatory Myositis (Polymyositis)
Rheumatoid Arthritis
Serology: positive anti U1-RNP Ab
Abreviated as MCTD

3. 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.

4. UCTD vs Overlap vs MCTD Undifferentiated Connective Tissue Disease
Polymyositis-Scleroderma Overlap
Mixed Connective Tissue Disease

5. Epidemiology of MCTD Prevalence 3-4 per 100,000 population
Female to Male Ratio is 3:1
Present in all races
Peak age of Onset: 15-25

6. Sensitivity of ANA in Rheumatology
RNP Antibody – Sensitivity is 100% in Mixed Connective Tissue Disease

7. Specific Antibodies in Rheumatology

8. Immunology of MCTD Extractable Nuclear antigens: U1-RNP Antibody
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

9. Immunology of MCTD U1-snRNP U1 RNA Gene Splicing
usmle287.wordpress.com
Gene Splicing
70KD protein is dominant antigen
U1RNA is another antigen
genome.wellcome.ac.uk

10. 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

11. Immunology of MCTD
Immunogenicity
Innate
Adaptive

12. Immunology of MCTD
Elevated IL-1 and IL-6 production

13. MCTD as separate entity

14. 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.

15. Raynauds in Rheumatology

16. Exam Findings In MCTD Scleroderma Features SLE (Lupus) Features
Inflammatory Myositis Features
Rheumatoid Arthritis

17. 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.

18. Scleroderma Features Calcinosis Raynaud’s Esophageal Dysmotility
Sclerodactyly (skin thickening of digits)
Telangiectases

19. CREST Features
ACR and Mayo Foundation

20. Calcinosis on x-ray
Gupta E., et al. Malaysian Family Physician. 2008;3(3):xx-xx
ACR

21. Scleroderma Skin Manifestations
ACR
Sclero.org
International Scleroderma Network
Kahaleh B. Rheum Dis Clin N Amer 2008:57-71

22. Nailfold Capillaroscopy

23. SLE (Lupus) Features Lupus: (MD SOAP N HAIR) 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

24. Malar Rash Often mildly scaly Typically involves bridge of nose
Spares Nasolabial fold
Generally non-pruritic but can be
American College of Rheumatology Slide Collection

25. 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

26. Serositis Chest Pain Acute Abdomen Pleural effusions Peritonitis
Pericarditis
reference.medscape.com
Chest Pain
Acute Abdomen
reference.medscape.com

27. Other Features of Lupus
Arthritis/Arthralgias
Photosensitivity
Oral Ulcers

28. Neurologic Manifestations of Lupus
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).

29. Other Lupus Manifestations
Specific Antibodies
Anti-RNP
Anti-ds-DNA
Anti-Smith
Anti-SSA
Antiphospholipid
Hair loss / Alopecia
ANA Positive
Raynaud’s Syndrome
Immunologic
en.wikipedia.org

30. 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

31. Inflammatory Myositis Exam
meded.ucsd.edu
at.uwa.edu

32. Inflammatory Myositis Manifestations & Workup

33. Inflammatory Myositis Manifestations & Workup
Olsen NJ, et al. Rheum Dis Clin N. Amer 1996;22(4):

34. Inflammatory Myositis Manifestations & Workup
Arq. Neuro-Psiquiatr. vol.62 no.4 São Paulo Dec. 2004
Biopsy helps to confirm disease

35. Classification Criteria for MCTD

36. MCTD Manifestations and frequency

37. Serologies in MCTD

38. Features of Diseases Feature MCTD SLE Scleroderma Polymyositis
Renal Involvment
Less Common
Common
Renal Crisis may occur
Rare
Pulmonary
PAH/ILD
Less common
ILD may occur
Esophageal Dysmotility
Uncommon, but dysphagia
Antiphospholipid Syndrome
Cytopenias
Can Occur
Sclerodactyly
Neurological
Less Common, (trigeminal)
More Common

39. Treatment of MCTD Arthritis Prednisone Hydroxychloroquine Methotrexate
Biologics (Rituxan, Orencia, anti-TNF) – generally with erosive disease and/or RF/CCP positive.

40. Treatment of MCTD Raynaud’s Digital Ischemia – acute
Nifedipine or amlodipine
Sildenafil
Nitroglycerine (not used as much – had been used as patch or ointment – cannot use with sildenafil)
Digital Ischemia – acute
Hospitalization with IV prostoglandins
Anticoagulation with heparin
Search for hypercoagulability (Antiphospholipid Ab)
Evaluation for vasculitis / arterial obstruction

41. Treatment of MCTD Scleroderma Skin
Often no treatment for limited disease
Methotrexate
Mycophenolate

42. Treatment of MCTD Inflammatory Myositis Prednisone Methotrexate
Azathioprine
Rituximab
mycophenolate
IVIG

43. Treatment of MCTD Pulmonary Involvement Interstitial Lung Disease
Prednisone
Mycophenolate
Cyclophosphamide
Rituximab
Azathioprine maintenence
Pulmonary Hypertension
Vasodilators (Ca chanel blockers, sildenafil, prostoglandin)

44. Treatment of MCTD Lupus Type Manifestations Depends on manifestations
Prednisone
Hydroxychloroquine
Mycophenolate
Azathioprine
Methotrexate
Belimumab (Benlysta)
Rituximab
IVIG

45. Treatment of MCTD Lupus Arthritis Oral Ulcers Raynaud’s Prednisone
Hydroxychloroquine
Methotrexate
Oral Ulcers
Topical steroids
Raynaud’s
Vasodilators

46. Treatment of MCTD Malar Rash Thrombocytopenia Prednisone
Hydroxychloroquine
Mycophenolate
Azathioprine
Thrombocytopenia
IVIG
Rituximab
Plaquenil

47. Treatment of MCTD Leukocytopenia Antiphospholipid Syndrome
Often no treatment required
Prednisone
Hydroxychloroquine
Mycophenolate
Antiphospholipid Syndrome
Anticoagulation
IVIG
Rituximab
Plaquenil
Avoid estrogen (avoid OCP’s with estrogen)

48. Treatment of MCTD Lupus Nephritis Pericarditis/Pleuritis Prednisone
Mycophenolate
Cyclophosphamide
Azathioprine
Pericarditis/Pleuritis
NSAIDs

49. Prognosis in MCTD Survival Rates Major causes of death 5 yrs: 98%
Pulmonary hypertension: 9/280 patients
Cardiovascular events: 7/280
TTP: 3/280
Infections 3/280
J Rheumatol Jul;40(7):

50. MCTD Phenotypes
Antiphospholipid
Myositis/ILD
RA/Scleroderma

51. Survival of Phenotypes
Myositis/ILD
RA/Scleroderma
Antiphospholipid

52. 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; anti-Smith/SSA/SSB/Jo-1/ds-DNA negative
What is the next step, diagnosis and treatment.

53. 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.

54. 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.

55. 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

56. 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.

57. 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

58. 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
Szodoray P, et al; Lupus 2012 (21);
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)
Prete M, et al; Autoimmunity Reviews xxx (2014) xxx–xxx