Introduction

Your body often gives you a hint before a serious illness begins. Considering those signs seriously and seeking medical assistance can help you prevent undesirable consequences. As it is rightly said, ‘Prevention is always better than cure’. 

In this article, we will discuss mixed connective tissue diseases (MCTDs).

• Brief introduction about MCTDs
• Incidence and Prevalence
• Etiology(causes) and pathogenesis
• Signs and symptoms
• Diagnosis
• Why is the diagnosis of MCTDs challenging?
• Investigations 
• Treatment

Mixed connective tissue diseases (MCTD) are rare systemic autoimmune diseases that share features with at least 2 other connective tissue diseases (CTDs), such as Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Polymyositis (PM), Dermatomyositis (DM), and Rheumatoid Arthritis (RA). These are distinguished by the presence of a unique antibody called anti-U1-ribonucleoprotein (RNP).¹

Epidemiology 

Mixed connective tissue diseases show female predominance with a female-to-male ratio of 3–5:1. The incidence of this disease is 2.1–19 per million per year, and the prevalence is 3 per 100,000 persons.²

Etiology

The exact cause of mixed connective tissue disorders is unknown, and these tend to run in families.¹ However, risk factors such as infections, mainly HIV (Human Immunodeficiency Virus Type-1), environmental and occupational exposure in predisposed patients, can lead to the development of this condition.²

Pathogenesis

The hallmark of the disease is the presence of an autoantibody called anti-U1RNP. U1 RNP complex is the intracellular proteins that help in mRNA maturation. These autoantibodies modify the structure of this complex. When the cell undergoes programmed cell death(apoptosis), this modified protein is exposed on the cell surface, which is recognised by the antigen-presenting cells(APCs). The APCs present them to T cells (T lymphocytes), which ultimately stimulate B cells(B lymphocytes). This process causes an increased production of chemical mediators, Interleukin IL-1 and IL-6, leading to inflammation. These autoantibodies have a direct effect on endothelial cells of blood vessels, causing tissue injury.¹

The diagnosis of MCTD is challenging because:

• MCTD is the rarest of all CTDs
• There are no well-defined specific guidelines for MCTD treatment; hence, the treatment is based on the clinician’s expertise from treating similar symptoms in other connective tissue disorders (CTDs) 
• There is no standard diagnostic and classification criterion. Four different criteria have been proposed, with varying defining features and sensitivities. These are the Sharp’s criteria, the Kasukawa diagnostic criteria, the Alarcón-Segovia criteria, and the Kahn’s criteria. Among them, Alarcón-Segovia and Kahn’s criteria are widely used⁴

The Alarcon-Segovia diagnostic criteria include 3 or more of the following clinical symptoms: 

• Hand edema
• Acrosclerosis
• Myositis(inflammation of muscles) with histological confirmation
• Synovitis(inflammation of the synovial membrane of the joints), and
• Raynaud’s phenomenon along with a high titre of positive anti-U1-RNP antibodies (above 1 per 1600)¹
• There is significant overlap between the symptoms of MCTD and other connective tissue disorders such as SSc, SLE, PM, or RA. That’s why it's difficult to assign the patient to one particular category³

Signs and symptoms 

When should you rush to a doctor?

At the onset of disease, the patients typically present with nonspecific symptoms such as low-grade fever, shortness of breath, joint pain, muscle pain, and fatigue. In the advanced stage, the systemic involvement occurs, which is described below:

Skin 

The skin is involved early in this disorder, characterised by Raynaud’s Phenomenon (RP), present in almost all MCTD patients. In Raynaud’s Phenomenon, the small blood vessels, mainly of the hands and toes, constrict on exposure to cold, which turns these extremities blue. Over a course of time, the person can develop typical clinical features of SSc, from puffy hands to sclerodactyly (tightening and thickening of skin of hands and toes limiting their mobility), acrosclerosis (tightening of skin of face, chest, forearms hands and feet along with RP), calcinosis (Calcification of skin), ulcers and digital necrosis. Mouth ulcers, discoid (disc-like) lesions, panniculitis(inflammation of adipose/fatty tissue), and the classical malar rash(rash around cheeks and nose) of SLE are also common in MCTD.

Joints

In the later stage of the disease, the joints are involved classically as seen in Rheumatoid Arthritis (RA). It is potentially erosive, leading to the typical deformities. Rheumatoid Factor (RF) and Anti-Citrullinated Protein Antibody (ACPA) positivity are noted in 70% and 50% of patients, respectively. 

Muscles

Muscle involvement is also very common in MCTD. Proximal weakness of limbs, typical alteration at electromyography, and increased serum level of muscle enzymes such as Creatine Phosphokinase (CPK), Lactic Dehydrogenase (LDH), and transaminases are noted.

Gastrointestinal system

Gastroesophageal Reflux with heartburn and dysphagia (painful swallowing) is present in about 50% of patients. Bowel movement disturbance, hepatitis, pancreatitis, malabsorption, and small bowel perforation can also occur.

Cardiovascular system

The heart and blood vessels are also commonly involved. 40% of patients typically present with pericarditis (inflammation of the outer layers of the heart), and nearly 20% of patients present with heart rhythm disturbances(arrhythmias). There is thickening and proliferation of the inner and middle muscular layer of medium- and small-sized vessels, which is responsible for ulcers in the fingers. When it affects the blood vessels of the lungs, it can potentially lead to Pulmonary Arterial Hypertension (PAH). 

Lungs

PAH affects about 20% of MCTD patients and can be a major cause of mortality in these patients. 60% of MCTD patients suffer from Interstitial Lung Disease (ILD).

Nerves

The most common neurological feature seen in almost 25% of the patients is trigeminal (5th cranial nerve)neuropathy. Other manifestations are generally mild, characterized by headaches, memory impairment, depression, hearing loss, psychosis, and seizures. 

Kidney

25% of MCTD patients can experience mild kidney damage characterized by membranous nephropathy.

Blood

MCTD patients can suffer from hemolytic anemia, autoimmune thrombocytopenia (decreased number of platelets), and leucopenia (decreased number of white blood cells).²

Diagnosis

The hallmark of the disease is the presence of anti-U1 RNP antibodies. However, a variety of other autoantibodies can also be positive in MCTD, such as Antinuclear antibodies (ANA), Anti-cyclic citrullinated peptide antibodies, Rheumatoid factor, Anti-Smith antibodies, Anticardiolipin antibodies (aCL), anti-double-stranded DNA, anti-Ro/SS-A, and anti-single-stranded DNA antibodies.¹

The diagnosis of MCTD requires serological positivity, i.e., Anti-U1 RNP antibodies, and at least three clinical criteria. However, four clinical criteria should be taken into account when the patient presents only with hand edema, Raynaud's phenomenon, or sausage-like appearance of the digits.⁵

Investigations

• A complete blood count can reveal hemolytic anemia, leucopenia, and thrombocytopenia
• Increased levels of transaminases(SGOT/SGPT) are possibly due to myositis or hepatitis, which is uncommon. In case of involvement of muscles, other specific parameters such as LDH (also associated with lung damage) and CPK levels are also raised
• Increased levels of gammaglobulin(Hypergammaglobulinemia), decreased levels of complement proteins (Hypocomplementemia), and the presence of proteins in the urine can support an early diagnosis of MCTD
• Nailfold Videocapillaroscopy (NVC) is a cost-effective, simple, and rapid method for the assessment of Raynaud’s phenomenon
• Pulmonary function tests (PFTs) and high-resolution Computed Tomography(HRCT) should be performed for the assessment of ILD in MCTD patients
• Transthoracic echocardiogram helps in screening pericardial effusion, mitral valve prolapse, diastolic dysfunction, accelerated atherosclerosis, and PAH²

Treatment

The patients diagnosed with MCTD show a variable clinical course, and their long-term prognosis depends on the organ system involved and the progression of the disease. Some patients can have mild disease and achieve complete remission, while others can suffer from fatal consequences. Hence, the therapy should be tailored according to each patient as per the specific organs involved and the severity of the underlying disease.¹

There is no specific treatment available for MCTD. For mild to moderate symptoms such as fever, serositis, myositis, arthritis, and skin rash, nonsteroidal anti-inflammatory drugs, corticosteroids (prednisone and methylprednisolone), and anti-malaria medications like hydroxychloroquine are used for symptomatic treatment. If the internal organs, such as the kidneys and brain, are affected and the patient has severe disease, immunosuppression with drugs such as cyclophosphamide can be considered.¹

Summary

Mixed connective tissue disorders are rare autoimmune diseases that involve various organs of predisposed persons. These disorders share overlapping symptoms and signs with other connective tissue disorders, such as SLE, RA, polymyositis, and dermatomyositis, and there are no specific diagnostic criteria. Anti-U1-RNP antibodies are the hallmark of this disease. The earlier symptoms and signs are non-specific, such as fever, joint pains, muscle pains, shortness of breath, and generalised weakness. In the majority of cases, the early involvement is of skin characterised by Raynaud’s phenomenon. Hence, the patient must seek help in case they encounter such symptoms in order to prevent organ damage and complications. Symptomatic treatment in the form of corticosteroids and immunosuppressants is provided to reduce morbidity and mortality.