Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm. They are defined as clinical syndromes involving nonmetastatic systemic effects that accompany malignant disease.[1, 2, 3]
In a broad sense, these syndromes are collections of symptoms that result from substances produced by the tumor, and they occur remotely from the tumor itself. The symptoms may be endocrine, neuromuscular or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature.
Although fever is the most common presentation, several clinical pictures may be observed, each of which specifically simulates more common benign conditions. These syndromes vary from dermatomyositis-polymyositis to Cushing syndrome to the malignant carcinoid syndrome.
A large number of cancer patients show central nervous system (CNS) involvement. The first report of a paraneoplastic syndrome has been attributed to a French physician, M. Auchè, who described peripheral nervous system involvement in cancer patients in 1890.
Paraneoplastic syndromes may be the first or most prominent manifestation of a cancer. When a patient without a known cancer presents with one of the “typical” paraneoplastic syndromes, a diagnosis of cancer should be considered and investigated. Because of their protean manifestations, paraneoplastic syndromes should be managed by a coordinated team of physicians, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, and dermatologists.
For discussion of specific paraneoplastic syndromes, see the following Medscape articles:
For patient education information, see the Cancer Center, as well as Brain Cancer, Bladder Cancer, and Breast Cancer.
The pathophysiology of paraneoplastic syndromes is complex and intriguing. When a tumor arises, the body may produce antibodies to fight it by binding to and destroying tumor cells. Unfortunately, in some cases these antibodies cross-react with normal tissues and destroy them, which may result in a paraneoplastic disorder. For example, antibodies or T cells directed against the tumor may mistakenly attack normal nerve cells. The detection of paraneoplastic anti-neural antibody was first reported in 1965.
In other cases, paraneoplastic syndromes result from the production and release of physiologically active substances by the tumor. Tumors may produce hormones, hormone precursors, a variety of enzymes, or cytokines. Several cancers produce proteins that are physiologically expressed in utero by embryonic and fetal cells but not expressed by normal adult cells. These substances may serve as tumor markers (eg, carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], carbohydrate antigen 19-9 [CA 19-9]). More rarely, the tumor may interfere with normal metabolic pathways or steroid metabolism. Finally, some paraneoplastic syndromes are idiopathic.
The causes of the paraneoplastic syndromes associated with underlying cancers are not well known. Only a few cases clearly demonstrate an etiologic and a pathogenetic factor.
Fever is thought to result from the release of endogenous pyrogens (ie, lymphokines or tissue pyrogenes). Fever may also be related to necrotic-inflammatory phenomena of the tumor and/or to alterations in liver function and consequent disorders of steroidogenesis.
Dysgeusia seems to be related to alterations in the body's level of copper and zinc or to a morphofunctional variation of the tasting bodies (ie, gustative papillae).
Cachexia is thought to be caused by bioactive molecules produced by the tumor, such as alpha-lymphotoxin (tumor necrosis factor [TNF] alpha), peptides, and nucleotides, which are able to affect metabolism. Such modifications include an increase in the serum levels of fatty acids; a decrease in urea, alanine, and carbon dioxide; and alterations of glucose metabolism.
The causes of hypertrophic osteoarthropathy remain unknown, although several hypotheses have been developed (eg, estrogen or growth hormone [GH] production by the tumor, vagal hyperactivity).
The autoimmune basis of polymyositis and dermatomyositis is confirmed by the presence of a lymphoplasma cellular infiltrate of the muscular interstices and by the presence of muscle necrosis, which is revealed by increased serum levels of creatine kinase and lactate dehydrogenase (LDH) and an elevated erythrocyte sedimentation rate (ESR).
Onset of scleroderma and SLE could be related to production of antinuclear antibody (ANA), because antigens normally restricted to connective tissues are expressed aberrantly in cancer.
Secondary kidney amyloidosis and sedimentation of immunocomplexes in nephrons (and subsequent membranoproliferative glomerulonephritis) is thought to be the underlying mechanism of nephrotic syndrome and, frequently, neoplastic hypoalbuminemia, which is also related to reduced albumin synthesis.
Gastrointestinal paraneoplastic disorders are related to production of molecules that affect the motility and secretory activity of the digestive tract, as follows:
Erythrocytosis results from an increase of erythropoietin (EPO), which may occur in response to hypoxia, or may result from ectopic production of EPO or EPO-like substances or from altered catabolism of EPO itself. Erythrocytosis is common in cancers of the liver, kidney, adrenal glands, lung, thymus, and CNS as well as in gynecologic tumors and myosarcomas. It always disappears after removal of the primary tumor.
Anemia is a common presenting symptom of several neoplasms and results from chronic hemorrhages from ulcerated tumors, altered intestinal absorption of vitamins B-6 and B-12, and increased destruction or insufficient production of RBCs. Three types of paraneoplastic anemias may be described, as follows:
Causes of cutaneous paraneoplastic syndromes are as follows:
The pathogenesis of paraneoplastic endocrine syndromes results from aberrant production by tumors of protein hormones, hormone precursors, or hormonelike substances. Cancers generally do not synthesize steroid hormones, except those arising in organs with physiological steroidogenesis (ie, gonads or adrenals).
The pathogenesis of neuromuscular paraneoplastic disorders is unknown, but they probably are multifactorial, correlated with a virus becoming virulent, autoantibody formation, or production of substances that alter nervous functions.
The muscular system is involved in myasthenic phenomena (on a toxic and metabolic basis) that can be either simple (affecting the pelvic girdle) or part of Eaton-Lambert myasthenic syndrome (ELMS). According to some recent reports, ELMS may be related to production of tumor proteins that may provoke production of anti–calcium-channel antibodies.
Autoantibodies directed against the central neurons and brain often are present in the serum and cerebrospinal fluid (CSF) of patients with sensory and mixed neuropathies. CSF analysis may reveal increased albumin and immunoglobulins. Patients with mixed neuropathy usually show a distal nervous demyelination, while patients with sensory neuropathy have ganglionic degeneration.
Patients with subacute necrotic myelitis show a characteristic extended necrosis of the spinal cord, while those with the more rare subacute myelitis have characteristic degeneration of the anterior horns of the spinal cord, which sometimes extends to the brain. Both types of myelitis probably have a toxic origin.
Patients with cerebellar paraneoplastic disorders usually have degenerative loss of the molecular, granular, and Purkinje layers of the cerebellar cortex. Sometimes a loss of neurons of the spinocerebellar tract and of the posterior cords of the spinal cord can occur. Elevation of CSF albumin and lymphocyte levels is usually observed in these patients.
Individuals with paraneoplastic encephalitis commonly have lymphocytic infiltration of the medial sections of the temporal lobes, with a loss of neurons.
Patients with involvement of the semioval center have an acute and ill-defined onset of disease. This condition is often called progressive multifactorial leukoencephalopathy and is related to the site of the nervous injury. This condition probably has a viral origin, resulting from the action of two papovaviruses, JV and an SV-40–like virus, both of which have been isolated in the brains of some patients. Some areas of demyelination that tend to be confluent and that spare central axons can be demonstrated by histologic examination.
The reported frequency of paraneoplastic syndromes ranges from 10-15% to 2-20% of malignancies, However, these could be underestimates. Neurological paraneoplastic syndromes are estimated to occur in fewer than 1% of patients with cancer. Similarly, the true incidence of deaths and complications related to paraneoplastic syndromes is unknown.
No race predilection for paraneoplastic syndromes is reported. No sex predilection is known. People of all ages may be affected by cancers and their related paraneoplastic syndromes.
Because paraneoplastic syndromes differ widely from individual to individual, prognosis may vary greatly. For example, disseminated intravascular coagulation indicates a poor prognosis, whereas hypertrophic osteoarthropathy is one of the few paraneoplastic syndromes that may indicate a more favorable prognosis. Some paraneoplastic disorders may resolve spontaneously.
Death may result from the underlying cancer or from an irreversible system impairment, usually acute heart failure or kidney failure. In a review of patients with paraneoplastic pemphigus, infection was a major cause of death.
Paraneoplastic syndromes most commonly occur in patients not known to have cancer, as well as in those with active cancer and those in remission after treatment. A complete history and physical examination findings can suggest neoplasia. Persons with a family history of malignancies (eg, breast,[12, 13] colon) may be at increased risk and should be screened for cancer. Nonspecific syndromes can precede the clinical manifestations of the tumor, and this occurrence is a negative prognostic factor.
Because of their complexity and variety, the clinical presentations of these syndromes may vary greatly. Paraneoplastic syndromes are usually divided into the following categories:
Fever, dysgeusia, anorexia, and cachexia are included in this category. Fever is frequently associated with the following:
Paraneoplastic arthropathies arise as rheumatic polyarthritis or polymyalgia, particularly in patients with myelomas; lymphomas; acute leukemia; malignant histiocytosis; and tumors of the colon, pancreas, prostate, and CNS. Hypertrophic osteoarthropathy may be observed in patients with lung cancers, pleural mesothelioma, or phrenic neurilemmoma.
Scleroderma may precede direct evidence of tumor. The widespread form is typical of malignancies of the breast, uterus, and lung (both alveolar and bronchial forms). The localized form is characteristic of carcinoids and lung tumors (bronchoalveolar forms).
Systemic lupus erythematosus (SLE) may develop in patients with lymphomas or cancers of the lung, breast, or gonads.
Secondary amyloidosis of the connective tissues is a rare presentation in patients with myeloma, renal carcinoma, and lymphomas.
Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more than 20 mEq per 24 hours, may develop in patients with tumors that secrete adrenocorticotropic hormone (ACTH) or ACTH-like substances. It occurs in 50% of individuals with ACTH-secreting tumors of the lung (ie, small cell lung cancer ).
Hypokalemia, hyponatremia or hypernatremia, hyperphosphatemia, and alkalosis or acidosis may result from other types of tumors that produce ACTH, antidiuretic hormone (ADH), or gut hormones (see Endocrine and neuromuscular, below).
Nephrotic syndrome is observed, although infrequently, in patients who have Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); leukemias; melanomas; or malignancies of lung, thyroid, colon, breast, ovary, or pancreatic head.
Secondary amyloidosis of the kidneys, heart, or CNS may rarely be a presenting feature in patients with myeloma, renal carcinoma, or lymphomas. The clinical picture of secondary amyloidosis is related to renal and cardiac injuries.
Watery diarrhea accompanied by an electrolyte imbalance leads to asthenia, confusion, and exhaustion. These problems are typical of patients with proctosigmoid tumors (both benign and malignant) and of medullary thyroid carcinomas (MTCs) that produce several prostaglandins (PGs; especially PG E2 and F2) that lead to malabsorption and, consequently, unavailability of nutrients.
These alterations also can be observed in patients with any of the following:
Symptoms related to erythrocytosis or anemia, thrombocytosis, disseminated intravascular coagulation (DIC), and leukemoid reactions may result from many types of cancers.
In some cases, symptoms result from migrating vascular thrombosis (ie, Trousseau syndrome) occurring in at least two sites. Leukemoid reactions, characterized by the presence of immature white blood cells in the bloodstream, are usually accompanied by hypereosinophilia and itching. These reactions are typically observed in patients with lymphomas or cancers of the lung, breast, or stomach. Cryoglobulinemia may occur in patients with lung cancer or pleural mesothelioma.
Itching is the most frequent paraneoplastic cutaneous manifestation. Herpes zoster, ichthyosis, flushes, alopecia, or hypertrichosis also may be observed. Acanthosis nigricans and dermic melanosis are characterized by a blackish pigmentation of the skin and usually occur in patients with abdominal cancers, especially gastric neoplasms and adenocarcinomas.
Endocrine symptoms related to paraneoplastic syndromes usually resemble the more common endocrine disorders. Cushing syndrome, accompanied by hypokalemia, very high plasma ACTH levels, and increased serum and urine cortisol concentrations, is the most common example of an endocrine disorder linked to a malignancy.[21, 22, 5, 23] Many tumors (eg, small cell cancer of the lung) can produce Cushing syndrome via ectopic production of ACTH or ACTH-like molecules.
Neuromuscular disorders related to cancers are now included among the paraneoplastic syndromes. Such disorders affect 6% of all patients with cancer and are prevalent in ovarian and pulmonary cancers. Neuromuscular symptoms may mimic common neurological conditions.
Myasthenia gravis is the most common paraneoplastic syndrome in patients with thymoma, a malignancy arising from epithelial cells of the thymus. Indeed, thymoma is the underlying cause in approximately 10% to 15% of cases of myasthenia gravis. Rarely, hypogammaglobulinemia and pure red cell aplasia occur as paraneoplastic syndromes in patients with thymoma.
Lambert-Eaton myasthenic syndrome (LEMS) manifests as asthenia of the scapular and pelvic girdles and a reduction of tendon reflexes. LEMS sometimes can be accompanied by xerostomia, sexual impotence, myopathy, and peripheral neuropathy. It is associated with cancer 40-70% of the time, most commonly small cell lung cancer (SCLC). It seems to result from interference with the release of acetylcholine due to immunologic attack against the presynaptic voltage-gated calcium channel.
Opsoclonus-myoclonus syndrome usually affects children younger than 4 years. It is associated with hypotonia, ataxia, and irritability. One in two patients has neuroblastoma.
Paraneoplastic limbic encephalitis is characterized by depression, seizures, irritability, and short-term memory loss. The neurologic symptoms develop rapidly and can resemble dementia. Paraneoplastic limbic encephalitis is most commonly associated with SCLC.
Encephalitis resulting from antibodies against the N-methyl-D-aspartate (NMDA) receptor may occur in patients with ovarian teratoma, many of whom are younger women. Involvement of NMDA receptors in the hippocampus may result in prodromal flulike symptoms, psychiatric disturbance progressing to coma, movement disorders, autonomic instability, and respiratory failure.
Paraneoplastic encephalomyelitis is characterized by a complex of symptoms arising from brainstem encephalitis, limbic encephalitis, cerebellar degeneration, myelitis, and autonomic dysfunction. Such neurologic deficits and signs seem to be related to an inflammatory process involving multiple areas of the nervous system.
Paraneoplastic cerebellar degeneration causes gait difficulties, dizziness, nausea, and diplopia, followed by ataxia, dysarthria, and dysphagia. Paraneoplastic cerebellar degeneration is frequently associated with Hodgkin lymphoma, breast cancer, SCLC, and ovarian cancer; it may occur in association with prostate carcinoma.
Paraneoplastic sensory neuropathy affects lower and upper extremities and is characterized by progressive sensory loss, either symmetric or asymmetric. It seems to be related to the loss of the dorsal root ganglia with early involvement of major fibers responsible for detecting vibration and position.
As with the history, physical examination findings in patients with paraneoplastic syndromes are divided into the following categories:
Miscellaneous paraneoplastic findings include the following:
Rheumatologic paraneoplastic syndromes include the following:
Hypertrophic osteoarthropathy presents as digital clubbing and painful swelling of the hip, wrist, and knee, accompanied by an articular effusion. The long bones may also be involved; in such cases, patients complain of pain and x-rays show a typical elevation (thickening and detachment) of the periosteum
Polymyositis and dermatomyositis may occur as paraneoplastic syndromes in patients with lymphomas or cancers of the lung, stomach, breast, or uterus. These syndromes are characterized clinically by asthenia, pain, and progressive hypertrophy of proximal muscles. Subsequent involvement of the skin manifests as violet-colored rashes of the face and hands.
A retrospective study by Fardet et al identified the following independent factors associated with an underlying malignancy in patients with dermatomyositis :
For patients with paraneoplastic scleroderma or systemic lupus erythematosus (SLE), the clinical picture is characteristic of nonparaneoplastic conditions
Renal paraneoplastic findings include the following:
The clinical picture of paraneoplastic disorders affecting the gastrointestinal system is similar to that of nontropical sprue.
Thrombocytosis (>500,000 platelets/dL) can be observed in patients with cancer of the lung, breast, digestive organs, or reproductive organs. This thrombocytosis leads to the following two phenomena:
Cutaneous paraneoplastic findings include the following:
Acanthosis nigricans and dermic melanosis are similar but differ by location. Dermic melanosis is diffuse; acanthosis nigricans usually is accompanied by confluent papillomas and affects the oral, umbilical, axillary, and inguinal areas. Three types of acanthosis nigricans are described: benign, pseudoacanthosis, and malignant. Unlike the benign form, which tends to develop slowly, the malignant form is characterized by sudden onset of extensive lesions with rapid growth. Leser-Trélat sign consists of multiple seborrheic keratoses (black, brown, or tan), often pruritic, primarily on the thorax and dorsum.
This is a heterogeneous group of disorders characterized by clinical signs that vary greatly according to the specific disorder, as follows:
One or more neurological paraneoplastic syndromes may be present in patients with cancer, especially those suffering from lung cancer. Neuropathies may be sensory, motor, or mixed.
Sensory neuropathy, which usually affects only patients with lung cancer, originates from ganglionic degeneration, and its onset is characterized by paresthesias and tabeticlike pain, acute hyporeflexia with a reduction of proprioceptive sensitivity and ataxia (both static and dynamic), vibratory anesthesia, deafness, cutaneous hypoesthesia or anesthesia, dysgeusia, and dysosmia.
Mixed neuropathy may occur with several malignancies and has an extremely variable presentation, with motor or sensory symptoms either preceding the clinical onset of tumor disease or accompanying it. The spinal cord can be affected by either subacute necrotic myelitis or subacute myelitis. These conditions lead to a progressive flaccid paraplegia with areflexia, lack of sphincteric control, and anesthesia of the lower limbs.
A lateral amyotrophic syndrome (LAS) may occur, presenting as the typical muscular asthenia and atrophy, hyperreflexia with pyramidal fasciculations, and degeneration of the second motor neuron. This form of LAS differs from the nonparaneoplastic form because it includes sensory involvement (ie, proprioception and pallesthesia).
The cerebellum may be the site of subacute neuronal degeneration in patients with small cell carcinoma or breast or gynecologic tumors. Such degeneration presents clinically as cerebellar ataxia, dysarthria, and nystagmus. Dysphagia, palpebral ptosis, deafness, and a positive Babinski sign may also occur.
The cerebellum of patients with lung cancer also may be affected by encephalitis. In such cases, the clinical picture is characterized by convulsions, delirium, and a lack of long-term memory. In other patients, the pathological process involves the medulla (ie, encephalomyelitis).
In some patients with leukemias, lymphomas, or epithelial cancers, a rare degenerative process involving the semioval center may be observed. This degenerative process is characterized by convulsions, cerebellar ataxia, progressive dementia, aphasia, hemiparesis, hemihypoesthesia, dysphagia, and nystagmus. The process develops rapidly, leading to death within 6 months of onset.
Eaton-Lambert myasthenic syndrome (ELMS) may occur in patients with lymphomas; thymomas; or cancers of the pancreas, rectum, kidney, breast, prostate, or uterus. ELMS may resolve after surgical resection of the primary tumor but not after radiotherapy or chemotherapy.
Patients with a suspected paraneoplastic disorder should undergo a complete panel of laboratory studies of blood, urine, and cerebrospinal fluid (CSF). Selection of further studies is dictated by the clinical presentation.
Protein electrophoresis of serum and CSF may demonstrate alterations of albumin levels and increased beta-globulins and gamma-globulins. Gamma-globulins are always increased in patients with autoimmune disorders, whether neoplastic or not. Oligoclonal bands are seen frequently on CSF electrophoresis.
Assays for autoantibodies may confirm the paraneoplastic origin of a patient’s condition. Most autoantibodies involved in paraneoplastic syndromes are directed against nervous system structures.
Endoscopy is useful to detect tumors of the respiratory tree and of the digestive tract. It also allows the examiner to obtain biopsy samples. Skin biopsy for histopathologic diagnosis is necessary in patients with facial papules, to distinguish benign lesions from those due to underlying malignancy.
Imaging studies may include whole-body scans for detection of the underlying tumor. Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans can detect extremely small tumors and are especially useful for patients with neurologic disorders.
The complete blood cell count (CBC) may demonstrate anemia. This anemia may be the result of any of several different types of cancer, or it may be the result of different benign conditions. A microscopic study of the white blood cells is helpful for diagnosis of leukemia or lymphoma-related disorders. Hypereosinophilia is frequently observed in patients with Hodgkin lymphoma. A platelet count must be performed in any patient with symptoms of disseminated intravascular coagulation (DIC).
The erythrocyte sedimentation rate (ESR) is usually increased in patients with cancers. However, the ESR is a nonspecific marker for inflammation that is also elevated in a variety of disorders, including infections and rheumatologic disorders.
Blood enzymes may be altered, even in healthy individuals or those who have benign conditions. Increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydryogenase (LDH), and alkaline phosphatase (ALP) are commonly observed in patients with malignancies of the digestive system as well as in patients with bone or muscle injuries.
Protein electrophoresis of serum may demonstrate alterations of albumin levels and increased beta-globulins and gamma-globulins. Gamma-globulins are always increased in patients with autoimmune disorders, whether neoplastic or not.
Tumor markers are very useful for diagnosis of cancers that are clinically silent, but most markers are not specific for determining the origin of the cancer. For example, carcinoembryonic antigen (CEA) is increased in patients with tumors of the breast, lung, and digestive tract, as well as in patients who are heavy smokers.
Although prostate-specific antigen (PSA) is increased only in patients with prostatic disorders, it is increased in benign disorders (including inflammatory diseases) as well as in prostate cancer. Calculating free PSA as a percentage of total PSA can help differentiate benign from malignant disorders; the higher the percentage of free PSA (a level above 25% is considered normal), the lower the likelihood of cancer.
Many patients with paraneoplastic disorders may have autoantibodies against several tissues of the body. Demonstration of these autoantibodies is very important to confirm the diagnosis of a paraneoplastic syndrome and distinguish it from nonneoplastic forms.
Most known autoantibodies are directed against nervous system structures. Note that there are two systems of nomenclature for onco-neural antibodies in current use: one system designates antibodies by the first two letters of the surname of the patient in whom the antibody was initially discovered, while the other system names antibodies according to their tissue distribution. Such antibodies are screened by indirect immunofluorescence.
Autoantibodies found in paraneoplastic syndromes include the following:
Any possible imaging study may be useful to detect the primary tumor in patients with paraneoplastic disorders, including the following:
Treatment varies with the type and location of the paraneoplastic disorder. Two general treatment options exist.
The first option is treatment of the underlying tumor. In general, the therapeutic protocols used are those that are applied to the disease in patients without paraneoplastic syndromes (ie, surgery, radiation, or chemotherapy, alone or in combination).
The second therapeutic option, in patients with clearly identifiable antibodies in their serum, is immunosuppression. This may be accomplished with intravenous immunoglobulins,[46, 47] steroids or other immunosuppressive drugs, or plasma exchange. Some patients with paraneoplastic pemphigus[49, 50, 51, 52] seem to derive some benefit from rituximab, but further studies are necessary to confirm this observation.
Standard perioperative care and monitoring before and after radiotherapy or chemotherapy are required. Systematic psychotherapeutic and rehabilitative interventions may also be helpful.
Surgical treatment for patients with paraneoplastic syndromes is typically directed toward the underlying neoplasm. On the other hand, some paraneoplastic disorders may resolve rapidly without surgery on the primary tumor (eg, in patients with hypertrophic osteoarthropathy, resection of either the tumor or the ipsilateral vagus nerve leads to rapid remission of symptoms).
Selected surgical options are as follows:
In patients with paraneoplastic syndromes, therapeutic protocols are those that are usually applied to the underlying neoplastic disorder. If autoantibodies are detected, the best drug to use may be cyclosporine.
Clinical Context: Cyclic polypeptide that suppresses some humoral immunity and, to greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease for variety of organs. Reserve IV use only for those who cannot take PO.
These agents promote immune suppressor cell function related to production of autoimmune reactions.
Clinical Context: Polyclonal IgG cluster against human T lymphocytes. Obtained from horses or rabbits hyperimmunized with human thymus lymphocytes.
Reduces lymphocyte count 85-90% after first dose, as long as circulating antibody concentrations remain high.
These agents may help suppress immune reactions.
Clinical Context: Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Four times as potent as natural glucocorticoids.
These agents may be useful in suppressing immune cell function.