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Mixed connective tissue disease (MCTD) was first described as a distinct entity in 1972. The original condition was identified among a group of patients who had overlapping clinical features of systemic lupus erythematosus (SLE), scleroderma and myositis. It has been further defined as a condition in which there is an undifferentiated connective tissue disorder in the presence of anti-U1-ribonucleoprotein antibody (anti-U1-RNP Ab) and Raynaud's phenomenon. Major advances in the immune pathogenesis of the disease have been made. As a condition, it usually evolves to become one of several other connective tissue disorders or an overlap syndrome and, because of this property, it remains a controversial diagnosis. The original criteria required in order to make the diagnosis are:
- For a definite diagnosis, 4 major criteria in the presence of raised levels of anti-U1-RNP Ab and absence of anti-smooth muscle antibodies.
- For a probable diagnosis, 3 major or 2 major (which must come from the first 3 on the list) and 2 minor criteria together with raised levels of anti-U1-RNP Ab.
- For a possible diagnosis, 3 major criteria with no rise in anti-U1-RNP Ab, or 1 major and 3 minor if anti-RNP is raised.
- In children, Raynaud's phenomenon, fatigue and pain (myalgia and arthralgia) are important presenting symptoms. Raynaud's phenomenon is a persisting symptom and all children presenting with this should be regularly assessed for other signs and symptoms of MCTD.
|Major Criteria||Minor Criteria|
Females are affected more frequently than males and it can occur at any age. The precise global incidence of mixed connective tissue disease (MCTD) is unknown, as in some cases it may be diagnosed as other connective tissue disorders or overlap syndromes. A Norwegian study reported a female-to-male ratio of 3.3:1 and a mean age of the adult-onset condition at diagnosis of 37.9 years. The incidence of adult-onset disease in Norway during the period from 1996 to 2005 was 2.1 per million per year.
A Taiwanese study reported a mean age of onset of the paediatric form of 10.7 years.
Mixed connective tissue disease (MCTD) must be suspected in any child presenting with Raynaud's phenomenon. Patients may also present with any combination of the following signs and symptoms:
- Rash, vasculitic, petechial or raised purpuric.
- Tight skin and/or 'sausage shaped' fingers.
- Dysphagia (probably related to autoimmune modulated effects on the oesophageal musculature).
- Epigastric pain and/or tenderness.
- Pleuritic chest pain.
- Systolic and/or diastolic heart failure.
- Pericardial rub.
- Muscle weakness.
- Trigeminal neuralgia.
- Sensorineural deafness.
- Subcutaneous calcification.
The differential diagnoses will include:
- Still's disease.
- Polyarteritis nodosa.
- Chronic fatigue syndrome.
- Goodpasture's syndrome.
- Nephrotic syndrome.
A patient presenting with features suggestive of mixed connective tissue disease (MCTD) may have the following investigations performed:
- FBC may show anaemia, thrombocytopenia and low white cell count.
- U&Es may show raised urea and creatinine if there is renal involvement.
- LFTs may show reduced albumin if there is renal involvement.
- Urinalysis - blood, protein and cells may be present.
- Lactate dehydrogenase (LDH) and creatine kinase may be raised with myositis.
- CRP and/or ESR may be raised.
- Antinuclear antibody is usually raised.
- Anti-double-stranded DNA is usually, but not always, negative.
- Anti-U1-RNP Ab is almost always raised.
- Anti-UA1-70 kd is characteristically present in MCTD.
- Anti-TS1-RNA Ab level appears to correlate with SLE-like activity in patients with MCTD.
- CXR is used to assess for infiltrates, effusion or cardiomegaly.
- ECG (with cardiac enzymes) is used to exclude myocardial infarction.
- Echocardiogram may be required to rule out effusion, pulmonary hypertension or valvular disease. Global impairment of right ventricular function is seen in MCTD patients with pulmonary hypertension. Global impairment of left ventricular function is seen in such patients irrespective of pulmonary hypertension.
- Barium swallow, abdominal ultrasound and/or CT scan may be necessary if the presentation is abdominal pain, to rule out serositis, pancreatitis or visceral perforation related to vasculitis. High-definition CT lung scanning may help to differentiate MCTD from other connective tissue diseases.
- MRI scan of the brain may be useful in assessing neuropsychiatric signs or symptoms.
All patients should be given advice on avoiding cold exposure, especially to hands and feet. Patients should be encouraged to keep active and mobile but to avoid over-exertion.
- Because of its relative rarity, there have been no large controlled clinical trials, so treatments have been used which have been of benefit in other rheumatic diseases.
- For patients with mild disease, the initial treatment is likely to be with non-steroidal anti-inflammatory agents such as ibuprofen to treat the pain and inflammation.
- Mild disease may also benefit from the antimalarial agent hydroxychloroquine.
- In more severe cases, or when there is secondary organ involvement, systemic corticosteroids are used in doses of 10-60 mg of prednisolone per day, depending on disease severity.
- Adjuvant therapy with steroid-sparing agents such as cyclophosphamide and ciclosporin may be used when prolonged treatment with high-dose steroids is required.
- Calcium-channel blocking agents such as nifedipine may be used for the treatment of the Raynaud's phenomenon.
- Prostaglandins such as epoprostenol may be used to treat patients who have developed secondary pulmonary hypertension.
- Symptoms of pulmonary hypertension and Raynaud's phenomenon can also be helped by phosphodiesterase inhibitors such as sildenafil.
- Endothelin receptor antagonists such as ambrisentan can help to reduce the symptoms of pulmonary hypertension and improve exercise tolerance.
All patients with mixed connective tissue disease (MCTD) should be regularly reviewed and reassessed, as many will go on to develop other connective tissue diseases such as SLE, scleroderma or an overlap syndrome. The prognosis is variable. One third of patients go into long-term remission, one third have intermittent chronic disabilities such as arthritis, chronic fatigue and dyspnoea on exertion and one third have severe systemic involvement with premature death. The mortality rate is lower in children than in adults. The most common cause of death is pulmonary hypertension. Careful management of the pulmonary complications improves prognosis. One case of pulmonary hypertension associated with severe pulmonary veno-occlusive disease has been reported.
Further reading & references
- Distler JH, Strapatsas T, Huscher D, et al; Dysbalance of angiogenic and angiostatic mediators in patients with mixed Ann Rheum Dis. 2011 Jul;70(7):1197-202.
- Hoffman RW et al; Mixed Connective-Tissue Disease, Medscape, Aug 2008
- Hoffman RW, Maldonado ME; Immune pathogenesis of Mixed Connective Tissue Disease: a short analytical review. Clin Immunol. 2008 Jul;128(1):8-17. Epub 2008 Apr 24.
- 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.
- Gunnarsson R, Molberg O, Gilboe IM, et al; The prevalence and incidence of mixed connective tissue disease: a national Ann Rheum Dis. 2011 Jun;70(6):1047-51. Epub 2011 Mar 11.
- Tsai YY, Yang YH, Yu HH, et al; Fifteen-year experience of pediatric-onset mixed connective tissue disease. Clin Rheumatol. 2010 Jan;29(1):53-8. Epub 2009 Sep 16.
- Uzuki M, Kamataki A, Watanabe M, et al; Histological analysis of esophageal muscular layers from 27 autopsy cases with Pathol Res Pract. 2011 Jun 15;207(6):383-90. Epub 2011 May 28.
- Schwagten B, Verheye S, Van den Heuvel P; Combined systolic and diastolic heart failure as the first presentation of mixed connective tissue disease. Acta Cardiol. 2007 Aug;62(4):421-3.
- Hajas A, Szodoray P, Barath S, et al; Sensorineural hearing loss in patients with mixed connective tissue disease: J Rheumatol. 2009 Sep;36(9):1930-6. Epub 2009 Aug 14.
- Yamamura K, Takahara M, Masunaga K, et al; Subcutaneous calcification of the lower legs in a patient with mixed connective J Dermatol. 2011 Mar 21. doi: 10.1111/j.1346-8138.2010.01177.x.
- Keith MP, Moratz C, Tsokos GC; Anti-RNP immunity: Implications for tissue injury and the pathogenesis of connective tissue disease. Autoimmun Rev. 2007 Mar;6(4):232-6. Epub 2006 Aug 28.
- Ikeda K, Takasaki Y, Hirokawa K, et al; Clinical significance of antibodies to TS1-RNA in patients with mixed connective tissue disease. J Rheumatol. 2003 May;30(5):998-1005.
- Vegh J, Hegedus I, Szegedi G, et al; Diastolic function of the heart in mixed connective tissue disease. Clin Rheumatol. 2007 Feb;26(2):176-81. Epub 2006 Jul 25.
- Devaraj A, Wells AU, Hansell DM; Computed tomographic imaging in connective tissue diseases. Semin Respir Crit Care Med. 2007 Aug;28(4):389-97.
- Kim P, Grossman JM; Treatment of mixed connective tissue disease. Rheum Dis Clin North Am. 2005 Aug;31(3):549-65, viii.
- Lundberg IE; The prognosis of mixed connective tissue disease. Rheum Dis Clin North Am. 2005 Aug;31(3):535-47, vii-viii.
- Hant FN, Herpel LB, Silver RM; Pulmonary manifestations of scleroderma and mixed connective tissue disease. Clin Chest Med. 2010 Sep;31(3):433-49.
- Zhang L, Visscher D, Rihal C, et al; Pulmonary veno-occlusive disease as a primary cause of pulmonary hypertension in a patient with mixed connective tissue disease. Rheumatol Int. 2007 Oct;27(12):1163-5. Epub 2007 May 23.
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Dr Laurence Knott
Dr Laurence Knott
Dr John Cox