Mixed connective tissue disease

What is mixed connective tissue disease?

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 are overlapping features between two or more systemic autoimmune diseases in the presence of anti-U1-ribonucleoprotein antibody (anti-U1-RNP Ab).¹ Major advances in the immune pathogenesis of the disease have been made.²

MCTD should be distinguished from undifferentiated connective tissue disease (UCTD). In MCTD, there are features of multiple different connective tissue disorders. In UCTD, patients have features of a connective tissue disorder, but do not meet the diagnostic criteria for any specific condition.³

MCTD sometimes evolves into other connective tissue disorders, and, historically, the idea that MCTD is a distinct clinical entity has been criticised. However, few authors reject it entirely.⁴ The original criteria (Sharp criteria) required in order to make the diagnosis are:

• For a definite diagnosis, four major criteria in the presence of raised levels of anti-U1-RNP Ab and absence of anti-smooth muscle antibodies.

• For a probable diagnosis, three major or two major (which must come from the first three on the list) and two minor criteria together with raised levels of anti-U1-RNP Ab.

• For a possible diagnosis, three major criteria with no rise in anti-U1-RNP Ab, or 1 major and three 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.⁵

• Other diagnostic criteria include the Alarcón-Segovia criteria, and the 2019 Japanese consensus criteria.⁶

How common is MCTD? (Epidemiology)

Females are affected more frequently than males and it can occur at any age. The precise global incidence of 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.⁷

A Taiwanese study reported a mean age of onset of the paediatric form of 10.7 years.⁸

Mixed connective tissue disease symptoms⁸

The most common clinical manifestations are Raynaud's phenomenon, arthralgias, swollen joints, oesophageal dysfunction, muscle weakness and fingers with sausage-like appearance. Patients may also present with any combination of the following signs and symptoms:

• Lethargy, fever, muscle weakness, polyarthritis, lymphadenopathy.

• Rash, vasculitic, petechial or raised purpuric; telangiectasia; alopecia; tight skin and/or 'sausage-shaped' fingers.⁹

• Dysphagia (probably related to autoimmune modulated effects on the oesophageal musculature).¹⁰

• Epigastric pain and/or tenderness; pleuritic chest pain.

• Cardiac involvement is common among patients but often clinically inapparent. Pericarditis is the most common cardiac diagnosis.¹¹ Other abnormalities include conduction abnormalities, pericardial effusion and mitral valve prolapse. Systolic and/or diastolic heart failure may occur.¹²

• Trigeminal neuralgia; sensorineural deafness.¹³

• Subcutaneous calcification.¹⁴

Differential diagnosis

The differential diagnoses are broad, and include:

• Scleroderma.

• Still's disease.

• Polymyositis and dermatomyositis.

• SLE.

• Sarcoidosis.

• Polyarteritis nodosa.

• Chronic fatigue syndrome.

• Goodpasture's syndrome.

• Nephrotic syndrome.

Investigations

A patient presenting with features suggestive of 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.¹⁵

• 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.¹⁶

• 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.¹⁷

• 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.¹⁸

• MRI scan of the brain may be useful in assessing neuropsychiatric signs or symptoms.

MCTD treatment and management

Non-drug

All patients should be given advice on smoking cessation if applicable and also avoiding cold exposure, especially to hands and feet. Patients should be encouraged to keep active and mobile but to avoid over-exertion.

Drug¹⁹

• 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.

• 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.

• Oesophageal dysfunction may require treatment with proton pump inhibitors.

• 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.

Prognosis²⁰

All patients with MCTD should be regularly reviewed and reassessed, as some 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.⁵

Thrombotic thrombocytopenic purpura (TTP) is a rare complication but is associated with a poor prognosis.²¹

The most common cause of death is pulmonary hypertension.²² Careful management of the pulmonary complications improves prognosis.²³ One case of pulmonary hypertension associated with severe pulmonary veno-occlusive disease has been reported.²⁴