MCTD combines features of scleroderma, myositis, systemic lupus erythematosus, and rheumatoid arthritis (with some sources adding polymyositis, dermatomyositis, and inclusion body myositis) and is thus considered an overlap syndrome.

MCTD commonly causes:

- joint pain/swelling,

- malaise,

- Raynaud phenomenon,

- muscle inflammation, and

- sclerodactyly (thickening of the skin of the pads of the fingers)

Symptoms vary but they mostly involve skin disorders. The signs to look for include Raynaud's phenomenon, arthritis, myositis and scleroderma.

Visual symptoms include discoloring of the skin and painful swelling.

Disease presentation varies widely from patient to patient, as UCTD is by definition nonspecific. Symptoms typically include constitutional complaints that are common to connective tissue diseases such as fatigue, a general sense of feeling unwell, and fever.

Other symptoms associated with UCTD include:

- dry eyes

- dry mouth

- hair loss

- joint inflammation

- joint pain

- oral ulcers

- positive ANA test

- raynaud's phenomenon

- sun sensitive rash

Lung involvement, such as nonspecific interstitial pneumonia, is a possible disease complication.

A connective tissue disease is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. These tissues form a framework, or matrix, for the body, and are composed of two major structural protein molecules: collagen and elastin. There are many different types of collagen protein in each of the body's tissues. Elastin has the capability of stretching and returning to its original length—like a spring or rubber band. Elastin is the major component of ligaments (tissues that attach bone to bone) and skin. In patients with connective tissue disease, it is common for collagen and elastin to become injured by inflammation (ICT). Many connective tissue diseases feature abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity).

Diseases in which inflammation or weakness of collagen tends to occur are also referred to as collagen diseases. Collagen vascular diseases can be (but are not necessarily) associated with collagen and blood vessel abnormalities and that are autoimmune in nature. See also vasculitis.

Connective tissue diseases can have strong or weak inheritance risks, and can also be caused by environmental factors.

These are also referred to as systemic autoimmune diseases. The autoimmune CTDs may have both genetic and environmental causes. Genetic factors may create a predisposition towards developing these autoimmune diseases. They are characterized as a group by the presence of spontaneous overactivity of the immune system that results in the production of extra antibodies into the circulation. The classic collagen vascular diseases have a "classic" presentation with typical findings that doctors can recognize during an examination. Each also has "classic" blood test abnormalities and abnormal antibody patterns. However, each of these diseases can evolve slowly or rapidly from very subtle abnormalities before demonstrating the classic features that help in the diagnosis. The classic collagen vascular diseases include:

- Systemic lupus erythematosus (SLE) – An inflammation of the connective tissues, SLE can afflict every organ system. It is up to nine times more common in women than men and strikes black women three times as often as white women. The condition is aggravated by sunlight.

- Rheumatoid arthritis – Rheumatoid arthritis is a systemic disorder in which immune cells attack and inflame the membrane around joints. It also can affect the heart, lungs, and eyes. Of the estimated 2.1 million Americans with rheumatoid arthritis, approximately 1.5 million (71 percent) are women.

- Scleroderma – an activation of immune cells that produces scar tissue in the skin, internal organs, and small blood vessels. It affects women three times more often than men overall, but increases to a rate 15 times greater for women during childbearing years, and appears to be more common among black women.

- Sjögren's syndrome – also called Sjögren's disease, is a chronic, slowly progressing inability to secrete saliva and tears. It can occur alone or with rheumatoid arthritis, scleroderma, or systemic lupus erythematosus. Nine out of 10 cases occur in women, most often at or around mid-life.

- Mixed connective tissue disease – Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymyositis (PM); anti-synthetase syndrome; and, occasionally, Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or Scleroderma.

- Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.

- Psoriatic arthritis is also a collagen vascular disease.

Scleroderma overlap syndrome: Scleroderma is a connective tissue disease that causes fibrosis and vascular abnormalities, but that also has an autoimmune component.

It is described by connective tissues complications. Blood testing includes screening for the positive antinuclear antibody.

Patients have symptoms of both systemic scleroderma and/or polymyositis and dermatomyositis.

1. Scleroderma: a group of rare diseases that involve the hardening and tightening of the skin and connective tissues

and/or:

Polymyositis: a rare inflammatory disease that causes muscle weakness affecting both sides of your body

Dermatomyositis: an inflammatory disease of skin and muscle marked especially by muscular weakness and skin rash.

Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.

The term is sometimes used interchangeably with mixed connective tissue disease, an overlap syndrome. However, MCTD is thought by some researchers to be a clinically distinct entity and is strongly associated with the presence of high titers of ribonucleoprotein (RNP) antibodies.

It is estimated that up to 25 percent of people with systemic autoimmune disease could be considered to have UCTD.

Distinguishing laboratory characteristics are a positive, speckled anti-nuclear antibody and an anti-U1-RNP antibody.

These conditions are sometimes considered together with the small vessel vasculitides.

Polyarteritis nodosa (PAN). Systemic necrotizing vasculitis and aneurysm formation affecting both medium and small arteries. If only small vessels are affected, it is called microscopic polyangiitis, although it is more associated with granulomatosis with polyangiitis than to classic PAN. At least 3 out of 10 criteria yields sensitivity and specificity of 82 and 87%:

- unexplained weight loss > 4 kg

- livedo reticularis

- testicular pain

- myalgias, weakness

- Abdominal pain, diarrhea, and GI bleeding

- mononeuropathy or polyneuropathy

- new onset diastolic blood pressure > 90 mmHg

- elevated serum BUN (> 40 mg/dL) or serum creatinine (> 1.5 mg/dL)

- hepatitis B infection

- arteriographic abnormalities

- arterial biopsy showing polymorphonuclear cells

Kawasaki disease. Usually in children(age<4), it affects large, medium, and small vessels, prominently the coronary arteries. Associated with a mucocutaneous lymph node syndrome. Diagnosis requires fever lasting five days or more with at least 4 out of 5 criteria:

- bilateral conjunctival injection

- injected or fissured lips, injected pharynx, or strawberry tongue

- erythema of palms/soles, edema of hands/feet, periungual desquamation

- polymorphous rash

- cervical lymphadenopathy (at least one node > 1.5 cm)

Isolated cerebral vasculitis. Affects medium and small arteries over a diffuse CNS area, without symptomatic extracranial vessel involvement. Patients have CNS symptoms as well as cerebral vasculitis by angiography and leptomeningeal biopsy.

Giant-cell arteritis and Takayasu's arteritis have much in common, but usually affect patients of different ages, with Takayasu's arteritis affecting younger people, and giant-cell arteritis having a later age of onset.

Aortitis can also be considered a large-vessel disease.

Takayasu arteritis. Primarily affects the aorta and its main branches. At least 3 out of 6 criteria yields sensitivity and specificity of 90.5 and 97.8%:

- onset < 40 years affects young and middle -aged women (ages 15–45)

- claudication of extremities

- decreased pulsation of one or both brachial arteries

- at least 10 mmHg systolic difference in both arms

- bruit over one or both carotid arteries or abdominal aorta

- arteriographic narrowing of aorta, its primary branches, or large arteries in upper or lower extremities

- Ocular manifestation

- visual loss or field defects

- Retinal hemorrhages

- Neurological abnormalitis

- Treatment: steroids

Giant cell (temporal) arteritis. Chronic vasculitis of both large and medium vessels, primarily affecting cranial branches of the arteries arising from the aortic arch. At least 3 out of 5 criteria yields sensitivity and specificity of 95 and 91%:

- Age at onset ≥ 50 years

- New onset headache with localized tenderness

- Temporal artery tenderness or decreased pulsation

- Elevated ESR ≥ 50 mm/hour Westergren

- Temporal artery biopsy showing vasculitis with mononuclear cell infiltrate or granulomatous inflammation, usually with multinucleated giant cells

Potential signs and symptoms include:

- Cardiovascular: Raynaud's phenomenon (is the presenting symptom in 30% of affected persons, occurs in 95% of affected individuals at some time during their illness); healed pitting ulcers on the fingertips; skin and mucousal telangiectasis; palpitations, irregular heart rate and fainting due to conduction abnormalities, hypertension and congestive heart failure.

- Digestive: gastroesophageal reflux disease, bloating, indigestion, loss of appetite, diarrhoea alternating with constipation, sicca syndrome and its complications, loosening of teeth and hoarseness (due to acid reflux).

- Pulmonary: progressive worsening of shortness of breath, chest pain (due to pulmonary artery hypertension) and dry, persistent cough due to interstitial lung disease.

- Musculoskeletal: joint, muscle aches, loss of joint range of motion, carpal tunnel syndrome and muscle weakness.

- Genitourinary: erectile dysfunction, dyspareunia, scleroderma renal crises and kidney failure.

- Other: facial pain due to trigeminal neuralgia, hand paresthesias, headache, stroke, fatigue, calcinosis and weight loss.

Raynaud's phenomenon is frequently the first manifestation of CREST/lcSSc, preceding other symptoms by years. Stress and cold temperature induce an exaggerated vasoconstriction of the small arteries, arterioles, and thermoregulatory vessels of the skin of the digits. Clinically this manifests as a white-blue-red transitions in skin color. Underlying this transition is pallor and cyanosis of the digits, followed by a reactive hyperemia as they rewarm. When extreme and frequent, this phenomenon can lead to digital ulcerations, gangrene, or amputation.

Ulceration can predispose to chronic infections of the involved site.

CREST causes thickening and tightening of the skin with deposition of calcific nodules ("calcinosis").

An overlap syndrome is an autoimmune disease of connective tissue in which a person presents with symptoms of two or more diseases.

Examples of overlap syndromes include mixed connective tissue disease and scleromyositis. Diagnosis depends on which diseases the patient shows symptoms and has positive antibodies for in their lab serology.

In overlap syndrome, features of the following diseases are found (most common listed):

- Systemic lupus erythematosus (SLE),

- Systemic sclerosis,

- Polymyositis,

- Dermatomyositis,

- Rheumatoid arthritis (RA)

- Sjögren's syndrome

- Eosinophilic granulomatosis with polyangiitis (EGPA)

- Autoimmune thyroiditis

- Antiphospholipid antibody syndrome

The treatment of overlap syndrome is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNFα or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. There are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations.

Scleroderma is characterised by the appearance of circumscribed or diffuse, hard, smooth, ivory-colored areas that are immobile and which give the appearance of hidebound skin, a disease occurring in both localised and systemic forms:

- Localised scleroderma

- Localised morphea

- Morphea-lichen sclerosus et atrophicus overlap

- Generalised morphea

- Atrophoderma of Pasini and Pierini

- Pansclerotic morphea

- Morphea profunda

- Linear scleroderma

- Systemic scleroderma

- CREST syndrome

- Progressive systemic sclerosis

The characteristic symptom of Degos disease is the development of papules. Initially, individuals may have skin lesions or rashes, but they will proceed to develop distinct bumps, or papules. Papules are circular in shape, have a porcelain-white center and red border. As papules age, the white centers will skin in and only the border will remain raised. Typically, papules range from 0.5 to 1 cm in width. Papules appear on the trunk and upper extremities and are not found on the individual's palms, soles, scalp, or face.

Depending on whether an individual has the benign variant or malignant variant of the disease symptoms will vary. Both the benign and malignant forms have development of the characteristic papules. Individuals with the benign form will have the typical papules persisting anywhere from a few years to throughout their whole lives. In the benign form, no inner organs are affected. If an individual develops the malignant form, it means that not only are the papules present, but inner organs are involved. Most malignant cases involve problems of the gastrointestinal tract leading to small intestine lesions, abdominal pain, diarrhea, and bowel perforation. If the central nervous system is involved, symptoms can include headaches, dizziness, seizures, paralysis of cranial nerves, weakness, stroke, damage to small areas of the brain due to artery blockage (cerebral infarcts, and cerebral hemorrhage). Additional organs commonly impacted include the heart, lungs, and kidneys. Symptoms that may develop from damage to these organs include double vision (diploplia), clouding of lenses of eyes, swelling of the optic disc (papilledema), partial loss of vision, shortness of breath, chest pain, epilepsy,and thickening of pericardium.

Someone with the benign form may suddenly develop symptoms of the malignant form. Symptoms can last anywhere from a few weeks to several years. Onset of symptoms typically begins to manifest between the ages of 20-50. A few cases of this condition in newborns have also been described.

The condition can cause pain within the affected extremities, discoloration (paleness), and sensations of cold and/or numbness. This can often be distressing to those who are undiagnosed, and sometimes it can be obstructive. If someone with Raynaud's is placed into a cold climate, it could potentially become dangerous.

1. When exposed to cold temperatures, the blood supply to the fingers or toes, and in some cases the nose or earlobes, is markedly reduced; the skin turns pale or white (called pallor) and becomes cold and numb.

2. When the oxygen supply is depleted, the skin color turns blue (called cyanosis).

3. These events are episodic, and when the episode subsides or the area is warmed, the blood flow returns, and the skin color first turns red (rubor), and then back to normal, often accompanied by swelling, tingling, and a painful "pins and needles" sensation.

All three color changes are observed in classic Raynaud's. However, not all patients see all of the aforementioned color changes in all episodes, especially in milder cases of the condition. Symptoms are thought to be due to reactive hyperemias of the areas deprived of blood flow.

In pregnancy, this sign normally disappears owing to increased surface blood flow. Raynaud's has also occurred in breastfeeding mothers, causing nipples to turn white and become extremely painful. Nifedipine, a calcium channel blocker and vasodilator, was recommended to increase blood flow to the extremities and noticeably relieved pain in the breast in an extremely small study group.

Raynaud's phenomenon, or "Secondary Raynaud's", occurs "secondary to" a wide variety of other conditions.

Secondary Raynaud's has a number of associations:

- Connective tissue disorders:

- scleroderma

- systemic lupus erythematosus

- rheumatoid arthritis

- Sjögren's syndrome

- dermatomyositis

- polymyositis

- mixed connective tissue disease

- cold agglutinin disease

- Ehlers-Danlos syndrome

- Eating disorders:

- anorexia nervosa

- Obstructive disorders:

- atherosclerosis

- Buerger's disease

- Takayasu's arteritis

- subclavian aneurysms

- thoracic outlet syndrome

- Drugs:

- beta-blockers

- cytotoxic drugs – particularly chemotherapeutics and most especially bleomycin

- ciclosporin

- bromocriptine

- ergotamine

- sulfasalazine

- anthrax vaccines whose primary ingredient is the Anthrax Protective Antigen

- stimulant medications, such as those used to treat ADHD (amphetamine and methylphenidate)

- OTC pseudoephedrine medications (Chlor-Trimeton, Sudafed, others)

- Occupation:

- jobs involving vibration, particularly drilling and prolonged use of a String trimmer (weed whacker), suffer from vibration white finger

- exposure to vinyl chloride, mercury

- exposure to the cold (e.g., by working as a frozen food packer)

- Others:

- physical trauma, such as that sustained in auto accidents or other traumatic events

- Lyme disease

- hypothyroidism

- cryoglobulinemia

- malignancy

- chronic fatigue syndrome

- reflex sympathetic dystrophy

- carpal tunnel syndrome

- magnesium deficiency

- multiple sclerosis

- erythromelalgia (clinically presenting as the opposite of Raynaud's, with hot and warm extremities) often co-exists in patients with Raynaud's)

Raynaud's can "herald" these diseases by periods of more than twenty years in some cases, making it effectively their first presenting symptom. This may be the case in the CREST syndrome, of which Raynaud's is a part.

Patients with Secondary Raynaud's can also have symptoms related to their underlying diseases. Raynaud's phenomenon is the initial symptom that presents for 70% of patients with scleroderma, a skin and joint disease.

When Raynaud's phenomenon is limited to one hand or one foot, it is referred to as Unilateral Raynaud's. This is an uncommon form, and it is always secondary to local or regional vascular disease. It commonly progresses within several years to affect other limbs as the vascular disease progresses.

Degos disease, also known as Köhlmeier-Degos disease or malignant atrophic papulosis (MAP), is an extremely rare condition caused by blockage of arteries and veins. Individuals with this condition will develop papules. Those diagnosed with this disease may also develop complications due to impairment of internal organs. The exact underlying mechanism is still unknown, and an effective treatment is still being developed. There are fewer than 50 living patients presently known worldwide, and fewer than 200 reported in medical literature. However, it is important to note that many individuals may go undiagnosed due to rarity of the disease. Most individuals develop symptoms between the ages of 20-50; however, cases outside of this age range have been reported as well.

Initial facial changes usually involve the area of the face covered by the temporal or buccinator muscles. The disease progressively spreads from the initial location, resulting in atrophy of the skin and its adnexa, as well as underlying subcutaneous structures such as connective tissue, (fat, fascia, cartilage, bones) and/or muscles of one side of the face. The mouth and nose are typically deviated towards the affected side of the face.

The process may eventually extend to involve tissues between the nose and the upper corner of the lip, the upper jaw, the angle of the mouth, the area around the eye and brow, the ear, and/or the neck. The syndrome often begins with a circumscribed patch of scleroderma in the frontal region of the scalp which is associated with a loss of hair and the appearance of a depressed linear scar extending down through the midface on the affected side. This scar is referred to as a "coup de sabre" lesion because it resembles the scar of a wound made by a sabre, and is indistinguishable from the scar observed in frontal linear scleroderma.

In 20% of cases, the hair and skin overlying affected areas may become hyperpigmented or hypopigmented with patches of unpigmented skin. In up to 20% of cases the disease may involve the ipsilateral (on the same side) or contralateral (on the opposite side) neck, trunk, arm, or leg. The cartilage of the nose, ear and larynx can be involved. The disease has been reported to affect both sides of the face in 5-10% of the cases.

Symptoms and physical findings usually become apparent during the first or early during the second decade of life. The average age of onset is nine years of age, and the majority of individuals experience symptoms before 20 years of age. The disease may progress for several years before eventually going into remission (abruptly ceasing).

Enophthalmos (recession of the eyeball within the orbit) is the most common eye abnormality observed in Parry–Romberg syndrome. It is caused by a loss of subcutaneous tissue around the orbit. Other common findings include drooping of the eyelid (ptosis), constriction of the pupil (miosis), redness of the conjunctiva, and decreased sweating (anhidrosis) of the affected side of the face. Collectively, these signs are referred to as Horner's syndrome. Other ocular abnormalities include ophthalmoplegia (paralysis of one or more of the extraocular muscles) and other types of strabismus, uveitis, and heterochromia of the iris.

Genetic changes are related to the following types of collagenopathy, types II and XI.

The system for classifying collagenopathies is changing as researchers learn more about the genetic causes of these disorders.The clinical features of the type II and XI collagenopathies vary among the disorders, but there is considerable overlap. Common signs and symptoms include problems with bone development that can result in short stature, enlarged joints, spinal curvature, and arthritis at a young age. For some people, bone changes can be seen only on X-ray images. Problems with vision and hearing, as well as a cleft palate with a small lower jaw, are common. Some individuals with these disorders have distinctive facial features such as protruding eyes and a flat nasal bridge.

Jaccoud arthropathy (JA), Jaccoud deformity or Jaccoud's arthopathy is a chronic non-erosive reversible joint disorder that may occur after repeated bouts of arthritis. It is caused by inflammation of the joint capsule and subsequent fibrotic retraction, causing ulnar deviation of the fingers, through metacarpophalangeal joint (MCP) subluxation, primarily of the ring and little-finger. Joints in the feet, knees and shoulders may also get affected. It is commonly associated with systemic lupus erythematosus (SLE), and occurs in roughly 5% of all cases.

When associated with rheumatic fever it is also called chronic post–RF arthropathy.

Originally thought to be associated only with rheumatic fever, it has since been shown to occur also in SLE, Sjögren syndrome, scleroderma, dermatomyositis, psoriatic arthritis, vasculitis, ankylosing spondylitis, mixed connective tissue disease, and pyrophosphate deposition disease. It is distinct from bone erosion which is commonly associated with rheumatic arthritis, and also distinct from mild deforming arthropathy which is associated with SLE. There have also been cases of non-rheumatic JA associated with Lyme disease, HIV-infection and a number of other conditions.

Treatment focuses toward alleviating pain and in maintaining functionality of the affected joints through use of nonsteroidal anti-inflammatory drugs, corticosteroids, antimalarial drugs and physiotherapy. Surgery is also a possibility, with osteotomy or stabilization with Kirschner intramedullary wire. Tendon relocation, however, has been shown to only work in 30% of cases. The condition is named after the French 19th century physician Sigismond Jaccoud.

Catastrophic antiphospholipid syndrome (CAPS), also known as Asherson's syndrome, is an acute and complex biological process that leads to occlusion of small vessels of various organs. It was first described by Ronald Asherson in 1992. The syndrome exhibits thrombotic microangiopathy, multiple organ thrombosis, and in some cases tissue necrosis and is considered an extreme or catastrophic variant of the antiphospholipid syndrome.

CAPS has a mortality rate of about 50%. With the establishment of a CAPS-Registry more has been learned about this syndrome, but its cause remains unknown. Infection, trauma, medication, and/or surgery can be identified in about half the cases as a "trigger". It is thought that cytokines are activated leading to a cytokine storm with the potentially fatal consequences of organ failure. A low platelet count is a common finding. Individuals with CAPS often exhibit a positive test to antilipid antibodies, typically IgG, and may or may not have a history of lupus or another connective tissue disease. Association with another disease such as lupus is called a secondary APS unless it includes the defining criteria for CAPS.

Clinically, the syndrome affects at least three organs and may affect many organs systems. Peripheral thrombosis may be encountered affecting veins and arteries. Intraabdominal thrombosis may lead to pain. Cardiovascular, nervous, kidney, and lung system complications are common. The affected individual may exhibit skin purpura and necrosis. Cerebral manifestations may lead to encephalopathy and seizures. Myocardial infarctions may occur. Strokes may occur due to the arterial clotting involvement. Death may result from multiple organ failure.

Treatments may involve the following steps:

- Prevention includes the use of antibiotics for infection and parenteral anticoagulation for susceptible patients.

- Specific therapy includes the use of intravenous heparin and corticosteroids, and possibly plasma exchanges, intravenous immunoglobulin.

- Additional steps may have to be taken to manage circulatory problems, kidney failure, and respiratory distress.

- When maintaining survival of the disease treatments also include high doses of Rituxan (Rituximab) to maintain stability.

The type II and XI collagenopathies are a group of disorders that affect connective tissue, the tissue that supports the body's joints and organs. These disorders are caused by defects in type II or type XI collagen. Collagens are complex molecules that provide structure, strength, and elasticity to connective tissue. Type II and type XI collagen disorders are grouped together because both types of collagen are components of the cartilage found in joints and the spinal column, the inner ear, and the jelly-like substance that fills the eyeball (the vitreous). The type II and XI collagenopathies result in similar clinical features.