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51-421: In pemphigus, autoantibodies form against desmoglein , which forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes . When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes detached, a phenomenon called acantholysis . This causes blisters that slough off and turn into sores . In some cases, these blisters can cover

102-469: A chronic, progressive fibrosis . Cardiotoxicity is a major problem with people treated with higher dose regimens. High-dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis. While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with

153-433: A foreign protein or substance within the body. Initially, one B cell produces one specific kind of antibody. In either case, the B cell is allowed to proliferate or is killed off through a process called clonal deletion . Normally, the immune system is able to recognize and ignore the body's own healthy proteins, cells, and tissues, and to not overreact to non-threatening substances in the environment, such as foods. Sometimes,

204-496: A half matched or haploidentical donor hematopoietic stem cell transplantation reduces GVHD, even after using a reduced conditioning regimen . Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women ( pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include lactation , active infection, neutropenia or bladder toxicity. Cyclophosphamide

255-524: A high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo . Cyclophosphamide and the related nitrogen mustard –derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds. They converted

306-457: A hormonal component as many of the autoimmune conditions are much more prevalent in women of childbearing age. While the initial event that leads to the production of autoantibodies is still unknown, there is a body of evidence that autoantibodies may have the capacity to maintain their production. The type of autoimmune disorder or disease that occurs and the amount of destruction done to the body depends on which systems or organs are targeted by

357-641: A large area of the skin. Originally, the cause of this disease was unknown, and "pemphigus" was used to refer to any blistering disease of the skin and mucosa. In 1964, researchers found that the blood of patients with pemphigus contained antibodies to the layers of skin that separate to form the blisters. In 1971, an article investigating the autoimmune nature of this disease was published. The several types of pemphigus (pemphigus vulgaris, pemphigus foliaceus, intraepidermal neutrophilic IgA dermatosis, and paraneoplastic pemphigus) vary in severity. Skin lesions caused by pemphigus can lead to fatal infections, so treatment

408-404: A mildly beneficial effect on the disease and are sometimes enough for pemphigus foliaceus. In addition, talcum powder is helpful to prevent oozing sores from adhering to bedsheets and clothes. Wound care and treatments are often akin to those used in burn units, including careful use of dressings that don't stick to the wounds, etc. If paraneoplastic pemphigus is diagnosed with pulmonary disease,

459-413: A person by analyzing the antibodies in body fluids. A unique, individual set of antibodies, called individual specific autoantibodies (ISA), is found in blood, serum, saliva, urine, semen, perspiration, tears, and body tissues, and the antibodies are not affected by illness, medication, or food/drug intake. An unskilled technician using inexpensive equipment can complete a test in a couple of hours. Note:

510-468: A positive double strand anti-double stranded DNA (anti-dsDNA) autoantibody test, but only about 25–30% will have a positive RNP. Some individuals who do have an autoimmune disorder will have negative autoantibody test results, but at a later date – as the disorder progresses - the autoantibodies may develop. Systemic autoantibody tests are used to: Antibody profiling is used for identifying persons from forensic samples. The technology can uniquely identify

561-585: A powerful cocktail of immunosuppressant drugs is sometimes used in an attempt to halt the rapid progression of bronchiolitis obliterans , including methylprednisolone , ciclosporin , azathioprine , and thalidomide . Plasmapheresis may also be useful. Pemphigus foliaceus has been recognized in pet dogs, cats, and horses, and is the most common autoimmune skin disease diagnosed in veterinary medicine. PF in animals produces clusters of small vesicles that quickly evolve into pustules. Pustules may rupture, forming erosions or become crusted. Left untreated, PF in animals

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612-423: A single autoantibody, ribonucleic protein (RNP), is the only one present. Those who have more than one autoimmune disorder may have several detectable autoantibodies. Whether a particular autoantibody will be present is both very individual and a matter of statistics. Each will be present in a certain percentage of people who have a particular autoimmune disorder. For instance, up to 80% of those with SLE will have

663-671: A sulfhydryl donor which binds and detoxifies acrolein. Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of lupus nephritis . Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial , fungal and opportunistic infections . No published guidelines cover PCP prophylaxis for people with rheumatological diseases receiving immunosuppressive drugs , but some advocate its use when receiving high-dose medication. Cyclophosphamide has been found to significantly increase

714-565: Is carcinogenic and may increase the risk of developing lymphomas , leukemia , skin cancer , transitional cell carcinoma of the bladder or other malignancies. Myeloproliferative neoplasms , including acute leukemia , non-Hodgkin lymphoma and multiple myeloma , occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients with no history. Secondary acute myeloid leukemia (therapy-related AML, or "t-AML")

765-567: Is a pregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction , ear and facial abnormalities, absence of digits and hypoplastic limbs . Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting , bone marrow suppression , stomach ache , hemorrhagic cystitis , diarrhea , darkening of

816-603: Is also used to treat minimal change disease , severe rheumatoid arthritis , granulomatosis with polyangiitis , Goodpasture syndrome and multiple sclerosis . Because of its potential side effects such as amenorrhea or ovarian failure , cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or azathioprine . Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an off-label treatment of AL amyloidosis . It appears to be an alternative to

867-791: Is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH . Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis . Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells , liver and intestinal epithelium . ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to

918-492: Is extremely important. Hailey-Hailey disease , also called familial benign pemphigus, is an inherited skin disease, not an autoimmune disease, so it is not considered part of the pemphigus group of diseases. Pemphigus defines a group of autoimmune intraepithelial blistering diseases that are characterized by loss of normal cell-cell adhesion (acantholysis), and by the presence of pathogenic (predominantly IgG) autoantibodies reacting against epithelial adhesion molecules. Pemphigus

969-561: Is further divided in two major subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). However, several other disorders such as IgA pemphigus, IgE pemphigus, pemphigus herpetiformis, drug-induced pemphigus, Senear Usher syndrome, and endemic pemphigus foliaceus exist, and are recognized by a dermatologist from the appearance and distribution of the skin lesions. It is also commonly diagnosed by specialists practicing otolaryngology- head and neck surgery , periodontists, oral and maxillofacial surgeons, and eye doctors , as lesions can affect

1020-565: Is in the alkylating agent and nitrogen mustard family of medications. It is believed to work by interfering with the duplication of DNA and the creation of RNA . Cyclophosphamide was approved for medical use in the United States in 1959. It is on the World Health Organization's List of Essential Medicines . Cyclophosphamide is used to treat cancers and autoimmune diseases . It is used to quickly control

1071-579: Is life-threatening, leading to not only loss of condition, but also secondary infection. PV is a very rare disorder described in pet dogs and cats. Paraneoplastic pemphigus has been identified in pet dogs. Autoantibody An autoantibody is an antibody (a type of protein ) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus ) are associated with such antibodies. Antibodies are produced by B cells in two ways: (i) randomly, and (ii) in response to

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1122-399: Is not diagnostic, but may give clues as to whether a particular disorder is likely or unlikely to be present. Each autoantibody result should be considered individually and as part of the group. Some disorders, such as systemic lupus erythematosus (SLE) may be more likely if several autoantibodies are present, while others, such as mixed connective tissue disease (MCTD) may be more likely if

1173-460: Is often ordered first. ANA is a marker of the autoimmune process – it is positive with a variety of different autoimmune diseases but not specific. Consequently, if an ANA test is positive, it is often followed up with other tests associated with arthritis and inflammation , such as a rheumatoid factor (RF), an erythrocyte sedimentation rate (ESR), a c-reactive protein (CRP), and/or complement protein|complement levels. A single autoantibody test

1224-525: Is often reduced, to lessen side effects. A meta-analysis of the literature found insufficient evidence to determine the optimal treatment regimen for pemphigus vulgaris and pemphigus foliaceus, but it found that adding cyclophosphamid and azathioprine to a glucocorticoid regimen reduced the amount of glucocorticoid needed for treatment, and topical epidermal growth factor significantly reduced lesion healing time. If skin lesions do become infected, antibiotics may be prescribed. Tetracycline antibiotics have

1275-411: Is the administration of oral steroids, especially prednisone , often in high doses. The side effects of corticosteroids may require the use of so-called steroid-sparing or adjuvant drugs. One of the most dangerous side effects of high-dosage steroid treatments is intestinal perforations , which may lead to sepsis. Steroids and other medications being taken to treat pemphigus may also mask the effects of

1326-465: Is thought that some autoantibody production is due to a genetic predisposition combined with an environmental trigger, such as a viral illness or a prolonged exposure to certain toxic chemicals. There is generally not a direct genetic link however. While families may be susceptible to autoimmune conditions, individual family members may have different autoimmune disorders, or may never develop an autoimmune condition. Researchers believe that there may also be

1377-799: Is thought to occur either by cyclophosphamide-inducing mutations or selecting for a high-risk myeloid clone. This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy ), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years,

1428-500: Is used in nephrotic syndrome , granulomatosis with polyangiitis , and following organ transplant , among other conditions. It is taken by mouth or injection into a vein . Most people develop side effects. Common side effects include low white blood cell counts , loss of appetite, vomiting, hair loss , and bleeding from the bladder . Other severe side effects include an increased future risk of cancer, infertility , allergic reactions , and pulmonary fibrosis . Cyclophosphamide

1479-545: The placenta and are known to be present in breast milk . It is specifically in the oxazaphosphorine group of medications. Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction. Drugs altering hepatic microsomal enzyme activity (e.g., alcohol , barbiturates , rifampicin , or phenytoin ) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of

1530-470: The autoantibodies, and how strongly. Disorders caused by organ specific autoantibodies, those that primarily target a single organ, (such as the thyroid in Graves' disease and Hashimoto's thyroiditis ), are often the easiest to diagnose as they frequently present with organ related symptoms. Disorders due to systemic autoantibodies can be much more elusive. Although the associated autoimmune disorders are rare,

1581-464: The base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently actively transported into cancer cells. Once in the cells, the prodrug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s. In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA . The abbreviation CP

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1632-442: The breaking apart of epidermal cells (acantholysis). Thus, the superficial (upper) portion of the epidermis sloughs off, leaving the bottom layer of cells on the "floor" of the blister. This bottom layer of cells is said to have a "tombstone" appearance. Definitive diagnosis also requires the demonstration of antidesmoglein autoantibodies by direct immunofluorescence on the skin biopsy. These antibodies appear as IgG deposits along

1683-453: The desmosomes between epidermal cells, a pattern reminiscent of chicken wire. Antidesmoglein antibodies can also be detected in a blood sample using the ELISA technique. Pemphigus is a group of autoimmune blistering diseases that may be classified into these types: If not treated, pemphigus can be fatal, usually from overwhelming opportunistic infection of lesions. The most common treatment

1734-428: The development of cyclophosphamide and its clinical applications, Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954 ...It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had

1785-471: The disease. Due to its toxicity, it is replaced as soon as possible by less toxic drugs. Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity . The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas , some forms of brain cancer , neuroblastoma , leukemia and some solid tumors. Cyclophosphamide decreases

1836-501: The doctor may request one or more diagnostic studies that will help to identify a specific disease. As a rule, information is required from multiple sources, rather than a single laboratory test to accurately diagnose disorders associated with systemic autoantibodies. Tests may include: Autoantibody tests may be ordered as part of an investigation of chronic progressive arthritis type symptoms and/or unexplained fevers, fatigue, muscle weakness and rashes. The antinuclear antibody (ANA) test

1887-627: The drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. corticosteroids , tricyclic antidepressants , or allopurinol ) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects. Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine . Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein. The main effect of cyclophosphamide

1938-456: The eyes and mucous membranes of the oral cavity. Intraorally, it resembles the more common diseases lichen planus and mucous membrane pemphigoid . Definitive diagnosis requires examination of a skin or mucous membrane biopsy by a dermatopathologist or oral pathologist. The skin biopsy is taken from the edge of a blister, prepared for histopathology and examined with a microscope. The pathologist looks for an intraepidermal vesicle caused by

1989-404: The fact that a person may have more than one autoantibody, and thus have more than one autoimmune disorder, and/or have an autoimmune disorder without a detectable level of an autoantibody, complicating making a diagnosis. The diagnosis of disorders associated with systemic autoantibodies starts with a complete medical history and a thorough physical exam. Based on the patient's signs and symptoms,

2040-463: The immune system ceases to recognize one or more of the body's normal constituents as "self", leading to production of pathological autoantibodies. Autoantibodies may also play a nonpathological role; for instance they may help the body to destroy cancers and to eliminate waste products. The role of autoantibodies in normal immune function is also a subject of scientific research. The causes of autoantibody production are varied and not well understood. It

2091-405: The immune system's response , and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide

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2142-554: The liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide , which exists in equilibrium with its tautomer , aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide . A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein. The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross

2193-399: The lower doses used in the management of inflammatory disorders. Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis , which is associated with microscopic or gross hematuria and occasionally dysuria . Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and mesna (sodium 2-mercaptoethane sulfonate),

2244-416: The more traditional treatment with melphalan in people who are ill-suited for autologous stem cell transplant. Graft-versus-host disease (GVHD) is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them. GVHD can often be avoided by T-cell depletion of the graft. The use of a high dose cyclophosphamide post-transplant in

2295-404: The perforations. Patients on high dosages of oral steroids should closely monitor their gastrointestinal health. As lesions are usually terribly painful, pain medication likely complicates and exacerbates the gastrointestinal issues caused by steroids. All of these drugs may cause severe side effects, so patients should be closely monitored by doctors. Once the outbreaks are under control, dosage

2346-412: The risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics , which carries a worse prognosis than de novo AML. Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes ( cytochrome P450 system) in

2397-437: The risk of premature menopause in females and of infertility in males and females, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary, but can be permanent. The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility. Cyclophosphamide

2448-503: The sensitivity and specificity of various autoantibodies for a particular disease is different for different diseases. Cyclophosphamide Cyclophosphamide ( CP ), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system . As chemotherapy it is used to treat lymphoma , multiple myeloma , leukemia , ovarian cancer , breast cancer , small cell lung cancer , neuroblastoma , and sarcoma . As an immune suppressor it

2499-512: The signs and symptoms they cause are relatively common. Symptoms may include: arthritis -type joint pain, fatigue, fever, rashes, cold or allergy-type symptoms, weight loss, and muscular weakness. Associated conditions include vasculitis which are inflammation of blood vessels and anemia . Even if they are due to a particular systemic autoimmune condition, the symptoms will vary from person to person, vary over time, vary with organ involvement, and they may taper off or flare unexpectedly. Add to this

2550-529: The skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, lethargy , and profound gonadotoxicity. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine or unusual tiredness or weakness. Potential side effects also include leukopenia, infection, bladder toxicity, and cancer. Pulmonary injury appears rare, but can present with two clinical patterns: an early, acute pneumonitis and

2601-737: The toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation . Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy . Suggested mechanisms include: Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity. As reported by O. M. Colvin in his study of

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