26th January 2024

Mixed Connective Tissue Disease (MCTD)

Background

Epidemiology

Mixed Connective Tissue Disease is an autoimmune overlap syndrome that presents with clinical features of SLE, systemic sclerosis and polymyositis. It is characterised by presence of high titers of a distinctive autoantibody, now called anti-U1 ribonucleoprotein (RNP) (previously termed antibody to extractable nuclear antigens, anti-ENA).

Worldwide, the prevalence is estimated to be between 2-3.8 cases per 100,000 population. It is much more common in females than males, with an estimated ratio of 3:1 and the typical age of onset is between 15-25 years; however, it can occur at any age. MCTD occurs in patients of all ethnicities, but the clinical manifestations, particularly the frequency of end-organ involvement can vary.

Pathophysiology

Whilst the exact genetic cause is unknown, DNA methylation levels may be relevant as patients with MCTD have been found to have decreased levels of DNA methylation. There has also been a genetic association with major histocompatibility genes such as HLA-B*08 and HLA-B1*04. 

These genetic abnormalities lead to B-lymphocyte hyperactivity, resulting in high levels of auto-antibodies (namely anti–U1-RNP and anti–U1-70 kd autoantibodies). These auto-antibodies then cause T-lymphocyte activation, which leads to lymphocytic and plasmacytic infiltration of tissues, causing increased vascular endothelial apoptosis.

Presentation

• The initial clinical symptoms of MCTD tend to be non-specific features such as malaise, arthralgia, fever and Raynaud’s phenomenon. 
• The most common presenting symptoms are arthralgia with swollen hands, Raynaud’s and gastro-oesophageal reflux.
  • RP almost always presents initially and occurs in about 96% of patients with MCTD.
  • Arthritis: Swollen fingers and diffuse oedema, sometimes with arthritis and bone deformities in the hands, are present in 96% of patients. 
  • Oesophageal hypomotility: symptoms of GORD are present in 66% of patients 
• Myalgias: Muscle aches are common. However, elevation of inflammatory muscle enzymes and changes on EMG are not usually seen. 
• Rash: A skin rash may be observed in 53% of patients and is usually vasculitic in nature.
• Pulmonary involvement: This occurs in approximately 75% of patients and may present as pleural effusion, interstitial lung disease, thromboembolic events or rarely, pulmonary hypertension. 
• Haematological manifestations: Leukopenia is present in 53% of patients, and findings of anaemia or hypergammaglobulinemia are also common.

Image Source: Rahmouni S et al. (2020) Mixed connective tissue disease: Not always an obvious diagnosis. Clinical case reports. 2020 Oct; 8(10): 1979-1983. Licensed under a commercial Creative Commons license Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/ccr3.3045 (Accessed: 21 Decemvber 2023). 

Image Source: Rahmouni S et al. (2020) Mixed connective tissue disease: Not always an obvious diagnosis. Clinical case reports. 2020 Oct; 8(10): 1979-1983. Licensed under a commercial Creative Commons license. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/ccr3.3045 (Accessed: 21 December 2023). 

Diagnosis 

In the early stages, differentiating MCTD from other autoimmune diseases, such as SLE and polymyositis, can be difficult. However, the most prominent initial features, such as puffy fingers, arthralgia and myalgia, should be further investigated by specific antibody testing, including ANA, ENA and Anti-U1 RNP. 

One of the most widely used diagnostic criteria is that of the Alarcon-Segovia’s criteria, which has a sensitivity of 63% and a specificity of 86%. To fulfil the criteria, patients must have Anti-RNP antibodies with a hemagglutination titer of ≥1:1600 and three or more of the following clinical features (one of which must include myositis or synovitis): swollen hands, Raynaud’s phenomenon, acrosclerosis, synovitis and myositis. 

The laboratory testing for MCTD hinges on the presence of the specific auto-antibodies, as mentioned previously, in particular ENA and Anti-U1 RNP. However, antibodies Sm, Ro, and La are occasionally, transiently seen in patients with MCTD. 

Differential Diagnosis 

MCTD was initially thought to be a type of overlap syndrome, and thus, other autoimmune illnesses can present similarly. 

Systemic Lupus Erythematosus (SLE)

 Both MCTD and SLE patients have similar symptoms of arthritis and synovitis. However, symptoms such as photosensitivity are prominent with SLE but not MCTD and antibodies such Anti-ds DNA would be expected to be positive in SLE while Anti- U1 RNP would be positive in MCTD. 

Rheumatoid Arthritis (RA)

Both RA and MCTD may present with symptoms such as fatigue, arthralgia and some degree of swelling. However, in RA, the swelling would be more around the joints, whereas in MCTD, the swelling would be more in the subcutaneous connective tissue of the hands. This swelling can be determined both on physical examination as well as on radiographs of the hands. In addition, the auto-antibodies again will differ where Anti-CCP would be more specific with RA and Anti-U1 RNP more specific for MCTD. 

Inflammatory Myopathy – Polymyositis

 In both polymyositis and MCTD, there are features of myositis and end-organ involvement, such as interstitial lung disease and oesophageal dysmotility. However, there are significantly elevated inflammatory markers such as CK and CRP in polymyositis, but in MCTD, these markers would be expected to be within the normal range or mildly elevated. 

Systemic Sclerosis

 Raynaud’s phenomenon can occur both in systemic sclerosis and MCTD. However, it tends to be more severe in systemic sclerosis, and the characteristic skin changes seen in systemic sclerosis, such as skin thickening and telangiectasia, are not seen in MCTD. In addition, renal involvement is rarely seen in MCTD and is a more common feature of systemic sclerosis. Laboratory testing again would help differentiate by testing for autoantibodies where Anti-centromere or Anti-Scl-70 would be expected to be positive in systemic sclerosis while Anti-U1 RNP is positive in MCTD. 

Management 

Although there have been no controlled trials to guide the management of MCTD, general principles are guided by effective therapies for SLE, systemic sclerosis and polymyositis. 

• Glucocorticoids: Oral prednisolone is the steroid of choice initially and is effective in treating pleurisy, pericarditis, myocarditis and oesophageal dysmotility. Corticosteroids need to be weaned due to the adverse effects of long-term steroid therapy. 
•  Immunosuppressants/Steroid-sparing agents: Methotrexate or Hydroxychloroquine may be started while weaning off steroids; they are effective in preventing flares and symptom control. 
• Anti-hypertensives: Pulmonary arterial hypertension is a major cause of death in patients with MCTD. As such, routine echocardiography is recommended. Treatment for PAH includes anti-hypertensives such as calcium channel blockers and ACE-i. Other treatments include intravenous prostacyclins and anti-coagulation, endothelin -1 antagonist (e.g. Bosentan) and phosphodiesterase inhibitors (e.g. Sildenafil). 
• Rituximab: This is used in patients who have steroid-resistant thrombocytopenia, autoimmune haemolytic anaemia, myositis and severe eruptive skin disease. 

References: 

• Greidinger, Eric L.; Hoffman, Robert W. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheumatic Disease Clinics of North America. 31 (3): 437–450.
• Axford J. UpToDate. Definition and diagnosis of mixed connective tissue disease [Internet]. 2022 [cited 2022 May 22]. Available from: https://www.uptodate.com/contents/definition-and-diagnosis-of-mixed-connective-tissue-disease?search=mixed%20connective%20tissue%20disease%20adult&source=search_result&selectedTitle=1~121&usage_type=default&display_rank=1#H4
• Axford J. UpToDate. Prognosis and treatment of mixed connective tissue disease [Internet]. 2022 [cited 2022 May 22]. Available from: https://www.uptodate.com/contents/prognosis-and-treatment-of-mixed-connective-tissue-disease?search=management%20of%20mixed%20connective%20tissue%20disease&source=search_result&selectedTitle=1~121&usage_type=default&display_rank=1#H5