For the diagnosis of lupus 4 out of 11 signs must be present.

Testing may include:

- Antinuclear antibody (ANA)

- CBC with differential

- Chest x-ray

- Serum creatinine

- Urinalysis

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.

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.

Lupus erythematosus may manifest as systemic disease or in a purely cutaneous form also known as "incomplete lupus erythematosus". Lupus has four main types:

- systemic

- discoid

- drug-induced

- neonatal

Of these, systemic lupus erythematosus (also known as SLE) is the most common and serious form.

A more thorough categorization of lupus includes the following types:

- acute cutaneous lupus erythematosus

- subacute cutaneous lupus erythematosus

- discoid lupus erythematosus (chronic cutaneous)

- childhood discoid lupus erythematosus

- generalized discoid lupus erythematosus

- localized discoid lupus erythematosus

- chilblain lupus erythematosus (Hutchinson)

- lupus erythematosus-lichen planus overlap syndrome

- lupus erythematosus panniculitis (lupus erythematosus profundus)

- tumid lupus erythematosus

- verrucous lupus erythematosus (hypertrophic lupus erythematosus)

- cutaneous lupus mucinosis

- complement deficiency syndromes

- drug-induced lupus erythematosus

- neonatal lupus erythematosus

- systemic lupus erythematosus

Antinuclear antibodies are usually positive in drug induced Lupus. Anti-Neutrophil Cytoplasmic antibodies (ANCA) can also be positive in association with certain drugs. Furthermore, Anti-Histone antibodies can also be positive in drug induced lupus.

Anti-Histone antibodies are positive in up to 95% of patients with drug induced lupus. DIThe most common medications associated with drug induced lupus are hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, and minocycline.

There is no official diagnostic criteria for UCTD. Diagnostic testing generally aims to determine whether a patient has a "definite" or "undifferentiated" connective tissue disease.

Most patients will maintain a diagnosis of undifferentiated connective tissue disease. However, about one third of UCTD patients will differentiate to a specific autoimmune disease, like rheumatoid arthritis or systemic sclerosis. About 12 percent of patients will go into remission.

Severe vitamin D deficiency has been associated with the progression of UCTD into defined connective tissue diseases. The presence of the autoantibodies anti-dsDNA, anti-Sm, and anti-cardiolipin has been shown to correlate with the development of systemic lupus erythematosus, specifically.

It is important to recognize early that these drugs are causing DIL like symptoms and discontinue use of the drug. Symptoms of drug-induced lupus erythematosus generally disappear days to weeks after medication use is discontinued. Non-steroidal anti-inflammatory drugs (NSAIDs) will quicken the healing process. Corticosteroids may be used if more severe symptoms of DIL are present.

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

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).

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.

The diagnosis of lupus nephritis depends on blood tests, urinalysis, X-rays, ultrasound scans of the kidneys, and a kidney biopsy. On urinalysis, a nephritic picture is found and red blood cell casts, red blood cells and proteinuria is found. The World Health Organization has divided lupus nephritis into five stages based on the biopsy. This classification was defined in 1982 and revised in 1995.

- Class I is minimal mesangial glomerulonephritis which is histologically normal on light microscopy but with mesangial deposits on electron microscopy. It constitutes about 5% of cases of lupus nephritis. Kidney failure is very rare in this form.

- Class II is based on a finding of mesangial proliferative lupus nephritis. This form typically responds completely to treatment with corticosteroids. It constitutes about 20% of cases. Kidney failure is rare in this form.

- Class III is focal proliferative nephritis and often successfully responds to treatment with high doses of corticosteroids. It constitutes about 25% of cases. Kidney failure is uncommon in this form.

- Class IV is diffuse proliferative nephritis. This form is mainly treated with corticosteroids and immunosuppressant drugs. It constitutes about 40% of cases. Kidney failure is common in this form.

- Class V is membranous nephritis and is characterized by extreme edema and protein loss. It constitutes about 10% of cases. Kidney failure is uncommon in this form.

SLE causes an increased rate of fetal death "in utero" and spontaneous abortion (miscarriage). The overall live-birth rate in SLE patient has been estimated to be 72%. Pregnancy outcome appears to be worse in SLE patients whose disease flares up during pregnancy.

Miscarriages in the first trimester appear either to have no known cause or to be associated with signs of active SLE. Later losses appear to occur primarily due to the antiphospholipid syndrome, in spite of treatment with heparin and aspirin. All women with lupus, even those without previous history of miscarriage, are recommended to be screened for antiphospholipid antibodies, both the lupus anticoagulant (the RVVT and sensitive PTT are the best screening battery) and anticardiolipin antibodies.

Neonatal lupus is the occurrence of SLE symptoms in an infant born from a mother with SLE, most commonly presenting with a rash resembling discoid lupus erythematosus, and sometimes with systemic abnormalities such as heart block or hepatosplenomegaly. Neonatal lupus is usually benign and self-limited. Still, identification of mothers at highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare up during pregnancy, and proper treatment can maintain the health of the mother for longer.

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.

For diagnosis of NPSLE, it must be determined whether neuropsychiatric symptoms are indeed caused by SLE, whether they constitute a separate comorbid condition, or whether they are an adverse effect of disease treatment. In addition, onset of neuropsychiatric symptoms may happen prior to the diagnosis of lupus. Due to the lack of uniform diagnostic standards, statistics about NPSLE vary widely.

Tests which aid in diagnosis include MRI, electrophysiological studies, psychiatric evaluation, and autoantibody tests.

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.

Treatment for a lupus anticoagulant is usually undertaken in the context of documented thrombosis, such as extremity phlebitis or dural sinus vein thrombosis. Patients with a well-documented (i.e., present at least twice) lupus anticoagulant and a history of thrombosis should be considered candidates for indefinite treatment with anticoagulants. Patients with no history of thrombosis and a lupus anticoagulant should probably be observed. Current evidence suggests that the risk of recurrent thrombosis in patients with an antiphospholipid antibody is enhanced whether that antibody is measured on serological testing or functional testing. The Sapporo criteria specify that both serological and functional tests must be positive to diagnose the antiphospholipid antibody syndrome.

Miscarriages may be more prevalent in patients with a lupus anticoagulant. Some of these miscarriages may "potentially" be prevented with the administration of aspirin and unfractionated heparin. The Cochrane Database of Systematic Reviews provide a deeper understanding on the subject.

Thrombosis is treated with anticoagulants (LMWHs and warfarin).

Chilblain lupus erythematosus (also known as "chilblain lupus erythematosus of Hutchinson") is a chronic, unremitting form of lupus erythematosus with the fingertips, rims of ears, calves, and heels affected, especially in women.

Tumid lupus erythematosus (also known as "lupus erythematosus tumidus") is a rare, but distinctive entity in which patients present with edematous erythematous plaques, usually on the trunk.

Lupus erythematosus tumidus (LET) was reported by Henri Gougerot and Burnier R. in 1930. It is a photosensitive skin disorder, a different subtype of cutaneous lupus erythematosus (CLE) from discoid lupus erythematosus (DLE) or subacute CLE (SCLE). LET is usually found on sun-exposed areas of the body. Skin lesions are edematous, urticarialike annular papules and plaques. Topical corticosteroids are not effective as treatment for LET, but many will respond to chloroquine. LET resolves with normal skin, no residual scarring, no hyperpigmentation or hypopigmentation. Cigarette smokers who have LET may not respond very well to chloroquine.

It has been suggested that it is equivalent to Jessner lymphocytic infiltrate of the skin.

Alpha-1 antitrypsin deficiency panniculitis is a panniculitis associated with a deficiency of the α-antitrypsin enzyme.

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.

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.

Subacute cutaneous lupus erythematosus (SCLE) is a clinically distinct subset of cases of lupus erythematosus that is most often present in white women aged 15 to 40, consisting of skin lesions that are scaly and evolve as polycyclic annular lesions or plaques similar to those of plaque psoriasis.

Characteristically the lesions appear in sun-exposed areas such as the vee of the neckline or the forearms, but not the face. It may be brought on by sun-sensitizing medications, but is usually associated with autoimmune disorders such as rheumatoid arthritis and Sjögren's syndrome.

Treatment generally involves sun avoidance and protection and topical corticosteroids. Sometimes systemic drug treatment is necessary. Besides corticosteroids other immunosuppressants such as methotrexate are also used.

Lesions of SCLE may have an annular configuration, with raised red borders and central clearing.

Drug regimens prescribed for lupus nephritis include mycophenolate mofetil (MMF), intravenous cyclophosphamide with corticosteroids, and the immune suppressant azathioprine with corticosteroids. MMF and cyclophosphamide with corticosteroids are equally effective in achieving remission of the disease. MMF is safer than cyclophosphamide with corticosteroids, with less chance of causing ovarian failure, immune problems or hair loss. It also works better than azathioprine with corticosteroids for maintenance therapy. Individuals with lupus nephritis have a high risk for B-cell lymphoma (which begins in the immune system cells).