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Mixed Connective Tissue Disease: Differential Diagnoses & Workup

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland; Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Contributor Information and Disclosures

Updated: Oct 5, 2009

Differential Diagnoses

Dermatomyositis
Systemic Sclerosis

Other Problems to Be Considered

Kikuchi disease10

Workup

Laboratory Studies

  • Abnormal laboratory results are dependent on the spectrum of connective tissue disease symptoms, which can be similar to those recognized in systemic lupus erythematosus, systemic sclerosis (SSc), dermatomyositis, and polymyositis.
  • The complete blood cell count may reveal the following:
    • Anemia
    • Thrombocytopenia (unusual in adults but may be marked in children)
    • Decreased white blood cell count
  • Urine analysis may be helpful in detecting the following:
    • Proteinuria
    • Hematuria
  • An assessment of kidney function may show the following results:
    • Elevated creatinine level
    • Elevated urea level
  • Muscle enzyme tests may demonstrate the following:
    • Elevated aldolase level
    • Elevated creatine kinase (CK) level: CK is an enzyme in muscle cells that may be released into blood stream upon damage of myocytes. CK consists of 3 isoenzymes designated MM, MB, and BB. Adult skeletal muscle contains mainly CK-MM, cardiac muscle CK-MB, and smooth muscle CK-BB.
  • Tests for myocarditis may reveal elevated cardiac isoform troponin-I (cTnI) levels, which has the highest specificity for cardiac muscle and is the most reliable serum marker for detection of myocardial damage in patients with inflammatory muscle disease.
  • The erythrocyte sedimentation rate may be increased.
  • Hypergammaglobulinemia may be present.

Imaging Studies

  • Radiologic, manometric, videoendoscopic, and scintigraphic examination may reveal abnormal esophageal motility.
    • Technetium Tc 99m-pyrophosphate scintigraphy permits detection of left ventricular global and regional wall abnormalities.
    • Gadolinium diethylenetriaminepentaacetic–enhanced MRI is used to distinguish active myocardial inflammation from myocardial damage in humans with myocarditis with viral infections, sarcoidosis, or ischemic myocardial damage.
  • Chest x-ray films may show pleural thickening, fibrosis, and pericarditis.
  • Echocardiography can reveal pericarditis.
  • Angiography shows obstruction of the small blood vessels in some cases.11

Other Tests

  • Electromyography findings can reveal muscle destruction.
  • ECG is the basic method to detect arrhythmias, conduction defects, and ST-T changes.
  • Immunologic findings may be helpful in diagnosing mixed connective-tissue disease (MCTD).
    • Indirect immunofluorescence: The presence of a high titer of immunoglobulin G antibodies against U1-ribonucleoprotein (RNP) as the only autoantibodies strongly supports a diagnosis of MCTD. These antibodies are directed against small ribonucleoproteins, which are referred to as extractable nuclear antigens.12 The fluorescent antinuclear antibody test typically reveals a speckled pattern of staining on HEp-2 substrate. More sophisticated analysis identifies the target protein as the 68- to 70-kd U1-RNP complex. Recent studies revealed that antibodies directed to an apoptotic-specific epitope on 70K are more specifically associated with MCTD than other anti-70K antibodies.13 Other antibodies such as dsDNA, anti-Ro/SS-A, and anti-La/SS-B occur incidentally.14
Indirect immunofluorescence testing shows the typ...

Indirect immunofluorescence testing shows the typical speckled pattern for ribonucleoprotein antibodies on a HEp-2 substrate.

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Indirect immunofluorescence testing shows the typ...

Indirect immunofluorescence testing shows the typical speckled pattern for ribonucleoprotein antibodies on a HEp-2 substrate.


    • Direct immunofluorescence: Performed on lesional skin of patients with MCTD, this may reveal epidermal nuclear immunoglobulin G staining. This staining is thought to be related to the high titers of U1-RNP antibodies in the patient's sera. In some cases, the lupus band test might be positive, with linear deposits of immunoglobulins, fibrin, and/or complement components present at the basement membrane. Immunoglobulin M is usually the main compound.


Direct immunofluorescence testing shows epidermal...

Direct immunofluorescence testing shows epidermal nuclear immunoglobulin G staining.

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Direct immunofluorescence testing shows epidermal...

Direct immunofluorescence testing shows epidermal nuclear immunoglobulin G staining.

  • Pulmonary function testing may reveal ventilator disorders of the restrictive type, such as diminished vital capacity, normal residual volume, and total lung capacity. Respiratory function tests are usually consistent with radiographic findings (see Imaging Studies).

Histologic Findings

The histologic findings in mixed connective-tissue disease (MCTD) are not conclusive.

More on Mixed Connective Tissue Disease

Overview: Mixed Connective Tissue Disease
Differential Diagnoses & Workup: Mixed Connective Tissue Disease
Treatment & Medication: Mixed Connective Tissue Disease
Follow-up: Mixed Connective Tissue Disease
Multimedia: Mixed Connective Tissue Disease
References
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References

  1. Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist? Yes. Rheum Dis Clin North Am. Aug 2005;31(3):411-20, v. [Medline].

  2. Grader-Beck T, Wigley FM. Raynaud's phenomenon in mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):465-81, vi. [Medline].

  3. Hall S, Hanrahan P. Muscle involvement in mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):509-17, vii. [Medline].

  4. Swart JF, Wulffraat NM. Diagnostic workup for mixed connective tissue disease in childhood. Isr Med Assoc J. Aug-Sep 2008;10(8-9):650-2. [Medline].

  5. Oh YB, Jun JB, Kim CK, et al. Mixed connective tissue disease associated with skin defects of livedoid vasculitis. Clin Rheumatol. 2000;19(5):381-4. [Medline].

  6. Weber P, Ganser G, Frosch M, Roth J, Hülskamp G, Zimmer KP. Twenty-four hour intraesophageal pH monitoring in children and adolescents with scleroderma and mixed connective tissue disease. J Rheumatol. Nov 2000;27(11):2692-5. [Medline].

  7. Fagundes MN, Caleiro MT, Navarro-Rodriguez T, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med. Jun 2009;103(6):854-60. [Medline].

  8. Aalokken TM, Lilleby V, Soyseth V, et al. Chest abnormalities in juvenile-onset mixed connective tissue disease: assessment with high-resolution computed tomography and pulmonary function tests. Acta Radiol. May 2009;50(4):430-6. [Medline].

  9. Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus. 2005;14(9):708-12. [Medline].

  10. Gourley I, Bell AL, Biggart D. Kikuchi's disease as a presenting feature of mixed connective tissue disease. Clin Rheumatol. Jan 1995;14(1):104-7. [Medline].

  11. Peller JS, Gabor GT, Porter JM, Bennett RM. Angiographic findings in mixed connective tissue disease. Correlation with fingernail capillary photomicroscopy and digital photoplethysmography findings. Arthritis Rheum. Jul 1985;28(7):768-74. [Medline].

  12. 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. Feb 1972;52(2):148-59. [Medline].

  13. Hof D, Raats JM, Pruijn GJ. Apoptotic modifications affect the autoreactivity of the U1 snRNP autoantigen. Autoimmun Rev. Jul 2005;4(6):380-8. [Medline].

  14. Hasegawa EM, Caleiro MT, Fuller R, Carvalho JF. The frequency of anti-beta2-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease. Lupus. Jun 2009;18(7):618-21. [Medline].

  15. Seguchi M, Soejima Y, Tateishi A, et al. Mixed connective tissue disease with multiple organ damage: successful treatment with plasmapheresis. Intern Med. Dec 2000;39(12):1119-22. [Medline].

  16. Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].

  17. Jablonska S, Blaszczyk M. Scleroderma overlap syndromes. Adv Exp Med Biol. 1999;455:85-92. [Medline].

  18. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective tissue disease: high-resolution CT findings in 41 patients. J Thorac Imaging. Apr 2001;16(2):94-8. [Medline].

  19. Maddison PJ. Mixed connective tissue disease: overlap syndromes. Baillieres Best Pract Res Clin Rheumatol. Mar 2000;14(1):111-24. [Medline].

  20. Pope JE. Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am. Aug 2005;31(3):519-33, vii. [Medline].

  21. Yang YH, Tsai MJ, Lin SC, Lin MT, Chiang BL. Childhood mixed connective tissue disease. J Formos Med Assoc. Feb 2000;99(2):158-61. [Medline].

  22. Zdrojewicz Z, Budzyn-Koziol E, Pulawska J. [Mixed connective tissue disease--etiology, pathogenesis, clinical significance, treatment]. Postepy Hig Med Dosw. 1999;53(5):751-66. [Medline].

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Further Reading

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Keywords

mixed connective-tissue disease, MCTD, CTD, Sharp syndrome, Sharp's syndrome, systemic lupus erythematosus, SLE, systemic sclerosis, SSc, dermatomyositis, DM, polymyositis, PM, Sjögren syndrome, U1-ribonucleoprotein antibodies, U1-RNP

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Anna Wozniacka, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology
Disclosure: Nothing to disclose.

Medical Editor

Russell Hall, MD, Chief, Professor, Department of Internal Medicine, Division of Dermatology, Duke University
Russell Hall, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Federation for Medical Research, American Society for Clinical Investigation, and Society for Investigative Dermatology
Disclosure: Genetech Grant/research funds Principle Investigator; Centecor  Grant/research funds Principle Investigator

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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