Misplaced Pages

Revision as of 18:31, 2 December 2006

Lupus
Specialty	Immunology, rheumatology, dermatology

Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that is potentially debilitating and sometimes fatal as the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage. SLE can affect any part of the body, but most often harms the heart, joints, skin, lungs, blood vessels, kidneys and nervous system. The course of the disease is unpredictable, with periods of illness (called flares) alternating with remission. Lupus can occur at any age, but is more common in women and particularly non-Caucasian women. Lupus is treatable, mainly with corticosteroids and immunesuppressants, though there is currently no cure for it. The name lupus (Latin for "wolf"), is thought to derive from the crude similarity between the facial rash that some lupus patients develop and a wolf's face, though other explanations have been proposed.

Classification

Lupus is a chronic autoimmune disease in which the body's own defense system attacks otherwise healthy tissue. Clinically, it can affect multiple organ systems including the skin, joints, kidneys and nervous system. There are several types of lupus; generally when the word 'lupus' alone is used, it refers to the systemic lupus erythematosus or SLE as discussed in this article. Other types include:

• Drug-induced lupus erythematosus, a drug-induced form of SLE
• Lupus nephritis, an inflammation of the kidneys caused by SLE
• Discoid lupus erythematosus, a skin disorder which causes a red, raised rash on the face, scalp or rest of the body, which can develop into SLE
• Subacute cutaneous lupus erythematosus, which causes non-scarring skin lesions on patches of skin exposed to sunlight
• Neonatal lupus, a rare disease affecting babies born to women with SLE, Sjögren's syndrome or sometimes no autoimmune disorder. It is theorized that maternal antibodies attack the fetus, causing skin rash, liver problems, low blood counts (which gradually fade) and rarely bradycardia New York University is a main center for research into neonatal lupus.

Signs and symptoms

SLE is known as "the great imitator" because its symptoms vary so widely it often mimics or is mistaken for other illnesses, and because the symptoms come and go unpredictably. Diagnosis can be elusive, with patients sometimes suffering unexplained symptoms and untreated SLE for years. Common initial and chronic complaints are fever, malaise, joint pains, myalgias and fatigue. Because they are so often seen with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms (below), however, they are considered suggestive.

Dermatological manifestations

As many as 30% of patients present with some dermatological symptoms (and 65% suffer such symptoms at some point), with 30% to 50% suffering from the classic malar rash (or butterfly rash) associated with the disease. Patients may present with discoid lupus (thick, red scaly patches on the skin). Alopecia, mouth, nasal, and vaginal ulcers, and lesions on the skin are also possible manifestations.

Musculoskeletal manifestations

Patients most often seek medical attention for joint pain, with small joints of the hand and wrist usually affected, although any joint is at risk. Unlike rheumatoid arthritis, SLE arthropathy is not usually destructive of bone, however, deformities caused by the disease may become irreversible in as many as 20% of patients.

Hematological manifestations

Anemia and iron deficiency may develop in as many as half of patients. Low platelet and white blood cell counts may be due to the disease or a side-effect of pharmacological treatment. Patients may have an association with antiphospholipid antibody syndrome (a thrombotic disorder) where autoantibodies to phospholipids are present in the patient's serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged PTT (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies, the combination of such findings have earned the term "lupus anticoagulant positive". Another autoantibody finding in lupus is the anticardiolipin antibody which can cause a false positive test for syphillis.

Cardiac manifestations

Patients may present with inflammation of various parts of the heart, such as pericarditis, myocarditis and endocarditis. The endocarditis of SLE is characteristically non-infective (Libman-Sacks endocarditis), and involves either the mitral valve or the tricuspid valve. Atherosclerosis also tends to occur more often and advance more rapidly in SLE patients than in the general population.

Pulmonary manifestations

Lung and pleura inflammation can cause pleuritis, pleural effusion, lupus pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage.

Renal involvement

Painless hematuria or proteinuria may often be the only presenting renal symptom. Acute or chronic renal impairment may develop with lupus nephritis, leading to acute or end stage renal failure. Because of early recognition and management of SLE, end stage renal failure occurs in less than 5% of patients.

Histologically, a hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding is due to immune complex deposition along the glomerular basement membrane leading to a typical granular appearance in immunofluorescence testing.

Neurological manifestations

About 10% of patients may present with seizures or psychosis. A third may test positive for abnormalities in the cerebrospinal fluid.

T-cell abnormalities

Abnormalities in T cell signaling are associated with SLE, including deficiency in CD45 phosphatase and increased expression of CD40 ligand.

Other rarer manifestations

Lupus gastroenteritis, lupus pancreatitis, lupus cystitis, autoimmune inner ear disease, parasympathetic dysfunction, retinal vasculitis, and systemic vasculitis.

Other abnormalities include:

• Increased expression of FcεRIγ, which replaces the sometimes deficient TCR ζ chain
• Increased and sustained calcium levels in T cells
• Moderate increase of inositol triphosphate
• Reduction in PKC phosphorylation
• Reduction in Ras-MAP kinase signaling
• Deficiencies in protein kinase A I activity

Causes

Lupus research has dramatically increased in recent years but the exact cause of the disease is unknown and there is still no consensus on whether it is a single condition or a group of related diseases. SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement, characterised by the body's production of antibodies against the nuclear components of its own cells. There are three mechanisms by which lupus is thought to develop: genetic predisposition, environmental triggers and drug reaction (drug-induced lupus).

Genetics

The first mechanism may arise genetically. Research indicates that SLE may have a genetic link. Lupus does run in families, but no single "lupus gene" has yet been identified. Instead, multiple genes appear to influence a person's chance of lupus developing when triggered by environmental factors. The most important genes are located on chromosome 6, where mutations may occur randomly (de novo) or be inherited. Additionally, people with SLE have an altered RUNX-1 binding site, which may be either cause or contributor (or both) to the condition. Altered binding sites for RUNX-1 have also been found in people with psoriasis and rheumatoid arthritis.

Environmental triggers

The second mechanism may be due to environmental factors. These factors can not only exacerbate existing lupus conditions, but can trigger the initial onset. They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections. Some researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease. UV radiation has been shown to trigger the photosensitive lupus rash, but some evidence also suggests that UV light is capable of altering the structure of the DNA, leading to the creation of autoantibodies. Some researchers have found that women with silicone gel-filled breast implants have produced antibodies to their own collagen, but it is not known how often these antibodies occur in the general population and there are no data that show these antibodies cause connective tissue diseases such as lupus.

Drug reactions

Drug-induced lupus erythematosus is a reversible condition that usually occurs in patients being treated for a long-term illness. Drug-induced lupus mimics systemic lupus. However, symptoms of drug-induced lupus generally disappear once a patient is taken off of the medication which triggered the episode. There are about 400 medications currently in use that can cause this condition, though the most common drugs are procainamide, hydralazine and quinidine.

Non-SLE forms of lupus

Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed via biopsy of skin rash on the face, neck or scalp. Often an anti-nuclear antibody (ANA) test for discoid patients is negative or a low-titre positive. About 10% of discoid lupus patients eventually develop SLE.

Pathophysiology

Pathophysiology is the study of the disturbances of the normal functioning of the body causing pathology (as opposed to bacterial, fungal, viral or traumatic pathology, in which the source of the disturbance is an external agent). Autoimmune disorders (and hence lupus) is an example, in which the body's own defences act against healthy tissues rather than infection. One manifestation of lupus is abnormalities in apoptosis, a type of programmed cell death in which aging or damaged cells are neatly disposed of as a part of normal growth or functioning.

Abnormalities in apoptosis

• Apoptosis is increased in monocytes and keratinocytes
• Expression of Fas by B cells and T cells is increased
• There are correlations between the apoptotic rates of lymphocytes and disease activity

Tingible body macrophages (TBMs) are large phagocytic cells in the germinal centers of secondary lymph nodes. They express CD68 protein. These cells normally engulf B cells which have undergone apoptosis after somatic hypermutation. In some patients with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells which may have randomly acquired self-specificity through somatic hypermutation.

Diagnosis

Some physicians make a diagnosis on the basis of the ACR classification criteria (see below). The criteria, however, were established mainly for use in scientific research (i.e. inclusion in randomized controlled trials), and patients may have lupus despite never meeting the criteria.

Anti-nuclear antibody testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for lupus. Antiphospholipid antibodies occur more often in SLE, and can predispose for thrombosis. More specific are the anti-smith and anti-dsDNA antibodies. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and renal function (disturbed if the kidney is involved), liver enzymes and a complete blood count.

Formerly, the lupus erythematosus (LE) cell test was used for diagnosis, however those LE cells are only found in 50-75% of SLE patients, and are also found in some patients 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.

Diagnostic criteria

The American College of Rheumatology (ACR) has established eleven criteria in 1982, which were revised in 1997 as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individual patients and do not do well in that capacity. For inclusion in clinical trials, patients must meet the following three criteria to be classified as having SLE: (i) patient must present with four of the below eleven symptoms (ii) either simultaneously or serially (iii) during a given period of observation.

1. Malar rash (rash on cheeks)
2. Discoid lupus (red, scaly patches on skin which cause scarring)
3. Photosensitivity (adverse reaction to sunlight)
4. Mouth or nose ulcers
5. Arthritis
6. More than 0.5g per day protein in urine, or cellular casts seen in urine under a microscope.
7. Seizures or psychosis
8. Pleuritis (inflammation of the membrane around the lungs) or pericarditis (inflammation of the membrane around the heart)
9. Hemolytic anemia (low red blood cell count), leukopenia (low white blood cell count), lymphopenia (low lymphocyte count) or thrombocytopenia (low platelet count)
10. Anti-nuclear antibody test (positive ANA), very sensitive (98%) but non specific.
11. Anti-Sm antibody or false positive serological test for syphilis or antiphospholipid antibody positivity, presence of Anti-ss DNA in 70% of patients.

A useful mnemonic for these 11 criteria is SOAP BRAIN MD: Serositis (8), Oral ulcers (4), Arthritis (5), Photosensitivity (3), Blood Changes (9), Renal involvement (proteinuria or casts) (6), ANA (11), Immunological changes (10), Neurological signs (seizures, frank psychosis) (7), Malar Rash (1), Discoid Rash (2).

Some patients may have SLE without four criteria and SLE is associated with manifestations other than those listed in the criteria. Dr Graham R.V. Hughes, an authority on lupus in the UK, has published alternative criteria to diagnose SLE in 1982.

Common misdiagnoses

Porphyria

Porphyrias are complex genetic disorders that share many symptoms with lupus, but impact the enzymes responsible for building heme, a component needed in heme proteins. Porphyrias are ecogenic disorders requiring both environmental and genetic backgrounds to manifest with a variety of symptoms and medical complications. They are noted for photosensitivity and have been associated with transient and permanent production of autoantibodies. The five major forms of dominantly inherited porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been detected in systemic lupus erythematosus and discoid lupus patients over the past 50 years. Physicians should have a high degree of suspicion of porphyrias in all lupus cases and act accordingly when patients are in a medical crisis that may be due to an underlying acute hepatic porphyria. Drug-induced lupus and photosensitivity warrant an investigation for an underlying porphyria since multiple drug reactions are a hallmark complication of porphyrias. Patients with both lupus and porphyrias should avoid porphyrinogenic drugs and hormone preparations.

Patients with acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been detected in lupus patients with severe life-threatening "lupus" complications known as neurolupus. Symptoms are identical to acute hepatic porphyria attacks and include seizures, psychosis, peripheral neuropathy and syndrome of inappropriate antidiuretic hormone (SIADH) associated with dangerously low sodium levels (hyponatremia). Porphyria attacks require intervention with intravenous glucose, heme preparations and the discontinuation of dangerous porphyrinogenic drugs including antiseizure drugs. Several other lupus complications have been associated with porphyrias including pancreatitis and pericarditis. Porphyrin testing should be performed on urine, stool/bile and blood to detect all types of porphyrias, and repeat testing should be performed in suspicious cases. Appropriate enzyme tests or DNA testing should also be pursued to obtain a complete diagnosis which could include a dual porphyria.

Common dual diagnoses

SLE is sometimes diagnosed in conjuction with other conditions, including Rheumatoid Arthritis and Fibromyalgia.

Treatment

Drug therapy

Lupus SLE is a chronic disease with no known cure. Due to the variety of symptoms and organ system involvement with Lupus patients, the severity of the SLE in a particular patient must be assessed in order to treat successfully treat SLE.

Mild or remittant disease can sometimes be safely left untreated. If required, NSAIDS and Hydroxychloroquine, quinacrine,(trade name Plaquenil) or chloroquine may be used.

In severe cases, medications that modulate the immune system (primarily corticosteroids and immunosuppressants) are used to control the disease and prevent re-occurence of symptoms (known as flares). Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce incidence of flares, the process of the disease, and lower the need for steroid use; when flares occur, they are treated with corticosteroids. DMARDs commonly in use are the antimalarials (e.g. hydroxychloroquine, methotrexate and azathioprine). Hydroxychloroquine (trade name Plaquenil) is an FDA approved anti-malarial used for constitutional, cutaneous, and articular manifestations, while Cyclophosphamide (trade names Cytoxan and Neosar) is used for severe glomerulonephritis or other organ-damaging complications, and in 2005, CellCept became accepted for treatment of lupus nephritis.

Patients who require steroids frequently may develop obesity, diabetes and osteoporosis. Depending on the dosage, corticosteroids can cause other side effects such as a puffy face, an unusually large appetite and difficulty sleeping. Those side effects can subside if and when the large initial dosage is reduced, but long term use of even low doses can cause elevated blood pressure and cataracts. Due to these side effects, steroids are avoided if possible.

Alternative medicine

Traditional Chinese medicine may be useful in the treatment of lupus. A 1985 study on lupus and acupuncture reported improvement of lupus sufferers over matched controls, though there was no placebo group for comparison. It is possible that acupuncture may be useful for the treatment some of the symptoms of lupus, but there needs to be more research done before a definitive statement can be made regarding acupuncture, and alternative medicine as a whole.

Lifestyle changes

Other measures such as avoiding sunlight or covering up with sun protective clothing can also be effective in preventing problems due to photosensitivity. Weight loss is also recommended in overweight and obese patients to alleviate some of the effects of the disease, especially where joint involvement is significant.

Treatment Research

Other immunosuppressants and autologous stem cell transplants are under investigation as a possible cure. Recently, treatments that are more specific in modifying the particular subset of the immune cells (e.g. B- or T- cells) or cytokine proteins they secrete have been gaining attention. Research into new treatments has recently been accelerated by genetic discoveries, especially mapping of the human genome. According to a June 2006 market analysis report by Datamonitor, treatment for SLE could be on the verge of a breakthrough as there are numerous late-Phase trials currently being carried out.

The largest research funding organization for SLE in the United States, as of 2006, is the Alliance for Lupus Research.

Prevention

Lupus is not understood well enough to be prevented, but when the disease develops, quality of life can be improved through flare prevention. The warning signs of an impending flare include increased fatigue, pain, rash, fever, abdominal discomfort, headache and dizziness. Early recognition of warning signs and good communication with a doctor can help individuals with lupus remain active, experience less pain and reduce medical visits.

Prevention of complications during pregnancy

While most infants born to mothers with lupus are healthy, pregnant mothers with SLE should remain under a doctor's care until delivery. Neonatal lupus is rare, but identification of mothers at highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare during pregnancy and proper treatment can maintain the health of the mother for longer. Women pregnant and known to have the antibodies for anti-Ro (SSA) or anti-La (SSB) should have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature.

Prognosis

In the 1950s, most patients diagnosed with SLE lived fewer than five years. Advances in diagnosis and treatment have improved survival to the point where over 90% of patients now survive for more than ten years and many can live relatively asymptomatically. The most common cause of death is infection due to immunosuppression as a result of medications used to manage the disease. Prognosis is normally worse for men and children than for women. Fortunately, if symptoms present after age 60, the disease tends to run a more benign course. The Anti-dsDNA antibody test is the only marker of prognosis in lupus, while Anti-Sm (Anti Smith) is the most sensitive.

Epidemiology

Previously believed to be a rare disease, Lupus has seen an increase in awareness and education since the 1960s. This has helped many more patients get an accurate diagnosis making it possible to estimate the number of people with lupus. In the United States alone, it is estimated that between 270,000 and 1.5 million people have lupus, making it more common than cystic fibrosis or cerebral palsy. The disease affects both females and males, though young women are diagnosed nine times more often than men. SLE occurs with much greater severity among African-American women, who suffer more severe symptoms as well as a higher mortality rate. Worldwide, a conservative estimate states that over 5 million people have lupus.

Although SLE can occur in anyone at any age, it is most common in women of childbearing age. It affects 1 in 4000 people in the United States, with women becoming afflicted far more often in men. The disease appears to be more prevalent in women of African, Asian, Hispanic and Native American origin but this may be due to socioeconomic factors. People with relatives who suffer from SLE, rheumatoid arthritis or thrombotic thrombocytopenic purpura are at a slightly higher risk than the general population.

History

The source of the name "lupus" is unclear. All explanations originate with the characteristic butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks. In various accounts, some doctors thought the rash resembled a wolf pattern. In other accounts doctors thought that the rash, which was often more severe in earlier centuries, created lesions that resembled wolf bites or scratches. Stranger still is the account that the term "Lupus" didn't come from Latin at all, but from the term for a French style of mask which women reportedly wore to conceal the rash on their faces. Medical historians have theorized people with porphyrias (a disease that shares many symptoms with Lupus) generated folklore stories of vampires and werewolves due to the photosensitivity, scarring, hair growth and porphyrin brownish-red stained teeth in severe recessive forms of porphyria or combinations of the disorders known as dual, homozygous or compound heterozygous porphyrias.

The history of lupus erythematosus can be divided into three periods: the classical, neoclassical, and modern. The classical period began when the disease was first recognised in the Middle Ages and saw the description of the dermatological manifestation of the disorder. The term lupus is attributed to the 12th century physician Rogerius, who used it to describe the classic malar rash. The neoclassical period was heralded by Móric Kaposi's recognition in 1872 of the systemic manifestations of the disease. The modern period began in 1948 with the discovery of the LE cell (the Lupus Erythematosus cell, a misnomer as it occurs with other diseases as well) and is characterised by advances in our knowledge of the pathophysiology and clinical-laboratory features of the disease, as well as advances in treatment.

Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment to patients until the middle of the twentieth century, when Hench discovered the efficacy of corticosteroids in the treatment of SLE.

Famous patients

• Ferdinand Marcos, former Philippine dictator.
• Flannery O'Connor, American fiction writer.
• Hugh Gaitskell, British politician.
• Elaine Paige, British actress and singer.
• Michael Jackson, famous singer/songwriter, was supposedly diagnosed with discoid lupus and vitiligo in the early 1980s.

• Seal, a British musician, had non-SLE lupus in his childhood.
• Millie, the pet dog of former President George H. W. Bush & Barbara Bush, was diagnosed with discoid lupus erythematosus.
• Charles Kuralt, former anchor of CBS Sunday Morning
• J Dilla, a hip-hop producer and beatmaker.
• Inday Ba (also known as N'Deaye Ba), a Swedish-born actress. She died from complications of lupus, aged 32.
• Caroline Dorough-Cochran, sister of Howie D. of the Backstreet Boys, who founded the Dorough Lupus Foundation in her memory.
• Mercedes Yvette, runner-up of season two of America's Next Top Model

See also

• Abzyme
• Anti-nuclear antibody
• Discoid lupus erythematosus in dogs

Footnotes

1. Discoid Lupus Erythematosus
2. ^ National Instutite of Arthritis and Musculoskeletal and Skin Diseases handout on Lupus
3. Lupus: The Great Imitator
4. Excerpt from NINDS Neurological Sequelae Of Lupus Information Page
5. Yu Asanuma, M.D., Ph.D., Annette Oeser, B.S., Ayumi K. Shintani, Ph.D., M.P.H., Elizabeth Turner, M.D., Nancy Olsen, M.D., Sergio Fazio, M.D., Ph.D., MacRae F. Linton, M.D., Paolo Raggi, M.D., and C. Michael Stein, M.D. (2003). "Premature coronary-artery atherosclerosis in systemic lupus erythematosus". New England Journal of Medicine. 349 (Dec. 18): 2407–2414. PMID 14681506 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. Bevra Hannahs Hahn, M.D. (2003). "Systemic lupus erythematosus and accelerated atherosclerosis". New England Journal of Medicine. 349 (Dec. 18): 2379–2380. PMID 14681501 Extract (full text requires registration).
7. Mary J. Roman, M.D., Beth-Ann Shanker, A.B., Adrienne Davis, A.B., Michael D. Lockshin, M.D., Lisa Sammaritano, M.D., Ronit Simantov, M.D., Mary K. Crow, M.D., Joseph E. Schwartz, Ph.D., Stephen A. Paget, M.D., Richard B. Devereux, M.D., and Jane E. Salmon, M.D. (2003). "Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus". New England Journal of Medicine. 349 (Dec. 18): 2399–2406. PMID 14681505 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. University of South Carolina lecture on immunology
9. Gaipl, U S; Kuhn, A; Sheriff, A; Munoz, L E; Franz, S; Voll, R E; Kalden, J R; Herrmann, M (2006). "Clearance of apoptotic cells in human SLE". Current directions in autoimmunity. 9: 173–87. PMID: 1639466 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)
10. NIM encyclopedic article on the LE cell test
11. Rheumatology.org article on the classification of rheumatic diseases
12. Revision of Rheumatology.org's diagnostic criteria
13. Alternative criteria for diagnosis of Lupus in the United Kingdom
14. Merck manual discussion of Lupus
15. Review of different alternative treatments for lupus
16. Hospital for Special Surgery article on acupuncture and lupus
17. Lead Discovery article on treatment of Lupus
18. Lupus and African-American women

External links

• Website listing Lupus support groups around the world
• Lupus International
• Lupus Foundation of America
• Lupus UK
• History of Lupus (NZ Lupus Trust)
• Lupus Erythematosus of the skin, New Zealand Dermatological Society Incorporated

• Arthritis
• Rheumatology
• Nephrology
• Autoimmune diseases