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.

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.

There is no clear obvious cause for scleroderma and systemic sclerosis. Genetic predisposition appears to be limited: genetic concordance is small; still, there is often a familial predisposition for autoimmune disease. Polymorphisms in "COL1A2" and "TGF-β1" may influence severity and development of the disease. There is limited evidence implicating cytomegalovirus (CMV) as the original epitope of the immune reaction, as well as parvovirus B19. Organic solvents and other chemical agents have been linked with scleroderma.

One of the suspected mechanisms behind the autoimmune phenomenon is the existence of microchimerism, i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material.

A distinct form of scleroderma and systemic sclerosis may develop in patients with chronic renal failure. This form, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis, has been linked to exposure to gadolinium-containing radiocontrast.

Bleomycin (a chemotherapeutic agent) and possibly taxane chemotherapy may cause scleroderma, and occupational exposure to solvents has been linked with an increased risk of systemic sclerosis.

Systemic scleroderma is a rare disease with an annual incidence of 1 to 2 per 100,000 individuals in the United States. The interval of peak onset starts at age 30 to 35 and ends at age 50 to 55.

In the United States, the prevalence of systemic scleroderma is about 50,000, with different studies giving different estimates, usually ranging between 40,000 and 165,000.

Annual incidence of systemic sclerosis is 19 per million, and prevalence is 19–75 per 100,000, with a female:male ratio of 3:1 (8:1 in mid- to late childbearing years). Incidence is twice as high among African Americans. The Choctaw Native Americans in Oklahoma have the highest prevalence in the world (469 per 100,000).

The disease has some hereditary association. It may also be caused by an immune reaction to a virus (molecular mimicry) or by toxins.

Collagen disease is a term previously used to describe systemic autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue.

The term "collagen disease" was coined by Dr. Alvin F. Coburn in 1932, on his quest to discover streptococcal infection as the cause for rheumatic fever.

CREST syndrome can be noted in up to 10% of patients with primary biliary cirrhosis.

Physicians and scientists do not know what causes morphea. Case reports and observational studies suggest there is a higher frequency of family history of autoimmune diseases in patients with morphea. Tests for autoantibodies associated with morphea have shown results in higher frequencies of anti-histone and anti-topoisomerase IIa antibodies. Case reports of morphea co-existing with other systemic autoimmune diseases such as primary biliary cirrhosis, vitiligo, and systemic lupus erythematosus lend support to morphea as an autoimmune disease.

B burgdorferi infection may be relevant for the induction of a distinct autoimmune type of scleroderma; it may be called "Borrelia-associated early onset morphea" and is characterized by the combination of disease onset at younger age, infection with B burgdorferi, and evident autoimmune phenomena as reflected by high-titer antinuclear antibodies.

Crest syndrome involves the production of autoimmune anti-nuclear and anti-centromere antibodies, though their cause is not currently understood. There is no known infectious cause.

Morphea is a form of scleroderma that is more common in women than men, in a ratio 3:1. Morphea occurs in childhood as well as in adult life. Beth Ziebert is the most famous person with it.

Morphea is an uncommon condition that is thought to affect 2 to 4 in 100,000 people. Adequate studies on the incidence and prevalence have not been performed. Morphea also may be under-reported, as physicians may be unaware of this disorder, and smaller morphea plaques may be less often referred to a dermatologist or rheumatologist.

Increased risk of developing knee and hip osteoarthritis was found in those who:

- work with manual handling (e.g. lifting)

- have physically demanding work

- walk at work

- have climbing tasks at work (e.g. climb stairs or ladders)

Increased risk of developing hip osteoarthritis over time was found among those who work in bent or twisted positions.

Increased risk of knee osteoarthritis was found in those who:

- work in a kneeling or squatting position

- experience heavy lifting in combination with a kneeling or squatting posture

- work standing up

This type of osteoarthritis is caused by other factors but the resulting pathology is the same as for primary osteoarthritis:

- Alkaptonuria

- Congenital disorders of joints

- Diabetes doubles the risk of having a joint replacement due to osteoarthritis and people with diabetes have joint replacements at a younger age than those without diabetes.

- Ehlers-Danlos Syndrome

- Hemochromatosis and Wilson's disease

- Inflammatory diseases (such as Perthes' disease), (Lyme disease), and all chronic forms of arthritis (e.g., costochondritis, gout, and rheumatoid arthritis). In gout, uric acid crystals cause the cartilage to degenerate at a faster pace.

- Injury to joints or ligaments (such as the ACL), as a result of an accident or orthopedic operations.

- Ligamentous deterioration or instability may be a factor.

- Marfan syndrome

- Obesity

- Joint infection

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.

Mutations in the "COL11A1", "COL11A2", and "COL2A1" genes cause collagenopathy, types II and XI. These genes carry instructions for the protein strands that make up type II and type XI collagen. All collagen molecules are made of three protein strands (called alpha chains). The alpha chains may be identical or different, depending on the type of collagen. Type II collagen is made by combining three copies of the alpha chain made by the "COL2A1" gene. Type XI collagen, on the other hand, is composed of three different alpha chains: the products of the "COL2A1", "COL11A1", and "COL11A2" genes.

Mutations in these genes interfere with the proper assembly of type II and XI collagens or reduce the amount of these collagens. Defective or reduced numbers of collagen molecules affect the development of bones and other connective tissues, causing the signs and symptoms of the type II and XI collagenopathies.

Epidermolysis bullosa acquisita is a chronic subepidermal blistering disease associated with autoimmunity to type VII collagen within anchoring fibril structures that are located at the dermoepidermal junction.

Sack–Barabas syndrome is rare and has an estimated prevalence of 1 in 100,000 to 200,000.

The initial clinical manifestation of vascular problems in patients with SBS is early, about 25% have their first symptoms at age 20 and more than 80% of patients have had at least one complication by the age of 40.

The median survival for one study of SBS patients was only 48 years.

Although many types of medications have been tried as treatments, none of them have been proven effective in treating scleredema. Those treatments, such as corticosteroids, may benefit the patient, but will not cure their condition. If the affected area is infected, it is usually treated immediately. The symptoms of the condition usually resolve within six months to two years after onset. However, patients whose condition was associated to diabetes may suffer for longer periods of time.

Myocarditis resulting as a complication from the disease has been successfully treated with penicillin and steroids.

In most cases of bullous pemphigoid, no clear precipitating factors are identified. Potential precipitating events that have been reported include exposure to ultraviolet light and radiation therapy. Onset of bullous pemphigoid has also been associated with certain drugs, including furosemide, and other nonsteroidal anti-inflammatory agents, captopril, penicillamine, and antibiotics.

Epidermolysis bullosa dystrophica or dystrophic EB (DEB) is an inherited disease affecting the skin and other organs.

"Butterfly child" is the colloquial name for a child born with the disease, as their skin is seen to be as delicate and fragile as that of a butterfly.

Junctional epidermolysis bullosa is an inherited disease affecting laminin and collagen. This disease is characterised by blister formation within the lamina lucida of the basement membrane zone and is inherited in an autosomal recessive manner. It also presents with blisters at the site of friction, especially on the hands and feet, and has variants that can occur in children and adults. Less than one person per million people is estimated to have this form of epidemolysis bullosa.

Bullous pemphigoid may be self-resolving in a period ranging from several months to many years even without treatment. Poor general health related to old age is associated with a poorer prognosis.

Steps to prevent diabetic foot ulcers include frequent review by a foot specialist, good foot hygiene, diabetic socks and shoes, as well as avoiding injury.

- Foot-care education combined with increased surveillance can reduce the incidence of serious foot lesions.

Epidermolysis bullosa refers to a group of disorders that involve the formation of blisters following trivial trauma. Over 300 mutations have been identified in this condition. They have been classified into the following types:

Scleredema, also known as Buschke disease, scleredema of Buschke, and scleredema adultorum, is a rare, self-limiting skin condition defined by progressive thickening and hardening of the skin, usually on the areas of the upper back, neck, shoulders and face. The skin may also change color to red or orange. The disease was discovered by Abraham Buschke. Although the cause of scleredema is unknown, it is usually associated with a disease, usually diabetes, a viral illness or strep throat. It is usually not fatal, but it may cause death if the disease spreads to the internal organs. It may also cause an infection.

Acroosteolysis is resorption of the distal bony phalanges. Acroosteolysis has two patterns of resorption in adults: diffuse and bandlike.

The diffuse pattern of resorption has a widely diverse differential diagnosis which includes: pyknodysostosis, collagen vascular disease and vasculitis, Raynaud's neuropathy, trauma, epidermolysis bullosa, psoriasis, frostbite, sarcoidosis, hypertrophic osteoarthropathy, acromegaly, and advanced leprosy.

The bandlike pattern of resorption may be seen with polyvinyl chloride exposure and Hadju-Cheney syndrome.

A mnemonic commonly used for acro-osteolysis is PINCHFO.

Pyknodysostosis, Psoriasis,

Injury (thermal burn, frostbite),

Neuropathy (diabetes),

Collagen vascular disease (scleroderma, Raynaud's),

Hyperparathyroidism,

Familial (Hadju-Cheney, progeria),

Occupational (polyvinyl exposure),

Acroosteolysis may be associated with minimal skin changes or with ischemic skin lesions that may result in digital necrosis.

Stem cell therapy may represent a treatment for promoting healing of diabetic foot ulcers. Diabetic foot ulcers develop their own, distinctive microbiota. Investigations into characterizing and identifying the phyla, genera and species of nonpathogenic bacteria or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.