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Mixed connective tissue disease

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Mixed Connective Tissue Disease (MCTD): Overview and Symptoms

Mixed Connective Tissue Disease (MCTD) is a distinct systemic autoimmune condition characterized by overlapping clinical features commonly seen in Systemic Sclerosis (Scleroderma), Systemic Lupus Erythematosus (SLE), and Polymyositis [1, 2]. Some features of Rheumatoid Arthritis (RA) may also be present [1]. It is considered an "overlap syndrome."

Key clinical features often include [1, 2]:

  • Raynaud's phenomenon: Episodic color changes (white, blue, red) in fingers and toes due to cold or stress (present in almost all patients).
  • Swollen hands/fingers ("puffy hands"): Often an early sign.
  • Arthritis/Arthralgia: Joint pain and swelling, often involving the hands.
  • Myositis: Muscle inflammation causing weakness, primarily in proximal muscles (shoulders, hips).
  • Sclerodactyly: Thickening/tightening of the skin on the fingers (less severe than in diffuse SSc).
  • Esophageal dysmotility: Difficulty swallowing or heartburn.
  • Pulmonary involvement: Interstitial lung disease and pulmonary hypertension are significant potential complications.

While severe kidney disease (lupus nephritis) is a hallmark of SLE, clinically significant renal involvement is less common and generally milder in MCTD compared to SLE, although it can occur, particularly in children [1, 2].

Antibodies to U1-RNP (including RNP-70) in MCTD

The immunological hallmark of MCTD is the presence of high titers of autoantibodies targeting the U1 ribonucleoprotein (U1-RNP) complex [1, 2]. The U1-RNP complex contains several proteins, including one historically referred to as the 70-kDa protein (RNP-70), as well as proteins A and C [1]. Therefore, testing positive specifically for anti-U1-RNP antibodies (often detected by ELISA or immunoblot) at high levels is a key diagnostic criterion for MCTD [1, 2].

While anti-U1-RNP antibodies are characteristic of MCTD (found in virtually 100% of cases), they can occasionally be found at lower titers in other conditions like SLE or scleroderma [1]. Crucially, in classic MCTD, other highly specific autoantibodies typically associated with SLE (like anti-dsDNA and anti-Sm) or specific forms of scleroderma (like anti-Scl-70 or anti-centromere) are usually absent or present only in low titers [1, 2].

 

Differential Diagnosis of Mixed Connective Tissue Disease (MCTD)

Condition Key Overlapping Features with MCTD Distinguishing Features / Antibodies
Mixed Connective Tissue Disease (MCTD) Overlap of SLE, SSc, PM features (Raynaud's, puffy hands, arthritis, myositis, esophageal dysmotility, +/- sclerodactyly). High titer Anti-U1-RNP required. Absence of highly specific markers for SLE (Anti-dsDNA, Anti-Sm) or SSc (Anti-Scl-70, Anti-centromere). Renal/CNS involvement less common than SLE.
Systemic Lupus Erythematosus (SLE) Raynaud's, arthritis, myositis, photosensitivity, rash, serositis can occur. Often has more prominent rash (malar, discoid), nephritis, cytopenias, serositis. Anti-dsDNA and/or Anti-Sm often positive (specific). Anti-U1-RNP may be present but usually not in isolation at high titer.
Systemic Sclerosis (Scleroderma - SSc) Raynaud's, puffy hands (early), sclerodactyly, esophageal dysmotility, arthritis, myositis, ILD, PAH can occur. More prominent/extensive skin thickening usually develops. Specific autoantibodies often present: Anti-Scl-70 (diffuse SSc), Anti-centromere (limited SSc), Anti-RNA Pol III. Anti-U1-RNP less common or lower titer.
Polymyositis (PM) / Dermatomyositis (DM) Proximal muscle weakness (myositis), Raynaud's, arthritis, ILD can overlap. Weakness is the dominant feature. DM has characteristic rash (Gottron's, heliotrope). Specific myositis antibodies often present (e.g., Anti-Jo-1, Anti-Mi-2). Anti-U1-RNP less common. Elevated CK typical. Muscle biopsy confirms myositis.
Rheumatoid Arthritis (RA) Symmetric polyarthritis, especially hands/wrists. Fatigue, Raynaud's can occur. Erosive arthritis typical on X-ray. Features like significant skin thickening, myositis, severe Raynaud's less common. RF and/or Anti-CCP often positive. Anti-U1-RNP usually negative.
Undifferentiated Connective Tissue Disease (UCTD) Symptoms suggestive of systemic autoimmune disease (e.g., Raynaud's, arthralgia, positive ANA) but does not meet criteria for any specific CTD. Positive ANA common. Specific antibodies like Anti-U1-RNP, Anti-dsDNA, Anti-Sm etc., are typically absent. May evolve into a defined CTD (like MCTD, SLE, SSc) over time or remain undifferentiated.

References

  1. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972 Feb;52(2):148-59. (Original description).
  2. Hoffman RW, Greidinger EL. Mixed Connective Tissue Disease. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell JR. Kelley & Firestein's Textbook of Rheumatology. 10th ed. Elsevier; 2017. Chapter 82.
  3. Venables PJW. Mixed connective tissue disease. Lupus. 2006;15(3):132-7. (Review article).