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.

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

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

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.

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.

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).

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.

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.

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.

The presence of prolonged clotting times on a routine plasma test often triggers functional testing of the blood clotting function, as well as serological testing to identify common autoantibodies such as antiphospholipid antibodies. These antibodies tend to delay in-vitro coagulation in phospholipid-dependent laboratory tests such as the partial thromboplastin time.

The initial workup of a prolonged PTT is a mixing test whereby the patient's plasma is mixed with normal pooled plasma and the clotting is re-assessed. If a clotting inhibitor such as a lupus anticoagulant is present, the inhibitor will interact with the normal pooled plasma and the clotting time will remain abnormal. However, if the clotting time of the mixed plasma corrects towards normal, the diagnosis of an inhibitor such as the lupus anticoagulant is excluded; the diagnosis is a deficient quantity of clotting factor that is replenished by the normal plasma.

If the mixing test indicates an inhibitor, diagnosis of a lupus anticoagulant is then confirmed with phospholipid-sensitive functional clotting testing, such as the dilute Russell's viper venom time, or the Kaolin clotting time. Excess phospholipid will eventually correct the prolongation of these prolonged clotting tests (conceptually known as "phospholipid neutralization" in the clinical coagulation laboratory), confirming the diagnosis of a lupus anticoagulant.

Antiphospholipid syndrome is tested for in the laboratory using both liquid phase coagulation assays (lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).

Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. Thus genetic thrombophilia screening can consist of:

- Further studies for factor V Leiden variant and the prothrombin G20210A mutation, factor VIII levels, MTHFR mutation.

- Levels of protein C, free and total protein S, factor VIII, antithrombin, plasminogen, tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)

The testing of antibodies to the possible individual targets of aPL such as β glycoprotein 1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an in vivo target for antiphospholipid antibodies.

Classification with APS requires evidence of both one or more specific, documented clinical events (either a vascular thrombosis and/or adverse obstetric event) and the confirmed presence of a repeated aPL. The Sapporo APS classification criteria (1998, published in 1999) were replaced by the Sydney criteria in 2006. Based on the most recent criteria, classification with APS requires one clinical and one laboratory manifestation:

- Clinical:

- A documented episode of arterial, venous, or small vessel thrombosis — other than superficial venous thrombosis — in any tissue or organ by objective validated criteria with no significant evidence of inflammation in the vessel wall, and/or

- 1 or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or direct examination of the fetus) at or beyond the 10th week of gestation and/or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded or at least 1 premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia or severe pre-eclampsia according to standard definitions, or recognized features of placental insufficiency "plus"

- Laboratory:

- Anti-cardiolipin IgG and/or IgM measured by standardized, non-cofactor dependent ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (i.e., > 40 GPL or MPL, or > the 99th percentile) and/or

- Anti-β2 glycoprotein I IgG and/or IgM measured by standardized ELISA on 2 or more occasions, not less than 12 weeks apart; medium or high titre (> the 99th percentile) and/or

- Lupus anticoagulant detected on 2 occasions not less than 12 weeks apart according to the guidelines of the International Society of Thrombosis and Hemostasis.

There are 3 distinct APS disease entities: primary (the absence of any comorbidity), secondary (when there is a pre-existing autoimmune condition, most frequently systemic lupus erythematosus, SLE), and catastrophic (when there is simultaneous multi-organ failure with small vessel occlusion).

According to a 2006 consensus statement, it is advisable to classify APS into one of the following categories for research purposes:

- I: more than one laboratory criterion present in any combination;

- IIa: lupus anticoagulant present alone

- IIb: anti-cardiolipin IgG and/or IgM present alone in medium or high titers

- IIc: anti-β2 glycoprotein I IgG and/or IgM present alone in a titer greater than 99th percentile

The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires:

- a) Vascular thrombosis in three or more organs or tissues and

- b) Development of manifestations simultaneously or in less than a week and

- c) Evidence of small vessel thrombosis in at least one organ or tissue and

- d) Laboratory confirmation of the presence of aPL.

VDRL, which detects antibodies against syphilis, may have a false positive result in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive), although the more specific test for syphilis, FTA-Abs, that use recombinant antigens will not have a false-positive result.

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

Neonatal lupus erythematosus is the occurrence of systemic lupus erythematosus (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 complete heart block or hepatosplenomegaly.

The infants have no skin lesions at birth, but develop them during the first weeks of life. Neonatal lupus is usually benign and self-limited.

It is associated with mothers who carry the Ro/SSA antibodies.

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.

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).

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.

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.

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).

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.

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.