In the skin, systemic sclerosis causes hardening and scarring. The skin may appear tight, reddish, or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage may weaken limbs and affect appearance. Patients report severe and recurrent itching of large skin areas. The severity of these symptoms varies greatly among patients: Some having scleroderma of only a limited area of the skin (such as the fingers) and little involvement of the underlying tissue, while others have progressive skin involvement. Digital ulcers — open wounds on especially on fingertips and less commonly the knuckles — are not uncommon.

CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) is associated with limited scleroderma. Other symptoms include:

Patients usually present with systemic symptoms with single or multiorgan dysfunction. Common (and nonspecific) complaints include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction. The following symptoms should raise a strong suspicion of a vasculitis:

- Mononeuritis multiplex. Also known as asymmetric polyneuropathy, in a non-diabetic this is suggestive of vasculitis.

- Palpable purpura. If patients have this in isolation, it is most likely due to cutaneous leukocytoclastic vasculitis. If the purpura is in combination with systemic organ involvement, it is most likely to be Henoch-Schonlein purpura or microscopic polyarteritis.

- Pulmonary-renal syndrome. Individuals who are coughing up blood and have kidney involvement are likely to have granulomatosis with polyangiitis, microscopic polyangiitis, or anti-GBM disease (Goodpasture's syndrome).

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.

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.

Symptoms vary from person to person, and may come and go. Almost everyone with lupus has joint pain and swelling. Some develop arthritis. Frequently affected joints are the fingers, hands, wrists, and knees.

Other common symptoms include:

- chest pain during respiration

- joint pain

- oral ulcer

- fatigue

- fever with no other cause

- general discomfort, uneasiness, or ill feeling (malaise)

- hair loss

- sensitivity to sunlight

- skin rash – a "butterfly" rash in about half people with SLE

- swollen lymph nodes

Hypersensitivity vasculitis (allergic vasculitis). Usually due to a hypersensitivity reaction to a known drug. Drugs most commonly implicated are penicillin, sulphonamides and thiazide diuretics. There is presence of skin vaculitis with palpable petechiae or purpura. Biopsy of these lesions reveal inflammation of the small vessels, termed leukocytoclastic vasculitis, which is most prominent in postcapillary venules. At least 3 out of 5 criteria yields sensitivity and specificity of 71 and 84%:

- age > 16

- use of possible triggering drug in relation to symptoms

- palpable purpura

- maculopapular rash

- skin biopsy showing neutrophils around vessel

IgA vasculitis (IgAV; formerly known as Henoch-Schonlein purpura). Systemic vasculitis due to tissue deposition of IgA-containing immune complexes. Biopsy of lesions shows inflammation of small vessels. It is considered a form of hypersensitivity vasculitis but is distinguished by prominent deposits of IgA. This is the most common vasculitis in children. Presence of 3 or more criteria yielded sensitivity of 87% while less than 2 criteria yielded hypersensitivity vasculitis in 74%:

- palpable purpura (usually of buttocks & legs)

- bowel angina

- GI bleed

- hematuria

- onset < 20 years

- no new medications

Essential cryoglobulinemic vasculitis. Most often due to hepatitis C infection, immune complexes of cryoglobulins --- proteins that consists of immunoglobulins and complement and precipitate in the cold while dissolving upon rewarming --- are deposited in walls of capillaries, venules, or arterioles. Therefore, complement will be low with histology showing vessel inflammation with immune deposits.

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.

Lupus erythematosus is a name given to a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs. The most common and severe form is systemic lupus erythematosus.

Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs in addition to the skin. Symptoms may include areas of thickened skin, stiffness, feeling tired, and poor blood flow to the fingers or toes with cold exposure. One form of the condition, known as CREST syndrome, classically results in calcium deposits, Raynaud's syndrome, esophageal problems, thickening of the skin of the fingers and toes, and areas of small dilated blood vessels.

The cause is unknown. Risk factors include family history, certain genetic factors, and exposure to silica. The underlying mechanism involves the abnormal growth of connective tissue which is believed to occur as a result of the body's immune system attacking healthy tissues. Diagnosis is typically based on a person's symptoms and may be supported by a skin biopsy or blood tests.

While there is no cure, treatments may improve symptoms. Medications used include corticosteroids, methotrexate, and non-steroidal anti-inflammatory drugs (NSAIDs). Outcomes depend on the extent of disease. Those with localized disease generally have a normal life expectancy. In those with systemic disease typical life expectancy is about 11 years from onset. Death is often due to lung, gastrointestinal, or heart complications.

About 3 per 100,000 people develop the systemic form a year. The condition most often begins in middle age. Women are more often affected than men. Scleroderma was likely first described in 1753 by Carlo Curzio and then well documented in 1842. The term is from the Greek "sklerosis" meaning "hardness" and "derma" meaning "skin".

The signs and symptoms of Kikuchi disease are fever, enlargement of the lymph nodes (lymphadenopathy), skin rashes, and headache. Rarely, enlargement of the liver and spleen and nervous system involvement resembling meningitis are seen. Often a bout of extreme fatigue can occur - often taking hold during latter parts of the day and the affected person can be more prone to fatigue from exercise.

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.

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

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.

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.

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.

The vegetations are small and formed from strands of fibrin, neutrophils, lymphocytes, and histiocytes. The mitral valve is typically affected, and the vegetations occur on the ventricular and atrial surface of the valve. Libman–Sacks lesions rarely produce significant valve dysfunction and the lesions only rarely embolize. However, there is data to suggest an association between Libman–Sacks endocarditis and a higher risk for embolic cerebrovascular disease in people with systemic lupus erythematosus (SLE).

The pathology is the same as nonbacterial thrombotic endocarditis except focal necrosis with hematoxylin bodies can be found only in Libman–Sacks endocarditis.

Kikuchi disease or Kikuchi-Fujimoto disease was described in 1972 in Japan. It is also known as histiocytic necrotizing lymphadenitis, Kikuchi necrotizing lymphadenitis, phagocytic necrotizing lymphadenitis, subacute necrotizing lymphadenitis, and necrotizing lymphadenitis.

It was first described by Dr Masahiro Kikuchi (1935–2012) in 1972 and independently by Y. Fujimoto.

Erythema nodosum is a form of panniculitis characterised by tender red nodules, 1–10 cm, associated with systemic symptoms including fever, malaise, and joint pain. Nodules may become bluish-purple, yellowing, and green, and subside over a period of 2–6 weeks without ulcerating or scarring. Erythema nodosum is associated with infections, including Hepatitis C, EBV and tuberculosis, Crohn's disease and sarcoidosis, pregnancy, medications including sulfonamides, and some cancers, including Non-Hodgkin lymphoma and pancreatic cancer.

Patients with acute GPP experience the eruption of multiple isolated sterile pustules generalized over the body, recurrent fevers, fatigue, and laboratory abnormalities (elevated ESR, elevated CRP, combined with leukocytosis).

Acute, tender, erythematous plaques, nodes, pseudovesicles and, occasionally, blisters with an annular or arciform pattern occur on the head, neck, legs, and arms, particularly the back of the hands and fingers. The trunk is rarely involved. Fever (50%); arthralgia or arthritis (62%); eye involvement, most frequently conjunctivitis or iridocyclitis (38%); and oral aphthae (13%) are associated features.

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.