““Mixed Connective Tissue Mixed Connective Tissue Disease:Disease:

Still Crazy After All These Still Crazy After All These Years”Years”

Christina KahlChristina KahlMarch 12, 2008March 12, 2008

Rheum Dis Clin N Am 31 (2005) 421-426

HistoryHistory 1972 Sharp and colleagues1972 Sharp and colleagues

Identified patients with high levels of Identified patients with high levels of antibodies against a ribonucleic protein antibodies against a ribonucleic protein (RNP)(RNP)

These patients shared several clinical These patients shared several clinical features including Raynaud’s phenomenom, features including Raynaud’s phenomenom, arthralgias, mild arthritis, puffy hands, arthralgias, mild arthritis, puffy hands, abnormal esophageal mobility, and myositisabnormal esophageal mobility, and myositis

Additional findings – Additional findings – hypergammaglobulinemia (80%), anemia and hypergammaglobulinemia (80%), anemia and leukopenia (50%); pulmonary, renal and CNS leukopenia (50%); pulmonary, renal and CNS involvement was “rare”involvement was “rare”

HistoryHistory 1980 Nimelstein and colleagues1980 Nimelstein and colleagues

Doubts after reviewing 22/25 original Doubts after reviewing 22/25 original patientspatients

Many patients evolved into sclerodermaMany patients evolved into scleroderma High mortality rate (8/22)High mortality rate (8/22) Not everyone had antibodies to RNPNot everyone had antibodies to RNP Some patients had antibodies without clear Some patients had antibodies without clear

clinical features of the syndromeclinical features of the syndrome Then, 20 years of contradictory views Then, 20 years of contradictory views

regarding the existence and nature of regarding the existence and nature of MCTD MCTD

Diagnostic CriteriaDiagnostic Criteria Features of SLE, systemic sclerosis, RA, and Features of SLE, systemic sclerosis, RA, and

polymyositispolymyositis Four different diagnostic criteria have been Four different diagnostic criteria have been

proposedproposed SharpSharp KasukawaKasukawa Alarcon-SegoviaAlarcon-Segovia KahnKahn

Highest sensitivity (62%) and specificity (86%) Highest sensitivity (62%) and specificity (86%) with Alarcon-Segovia and Kahn in 45 patientswith Alarcon-Segovia and Kahn in 45 patients

Diagnostic Criteria – SharpDiagnostic Criteria – Sharp Major CriteriaMajor Criteria

MyositisMyositis Pulmonary InvolvementPulmonary Involvement Raynaud phenomenomRaynaud phenomenom

or esophageal or esophageal dysmobilitydysmobility

Swollen hands or Swollen hands or sclerodactylysclerodactyly

High anti-U1-RNP with High anti-U1-RNP with negative anti-Smnegative anti-Sm

Definite Definite – 4 major plus – 4 major plus serologyserology

ProbableProbable – 3 major or 2 major – 3 major or 2 major (1(1stst 3 listed) and 2 minor; and 3 listed) and 2 minor; and serologyserology

Minor CriteriaMinor Criteria AlopeciaAlopecia LeukopeniaLeukopenia AnemiaAnemia PleuritisPleuritis PericarditisPericarditis ArthritisArthritis Trigeminal Trigeminal

NeuralgiaNeuralgia Malar RashMalar Rash ThrombocytopeniaThrombocytopenia Mild MyositisMild Myositis h/o swollen handsh/o swollen hands

Diagnostic CriteriaDiagnostic CriteriaAlarcon-SegoviaAlarcon-Segovia

Clinical Criteria 3/5 (must have synovitis or Clinical Criteria 3/5 (must have synovitis or myositis)myositis) Edema of the handsEdema of the hands SynovitisSynovitis MyositisMyositis Raynaud’s phenomenonRaynaud’s phenomenon AcrosclerosisAcrosclerosis

Serologic: high titers of anti-U1 RNPSerologic: high titers of anti-U1 RNP

Diagnostic CriteriaDiagnostic Criteria ““The crux of the MCTD diagnosis is the The crux of the MCTD diagnosis is the

presence of high titers of antibodies to U1-presence of high titers of antibodies to U1-RNP.”RNP.”

Many patients who satisfy criteria for MCTD Many patients who satisfy criteria for MCTD also satisfy ACR criteria for RA or SLE, and also satisfy ACR criteria for RA or SLE, and many had symptoms of systemic sclerosis.many had symptoms of systemic sclerosis.

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

Clinical PresentationClinical Presentation Early Clinical Early Clinical

FindingsFindings Malaise, easy Malaise, easy

fatiguabilityfatiguability ArthralgiasArthralgias MyalgiasMyalgias Raynaud’s Raynaud’s

phenomenomphenomenom Low-grade feversLow-grade fevers

Unusual Unusual PresentationsPresentations FUOFUO SerositisSerositis Trigeminal Trigeminal

neuropathyneuropathy Severe polymyositisSevere polymyositis Acute arthritisAcute arthritis Aseptic meningitisAseptic meningitis Digital gangreneDigital gangrene

CharacteristicCharacteristic At DiagnosisAt Diagnosis Cumulative at 5 Cumulative at 5 yearsyears

Raynaud’s Raynaud’s PhenomenomPhenomenom

89%89% 96%96%

Arthralgia/ArthritisArthralgia/Arthritis 85%85% 96%96%Swollen HandsSwollen Hands 60%60% 66%66%Esophageal Esophageal DysmotilityDysmotility

47%47% 66%66%

Pulmonary Pulmonary DysfunctionDysfunction

43%43% 66%66%

SerositisSerositis 34%34% 43%43%HematologicHematologic 30%30% 53%53%Erythematous Skin Erythematous Skin RashRash

30%30% 53%53%

Muscle MyositisMuscle Myositis 28%28% 51%51%Pulmonary Pulmonary HypertensionHypertension

9%9% 23%23%

Sclerodermatous Sclerodermatous ChangesChanges

4%4% 19%19%

CNS (or peripheral)CNS (or peripheral) 0%0% 17%17%RenalRenal 2%2% 11%11%

Cohort of 47 MCTD patients.

Pulmonary Pulmonary ManifestationsManifestations

Pleural EffusionsPleural Effusions Pulmonary Pulmonary

HypertensionHypertension Pleuritic PainPleuritic Pain Intersitial Lung Intersitial Lung

Disease (30-50%)Disease (30-50%) Thromboembolic Thromboembolic

DiseaseDisease Obstructive DiseaseObstructive Disease Pulmonary VasculitisPulmonary Vasculitis

75% of patients75% of patients Early SymptomsEarly Symptoms

Dry coughDry cough DyspneaDyspnea Pleuritic Chest PainPleuritic Chest Pain

Pericardial DiseasePericardial Disease Pericardial InvolvementPericardial Involvement

SclerodermaScleroderma 59%59% SLESLE 44%44% MCTDMCTD 30%30% RARA 24%24%

MCTDMCTD At autopsy – 56% had pericardial diseaseAt autopsy – 56% had pericardial disease Asymptomatic pericardial effusion – 24-Asymptomatic pericardial effusion – 24-

38%38%

Laboratory FindingsLaboratory Findings High titer, speckled ANA patternHigh titer, speckled ANA pattern Leukopenia, anemia, thrombocytopeniaLeukopenia, anemia, thrombocytopenia Elevated ESRElevated ESR Very high serum immunoglobulinsVery high serum immunoglobulins Complement levels usually normal or highComplement levels usually normal or high Rheumatoid Factors increased in 70% of Rheumatoid Factors increased in 70% of

patientspatients Negative findings include anti-dsDNA and Negative findings include anti-dsDNA and

anti-Sm antibodies (if positive, some argue anti-Sm antibodies (if positive, some argue that it represents exclusion criteria for MCTD)that it represents exclusion criteria for MCTD)

Antibody FindingsAntibody Findings

DiseaDiseasese

ANAANA RFRF dsDNdsDNAA

SmSm Scl-Scl-7070

RNPRNP

SLESLE 95-9995-99 2020 50-7050-70 3030 00 30-5030-50RARA 15-3515-35 8585 <5<5 00 00 1010DiffusDiffuseeSScSSc

>90>90 3030 00 00 4040 3030

MCTMCTDD

95-9995-99 5050 00 <5<5 00 100100

Follow-UpFollow-Up 39 MCTD patients at 10 year follow-up39 MCTD patients at 10 year follow-up

64% “differentiated” into another syndrome64% “differentiated” into another syndrome 11 systemic sclerosis, 10 SLE, 2 RA, 2 11 systemic sclerosis, 10 SLE, 2 RA, 2

overlap syndromeoverlap syndrome Other studies have found similar resultsOther studies have found similar results About 40% of patients with anti-U1RNP About 40% of patients with anti-U1RNP

antibodies retain the diagnosis of MCTD antibodies retain the diagnosis of MCTD and others are “reclassified” within 5 and others are “reclassified” within 5 years of presentationyears of presentation

Undifferentiated and Overlap Undifferentiated and Overlap SyndromesSyndromes

MCTDMCTD SLE, SSc, PM, RASLE, SSc, PM, RA

Undifferentiated Undifferentiated Systemic Rheumatic Systemic Rheumatic DiseaseDisease Undifferentiated Undifferentiated

connective tissue, collagen, connective tissue, collagen, vascular, or autoimmune vascular, or autoimmune diseasedisease

Nonclassical SLENonclassical SLE ““Atypical” rheumatic Atypical” rheumatic

diseasedisease Undiiferentiated Undiiferentiated

Polyarthritis SyndromePolyarthritis Syndrome Undifferentiated Undifferentiated

SpondylparthritisSpondylparthritis

Overlap SyndromesOverlap Syndromes RA-lupusRA-lupus

RhupusRhupus Scleroderma-PM/DMScleroderma-PM/DM Scleroderma-lupusScleroderma-lupus Scleroderma-PBC-Scleroderma-PBC-

Sjogren’sSjogren’s Scleroderma-RAScleroderma-RA JRA-lupusJRA-lupus Psoriatic arthritis-lupusPsoriatic arthritis-lupus

PsupusPsupus Sjogren’s overlapsSjogren’s overlaps PM overlapsPM overlaps Raynaud’s phenomenom Raynaud’s phenomenom

overlapsoverlaps

SLE CriteriaSLE Criteria Malar RashMalar Rash Discoid RashDiscoid Rash PhotosensitivityPhotosensitivity Oral UlcersOral Ulcers ArthritisArthritis SerositisSerositis Renal DiseaseRenal Disease Neurologic DiseaseNeurologic Disease

Hematologic DiseaseHematologic Disease Hemolytic anemiaHemolytic anemia Leukopenia, Leukopenia,

lymphopenialymphopenia ImmunologicImmunologic

Anti-dsDNAAnti-dsDNA Anti-SmAnti-Sm

ANAANA

4/11 Criteria4/11 Criteria

Patient CoursePatient Course Prednisone 1mg/kg Prednisone 1mg/kg

started on day #4started on day #4 Patient became Patient became

afebrileafebrile Tachycardia and Tachycardia and

tachypnea resolvedtachypnea resolved Discharge on day #7Discharge on day #7

Few weeks later – Few weeks later – anti-dsDNA positiveanti-dsDNA positive

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38

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20

40

60

80

100

120

140

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ReferencesReferences Bennett RM. “Definition and diagnosis of mixed connective tissue Bennett RM. “Definition and diagnosis of mixed connective tissue

disease.” UpToDate.disease.” UpToDate. Bennett RM. “Clinical manifestations of mixed connective tissue Bennett RM. “Clinical manifestations of mixed connective tissue

disease.” UpToDate.disease.” UpToDate. Kumar MS, Smith M, Pischel KD. “Case Report and Review of Kumar MS, Smith M, Pischel KD. “Case Report and Review of

Cardiac Tamponade in Mixed Connective Tissue Disease.” Cardiac Tamponade in Mixed Connective Tissue Disease.” Arthritis & Rheumatism, 2006. 55: 826-830.Arthritis & Rheumatism, 2006. 55: 826-830.

Swanton J, Isenberg D. “Mixed Connective Tissue Disease: Still Swanton J, Isenberg D. “Mixed Connective Tissue Disease: Still Crazy After All These Years.” Rheum Dis Clin N Am, 2005. 31: Crazy After All These Years.” Rheum Dis Clin N Am, 2005. 31: 421-436.421-436.

Venables PJW. “Mixed Connective Tissue Disease.” Lupus, 2006. Venables PJW. “Mixed Connective Tissue Disease.” Lupus, 2006. 15: 132-137.15: 132-137.

American College of Rheumatology, classification criteria for American College of Rheumatology, classification criteria for SLE.SLE.