Mixed connective tissue disorder - MCTD Autoimmune SLE RA Sjogrens Dermatomyositis Polymyositis Systemic Lupus Rheumatoid Arthritis

1. MIXED CONNECTIVE
TISSUE DISEASE
Chair person: Dr. Kalinga. B E
Student: Dr. Raghu. G

2. History
 1972 Sharp and colleagues
 Identified a group of patients who have mixed
clinical features of SLE , SYSTEMIC SCLEROSIS
AND POLYMYOSITIS.

3. Mixed Connective Tissue
Disease
 Autoimmune Disease.
 Features of:
 SLE
 Scleroderma
 Inflammatory Myositis (Polymyositis)
 Rheumatoid arthritis
 Serology: positive anti U1-RNP Ab

4. 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
 features of two or more distinctly recognizable
rheumatic diseases but lacks sufficient features to
meet the criteria for any classification.

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

6. 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

7. MCTD In India
 Rare entity in india.
 16 patients were MCTD out of 441 pateints
studied during 13 years. ( Lawrence, Agarwala
and Mishra)
 3/1000 ( A Sood, A Kumar. British society for
rheumatology)

8. ETIOLOGY
 The fundamental cause of MCTD remains
unknown.
 Autoimmunity to components of the U1-70 kd
snRNP is a hallmark of disease.

9.  U1nRNP is a subunit of spliceosomes.
 Two subunits of spliceosomes are antigenic
targets in autoimmunity. These are:
1. Small nuclear ribonucleoprotein particles
(snRNPs).
2. Heterogenous nuclear RNP (hnRNP).

10.  These snRNAs contain a high content of
uridine and are, therefore, called U RNAs.
 Five different types of URNAs are defined on
the basis of immunoprecipitation (U1, U2, U4,
U5, and U6).
 Antibodies directed exclusively against U1
subunit are known as antiU1RNP antibodies.

11.  They precipitate three proteins with molecular
weight of 68000, 33000, and 22000.
 The clinical correlates of MCTD appear to be
most closely associated with antibodies to the
68 kD and the 33000 proteins of the U1 RNP
complex.

13. IMMUNOPATHOLOGY

14.  Both adaptive immunity and innate immunity
are believed to play a role in the pathogenesis
of MCTD.
 The adaptive immune response included B
cells with the hallmark feature of anti-RNP
antibodies, as well as RNP-reactiveT cells.
 Innate immune signaling through Toll-like
receptors 7 and 3 appear to be involved.

15.  The loss of T-lymphocyte and B-lymphocyte
tolerance, due to cryptic self-antigens or
molecular mimicry by infectious agents, and
driven by U1-RNA-induced innate immune
responses, are proposed current theories of
pathogenesis.

16. Dignostic criteria
 Features of SLE, systemic sclerosis, RA, and
polymyositis
 Four different diagnostic criteria have been
proposed
 Sharp
 Kasukawa
 Alarcon-Segovia
 Kahn
 Highest sensitivity (62%) and specificity (86%)
with Alarcon-Segovia.

17. Alarcon-Segovia
 Clinical Criteria 3/5 (must have synovitis or myositis)
Edema of the hands
Synovitis
Myositis
Raynaud’s phenomenon
Acrosclerosis
 Serologic: high titers of anti-U1 RNP

18.  The crux of the MCTD diagnosis is the
presence of high titers of antibodies to U1-
RNP.”
 Absence of anti-Sm or anti-dsDNA.

19.  “With serology superseding the clinical
symptoms in the diagnosis, there is a risk of
fitting the clinical symptoms to the antibody
signs”

20. Clinical Features of MCTD
 Early Features
 Arthritis
 Raynaud’s
 Puffy Hands/sausage digits
 Esophageal reuflux
 Later features
 Can develop skin thickening typical of Scleroderma
 Can develop lupus manifestations
 Can develop organ involvement: lungs, kidneys,
muscle.

21. SKIN MANIFESTATIONS
 The most common skin change is the Raynaud
phenomenon.
 Raynauds phenomenon accompanied by
sausage shaped fingers and swelling of
dorsum of hand are typical.
 Rarely gangrene of hands also seen

22. Raynauds in Rheumatology

25.  Rashes- occur in 50% of patients and include
-Photosensitivity rash.
-Malar rash.
-Telangiectases.
-Gottron papules or a heliotrope rash.

26.  Oral ulcers similar to those found in lupus may
occur.

30. ARTHRITIS
 More common and frequently more severe
than in classic SLE.
 Approximately 60 percent of patients with
MCTD develop an obvious arthritis, often
with deformities .

31.  Arthralgia ultimately occurred in more than
90%.
 Inflammatory arthritis developed in 50% of
patients.
 Deformities can occur but joint erosions are
uncommon.

32. Muscles
 Myalgia - 25% to 50%.
 Myositis - 25% to 75% of patients.

33.  Muscle discomfort with elevated creatinine
kinase levels in the absence of significant
muscle weakness.
 This is typically an early feature of MCTD.
 Fibromyalgia has also been reported to occur
in MCTD.

34. Hematologic abnormalities
• Approximately 75% of patients have a low-grade
anemia.
•Leukopenia, mainly affecting the lymphocyte
series, is a common finding.
•The majority have hypergammaglobulinemia.
 Less common problems include
thrombocytopenia, hemolytic anemia.

35. Pulmonary
 About 85% of patients have pulmonary
involvement, which is often asymptomatic.

36.  Pleural Effusions
 Pulmonary Hypertension
 Pleuritic Pain
 Intersitial Lung Disease (30-50%)
 Thromboembolic Disease
 Obstructive Disease
 Pulmonary Vasculitis

37.  Pulmonary hypertension is the most common
disease-related cause of death in patients with
MCTD.
 It accounted for death in 13% during the
follow-up period

38. Gastrointestinal
 Gastrointestinal involvement is seen in about
70% patients.
 The most common manifestations are
oesophageal dysmotility, lower oesophageal
sphincter laxity, and gastrooesophageal reflux.

39.  the next most common gastrointestinal
features of MCTD are bacterial overgrowth
syndromes and malabsorption.
 Pseudodiverticula along the antimesenteric
border of colon can occur like in scleroderma.

40. Sicca
 Secondary Sjögren syndrome occurs in
approximately 25% of all patients with MCTD
 Anti-SSA (Ro) antibodies.
 Patients may have salivary or submandibular
gland enlargement.

41. Cardiac disease
All three layers of the heart may be involved in
MCTD.
 Pericarditis is the commonest clinical
manifestation of cardiac involvement being
reported in 10 to 30% of patients;

42. Pericardial Disease
 Pericardial Involvement
 Scleroderma 59%
 SLE 44%
 MCTD 30%
 RA 24%
 MCTD
 At autopsy – 56% had pericardial disease
 Asymptomatic pericardial effusion – 24-38%

43. Cardiac
 pulmonary hypertension is among the most
serious cardiac complication in MCTD.
 Less common- valvular abnormalities, septal
hypertrophy, and myocarditis.

44. Pregnancy
 40% prevalence of flares during pregnancy
 Small for gestational age infants occurred in
50% of pregnancies.
 The mechanism for pregnancy complications
is probably an autoimmune reaction against
placental tissues.

45. Nervous system
 Central nervous system (CNS) involvement is
rare in MCTD.
 Most common are trigeminal neuralgia, which
can be the initial feature of MCTD.

46. CNS
 Headache .
 Aseptic meningitis.
 Psychosis.
 Stroke.
 Seizures.
 Cauda equina syndrome and transverse
myelitis.
 Cerebral hemorrhage.

47. Renal
 The absence of severe renal disease is a
hallmark of MCTD.
 Renal involvement occurs in about 25 percent
of patients.
 Membranous nephropathy is the most
common finding.
 Less common- MPGN, Interstital nephritis.

48. 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

49. Laboratory Findings
 The diagnosis of MCTD depends on the
demonstration of anti U1RNP antibody in high
titres.
 Anti U1RNP antibodies by haemagglutination
test titre > 1:1600 is characteristic feature of
MCTD.
 The absence of anti-Sm antibodies and anti-
DNA antibodies.

50. Antibody Findings
Disease ANA RF dsDNA Sm Scl-70 RNP
SLE 95-99 20 50-70 30 0 30-50
RA 15-35 85 <5 0 0 10
Diffuse
SSc
>90 30 0 0 40 30
MCTD 95-99 50 0 <5 0 100

51. Anti-RNP Ab
 IgG form is generally more associated with
MCTD, while IgM form may often occur in
Lupus.
 When found in isolation suggests MCTD.
 Sensitivity- 71 to 100%.
 Specificity- 84%.

52.  Antinuclear antibody positivity is seen in 100%
of patients in high titre with coarse speckled
pattern.

54. Other lab features
 Leukopenia, anemia, thrombocytopenia.
 Elevated ESR.
 Very high serum immunoglobulins.
 Complement levels usually normal or high.
 Rheumatoid Factors increased in 50% of
patients.

55. IMAGING
• Chest radiography : infiltrates, effusion, or
cardiomegaly.
• Echocardiography: effusion ,pulmonary
hypertension.

56.  Ultrasonography/CT scanning:abdominal
pain (indicated for evidence of serositis,
pancreatitis, or visceral perforation related to
vasculitis)
 MRI - Used to assess neuropsychiatric signs
or symptoms

57. TREATMENT
 There is no specific treatment for MCTD.
 The overall goal of therapy is to control symptoms
and to maintain function.
 Monitoring for development of complications,
such as pulmonary hypertension or infection, is
important.

58. General
 Appropriate vaccines for age and risk;
 Modify cardiovascular risk; promote healthy
lifestyle, including exercise, diet, and risk
avoidance.
 Supplementary calcium and vitamin D.

59. Arthralgia/arthritis
 Mild- antimalarial, NSAIDs.
 Moderate to severe-
- systemic corticosteroids.
- Methotrexate.
- azathioprine.

60.  Avoiding Infliximab( TNF- alpha inhibitor)-
because of potential risk for disease flare.

61. Raynaud phenomenon
 Mild—protective measures.
 Moderate—calcium channel blockers may be
of benefit.
 Severe—scleroderma-like management

62. Rash
 Mild—protective measures to avoid the sun,
antimalarial, and topical corticosteroids
 Moderate to severe—systemic corticosteroids,
immunosuppressant, including azathioprine.

63. Esophageal reflux
 Mild—avoidance measures
 Moderate to severe—proton pump inhibitor,
endoscopy with screening for Barrett
esophagus.

64. Myositis
 Mild—antimalarial, corticosteroids.
 Moderate to severe—corticosteroids,
methotrexate, and IVIG.

65. Pulmonary involvement
 Yearly screening with pulmonary function
testing and pulmonary imaging may be
beneficial for the identification of early disease.

66.  Moderate to severe—cyclophosphamide
immunosuppression or treatment as for
primary pulmonary hypertension may be
beneficial

67. Cardiovascular
 Modify risk factors
 Yearly screening with ECG and
echocardiography may be beneficial for the
identification of early disease or as clinically
indicated.

68.  Pleurisy/Pericarditis- NSAIDs, low dose
Prednisone 10 to 30 mg/ day.
 Myocarditis - Steroids + monthly
cyclophosphamide.

69. Pregnancy and contraception
 Monitor as for a high-risk pregnancy; SSA (Ro)
and RNP have been associated with
congenital heart block in neonates; pregnancy
 Counsel on risk for sexually transmitted
diseases, contraceptive options, risk and
potential teratogenicity of medications.
 Avoid estrogen-containing contraceptives.

70. Corticosteroids
 These agents are reserved for more active or
severe disease.
 Corticosteroids are occasionally helpful
during early stage of disease.

71. Cortiocsteroids
 Aseptic meningitis.
 Myositis.
 Pleurisy.
 Pericarditis and myocarditis.
 Interstitial lung disease.

72.  Pulse therapy:
- IV methyl predinsolone 1gm for 3 to 5
days.
- Followed by oral predinsolone 0.5 to
1mg/kg for 4 to 6 wks.
 Maitaince therapy:
Oral predinsolone 5 to 10mg. And try Taper
once symptoms disappear.

73. Cytotoxic agents
 Major organ involvement may require
moderate-to-high divided daily doses of
cytotoxic agents.
 Pulmonary hypertension may respond well to
aggressive immunosuppression with cytotoxic
agents.

74.  Immunosuppressive drugs may be useful for
induction of remission.
 The commonly used agents are
 Azathioprine
 Cyclophosphamide
 Methotrexate.

75. NIH PROTOCOL FOR PULSE
CYCLOPHOSPHAMIDE
THERAPY
 Calculate body surface area (BSA) (m2):
BSA = Height (cm) × weight (kg)/3600.

76. ■ Initial dose 0.5 to 0.75 g/m2
- Administer CYC in 150 ml normal saline
intravenously over 30 to 60 minutes.
-Alternative: equivalent dose of pulse CYC may
be taken orally in highly motivated and
compliant patients.

77.  Obtain WBC count at days 14 after each CYC
treatment ( delay prednisone dose)

78.  Adjust subsequent doses of CYC to maximum
dosage of 1.0 g/m2 to keep WBC count above
1500/mL.
 If WBC count falls below 1500/mL, decrease
next dose by 25%.

79.  Repeat IV CYC pulses monthly (every 3
weeks in extremely aggressive disease) for
another 6 months (seven pulses).
 Then quarterly for 1 year after remission is
achieved.

80. Protect bladder against CYC-
induced hemorrhagic cystitis:
 Diuresis with 5% dextrose and 0.45% saline (2
L at 250 mL/hr)
 high-dose oral fluids for 24 hours.

81.  Mesna: (each dose is 20% of total CYC dose)
 intravenously or orally at 0, 2, 4, and 6 hours
after CYC dosing.
 Mesna is especially important to use if
sustained diuresis may be difficult to achieve
or if pulse CYC is administered in outpatient
setting.

82. Antiemetics
 Dexamethasone (10-mg single dose) plus
 Serotonin receptor antagonists: granisetron 1
mg with CYC dose (usually repeat dose in 12
hours); ondansetron 8 mg three times a day
for 1 to 2 days.

83. Complications of pulse CYC:
 Nausea and vomiting.
 Infection
 Herpes zoster
 Infertility (male and female).
 Amenorrhea.

84. Induction therapy
 Steroid plus
-Cyclophhasmide.
-Mycophenolate moeftil
-Azathioprine.

85. Maitance therapy
 Mycophenolate moeftil- 2 to 3 gm per day
 Azathioprine- 2 to 3 mg/kg/day

86. Follow-up
 39 MCTD patients at 10 year follow-up
 64% “differentiated” into another syndrome
 11 systemic sclerosis, 10 SLE, 2 RA, 2 overlap
syndrome
 Other studies have found similar results
 About 40% of patients with anti-U1RNP
antibodies retain the diagnosis of MCTD and
others are “reclassified” within 5 years of
presentation

87. Prognosis in MCTD
 Survival Rates
 5 yrs: 98%
 10 yrs: 96%
 15 yrs: 88%
 Major causes of death
 Pulmonary hypertension: 9/280 patients
 Cardiovascular events: 7/280
 TTP: 3/280
 Infections 3/280
J Rheumatol. 2013 Jul;40(7):1134-42

88. PROGNOSIS
 The prognosis is worse for
people with features of systemic sclerosis
and/or polymyositis.
 The most severe clinical manifestation is
pulmonary hypertension which contributes to
premature death
 Scleroderma renal crisis, myocarditis are other
causes of death

89. Summary
 Defintion.
 Intially presents with overlaping features.
 No specific treatment.
 Monitor for complications.

90. References
 Harrison’s principles of internal medicine 19th
edition.
 MARC C. HOCHBERG Rheumatology.
 kelly’s textbook of Rheumatology.
 Uptodate.

91. THANK YOU