“Mixed Connective Tissue Disease: Still Crazy After All These Years” Christina Kahl March 12, 2008 Rheum Dis Clin N Am 31 (2005) 421-426

History 1972 Sharp and colleagues Identified patients with high levels of antibodies against a ribonucleic protein (RNP) These patients shared several clinical features including Raynaud’s phenomenom, arthralgias, mild arthritis, puffy hands, abnormal esophageal mobility, and myositis Additional findings – hypergammaglobulinemia (80%), anemia and leukopenia (50%); pulmonary, renal and CNS involvement was “rare”

History 1980 Nimelstein and colleagues Doubts after reviewing 22/25 original patients Many patients evolved into scleroderma High mortality rate (8/22) Not everyone had antibodies to RNP Some patients had antibodies without clear clinical features of the syndrome Then, 20 years of contradictory views regarding the existence and nature of MCTD

Diagnostic 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 and Kahn in 45 patients

Diagnostic Criteria – Sharp Major Criteria Myositis Pulmonary Involvement Raynaud phenomenom or esophageal dysmobility Swollen hands or sclerodactyly High anti-U1-RNP with negative anti-Sm Definite – 4 major plus serology Probable – 3 major or 2 major (1st 3 listed) and 2 minor; and serology Minor Criteria Alopecia Leukopenia Anemia Pleuritis Pericarditis Arthritis Trigeminal Neuralgia Malar Rash Thrombocytopenia Mild Myositis h/o swollen hands

Diagnostic Criteria 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

Diagnostic Criteria “The crux of the MCTD diagnosis is the presence of high titers of antibodies to U1-RNP.” Many patients who satisfy criteria for MCTD also satisfy ACR criteria for RA or SLE, and many had symptoms of systemic sclerosis. “With serology superseding the clinical symptoms in the diagnosis, there is a risk of fitting the clinical symptoms to the antibody signs”

Clinical Presentation Early Clinical Findings Malaise, easy fatiguability Arthralgias Myalgias Raynaud’s phenomenom Low-grade fevers Unusual Presentations FUO Serositis Trigeminal neuropathy Severe polymyositis Acute arthritis Aseptic meningitis Digital gangrene

Characteristic At Diagnosis Cumulative at 5 years Raynaud’s Phenomenom 89% 96% Arthralgia/Arthritis 85% Swollen Hands 60% 66% Esophageal Dysmotility 47% Pulmonary Dysfunction 43% Serositis 34% Hematologic 30% 53% Erythematous Skin Rash Muscle Myositis 28% 51% Pulmonary Hypertension 9% 23% Sclerodermatous Changes 4% 19% CNS (or peripheral) 0% 17% Renal 2% 11% Cohort of 47 MCTD patients.

Pulmonary Manifestations Pleural Effusions Pulmonary Hypertension Pleuritic Pain Intersitial Lung Disease (30-50%) Thromboembolic Disease Obstructive Disease Pulmonary Vasculitis 75% of patients Early Symptoms Dry cough Dyspnea Pleuritic Chest Pain

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

Laboratory Findings High titer, speckled ANA pattern Leukopenia, anemia, thrombocytopenia Elevated ESR Very high serum immunoglobulins Complement levels usually normal or high Rheumatoid Factors increased in 70% of patients Negative findings include anti-dsDNA and anti-Sm antibodies (if positive, some argue that it represents exclusion criteria for MCTD)

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

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

Undifferentiated and Overlap Syndromes MCTD SLE, SSc, PM, RA Undifferentiated Systemic Rheumatic Disease Undifferentiated connective tissue, collagen, vascular, or autoimmune disease Nonclassical SLE “Atypical” rheumatic disease Undiiferentiated Polyarthritis Syndrome Undifferentiated Spondylparthritis Overlap Syndromes RA-lupus Rhupus Scleroderma-PM/DM Scleroderma-lupus Scleroderma-PBC-Sjogren’s Scleroderma-RA JRA-lupus Psoriatic arthritis-lupus Psupus Sjogren’s overlaps PM overlaps Raynaud’s phenomenom overlaps

SLE Criteria Malar Rash Discoid Rash Photosensitivity Oral Ulcers Arthritis Serositis Renal Disease Neurologic Disease Hematologic Disease Hemolytic anemia Leukopenia, lymphopenia Immunologic Anti-dsDNA Anti-Sm ANA 4/11 Criteria

Patient Course Prednisone 1mg/kg started on day #4 Patient became afebrile Tachycardia and tachypnea resolved Discharge on day #7 Few weeks later – anti-dsDNA positive

References Bennett RM. “Definition and diagnosis 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 in Mixed Connective Tissue Disease.” Arthritis & Rheumatism, 2006. 55: 826-830. Swanton J, Isenberg D. “Mixed Connective Tissue Disease: Still Crazy After All These Years.” Rheum Dis Clin N Am, 2005. 31: 421-436. Venables PJW. “Mixed Connective Tissue Disease.” Lupus, 2006. 15: 132-137. American College of Rheumatology, classification criteria for SLE.