Dermatologic Manifestations of Mixed Connective Tissue Disease Clinical Presentation
- Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD more...
Usually, patients with mixed connective-tissue disease (MCTD) present with Raynaud phenomenon, which frequently represents the initial manifestation of the disease. The decreasing frequency of attacks limits progressive vascular damage. The course of the entity is often mild, but the clinical appearance and the patient's complaints depend on the symptoms related to the specific forms of the connective-tissue disease most expressed in the individual patient.
During the course of the disease in some patients, the typical signs and symptoms of systemic lupus erythematosus develop and fulfill at least 4 of the American Rheumatism Association (ARA) criteria. In other patients, MCTD becomes systemic sclerosis that spreads to the face, scalp, and trunk, and the fingers become immobile, hard, and shiny.
See the image below.
Usually, patients with MCTD present with Raynaud phenomenon. Headaches may occur, and patients may report fatigue. While myalgia and arthralgia are important early symptoms of pediatric-onset MCTD, many adolescent girls report pain along with fatigue. Pediatric MCTD may show findings of arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, and systemic sclerosis. Raynaud phenomenon should hasten evaluation. Capillary findings should also be evaluated because they may correlate with the development of scleroderma spectrum disorders.
Mixed connective-tissue disease (MCTD) findings at physical examination may include the following:
Raynaud phenomenon, sausage-shaped fingers, and swelling of the dorsa of the hands that never becomes sclerodactyly are the most typical features (see the image below).
More than one half of patients have abnormal capillaries in the nail fold.
Small-vessel vasculitis with palpable purpura is present in about 25% of patients. Occasionally, vascular disturbances may be severe and lead to peripheral gangrene and leg ulcers.
Other skin manifestations are not universally expressed. Erythematous plaques similar to those seen in patients with chronic cutaneous (discoid) lupus erythematosus can be seen. Alopecia, facial erythema, periungual telangiectasia, and pigmentary disturbances can also occur. Painful dermal nodules may appear on the hands or elbows.
Cutaneous ulceration due to subcutaneous dystrophic calcification associated with mixed connective-tissue disease (MCTD) may occur.
Dry eye, or keratoconjunctivitis sicca, is common with MCTD; Sjögren syndrome is often underdiagnosed in individuals with MCTD.
About 60% of patients complain of arthralgia.
Arthritis without any visible joint deformation can occur.
Any joint may be involved.
Patients usually complain of morning stiffness.
Patients may be first evident with signs and symptoms of synovitis.
Myalgia, myositis, and muscle weakness are common features.
Dysphagia and dysfunction of esophageal motility resemble that occurring in systemic sclerosis.
Other abnormalities of the gut include esophagitis, constipation, diarrhea, and malabsorption.
Correlated pulmonary function data and high-resolution CT scan findings of interstitial lung disease in 50 consecutive patients with MCTD suggests but does not prove a strong association between esophageal motor dysfunction and interstitial lung disease.
Pleuropulmonary manifestations are common. The incidence varies from 20-85%.
Pleuropulmonary complications include pleural effusion, interstitial pulmonary fibrosis, pulmonary arterial hypertension, pulmonary vasculitis, pulmonary thromboembolic phenomena, aspiration pneumonia, serositis, and hypoventilatory failure.
Interstitial lung disease was identified in juvenile MCTD in one quarter of patients studied by high-resolution CT scanning. In most of them, it was subtle and without clinical correlation.
MCTD interstitial lung disease characteristics are nonspecific but seem to link pulmonary hypertension and progressive interstitial lung disease.
The incidence of renal involvement is only about 5%.
Nephritis is associated with a poor prognosis. In addition to myocarditis, pulmonary hypertension, and widespread vasculitis, nephritis is considered a common cause of death.
Nervous system involvement is rare.
Aseptic meningitis, trigeminal neuropathy, and psychosis are the prominent neurologic features.
Sporadic cases with autonomic neuropathy are described.
An assessment of cognitive functions in patients with MCTD showed cognitive deficits observed in MCTDs were connected with nervous system involvement.
Cardiac involvement is often clinically insignificant, but the rate varies from 11-85% depending on patient selection and methods used to detect cardiac manifestations. Pericarditis, pulmonary hypertension, mitral valve prolapse, myocarditis, conduction disturbances, and abnormal left ventricular diastolic filling pattern are the most frequently observed problems.
Lymph node enlargement is seldom a feature, but it may be present.
The cause of mixed connective-tissue disease (MCTD) is not completely known. HLA-DR4 is more common in patients with MCTD than in patients with other connective-tissue diseases (see Pathophysiology). A genetic predisposition is confirmed by reports of familial occurrence.
Tani C, Carli L, Vagnani S, Talarico R, Baldini C, Mosca M, et al. The diagnosis and classification of mixed connective tissue disease. J Autoimmun. 2014 Feb-Mar. 48-49:46-9. [Medline].
Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist? Yes. Rheum Dis Clin North Am. 2005 Aug. 31(3):411-20, v. [Medline].
Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. "To be or not to be," ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012 Feb. 41(4):589-98. [Medline].
Yoshida K, Inoue H, Komai K, Yamane T, Hashiramoto A, Shiozawa K, et al. Mixed connective tissue disease is distinct from systemic lupus erythematosus: study of major histocompatibility complex class I polypeptide-related sequence A and HLA gene polymorphisms. Tissue Antigens. 2013 Jan. 81(1):44-5. [Medline].
Kattah NH, Kattah MG, Utz PJ. The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Rev. 2010 Jan. 233(1):126-45. [Medline].
Paradowska-Gorycka A, Stypińska B, Olesińska M, Felis-Giemza A, Mańczak M, Czuszynska Z, et al. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients. HLA. 2016 Jan. 87 (1):13-8. [Medline].
Gunnarsson R, Molberg O, Gilboe IM, Gran JT. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis. 2011 Mar 11. [Medline].
Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. Epidemiology of Mixed Connective Tissue Disease 1985-2014: A Population Based Study. Arthritis Care Res (Hoboken). 2016 Mar 4. [Medline].
Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: An overview of clinical manifestations, diagnosis and treatment. Best Pract Res Clin Rheumatol. 2012 Feb. 26(1):61-72. [Medline].
Hajas A, Szodoray P, Nakken B, Gaal J, Zöld E, Laczik R, et al. Clinical Course, Prognosis, and Causes of Death in Mixed Connective Tissue Disease. J Rheumatol. 2013 Jul. 40(7):1134-1142. [Medline].
Grader-Beck T, Wigley FM. Raynaud's phenomenon in mixed connective tissue disease. Rheum Dis Clin North Am. 2005 Aug. 31(3):465-81, vi. [Medline].
Hall S, Hanrahan P. Muscle involvement in mixed connective tissue disease. Rheum Dis Clin North Am. 2005 Aug. 31(3):509-17, vii. [Medline].
Swart JF, Wulffraat NM. Diagnostic workup for mixed connective tissue disease in childhood. Isr Med Assoc J. 2008 Aug-Sep. 10(8-9):650-2. [Medline].
Berard RA, Laxer RM. Pediatric Mixed Connective Tissue Disease. Curr Rheumatol Rep. 2016 May. 18 (5):28. [Medline].
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].
Yamamura K, Takahara M, Masunaga K, Sawabe T, Kitano M, Mashino T, et al. Subcutaneous calcification of the lower legs in a patient with mixed connective tissue disease. J Dermatol. 2011 Mar 21. [Medline].
Usuba FS, Lopes JB, Fuller R, Yamamoto JH, Alves MR, Pasoto SG, et al. Sjögren's syndrome: An underdiagnosed condition in mixed connective tissue disease. Clinics (Sao Paulo). 2014 Mar. 69(3):158-62. [Medline]. [Full Text].
Sen S, Sinhamahapatra P, Choudhury S, Gangopadhyay A, Bala S, Sircar G, et al. Cutaneous manifestations of mixed connective tissue disease: study from a tertiary care hospital in eastern India. Indian J Dermatol. 2014 Jan. 59(1):35-40. [Medline]. [Full Text].
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. 2000 Nov. 27(11):2692-5. [Medline].
Fagundes MN, Caleiro MT, Navarro-Rodriguez T, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med. 2009 Jun. 103(6):854-60. [Medline].
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. 2009 May. 50(4):430-6. [Medline].
Colin G, Nunes H, Hatron PY, Cadranel J, Tillie I, Wallaert B. [Clinical study of interstitial lung disease in mixed connective tissue disease]. Rev Mal Respir. 2010 Mar. 27(3):238-46. [Medline].
Nowicka-Sauer K, Czuszynska Z, Majkowicz M, Smolenska Z, Jarmoszewicz K, Olesinska M, et al. Neuropsychological assessment in mixed connective tissue disease: comparison with systemic lupus erythematosus. Lupus. 2012 Mar 20. [Medline].
Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus. 2005. 14(9):708-12. [Medline].
Gourley I, Bell AL, Biggart D. Kikuchi's disease as a presenting feature of mixed connective tissue disease. Clin Rheumatol. 1995 Jan. 14(1):104-7. [Medline].
Latuskiewicz-Potemska J, Zygmunt A, Biernacka-Zielinska M, Stanczyk J, Smolewska E. Mixed connective tissue disease presenting with progressive scleroderma symptoms in a 10-year-old girl. Postepy Dermatol Alergol. 2013 Oct. 30(5):329-36. [Medline]. [Full Text].
Hoffmann-Vold AM, Gunnarsson R, Garen T, Midtvedt Ø, Molberg Ø. Performance of the 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis (SSc) in large, well-defined cohorts of SSc and mixed connective tissue disease. J Rheumatol. 2015 Jan. 42(1):60-3. [Medline].
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. 1985 Jul. 28(7):768-74. [Medline].
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. [Medline].
Hof D, Raats JM, Pruijn GJ. Apoptotic modifications affect the autoreactivity of the U1 snRNP autoantigen. Autoimmun Rev. 2005 Jul. 4(6):380-8. [Medline].
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. 2009 Jun. 18(7):618-21. [Medline].
Seguchi M, Soejima Y, Tateishi A, et al. Mixed connective tissue disease with multiple organ damage: successful treatment with plasmapheresis. Intern Med. 2000 Dec. 39(12):1119-22. [Medline].
Lage R, Biccigo DG, Santos FB, Chimara E, Pereira ES, Costa Ad. Mycobacterium chelonae cutaneous infection in a patient with mixed connective tissue disease. An Bras Dermatol. 2015 Jan-Feb. 90(1):104-7. [Medline]. [Full Text].