Overview
Definition:
Mixed connective tissue disease (MCTD) is an idiopathic, multisystem autoimmune disorder characterized by overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), and polymyositis
It is considered a distinct entity, although its nosological status remains debated.
Epidemiology:
MCTD is rare, with an estimated incidence of 1-2 per 100,000 individuals
It primarily affects women, with a female-to-male ratio of 4:1 to 10:1
Onset in adolescence is less common than in adulthood, but it can present during childhood and adolescence, often mimicking other pediatric rheumatic diseases.
Clinical Significance:
MCTD presents a diagnostic challenge due to its overlapping features, often leading to delayed diagnosis
Early recognition and appropriate management are crucial to prevent irreversible organ damage and improve long-term outcomes for adolescent patients preparing for higher medical examinations.
Clinical Presentation
Symptoms:
Arthralgias and arthritis
Raynaud's phenomenon
Esophageal dysmotility
Dyspnea on exertion due to interstitial lung disease
Myalgias and proximal muscle weakness
Gastrointestinal symptoms like abdominal pain and constipation
Fever
Fatigue
Swollen hands and fingers (puffy hands).
Signs:
Edema of hands (puffy fingers)
Sclerodactyly
Characteristic rash, often malar or heliotrope
Myositis (proximal muscle tenderness/weakness)
Signs of pulmonary hypertension (loud P2, RV heave)
Cardiac involvement (pericarditis, heart failure)
Renal involvement (less common than in SLE)
Neurological deficits.
Diagnostic Criteria:
The Kasukawa criteria (1979) remain widely used, requiring the presence of: 1
Nonspecific findings of SLE (e.g., polyarthritis, Raynaud's phenomenon, esophageal hypomotility, skin changes, myositis, leukopenia)
2
High titer of anti-U1 RNP antibodies
3
Absence of antibodies characteristic of SLE (anti-dsDNA, anti-Sm) and scleroderma (anti-Scl-70, anti-centromere)
Modified criteria and updated guidelines emphasize clinical manifestations and serology more broadly, considering a combination of features suggestive of overlap.
Diagnostic Approach
History Taking:
Detailed history focusing on constitutional symptoms, musculoskeletal complaints, Raynaud's phenomenon (color changes, triggers), gastrointestinal issues, respiratory symptoms, and skin changes
Inquire about family history of autoimmune diseases
Elicit timeline of symptom onset and progression
Ask about prior diagnoses of SLE, scleroderma, or polymyositis.
Physical Examination:
Comprehensive physical examination with emphasis on: Musculoskeletal system (joint swelling, tenderness, range of motion, muscle strength testing)
Skin (rashes, sclerodactyly, digital ulcers, telangiectasias)
Cardiovascular system (heart sounds, murmurs, peripheral pulses)
Respiratory system (lung auscultation for crackles, signs of pulmonary hypertension)
Neurological examination
Evaluate for features of SLE, scleroderma, and polymyositis.
Investigations:
Complete blood count with differential (anemia, leukopenia)
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (elevated)
Autoantibody profile: High titer anti-U1 RNP is critical
Also test for anti-dsDNA, anti-Sm, anti-Scl-70, anti-centromere, ANA, anti-Jo-1
Muscle enzymes (CK, aldolase) if myositis is suspected
Pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) of the chest for interstitial lung disease
Echocardiogram for pulmonary hypertension
Esophageal manometry for dysmotility
Renal function tests (urinalysis, BUN, creatinine).
Differential Diagnosis:
Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (Scleroderma), Juvenile Dermatomyositis (JDM), Rheumatoid Arthritis, Sjögren's syndrome
Differentiating features include the specific autoantibody profile (anti-U1 RNP), combination of symptoms not typical of a single disease, and overlapping features like Raynaud's, sclerodactyly, myositis, and interstitial lung disease simultaneously.
Management
Initial Management:
Goals are to control inflammation, prevent organ damage, and manage symptoms
Initial therapy often involves a combination of corticosteroids and immunosuppressive agents
Prompt treatment of any life-threatening organ involvement (e.g., severe ILD, pulmonary hypertension, myocarditis).
Medical Management:
Corticosteroids: Prednisolone is the mainstay, often initiated at 0.5-1 mg/kg/day, then tapered based on response
Immunosuppressants: Hydroxychloroquine for skin and arthritic manifestations
Methotrexate is often first-line for arthritis and myositis
Azathioprine or mycophenolate mofetil can be used for refractory disease or organ involvement
Cyclophosphamide may be used for severe pulmonary or renal involvement
Biologics like rituximab are considered in refractory cases.
Surgical Management:
Rarely indicated
May be considered for severe, refractory digital ischemia unresponsive to medical therapy, potentially involving sympathectomy or reconstructive surgery
Lung transplantation may be an option for end-stage interstitial lung disease or pulmonary hypertension.
Supportive Care:
Physical therapy and occupational therapy for joint mobility, muscle strength, and daily living activities
Nutritional support for gastrointestinal issues
Psychosocial support for adolescent patients and families
Sun protection for photosensitive rashes
Management of Raynaud's phenomenon with lifestyle modifications (avoiding cold) and vasodilators (e.g., calcium channel blockers).
Complications
Early Complications:
Acute respiratory distress syndrome (ARDS) from severe ILD
Myocarditis and pericarditis
Acute renal failure
Gastrointestinal bleeding or perforation
Significant muscle weakness leading to functional impairment
Pulmonary hypertension crisis.
Late Complications:
Progressive interstitial lung disease and restrictive lung disease
Pulmonary arterial hypertension
Cardiac fibrosis and heart failure
Chronic renal insufficiency
Esophageal strictures
Osteoporosis due to long-term corticosteroid use
Infections due to immunosuppression
Malignancy (lymphoma).
Prevention Strategies:
Aggressive and timely immunosuppressive therapy to control inflammation
Regular monitoring for organ involvement using PFTs, echocardiography, and renal function tests
Judicious use of corticosteroids and bone-sparing agents
Prophylaxis against Pneumocystis jirovecii pneumonia if on high-dose immunosuppression
Vaccination against common infections.
Prognosis
Factors Affecting Prognosis:
Severity of organ involvement at diagnosis (lung, heart, kidney)
Response to immunosuppressive therapy
Presence of specific autoantibodies
Adherence to treatment
Development of complications.
Outcomes:
Prognosis varies widely
Many adolescents with MCTD can achieve remission or stable disease with appropriate treatment, leading to good quality of life
However, significant morbidity and mortality can occur due to severe organ damage, particularly pulmonary and cardiac involvement
Long-term follow-up is essential.
Follow Up:
Regular follow-up every 3-6 months with a pediatric rheumatologist
Continued monitoring of clinical parameters, inflammatory markers, autoantibodies, PFTs, echocardiography, and renal function
Gradual tapering of medications as disease activity subsides, but often requires long-term low-dose maintenance therapy
Transition to adult care as appropriate.
Key Points
Exam Focus:
The hallmark autoantibody is anti-U1 RNP
Overlap of SLE, scleroderma, and polymyositis features
Raynaud's phenomenon, puffy fingers, esophageal dysmotility, and ILD are common
Renal involvement is less common than in SLE
Differentiating from other connective tissue diseases is crucial.
Clinical Pearls:
Always consider MCTD in an adolescent with overlapping features of CTDs, especially with a positive anti-U1 RNP
Early aggressive management of ILD and pulmonary hypertension is paramount
Watch for signs of myositis and renal involvement
Be prepared to discuss long-term management and potential complications.
Common Mistakes:
Misdiagnosing MCTD as solely SLE or scleroderma due to isolated features
Underestimating the severity of interstitial lung disease or pulmonary hypertension
Delaying immunosuppressive therapy for active organ involvement
Not screening for all relevant autoantibodies
Inadequate long-term follow-up leading to relapses or progressive damage.