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:

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.

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.

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

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.

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.

Morphea most often presents as macules or plaques a few centimeters in diameter, but also may occur as bands or in guttate lesions or nodules.

Morphea is a thickening and hardening of the skin and subcutaneous tissues from excessive collagen deposition. Morphea includes specific conditions ranging from very small plaques only involving the skin to widespread disease causing functional and cosmetic deformities. Morphea discriminates from systemic sclerosis by its supposed lack of internal organ involvement. This classification scheme does not include the mixed form of morphea in which different morphologies of skin lesions are present in the same individual. Up to 15% of morphea patients may fall into this previously unrecognized category.

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.

Morphea, also called localized scleroderma or circumscribed scleroderma, is a form of scleroderma that involves isolated patches of hardened skin on the face, hands, and feet, or anywhere else on the body, with no internal organ involvement.

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)

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.

Papular mucinosis is chronic and may be progressive. The dermal layer of the skin breaks out into small and solid bumps, usually conical in shape and measured from 2 to 4 mm or sometimes flat-topped papules. Unlike pustules, these bumps do not contain pus. Instead they contain mucin, a substance of mucus, the body's natural and protective lubricant found in saliva and epithelial cells in lungs and the sensitive part of the nose. They usually come in clusters such as linear arrays. Less frequently, urticarial, nodular, or sometimes annular lesions may be appreciated. The dorsal aspect of the hands, face, elbows, and extensor portions of the extremities are most frequently affected. Mucosal lesions are absent. The coalescence of papules on the face, particularly on the glabella, results in longitudinal folding and gives the appearance of a leonine facies.

In scleromyxedema, symptoms can occur on larger part of the body. Erythema and scleroderma-like induration occurs on the skin. In addition, the mobility of the lips, hands, arms, and legs is reduced. Proximal myopathy, inflammatory polyarthritis, central nervous system symptoms, esophageal aperistalsis, and hoarseness are among the notable systemic symptoms. If viscera is involved, the disease will be fatal. The dermatoneuro syndrome is a rare neurological complication of the disease presenting with fever, seizures and altered mental status.

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

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.

IgG4-related disease has been described as an indolent condition. Although possibly based on opinion rather than on objective assessments, symptoms, if any, are commonly described as mild in the medical literature. This can be in spite of considerable underlying organ destruction. People are often described as being generally well at the time of diagnosis, although some may give a history of weight loss.

Pain is generally not a feature of the inflammation. However it may occur as a secondary effect, for example due to either obstruction or compression.

Often diagnosis is made due to the presence of painless swellings or mass lesions, or due to complications of masses, e.g. jaundice due to involvement of the pancreas, biliary tree or liver. Symptoms are commonly attributed to other conditions and other diagnoses may have been made years before diagnosis, e.g. urinary symptoms in men attributed to common prostate conditions. Lesions may also be detected incidentally on radiological images, but can be easily misdiagnosed as malignancies.

Reported cases do include some significant symptoms or findings however:

The prognosis of mixed connective tissue disease is in one third of cases worse than that of systemic lupus erythematosus (SLE). In spite of prednisone treatment, this disease is progressive and may in many cases evolve into a progressive systemic sclerosis (PSS), also referred to as diffuse cutaneous systemic scleroderma (dcSSc) which has a poor outcome. In some cases though the disease is mild and may only need aspirin as a treatment and may go into remission where no Anti-U1-RNP antibodies are detected, but that is rare or within 30% of cases. Most deaths from MCTD are due to heart failure caused by pulmonary arterial hypertension (PAH).

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.

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.

IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic disease, is a chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and a usually prompt response to oral steroids. In approximately 51–70% of people with this disease, "serum" IgG4 concentrations are elevated during an acute phase.

It is a relapsing–remitting disease associated with a tendency to mass forming, tissue-destructive lesions in multiple sites, with a characteristic histopathological appearance in whichever site is involved. Inflammation and the deposition of connective tissue in affected anatomical sites can lead to organ dysfunction, or even organ failure, if not treated.

Early detection is important to avoid organ damage and potentially serious complications. Treatment is recommended in all symptomatic cases of IgG4-RD and also in asymptomatic IgG4-RD involving certain anatomical sites.

As it is a rare disease, a clear set of symptoms is difficult to define. Usually, patients show severe pain and swelling is reported but clinical presentations vary. It can have an 'orange peel' like appearance. Less common features are joint pain and carpal tunnel syndrome.

Papular mucinosis affects adults of both sexes equally and appears between ages 30 and 80. Recently, it has been reported in patients infected with the HIV/AIDS virus.

Serositis is seen in numerous conditions:

- Lupus erythematosus (SLE), for which it is one of the criteria,

- Rheumatoid arthritis

- Familial Mediterranean fever (FMF)

- Chronic renal failure

- Juvenile idiopathic arthritis

- Inflammatory bowel disease (especially Crohn's disease)

- Acute appendicitis

- Diffuse cutaneous systemic sclerosis

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.

The Great Imitator (also The Great Masquerader) is a phrase used for medical conditions that feature nonspecific symptoms and may be confused with a number of other diseases. Most great imitators are systemic in nature. Diseases sometimes referred to with this name include:

- Various cancers

- Intravascular large B-cell lymphoma

- Various rheumatic conditions, including:

- Fibromyalgia

- Psoriatic arthritis

- Lupus erythematosus

- Systemic lupus erythematosus

- Sarcoidosis

- Multiple sclerosis

- Celiac disease

- Addison's Disease

- Pulmonary embolism

- Various infectious diseases, including:

- Syphilis

- Lyme disease

- Nocardiosis

- Tuberculosis

- Brucellosis

- Malaria

- Breathing-related sleep disorders (chiefly sleep apnea/hypopnea and upper-airway resistance syndrome).