Some physicians make a diagnosis on the basis of the American College of Rheumatology (ACR) classification criteria. The criteria, however, were established mainly for use in scientific research including use in randomized controlled trials which require higher confidence levels, so many people with SLE may not pass the full criteria.

Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for SLE. Several techniques are used to detect ANAs. Clinically the most widely used method is indirect immunofluorescence (IF). The pattern of fluorescence suggests the type of antibody present in the people's serum. Direct immunofluorescence can detect deposits of immunoglobulins and complement proteins in the people's skin. When skin not exposed to the sun is tested, a positive direct IF (the so-called lupus band test) is an evidence of systemic lupus erythematosus.

ANA screening yields positive results in many connective tissue disorders and other autoimmune diseases, and may occur in normal individuals. Subtypes of antinuclear antibodies include anti-Smith and anti-double stranded DNA (dsDNA) antibodies (which are linked to SLE) and anti-histone antibodies (which are linked to drug-induced lupus). Anti-dsDNA antibodies are highly specific for SLE; they are present in 70% of cases, whereas they appear in only 0.5% of people without SLE. The anti-dsDNA antibody titers also tend to reflect disease activity, although not in all cases. Other ANA that may occur in people with SLE are anti-U1 RNP (which also appears in systemic sclerosis and mixed connective tissue disease), SS-A (or anti-Ro) and SS-B (or anti-La; both of which are more common in Sjögren's syndrome). SS-A and SS-B confer a specific risk for heart conduction block in neonatal lupus.

Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and kidney function (disturbed if the kidney is involved), liver enzymes, and complete blood count.

The lupus erythematosus (LE) cell test was commonly used for diagnosis, but it is no longer used because the LE cells are only found in 50–75% of SLE cases, and they are also found in some people with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance.

Rheumatoid factor and ANA tests are generally negative in systemic JIA.

Lab findings: anemia of chronic disease, neutrophilia, thrombocytosis, elevated acute phase reactants (ESR, CRP, ferritin).

In 1980, the American College of Rheumatology agreed on diagnostic criteria for scleroderma.

Diagnosis is by clinical suspicion, presence of autoantibodies (specifically anti-centromere and anti-scl70/anti-topoisomerase antibodies) and occasionally by biopsy. Of the antibodies, 90% have a detectable anti-nuclear antibody. Anti-centromere antibody is more common in the limited form (80-90%) than in the diffuse form (10%), and anti-scl70 is more common in the diffuse form (30-40%) and in African American patients (who are more susceptible to the systemic form).

Other conditions may mimic systemic sclerosis by causing hardening of the skin. Diagnostic hints that another disorder is responsible include the absence of Raynaud's phenomenon, a lack of abnormalities in the skin on the hands, a lack of internal organ involvement, and a normal antinuclear antibodies test result.

Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens. Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease.

The differential diagnosis of Kikuchi disease includes systemic lupus erythematosus (SLE), disseminated tuberculosis, lymphoma, sarcoidosis, and viral lymphadenitis. Clinical findings sometimes may include positive results for IgM/IgG/IgA antibodies.

For other causes of lymph node enlargement, see lymphadenopathy.

25% of cases progress to severe destructive arthritis. In the United States and Canada, mortality is estimated at about 4% and in Europe, mortality is estimated at 21.7%.

Diagnosing SS is complicated by the range of symptoms a patient may manifest, and the similarity between symptoms of SS and those of other conditions. Also, patients who have symptoms of SS approach different specialities regarding their symptoms which make the diagnosis difficult. Since the symptoms of this autoimmune disorder such as dry eyes and dry mouth are very common among people, and mostly observed from the age of 40 and above, it is often mistaken as age-related, thus ignored. However, some medications can also cause symptoms that are similar to those of SS. The combination of several tests, which can be done in a series, can eventually lead to the diagnosis of SS.

SS is usually classified as either 'primary' or 'secondary'. Primary Sjögren syndrome occurs by itself and secondary Sjögren syndrome occurs when another connective tissue disease is present.

Blood tests can be done to determine if a patient has high levels of antibodies that are indicative of the condition, such as antinuclear antibody (ANA) and rheumatoid factor (because SS frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical SS ANA patterns are SSA/Ro and SSB/La, of which Anti-SSB/La is far more specific; Anti-SSA/Ro is associated with numerous other autoimmune conditions, but are often present in SS. However, Anti-SSA and Anti-SSB tests are frequently not positive in SS.

The rose bengal test uses a stain that measures state and function of the lacrimal glands. This test involves placing the non-toxic dye rose bengal on the eyes. The dye’s distinctive colour helps in determining the state and functioning of tear film and the rate of tear evaporation. Any distinctive colour change observed will be indicative of SS, but many related diagnostic tools will be used to confirm the condition of SS.

Schirmer's test measures the production of tears: a strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler. Producing less than of liquid is usually indicative of SS. This measurement analysis varies among people depending on other eye-related conditions and medications in use when the test is taken. A slit-lamp examination can reveal dryness on the surface of the eye.

Symptoms of dry mouth and dryness in the oral cavity are caused by the reduced production of saliva from the salivary glands (parotid gland, submandibular gland, and sublingual gland). To check the status of salivary glands and the production of saliva, a salivary flow-rate test is performed, in which the person is asked to spit as much as they can into a cup, and the resulting saliva sample is collected and weighed. This test's results can determine whether the salivary glands are functioning adequately. Not enough saliva produced could mean the person has SS. An alternative test is non-stimulated whole saliva flow collection, in which the person spits into a test tube every minute for 15 minutes. A resultant collection of less than is considered a positive result.

A lip/salivary gland biopsy takes a tissue sample that can reveal lymphocytes clustered around salivary glands, and damage to these glands due to inflammation. This test involves removing a sample of tissue from a person’s inner lip/salivary gland and examining it under a microscope. In addition, a sialogram, a special X-ray test, is performed to see if any blockage is present in the salivary gland ducts (i.e. parotid duct) and the amount of saliva that flows into the mouth.

Also, a radiological procedure is available as a reliable and accurate test for SS. A contrast agent is injected into the parotid duct, which opens from the cheek into the vestibule of the mouth opposite the neck of the upper second molar tooth. Histopathology studies should show focal lymphocytic sialadenitis. Objective evidence of salivary gland involvement is tested through ultrasound examinations, the level of unstimulated whole salivary flow, a parotid sialography or salivary scintigraphy, and autoantibodies against Ro (SSA) and/or La (SSB) antigens.

SS can be excluded from people with past head and neck radiation therapy, acquired immunodeficiency syndrome (AIDS), pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use of anticholinergic drugs.

It is diagnosed by lymph node excision biopsy.

Kikuchi disease is a self-limiting illness which has symptoms which may overlap with Hodgkin's lymphoma leading to misdiagnosis in some patients.

Antinuclear antibodies, antiphospholipid antibodies, anti-dsDNA, and rheumatoid factor are usually negative, and may help in differentiation from systemic lupus erythematosus.

Prognosis varies with the type of amyloidosis. Prognosis for untreated AL amyloidosis is poor with median survival of one to two years. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like troponin and BNP. Survival diminishes with increasing stage, with estimated survival of 26, 11 and 3.5 months at stages I, II and III, respectively.

Outcomes in a person with AA amyloidosis depend on the underlying disease and correlate with the concentration of serum amyloid A protein.

People with ATTR have better prognosis and may survive for over a decade.

Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied.

Diagnosis of JIA is difficult because joint pain in children can be from many other causes. No single test can confirm the diagnosis, and most physicians use a combination of blood tests, X-rays, and clinical presentation to make an initial diagnosis of JIA. The blood tests measure antibodies and the rheumatoid factor. Unfortunately, the rheumatoid factor is not present in all children with JIA. Moreover, in some cases, the blood work is somewhat normal. X-rays are obtained to ensure that the joint pain is not from a fracture, cancer, infection, or congenital abnormality.

In most cases, fluid from the joint is aspirated and analyzed. This test often helps in making a diagnosis of JIA by ruling out other causes of joint pain.

Typical scleroderma is classically defined as symmetrical skin thickening, with about 70% of cases also presenting with Raynaud's phenomenon, nail-fold capillary changes and antinuclear antibodies. Affected individuals may or may not experience systemic organ involvement. There is no single test for scleroderma that works all of the time and hence the diagnosis is often a matter of exclusion. Atypical scleroderma may show any variation of these changes without skin changes or with finger swelling only.

Laboratory testing can show antitopoisomerase antibodies, like anti-scl70 (causing a diffuse systemic form), or anticentromere antibodies (causing a limited systemic form and the CREST syndrome). Other autoantibodies can be seen, such as anti-U3 or anti-RNA polymerase.

There is no prevention mechanism for SS due to its complexity as an autoimmune disorder. However, lifestyle changes can reduce the risk factors of getting SS or reduce the severity of the condition with patients who have already been diagnosed. Diet is strongly associated with inflammation that is mostly seen in many autoimmune related diseases including SS. An experimental study concludes that SS patients show high sensitivity to gluten that directly relates to inflammation. Moderate exercise is also found to be helpful in SS patients mainly reducing the effect of lung inflammation.

Diagnosis of amyloidosis requires tissue biopsy. The biopsy is assessed for evidence of characteristic amyloid deposits. The tissue is treated with various stains. The most useful stain in the diagnosis of amyloid is Congo red, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin T stain may be used.

Tissue can come from any involved organ, but in systemic disease the first-line site of the biopsy is subcutaneous abdominal fat, known as a "fat pad biopsy," due to its ease of acquisition versus biopsy of the rectum, salivary gland or internal organs. An abdominal fat biopsy is not completely sensitive, and sometimes, biopsy of an involved organ (such as the kidney) is required to achieve a diagnosis. For example, in AL amyloidosis only 85% of people will have a positive fatpad biopsy using Congo red stain. By comparison, rectal biopsy has sensitivity of 74–94%.

The type of the amyloid protein can be determined in various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination); binding of particular antibodies to the amyloid found in the tissue (immunohistochemistry); or extraction of the protein and identification of its individual amino acids. Immunohistochemistry can identify AA amyloidosis the majority of the time, but can miss many cases of AL amyloidosis. Laser microdissection with mass spectrometry is the most reliable method of identifying the different forms of amyloidosis.

AL is the most common form of amyloidosis, and a diagnosis often begins with a search for plasma cell dyscrasia, memory B cells producing aberrant immunoglobulins or portions of immunoglobulins. Immunofixation electrophoresis of urine or serum is positive in 90% of people with AL amyloidosis. Immunofixation electrophoresis is more sensitive than regular electrophoresis but may not be available in all centers. Alternatively immunohistochemical staining of a bone marrow biopsy looking for dominant plasma cells can be sought in people with a high clinical suspicion for AL amyloidosis but negative electrophoresis.

ATTR, or familial transthyretin-associated amyloidosis, is suspected in people with family history of idiopathic neuropathies or heart failure who lack evidence of plasma cell dyscrasias. ATTR can be identified using isoelectric focusing which separates mutated forms of transthyretin. Findings can be corroborated by genetic testing to look for specific known mutations in transthyretin that predispose to amyloidosis.

AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases. AA can be identified by immunohistochemistry staining.

Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child. Overall scleroderma is associated with reduced fetal weight for gestational age. The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate, mycophenolate, etc. and hence careful avoidance of such drugs during pregnancy is advised. In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control.

There is no cure for scleroderma, though there is treatment for some of the symptoms, including drugs that soften the skin and reduce inflammation. Some patients may benefit from exposure to heat. Holistic care of patient comprising patient education tailored to patient's education level is useful in view of the complex nature of the disease symptoms and progress.

New research shows that identifying what type of JIA a child has can help target treatment and lead to more positive outcomes. Identifying the specific biomarkers related to each type of JIA can help form more personalized treatment plans and decrease remission rates.

Children with JIA are more susceptible to cardiovascular disease, depression, sleep disturbance, anxiety and fatigue than healthy individuals. There is also limited information that suggests that children with JIA are at increased risk for malignancies when being treated with TNF blockers.

Prognosis is more positive when gene testing is undergone to identify what subtype of JIA is present in the child. Standardized treatment protocols are in place specific to each subtype of JIA. Treatment is more successful when targeted to the specific subtype of JIA.

Diagnosis is based on the demonstration of vascular lesions in large and middle-sized vessels on angiography, CT scan, magnetic resonance angiography or FDG PET. FDG PET can help in diagnosis of active inflammation not just in patients with active Takayasu arteritis prior to treatment but also in addition in relapsing patients receiving immunosuppressive agents.

Contrast angiography has been the gold standard. The earliest detectable lesion is a local narrowing or irregularity of the lumen. This may develop into stenosis and occlusion. The characteristic finding is the presence of "skip lesions," where stenosis or aneurysms alternate with normal vessels. Angiography provides information on vessel anatomy and patency but does not provide information on the degree of inflammation in the wall.

The age at onset helps to differentiate Takayasu's arteritis from other types of large vessel vasculitis. For example, Takaysu's arteritis has an age of onset of 60 years.

Takayasu arteritis is not associated with ANCA, rheumatoid factor, ANA, and anticardiolipin antibodies.

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.

Treatments for autoimmune disease have traditionally been immunosuppressive, anti-inflammatory, or palliative. Managing inflammation is critical in autoimmune diseases. Non-immunological therapies, such as hormone replacement in Hashimoto's thyroiditis or Type 1 diabetes mellitus treat outcomes of the autoaggressive response, thus these are palliative treatments. Dietary manipulation limits the severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS. Specific immunomodulatory therapies, such as the TNFα antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6 receptor tocilizumab and the costimulation blocker abatacept have been shown to be useful in treating RA. Some of these immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection.

Helminthic therapy is an experimental approach that involves inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently two closely related treatments available, inoculation with either Necator americanus, commonly known as hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs.

T cell vaccination is also being explored as a possible future therapy for autoimmune disorders.

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.

A complete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency (a microcytic anemia) or by vitamin B deficiency (a macrocytic anemia), usually caused by ileal disease impairing vitamin B absorption. Rarely autoimmune hemolysis may occur. Ferritin levels help assess if iron deficiency is contributing to the anemia. Erythrocyte sedimentation rate (ESR) and C-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation. Serum iron, total iron binding capacity and transferrin saturation may be more easily interpreted in inflammation. Anemia of chronic disease results in a normocytic anemia. Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result in folate deficiency. Testing for "Saccharomyces cerevisiae" antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine and to differentiate Crohn's disease from ulcerative colitis. Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohn's disease.

Low serum levels of vitamin D are associated with Crohn's disease. Further studies are required to determine the significance of this association.

The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.

Four subtypes are recognised, but the clinical utility of distinguishing subtypes is limited.

1. positive ANA and SMA, elevated immunoglobulin G (classic form, responds well to low dose steroids);

2. positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3;

3. positive antibodies against soluble liver antigen (this group behaves like group 1) (anti-SLA, anti-LP)

4. no autoantibodies detected (~20%) (of debatable validity/importance)

The diagnosis of autoimmune hepatitis is best achieved with a combination of clinical, laboratory, and histological findings after excluding other etiological factors (e.g. viral, hereditary, metabolic, cholestatic, and drug-induced diseases).

A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased Immunoglobulin G level. However, the diagnosis of autoimmune hepatitis always requires a liver biopsy.

Expert opinion has been summarized by the International Autoimmune Hepatitis Group, which has published criteria which utilize clinical and laboratory data that can be used to help determine if a patient has autoimmune hepatitis.

A calculator based on those criteria is available online.

Overlapping presentation with primary biliary cirrhosis and primary sclerosing cholangitis has been observed.