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““Mixed Connective Tissue Disease:Mixed Connective Tissue Disease:
Still Crazy After All These Years”Still Crazy After All...
HistoryHistory
 1972 Sharp and colleagues1972 Sharp and colleagues
 Identified patients with high levels of antibodiesId...
HistoryHistory
 1980 Nimelstein and colleagues1980 Nimelstein and colleagues
 Doubts after reviewing 22/25 original pati...
Diagnostic CriteriaDiagnostic Criteria
 Features of SLE, systemic sclerosis, RA, andFeatures of SLE, systemic sclerosis, ...
Diagnostic Criteria – SharpDiagnostic Criteria – Sharp
 Major CriteriaMajor Criteria
 MyositisMyositis
 Pulmonary Invol...
Diagnostic CriteriaDiagnostic Criteria
Alarcon-SegoviaAlarcon-Segovia
 Clinical Criteria 3/5 (must have synovitis or myos...
Diagnostic CriteriaDiagnostic Criteria
 ““The crux of the MCTD diagnosis is the presence ofThe crux of the MCTD diagnosis...
Clinical PresentationClinical Presentation
 Early Clinical FindingsEarly Clinical Findings
 Malaise, easy fatiguabilityM...
CharacteristicCharacteristic At DiagnosisAt Diagnosis Cumulative at 5 yearsCumulative at 5 years
Raynaud’s PhenomenomRayna...
Pulmonary ManifestationsPulmonary Manifestations
 Pleural EffusionsPleural Effusions
 Pulmonary HypertensionPulmonary Hy...
Pericardial DiseasePericardial Disease
 Pericardial InvolvementPericardial Involvement
 SclerodermaScleroderma 59%59%
 ...
Laboratory FindingsLaboratory Findings
 High titer, speckled ANA patternHigh titer, speckled ANA pattern
 Leukopenia, an...
Antibody FindingsAntibody Findings
DiseaseDisease ANAANA RFRF dsDNAdsDNA SmSm Scl-70Scl-70 RNPRNP
SLESLE 95-9995-99 2020 5...
Follow-UpFollow-Up
 39 MCTD patients at 10 year follow-up39 MCTD patients at 10 year follow-up
 64% “differentiated” int...
Undifferentiated and Overlap SyndromesUndifferentiated and Overlap Syndromes
 MCTDMCTD
 SLE, SSc, PM, RASLE, SSc, PM, RA...
SLE CriteriaSLE Criteria
 Malar RashMalar Rash
 Discoid RashDiscoid Rash
 PhotosensitivityPhotosensitivity
 Oral Ulcer...
Patient CoursePatient Course
 Prednisone 1mg/kgPrednisone 1mg/kg
started on day #4started on day #4
 Patient became afeb...
ReferencesReferences
 Bennett RM. “Definition and diagnosis of mixed connective tissue disease.”Bennett RM. “Definition a...
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Mixed Connective Tissue Disorder

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Transcript of "Mixed Connective Tissue Disorder"

  1. 1. ““Mixed Connective Tissue Disease:Mixed Connective Tissue Disease: Still Crazy After All These Years”Still Crazy After All These Years” Christina KahlChristina Kahl March 12, 2008March 12, 2008 Rheum Dis Clin N Am 31 (2005) 421-426
  2. 2. HistoryHistory  1972 Sharp and colleagues1972 Sharp and colleagues  Identified patients with high levels of antibodiesIdentified patients with high levels of antibodies against a ribonucleic protein (RNP)against a ribonucleic protein (RNP)  These patients shared several clinical featuresThese patients shared several clinical features including Raynaud’s phenomenom, arthralgias, mildincluding Raynaud’s phenomenom, arthralgias, mild arthritis, puffy hands, abnormal esophageal mobility,arthritis, puffy hands, abnormal esophageal mobility, and myositisand myositis  Additional findings – hypergammaglobulinemiaAdditional findings – hypergammaglobulinemia (80%), anemia and leukopenia (50%); pulmonary,(80%), anemia and leukopenia (50%); pulmonary, renal and CNS involvement was “rare”renal and CNS involvement was “rare”
  3. 3. HistoryHistory  1980 Nimelstein and colleagues1980 Nimelstein and colleagues  Doubts after reviewing 22/25 original patientsDoubts after reviewing 22/25 original patients  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 clinicalSome patients had antibodies without clear clinical features of the syndromefeatures of the syndrome  Then, 20 years of contradictory views regardingThen, 20 years of contradictory views regarding the existence and nature of MCTDthe existence and nature of MCTD
  4. 4. Diagnostic CriteriaDiagnostic Criteria  Features of SLE, systemic sclerosis, RA, andFeatures of SLE, systemic sclerosis, RA, and polymyositispolymyositis  Four different diagnostic criteria have been proposedFour different diagnostic criteria have been proposed  SharpSharp  KasukawaKasukawa  Alarcon-SegoviaAlarcon-Segovia  KahnKahn  Highest sensitivity (62%) and specificity (86%) withHighest sensitivity (62%) and specificity (86%) with Alarcon-Segovia and Kahn in 45 patientsAlarcon-Segovia and Kahn in 45 patients
  5. 5. Diagnostic Criteria – SharpDiagnostic Criteria – Sharp  Major CriteriaMajor Criteria  MyositisMyositis  Pulmonary InvolvementPulmonary Involvement  Raynaud phenomenomRaynaud phenomenom oror esophageal dysmobilityesophageal dysmobility  Swollen hands orSwollen hands or sclerodactylysclerodactyly  High anti-U1-RNP withHigh anti-U1-RNP with negative anti-Smnegative anti-Sm  DefiniteDefinite – 4 major plus serology– 4 major plus serology  ProbableProbable – 3 major or 2 major (1– 3 major or 2 major (1stst 3 listed) and 2 minor; and serology3 listed) and 2 minor; and serology  Minor CriteriaMinor Criteria  AlopeciaAlopecia  LeukopeniaLeukopenia  AnemiaAnemia  PleuritisPleuritis  PericarditisPericarditis  ArthritisArthritis  Trigeminal NeuralgiaTrigeminal Neuralgia  Malar RashMalar Rash  ThrombocytopeniaThrombocytopenia  Mild MyositisMild Myositis  h/o swollen handsh/o swollen hands
  6. 6. Diagnostic CriteriaDiagnostic Criteria Alarcon-SegoviaAlarcon-Segovia  Clinical Criteria 3/5 (must have synovitis or myositis)Clinical Criteria 3/5 (must have synovitis or 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
  7. 7. Diagnostic CriteriaDiagnostic Criteria  ““The crux of the MCTD diagnosis is the presence ofThe crux of the MCTD diagnosis is the presence of high titers of antibodies to U1-RNP.”high titers of antibodies to U1-RNP.”  Many patients who satisfy criteria for MCTD alsoMany patients who satisfy criteria for MCTD also satisfy ACR criteria for RA or SLE, and many hadsatisfy ACR criteria for RA or SLE, and many had symptoms of systemic sclerosis.symptoms of systemic sclerosis.  ““With serology superseding the clinical symptoms inWith serology superseding the clinical symptoms in the diagnosis, there is a risk of fitting the clinicalthe diagnosis, there is a risk of fitting the clinical symptoms to the antibody signs”symptoms to the antibody signs”
  8. 8. Clinical PresentationClinical Presentation  Early Clinical FindingsEarly Clinical Findings  Malaise, easy fatiguabilityMalaise, easy fatiguability  ArthralgiasArthralgias  MyalgiasMyalgias  Raynaud’s phenomenomRaynaud’s phenomenom  Low-grade feversLow-grade fevers  Unusual PresentationsUnusual Presentations  FUOFUO  SerositisSerositis  Trigeminal neuropathyTrigeminal neuropathy  Severe polymyositisSevere polymyositis  Acute arthritisAcute arthritis  Aseptic meningitisAseptic meningitis  Digital gangreneDigital gangrene
  9. 9. CharacteristicCharacteristic At DiagnosisAt Diagnosis Cumulative at 5 yearsCumulative at 5 years Raynaud’s PhenomenomRaynaud’s Phenomenom 89%89% 96%96% Arthralgia/ArthritisArthralgia/Arthritis 85%85% 96%96% Swollen HandsSwollen Hands 60%60% 66%66% Esophageal DysmotilityEsophageal Dysmotility 47%47% 66%66% Pulmonary DysfunctionPulmonary Dysfunction 43%43% 66%66% SerositisSerositis 34%34% 43%43% HematologicHematologic 30%30% 53%53% Erythematous Skin RashErythematous Skin Rash 30%30% 53%53% Muscle MyositisMuscle Myositis 28%28% 51%51% Pulmonary HypertensionPulmonary Hypertension 9%9% 23%23% Sclerodermatous ChangesSclerodermatous Changes 4%4% 19%19% CNS (or peripheral)CNS (or peripheral) 0%0% 17%17% RenalRenal 2%2% 11%11% Cohort of 47 MCTD patients.
  10. 10. Pulmonary ManifestationsPulmonary Manifestations  Pleural EffusionsPleural Effusions  Pulmonary HypertensionPulmonary Hypertension  Pleuritic PainPleuritic Pain  Intersitial Lung DiseaseIntersitial Lung Disease (30-50%)(30-50%)  ThromboembolicThromboembolic DiseaseDisease  Obstructive DiseaseObstructive Disease  Pulmonary VasculitisPulmonary Vasculitis  75% of patients75% of patients  Early SymptomsEarly Symptoms  Dry coughDry cough  DyspneaDyspnea  Pleuritic Chest PainPleuritic Chest Pain
  11. 11. 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 – 24-38%Asymptomatic pericardial effusion – 24-38%
  12. 12. 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 patientsRheumatoid Factors increased in 70% of patients  Negative findings include anti-dsDNA and anti-SmNegative findings include anti-dsDNA and anti-Sm antibodies (if positive, some argue that it representsantibodies (if positive, some argue that it represents exclusion criteria for MCTD)exclusion criteria for MCTD)
  13. 13. Antibody FindingsAntibody Findings DiseaseDisease ANAANA RFRF dsDNAdsDNA SmSm Scl-70Scl-70 RNPRNP SLESLE 95-9995-99 2020 50-7050-70 3030 00 30-5030-50 RARA 15-3515-35 8585 <5<5 00 00 1010 DiffuseDiffuse SScSSc >90>90 3030 00 00 4040 3030 MCTDMCTD 95-9995-99 5050 00 <5<5 00 100100
  14. 14. 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 overlap11 systemic sclerosis, 10 SLE, 2 RA, 2 overlap syndromesyndrome  Other studies have found similar resultsOther studies have found similar results  About 40% of patients with anti-U1RNPAbout 40% of patients with anti-U1RNP antibodies retain the diagnosis of MCTD andantibodies retain the diagnosis of MCTD and others are “reclassified” within 5 years ofothers are “reclassified” within 5 years of presentationpresentation
  15. 15. Undifferentiated and Overlap SyndromesUndifferentiated and Overlap Syndromes  MCTDMCTD  SLE, SSc, PM, RASLE, SSc, PM, RA  Undifferentiated SystemicUndifferentiated Systemic Rheumatic DiseaseRheumatic Disease  Undifferentiated connectiveUndifferentiated connective tissue, collagen, vascular, ortissue, collagen, vascular, or autoimmune diseaseautoimmune disease  Nonclassical SLENonclassical SLE  ““Atypical” rheumatic diseaseAtypical” rheumatic disease  Undiiferentiated PolyarthritisUndiiferentiated Polyarthritis SyndromeSyndrome  UndifferentiatedUndifferentiated SpondylparthritisSpondylparthritis Overlap SyndromesOverlap Syndromes  RA-lupusRA-lupus  RhupusRhupus  Scleroderma-PM/DMScleroderma-PM/DM  Scleroderma-lupusScleroderma-lupus  Scleroderma-PBC-Sjogren’sScleroderma-PBC-Sjogren’s  Scleroderma-RAScleroderma-RA  JRA-lupusJRA-lupus  Psoriatic arthritis-lupusPsoriatic arthritis-lupus  PsupusPsupus  Sjogren’s overlapsSjogren’s overlaps  PM overlapsPM overlaps  Raynaud’s phenomenomRaynaud’s phenomenom overlapsoverlaps
  16. 16. 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, lymphopeniaLeukopenia, lymphopenia  ImmunologicImmunologic  Anti-dsDNAAnti-dsDNA  Anti-SmAnti-Sm  ANAANA  4/11 Criteria4/11 Criteria
  17. 17. Patient CoursePatient Course  Prednisone 1mg/kgPrednisone 1mg/kg started on day #4started on day #4  Patient became afebrilePatient became afebrile  Tachycardia andTachycardia and tachypnea resolvedtachypnea resolved  Discharge on day #7Discharge on day #7  Few weeks later –Few weeks later – anti-dsDNA positiveanti-dsDNA positive 35.5 36 36.5 37 37.5 38 38.5 39 39.5 40 1 2 3 4 5 6 7 Day Tmax 0 20 40 60 80 100 120 140 1 2 3 4 5 6 7 Day HRmax
  18. 18. ReferencesReferences  Bennett RM. “Definition and diagnosis of mixed connective tissue disease.”Bennett RM. “Definition and diagnosis of mixed connective tissue disease.” UpToDate.UpToDate.  Bennett RM. “Clinical manifestations of mixed connective tissue disease.” UpToDate.Bennett RM. “Clinical manifestations of mixed connective tissue disease.” UpToDate.  Kumar MS, Smith M, Pischel KD. “Case Report and Review of Cardiac Tamponade inKumar MS, Smith M, Pischel KD. “Case Report and Review of Cardiac Tamponade in Mixed Connective Tissue Disease.” Arthritis & Rheumatism, 2006. 55: 826-830.Mixed Connective Tissue Disease.” Arthritis & Rheumatism, 2006. 55: 826-830.  Swanton J, Isenberg D. “Mixed Connective Tissue Disease: Still Crazy After All TheseSwanton J, Isenberg D. “Mixed Connective Tissue Disease: Still Crazy After All These Years.” Rheum Dis Clin N Am, 2005. 31: 421-436.Years.” Rheum Dis Clin N Am, 2005. 31: 421-436.  Venables PJW. “Mixed Connective Tissue Disease.” Lupus, 2006. 15: 132-137.Venables PJW. “Mixed Connective Tissue Disease.” Lupus, 2006. 15: 132-137.  American College of Rheumatology, classification criteria for SLE.American College of Rheumatology, classification criteria for SLE.
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