Overlap syndrome and mixed connective tissue disease: causes and symptoms

Overlap syndromes of systemic connective tissue diseases and mixed connective tissue disease, commonly abbreviated as MCTD,combine at least two or more conditions from this group in one person at the same time.

Rheumatological autoimmune diseases are considered to be dangerous diseases which, in addition to the musculoskeletal system, also affect the extra-articular (i.e. outside of or other than a joint) tissues, structures and organs.

Consequently, these diseases bring with them certain and serious risks.

An autoimmune disease is one in which the immune system is inadequate and overactive. An error occurred in the body's defense mechanism that caused the immune system to attack the body's own cells and tissues.

The obvious question is: Why?

The exact cause is not clear.

However, we assume that it is a multifactorial process and influence of a some kind of trigger which starts the whole disease cascade.

Although it is still not possible to completely cure these diseases, the treatment is rather promising. The treatment manages to prevent the progression of the disease, alleviates the difficulties, increases the quality of life, and to minimise the consequences.

However, in addition to pharmacological treatment, some lifestyle changes and adherence to regimental measures are required.

However, late detection of the disease or neglect of treatment can have a negative impact on health, due to irreversible damage to the body. That would also shorten the overall life expectancy of the patient.

Rheumatic diseases affect every age group, from young children, through puberty and adolescents, adults to the elderly.

They affect both sexes and some diseases are sex-related.

Want to know more about combined connective tissue diseases?
Read on.

Overlap syndromes and mixed connective tissue disease - the basics

Overlap syndromes and mixed connective tissue disease hide the presence of at least two connective tissue diseases, or sometimes several at the same time, of which the following are the most common:

• systemic sclerosis + polymyositis
• systemic sclerosis + dermatomyositis
• systemic lupus erythematosus + polymyositis
• systemic sclerosis + systemic lupus
• rheumatoid arthritis + systemic sclerosis
• the following may also occur:
  • Raynaud symptom
  • vasculitis
  • Sjögren's syndrome
  • and other combinations

Learn more about individual diseases in the following articles:

• scleroderma = systemic sclerosis
• polymyositis and dermatomyositis
• systemic lupus erythematosus
• rheumatoid arthritis
• vasculitis
• Raynaud syndrome
• Sjögren's syndrome

Systemic connective tissue diseases are chronic inflammatory diseases based on autoimmune and rheumatoid diseases.

Autoimmunity, put simply, is a faulty process of making antibodies against the antigens of one's own cells and tissues.

The response is directed against the connective tissue, especially to joints, tendons and muscles, but it also affects the skin, blood vessels and cardiovascular system, eyes, tissues of the nervous, respiratory and digestive systems.

It is a chronic process, i.e. a lastinng negative effect. It has a progressive character = it worsens over time.

Forms of overlap syndrome are characterised by the presence of clinical inflammatory rheumatic manifestations of at least two different autoimmune diseases.

More specifically, we differentiate between mixed connective tissue disease and undifferentiated connective tissue disease.

1. mixed connective tissue disease
   • it used to be called Sharp's syndrome
     after Gordon Sharp, who described it in 1972 
   • Mixed Connective Tissue Disease - MCTD
   • the presence of at least two autoimmune connective tissue diseases
   • the manifestations of individual diseases are well distinguishable
2. undifferentiated connective tissue disease
   • Undifferentiated Connective Tissue Disease - UCTD
   • the presence of symptoms of autoimmune diseases
   • do not meet the exact criteria
   • non-specific symptoms for any subunit of the connective tissue disease

This mixed form of the disease occurs at every age and in both sexes. However, it mostly affects women around the age of 30.

It is reported that up to 25% of cases with connective tissue disease are characterised by the presence of overlapping symptoms.

The exact causes of the autoimmune reaction are unknown. It is thought to be based on a multifactorial influence and the action of a certain trigger which starts the reaction cascade.

The trigger might be a stimulus from the external environment - environmental impact.

An example is the presence of certain genetic predispositions and the negative effects of a viral disease with another current external factor.

Examples of risk factors:

• genetic predisposition and familial occurrence
  • there is no direct inheritance, but the presence of rheumatic disease in a relative increases the risk of an outbreak
• the presence of HLA antigen
• viral or bacterial infection
• stress and long-term mental overload
• injury
• medications
• chemicals
• hormonal effect

An abnormal process in the immune response causes the components of immunity to destroy the body's own cells. The long-term process is the result of damage and manifestations of the disease.

The result is a malfunction of collagen and elastin.

Symptoms of overlap syndrome are associated with difficulties that occur in at least two or more rheumatic, autoimmune diseases.

General, systemic symptoms.

Initially, it is possible for the occurrence of general manifestations, such as fatigue, exhaustion, increase in body temperature to fever, sweating (night sweats), but also loss of appetite, nausea and weight loss.

Extra-articular conditions.

Plus, the disease can also affect other parts of the body, such as the musculoskeletal system.

It is frequently associated with an inflammation of the eye, redness of the conjunctiva, or inflammation of the iris or anterior segment of the eye. It manifests as itching and eye irritation, fatigue. With the progression of the condition and in the case of a severe course, visual impairment and blindness are also possible complications.

Inflammation of the blood vessels, pericardium or heart muscle are serious, but also damage to the lung tissue, pulmonary fibrosis and no less serious damage to the digestive tract, which can manifest itself in non-specific intestinal inflammation.

Other examples include:

• high blood pressure
• pulmonary hypertension
• aortic insufficiency
• esophageal dysfunction and decreased gastric and intestinal motility
• kidney damage and failure
• polyneuropathy
• impaired brain function
• lymph node enlargement

Table: information on rheumatic symptoms in brief

As can be seen from the table, the diseases are characterised by certain common features, but they also have their own specifics.

Thus, in the case of mixed connective tissue disease, the presence of manifestations of at least two diseases is necessary. Of course, there can be combinations.

The most common typical symptoms are as follows:

• fatigue
• exhaustion
• irritability
• loss of weight
• muscle and joint pain
• muscle weakness
• elevated body temperature, fever
• joint inflammation
• joint and finger swelling
• fading of the fingers, nose or ears and worsening of sensitivity in the area - Raynaud's syndrome, when exposed to cold and stress
• reddening of the skin above the joint
• skin rash
• psoriasis
• often eye inflammation, pink eye or conjunctivis
• lymph node enlargement

Joint pain and inflammation is the most common symptom of these diseases.

The diagnosis of mixed connective tissue disease is based on medical history. The examination is complemented by a physical examination to make an overall assessment of the skin, joints, and other systems that may be affected by rheumatism.

Medical history helps to find issues, problems, and signs that may be indicative of certain types of diseases.

Imaging methods such as X-ray, CT, MRI, USG are added to the screening. In some cases, arthroscopy or biopsy of synovial fluid, skin and other tissues will be needed as well.

It is necessary to carry out a blood test and urinanalysis. In the case of overlaid syndromes, doctors will typically screen for high levels of ANA (antinuclear antibodies) antibodies, anti-RNP (ribonucleoprotein) antibodies, anti-U1-70 antibodies, anti-PM antibodies, anti-Ku antibodies, anti-DsDNA antibodies, anti-Sm antibodies, anti-SSA antibodies and others.

It is also possible to detect anaemia, leukopenia (reduction in the number of white blood cells), thrombocytopenia (less platelets).

The criteria for diagnosis are also evaluated on the basis of:

1. serological examination and the presence of an increase in anti-RNP antibodies
2. clinical symptoms:
   • swollen hands, arms
   • synovitis - inflammation of the joint, more precisely the synovial membrane covering the joint capsule
   • myositis - inflammation and damage to muscle fibres
   • Raynaud syndrome
   • scleroderma

The results is positive result if 3 or more criteria are met. Inflammation of the joints or muscles must be present.

The course of the disease is described as the presence of symptoms characteristic of two or more connective tissue diseases.

An example of an early manifestation is the presence of Raynaud syndrome which can manifest itself several years earlier.

Of course, there are several problems, the main and most common of which are joint pain and inflammation, muscle weakness and other joint conditions.

As already mentioned, the presence of non-joint difficulties is not exceptional either. Inflammation of the eye and conjunctiva often occur. The heart, blood vessels, lungs, kidneys or the neurological and digestive systems are more risky and serious.

The course of the disease is individual and different in each case.
People can have different combinations of symptoms.

The exact combination of connective tissue disease is highly individual.

It mostly affects people around the age of 30 and above. However, children can also be affected.

A two-phase course is typical of this type of disease.

1. remission - the reduction or disappearance of the signs and symptoms of a disease
2. relapse/recidivism - a recurrence of a past (typically medical) condition

Alternating remission and relapse phases - a relapsing-remitting course.

The disease is both progressive and chronic. It develops over time and without adequate treatment it can be complicated by more severe damage to vital organs.

The prognosis is generally unfavourable, although there is still a risk of acute reversal and more serious organ damage. Of course, it depends on several characteristics of the disease.

The risk of death is mainly increased by the presence of lung damage, pulmonary hypertension, heart damage, renal failure and infections.

The disease reduces the quality of life and can cause disability. Early diagnosis and timely treatment of rheumatic disease are of great importance.