Immunosuppressive agents in Dermatology

Abstracts

Os imunossupressores são drogas que agem na divisão celular e têm propriedades anti-inflamatórias. Sendo assim, são essencialmente prescritos na prevenção de rejeição de transplantes e no tratamento das doenças autoimunes e inflamatórias crônicas, que, na Dermatologia, têm a psoríase como maior representante. Nesta sessão serão descritas as principais drogas imunossupressoras, com orientações para seu manejo adequado.

Azatioprina; Ciclofosfamida; Ciclosporina; Imunossupressores; Metotrexato

CONTINUING MEDICAL EDUCATION

Immunosuppressive agents in Dermatology^*

Aline Lopes Bressan^I; Roberto Souto da Silva^II; Elisa Fontenelle^III; Alexandre Carlos Gripp^IV

^IPostgraduate student of Dermatology at Hospital Universitario Pedro Ernesto - Rio de Janeiro (RJ), Brazil

^IIResident Physician in Dermatology at Hospital Universitario Pedro Ernesto - Rio de Janeiro (RJ), Brazil

^IIIEffective member of the Brazilian Society of Dermatology; Adjunct Professor of Dermatology at Hospital Universitario Pedro Ernesto; Dermatologist at Hospital Municipal Jesus; Head of the Pediatric Dermatology Ambulatory at Instituto de Dermatologia Prof. Azulay - Santa Casa de Misericordia do Rio de Janeiro - Rio de Janeiro (RJ), Brazil

^IVM.S. in Dermatology; Assistant Professor of Dermatology and Head of the Dermatology Unit at Hospital Universitario Pedro Ernesto - Rio de Janeiro (RJ), Brazil

Mailing Address

ABSTRACT

Immunosupressants are drugs that act in cell division and have anti-inflammatory effects. Therefore, they are essentially prescribed in the prevention of transplant rejection and in the treatment of autoimmune disorders and chronic inflammatory diseases, whose main example in Dermatology is psoriasis. In this work the most important immunosuppressive drugs and orientation to properly administer them are going to be described.

Keywords: Azathioprine; Cyclophosphamide; Cyclosporine; Immunosuppressive agents; Methotrexate

INTRODUCTION

Treatment with immunosuppressive drugs is necessary to prevent the rejection of a transplanted organ. They also act against inflammatory diseases, the main target in clinical Dermatology. These drugs inhibit cell division and have anti-inflammatory effects. Their use is indicated to treat psoriasis, pemphigus and pemphigoids, and lymphomas, among others.

Before starting an immunosuppressive therapy, it is crucial to know the indications, contraindications, adverse reactions, and drug interactions associated with the administration of these drugs, so that the risks of treatment are minimized. Some of them can be prescribed for children, but the child's immunization card must be up-to-date (they should be vaccinated 2-4 weeks before the start of treatment), and live-virus vaccines should be avoided during treatment.¹ Other procedures should be followed, such as: collection of a detailed anamnesis, considering the patient's age, drugs being used, and co-morbidities; prophylaxis of strongyloidiasis, and orientation to the patient about immunosuppressive therapy. Routine pretreatment examination, together with clinical findings, will determine the most appropriate drug and its respective dosage.

The objective of any medical therapy is to cure or alleviate the symptoms of diseases with the least harm to the patient. This is possible due to the vast arsenal of drugs and biologic agents available, which have adapted immunosuppressive therapies to the individual needs of patients. The basic premises of immunosuppression individualization are: different degrees of severity, susceptibility to the occurrence of side effects, and negative influence of co-morbidities. Consequently, individualization seeks to maximize success, reduce side effects, and adapt immunosuppressive therapy to the patient's clinical condition.^2,3

The goal is to make immunosuppressive therapy become progressively more used with individualization, given that the therapeutic drug arsenal currently available allows a rational combination of drugs with high efficiency.

The immunosuppressive drugs more frequently prescribed in Dermatology will be described below, together with their mechanisms of action, indications, posology, control, drug interactions, and adverse reactions.

AZATHIOPRINE

Introduction: Azathioprine is a synthetic analogue of purine, derivative of 6-mercaptopurine (6-MP), developed in the late 1950s.⁴ After discovery of its anti-inflammatory and immunosuppressive effects, Dermatology started using it to treat inflammatory diseases.

Mechanism of action and pharmacokinetics: The active metabolite of azathioprine is 6-thioguanine, an analogue of purine, structurally similar to guanine and adenine. Instead of having hidroxyl or amino groups, it has a thiol group. Incorporation of 6-thioguanine into DNA and RNA inhibits purine metabolism and cell division. Other activities of 6-thioguanine are suppression of T-cell function, suppression of B-cells antibody production, reduction in the number of epidermal Langerhans cells, and inhibition of their capacity to present antigens. In other words, it inhibits cell and humoral immunity and the effective phase of the immune response.

The bioavailability of azathioprine is around 88%. After oral administration, it is quickly absorbed and approximately 30% circulate in the blood bound to plasma proteins.⁴ In the liver the drug suffers the action of xanthine oxidase and is converted into 6- mercaptopurine. It then undergoes three major competing metabolic routes. The first two, of xanthine oxidase and thiopurine methyltransferase, produce inactive metabolites. The metabolic route of hypoxanthine-guanine phosphoribosyltransferase, the only anabolic route, produces the analogue of purine 6-thioguanine monophosphate, an active metabolite. When the metabolic routes of xanthine oxidase or thiopurine methyltransferase are blocked, 6-mercaptopurine is deviated in greater quantity to the anabolic route, thus producing more active metabolites, which can result in excessive immunosuppression and pancytopenia.⁵

The metabolic route of thiopurine methyltransferase is guided by genetic polymorphism, which produces three phenotypes with different activities. Studies have shown that 89% of Caucasians are homozygous for the high-activity allele, thus showing high enzymatic activity; 11% are heterozygous and show moderate activity; 1/300 are homozygous for one of the seven low-activity alleles, thus presenting reduced thiopurine methyltransferase activity.⁶ For better control and dose adjustment, a blood test that evaluates this activity has been developed. Its basal level may provide orientation regarding the need to increase the prescribed dosage (for patients with high enzymatic activity), thus avoiding the use of underdosage, or to reduce it (for patients with low enzymatic activity), in order to avoid myelotoxicity. Azathioprine crosses the placental barrier, but does not cause congenital abnormalities. Teratogenic effects primarily involving the skeletal system have been reported in patients submitted to azathioprine and prednisone combination regimens. It is classified as a category D drug (positive evidence of human fetal risk; use indicated only in cases where benefits outweigh the considered risks) and LMX (safety has not been established in nursing mothers). ⁷ There is higher risk of infections and fetal hematologic alterations because azathioprine alters leukocyte function. The risks of a long-term treatment to children's health are unknown.⁵

Azathioprine has a short half-life of about three hours, but metabolites remain active for a long time, allowing administration of the drug every 12 or 24 hours. Subsequently, it is degraded to nicotinic acid and excreted when it passes through the kidneys. Despite the fact that azathioprine is approved by the FDA for non-dermatologic use (for instance, in renal transplant), dermatologists have been using this drug for more than 35 years to treat severe dermatosis, always considering the risk-benefit ratio.

Indications (as monotherapy or corticosteroid sparer):⁴ pemphigus vulgaris; bullous pemphigoid; gestational pemphigoid; cicatricial pemphigoid; lupus erythematosus; dermatomyositis; vasculitis; atopic dermatitis. Other indications: relapsing polychondritis; scleroderma; psoriasis; pyoderma gangrenosum; chronic actinic dermatitis; acne fulminans; pityriasis rubra pilaris; Behcet's disease; sarcoidosis.

Contraindications: Hypersensitivity to the drug; gestation; active infection.

Routine laboratory pretreatment procedures: Complete blood count; glycemia; urea and creatinine; hepatography; serology tests for HIV and HTLV-1; βhCG; abnormal elements and urine sediments; parasitological fecal test; thoracic radiography; PPD test; evaluation of thiopurine methyltransferase activity (since it is not yet widely available, it should not delay the start of treatment).

Posology: Azathioprine is available in tablet form for oral administration. Each scored tablet contains 50 mg Azathioprine USP. It should be prescribed in the dosage of 1-3 mg/kg/day and taken with food. 8 It can be prescribed in a single dose or be divided into two doses. The second dose is associated with fewer incidences of nausea and vomiting.

Follow-up and dose adjustment: Patients should receive follow-up care by being submitted to clinical and laboratory examinations during treatment with azathioprine. In the first month, weekly complete blood counts are performed. In the second month, they should be done every fifteen days. After that, they are done every two months. Renal and hepatic functions are evaluated monthly in the first two months. From the third month on, they are evaluated every two months.

Azathioprine should be used with caution in patients with renal or hepatic insufficiency, and dose adjustment may be necessary. The clinical response of azathioprine is noticed 4-6 weeks after the start of treatment. If after 16 weeks clinical benefit of maximum therapeutic dosage is not observed, therapy must be suspended.⁴ When the disease is under control, the prescribed dose should be reduced by 0.5 mg/kg every 2-4 weeks. Leukocyte count inferior to 4,000 or thrombocytopenia < 150,000 indicate the need to reduce and monitor the dosage. if leukopenia < 2,000 or platelet count < 100,000, the drug must be suspended until levels are back to normal (after 2-3 weeks). azathioprine can then be reintroduced in a dose 25-50% inferior to that of initial therapy.⁴

The carcinogenic potential of azathioprine is well known. Its use has been associated with an increase in the incidence of cutaneous tumors, non-Hodgkin lymphomas, carcinoma of the cervix, vulva, and Kaposi's sarcoma (in renal transplant patients, used in combination with corticosteroids).⁴ Routine physical and gynecological exams must be done for early detection of cutaneous tumors, adenomegalies, and genital carcinomas. Neoplasm screening must be done yearly, but apparently there is no increase in the incidence of other tumors. Nontransplanted patients are at lower risk for the development of neoplasm, probably due to the use of lower azathioprine doses, for a shorter period of time, or even due to the absence of chronic antigenic stimulus by the transplanted organ.

Drug interactions: Several drugs interact with azathioprine, and the most well known is allopurinol, which is a xanthine oxidase inhibitor, thus increasing the risk of severe myelotoxicity. If both drugs need to be used in combination, the dose of azathioprine should be reduced by 25-30%. In addition, hematology tests must be performed frequently.⁹ Captopril may increase the risk of leukopenia. It can reduce the effects of warfarin and pancuronium, and higher doses of these drugs may be needed. Azathioprine can lower the effectiveness of intrauterine devices, so the patient needs to use alternative contraceptive methods.^5,10

Adverse reactions and conducts:

Hematology: bone marrow suppression is the most important side effect because the drug acts more evidently on rapid division cells. It is often dose-dependant and manifests itself through leukopenia, thrombocytopenia or even pancytopenia. Myelotoxic effects can appear later in the treatment.⁴ Most cases will improve with dose reduction or discontinuation of treatment.

Gastrointestinal: These are the most common reactions. 10-20% of patients who receive conventional dose present nausea and vomiting. These symptoms can occur only in the first weeks of treatment or become very intense and dose limiting. In most cases, dose reduction or fractioning or administration with food alleviate the symptoms. Less frequently, diarrhea, abdominal discomfort, and oral ulcerations may occur.⁴

Hepatic: Often occur when the dose used is greater than 2.5 mg/kg/day, and manifest themselves through hepatic enzymes alterations (more frequently in transplanted patients). The condition can be reverted with dose reduction or discontinuation of methotrexate administration.⁴

Hypersensitivity reactions: Develop during the first month of treatment and are characterized by fever, pneumonia, pancreatitis, hypotension, nephritis, diarrhea, and morbiliform exanthem.¹¹ Although relatively rare, it is a potentially serious complication.

METHOTREXATE

Introduction: In the 1940s, during tests to determine the effect of folic acid on acute leukemia in children, the antifolate (methotrexate) was synthesized. It was later approved by the FDA as an oncologic drug in 1953. Mechanism of action and pharmacokinetics: Methotrexate is a chemical analogue of folic acid capable of competitively and irreversibly inhibiting the enzyme dihydrofolate reductase. Therefore, the conversion of dihydrofolate into tetrahydrofolate does not occur, a necessary co-factor for the transfer of carbon atoms, essential to DNA and RNA synthesis.¹² It also inhibits, in a partially reversible way, the enzyme thymidylate synthase, involved in cell proliferation.

In 1951, the first effects of the drug were observed in the treatment of psoriasis. In 1971, methotrexate was approved by the FDA as a conventional treatment.¹³ Initially, it was thought that the effect of the drug was exclusively due to the inhibition of keratinocyte proliferation (antiproliferative property), but recently new discoveries have been made: the action of methotrexate on lymphocytes and its effects on adenosine, a potent anti-inflammatory mediator.

It has been shown that methotrexate acts both on circulating and cutaneous lymphocytes. In vitro , keratinocytes have proved to be a thousand times more resistant to its cytotoxic effects than lymphoid cells,¹³ confirming its immunosuppressive property. Methotrexate acts on the metabolism of adenosine, causing its accumulation.⁵ In excess, adenosine binds to A2A receptor in endothelial cells, inhibiting apoptosis, neutrophil chemotaxis, and release of TNFα, IFNγ, IL-12, IL-6 (Figure 1). This explains its anti-inflammatory activity.

One hour after administration of the drug, its distribution and cell entry are complete. Fifty percent of methotrexate is bound to proteins in blood circulation. It has particular affinity for hepatocytes, myeloid precursors, erythrocytes, and fibroblasts. It is converted into polyglutamate structure (predominantly active), which persists for months, allowing the prescription of weekly doses. It is excreted mainly by the kidneys (active secretion in the proximal renal tubules) and it is completed in 4 hours. Biliary excretion occurs to a lower degree. In the following 24 hours, the drug is slowly released from tissues.⁵

Indications: Psoriasis (erythrodermic; moderate to severe arthropathic; pustular; extensive chronic plaque psoriasis; refractory to phototherapy and/or retinoid; extensive ungual psoriasis; "social" psoriasis); Sézary syndrome; pityriasis rubra pilaris; pityriasis lichenoides and varioliformis acuta; Reiter's syndrome; bullosis (bullous pemphigoid; pemphigu vulgaris and foliaceus; cutaneous porphyria; epidermolysis bullosa acquisita); collagenoses (lupus erythematosus; dermatomyositis; scleroderma); vasculitis and neutrophilic dermatoses (polyarteritis nodosa, Behcet's disease, leukocytoclastic vasculitis, Kawasaki disease, pyoderma gangrenosum); atopic dermatitis. Other indications: Sarcoidosis, lymphomatoid papulosis; mycosis fungoides; keratoacanthoma; cutaneous Crohn's disease; chronic idiopathic urticaria; dyshidrotic syndrome.

Absolute contraindications: Pregnancy or breastfeeding; hepatic and/or renal insufficiency; active peptic ulceration;¹⁴ leukopenia (< 3,500); thrombocytopenia (< 100,000); anemia (Hb < 11); active infection. relative contraindications: hepatopathy;¹⁵ renal function alteration; chronic peptic disease; HIV infection; excessive alcohol intake; difficulty of comprehension.

The main risk factors are: obesity, alcoholism, hypoalbuminemia; hypocalcemia; systemic arterial hypertension; diabetes mellitus, and advanced age.

Routine laboratory pretreatment procedures: Complete blood count; urea and creatinine (small alterations in renal function can have a great effect on the serum level of methotrexate. In the elderly, the low level of creatinine may not reflect true renal function); glycemia; 24 hour creatinine and proteinuria clearance (if clearance > 50, the conventional dose is administered; between 10-50 ml/min, only 50% of the dose is given, and if it is < 10, avoid use); hepatography; total and fraction proteins; serum calcium; serology tests for hepatitis, hiv, and HTLV-1; βhcg; urine sediment exam; thoracic radiography, and PPD test.

Posology: Methotrexate is available in tablet form (2.5 mg) or 2 ml injection solution containing 50 mg of the drug (25mg/ml). The test dose for admitted adult patients should be 10 mg/week administered intra-muscularly; for ambulatory patients, the starting dose should be 7.5 mg/week administered orally. The weekly dose varies between 7.5 and 25 mg. The doses administered should be recorded by the patient so that accumulated doses can be monitored.

Oral methotrexate can be prescribed in a single weekly dose or divided into three administrations with 12-hour intervals. The single dose should be preferably taken in the evening before the patient's rest (if there is one), because it masks fatigue and nausea that may occur.

Injection solution can be an option for oral administration in children, mixed in fruit juices, for example. The dose for children should be between 0.25-0.75 mg/kg/week.

Oral administration of methotrexate maintains its bioavailability equivalent to that of IM administration up to the dose of 7.5 mg/week, because beyond this dose intestinal active transport becomes saturated, possibly reducing methotrexate absorption by up to 30%. Bioavailability of intramuscular administration of methotrexate is equivalent to that of IV administration, and the former is associated with lower gastrointestinal toxicity. The administration route can be altered any time during treatment due to gastrointestinal symptoms and/or low therapeutic response.

Methotrexate can also be administered intralesionally, being indicated for treatment of keratoacanthoma.

Follow-up and dose adjustment: Five days after administration of the first dose, the patient must be submitted to a complete blood count due to the risk of pancytopenia. In the first month, weekly blood counts and hepatographies are necessary. They should always be performed after increase of dosage. After the second month, blood count, hepatography, and nitrogenous waste products measurement should be done every 2 months. More frequent laboratory follow-ups should be considered when methotrexate is associated with other drugs and/or in the presence of co-morbidities. The weekly dose can be increased by 2.5-5.0 mg every week, until a satisfactory response is obtained, with minimum toxicity. It often does not go over 25 mg/week, for intramuscular administration, and 20 mg/week, for oral administration. After the disease has been under control for at least 2 months, due to the polyglutaminate structure, interval between doses may be increased (with consequent reduction of the dose administered).

Hepatic enzymes can suffer transitory alteration in the two days following administration of the drug. Therefore, it is recommended that exams be performed 5-7 after administration. Medium corpuscular volume (MCV) can be an early indicator of myelotoxicity, thus specifying the need to reduce the dosage.

Drug interactions: Drugs that increase methotrexate plasma level are: salycilates, non-hormonal antiinflammatories, sulphonamides, dipyridamole, probenecid, chloramphenicol, phenotyazine, phenytoin, tetracycline. Drugs that inhibit the synthesis of folates, increasing hematologic toxicity - dapsone, trimethoprim, sulphonamides, and those that have the liver as target organ, increasing hepatoxicity - retinoids and alcohol.

Adverse reactions and Conducts: The main adverse reactions associated with methotrexate are:

Short-term: Hematologic effects, especially pancytopenia. Patients at higher risk are the elderly, users of other drugs that inhibit the synthesis of folate, and patients with hypoalbuminemia (higher level of circulating drug). Alterations include: leukopenia, thrombocytopenia, megaloblastic or normocytic anemia, and pancytopenia. Red light for possible pancytopenia includes high MCV and mucositis. ¹⁶ Methotrexate dose must be reduced or discontinued, the dose of folic acid must be optimized, and the patient should be referred to a hematologist if diagnosed with pancytopenia.

Based on the mechanism of action and toxicity of methotrexate by means of folate depletion, studies have been conducted with daily folate or folic acid supplementation and administration of folinic acid following methotrexate. All of them confirmed reduction of side effects, without loss of efficacy. Folic acid (dihydrofolic acid) is ingested from food and folinic acid (tetrahydrofolic acid) is used effectively by metabolic routes. This is the antidote for overdosage of methotrexate (Leucovorin calcium® - 10mg/m2 of body surface).¹⁷ 1-5 mg/day of acid folic can be administered, of which 1 mg is the dose indicated regularly and 5 mg, the dose indicated when methotrexate is > 15mg/week or when there are signs of myelotoxicity. In children, the dose should be 1 mg/day if they are > 1 year old and 50 Ìg/kg/day if they are < 1 year old. its use apparently not only reduces myelotoxicity, but also mucositis, hepatoxicity, and nausea. other short-term side effects are: mucocutaneous - mucositis, oral and/or gastrointestinal ulcerations (deposit in peptic cells, with hemorrhage), rash, photosensitivity, burning, and ulceration of psoriasis lesions (may indicate toxicity by methotrexate),¹⁸ acne, alopecia, rheumatoid nodules; digestive system: anorexia, diarrhea, nausea (close to drug administration), and interstitial pneumonitis, especially in patients with hypoalbuminemia.

Long-term: hepatic alterations. The risk increases with excessive alcohol intake, diabetes mellitus, and obesity or combined use of retinoid. The following may occur: elevated transaminases, steatosis and cirrhosis (rare in children). The risk appears to be higher in psoriasis than rheumatoid arthritis, because the former is closely associated with plurimetabolic syndrome. The dosage of transaminases must be monitored and if their level is < 2 times the normal limit, exams must be repeated in 2-4 weeks. if their level is 2-3 times the normal limit, exams are repeated in 2-4 weeks and the dose may be reduced if necessary. if their level is >2 times persistent or >3 times, the drug must be suspended and the patient must be evaluated by a gastroenterologist.

Liver biopsy must be performed before therapy in the following cases: alcohol abuse, hepatic enzymes persistently abnormal; hepatopathy; previous use of methotrexate with no record of accumulated dose or use of other hepatotoxic drugs. During treatment, biopsy should be avoided and rotational therapy should be implemented. In patients without enzymatic alterations, it should be evaluated after accumulated dose of 1.5 g. If results are normal, it should be reevaluated after 4 g of accumulated dose. In patients with hepatography results continually altered, biopsy is indicated independently of the accumulated dose. Indications for continuing or interrupting treatment with methotrexate must consider the interpretation of findings and the following classification:¹⁹

Level I: normal liver tissue; maintenance of treatment.

Level II: moderate to severe steatosis; maintenance of treatment.

Level IIIA: light fibrosis; repeat biopsy after 6 months and change therapy.

Level IIIB: moderate to severe fibrosis; discontinuation of treatment.

Level IV: cirrhosis; discontinuation of treatment and evaluation by a gastroenterologist.

In some studies, high levels of procollagen type III aminoterminal peptide⁴ were observed to be serologic markers of fibrosis (without organ specificity). In the future, they may help determine which patients should be submitted to liver biopsy.

Other long-term adverse reactions:

Pulmonary fibrosis, which occurs idiosyncratically. Any respiratory symptom should be considered. It can determine an increase of procollagen type III aminoterminal peptide.

Malignancy: The risk of lymphomas is apparently greater in patients with psoriasis²⁰ or rheumatoid arthritis, but it is not known if this is related to the disease and/or the treatment.

Cardiovascular: The acid folic that has been ingested acts on the conversion of homocysteine into methionine. If there is deficiency of folic acid, methilation reactions become compromised. High plasma homocysteine concentrations have been associated with increased risks of occlusive vascular diseases. In reality, we notice a slight risk due to administration of folic acid and the anti-inflammatory properties of methotrexate.²¹

Reproductive organs: Methotrexate is classified as a GRX category drug (with well-established human fetal risks. It should not be used by pregnant women or women of childbearing potential) and as an LMX category drug (contraindicated in nursing mothers), based on the risk categories proposed by the FDA. 7 Methotrexate causes defective oogenesis or spermatogenesis, abortion, and teratogenicity. If the patient wishes to become pregnant, drug administration should be interrupted for at least 4 months and acid folic supplementation should be maintained throughout pregnancy. Male patients should also avoid conceiving in the three months following interruption of methotrexate therapy.²²

Osteoarticular: Long-term high doses of methotrexate may reduce bone density. Osteopathy induced by methotrexate is characterized by bone pain, osteoporosis, and fractures (particularly of the distal tibia and vertebral region).²³ The risk becomes greater if methotrexate is used in combination with corticosteroids. Early diagnosis can be established with magnetic nuclear resonance. Calcium supplementation is indicated for children in the following dosages: 1-3 years old: 500mg/day; 4-8 years old: 800mg/day; >9 years old: 1300mg/day, with combined intake of vitamin D (200UI/day).

Clinical response and therapeutic failure: The first clinical response is expected between 1-7 weeks, but maximum response should be observed in 2-3 months. Therapeutic failure is characterized when the patient follows treatment according to medical orientation, but remission is not observed. Some factors should be evaluated. The first is the route of administration, because there is great individual variability in the absorption of the drug, as well as in intestinal absorption saturation (substitute oral administration for intramuscular or subcutaneous administration, with the advantage of allowing self-administration); observe if there is high intake of caffeine, because caffeine is an antagonist of adenosine receptor; lastly, do not take the drug with food (especially milk derivative products), since they can alter the bioavailability of the drug.

CYCLOPHOSPHAMIDE

Introduction: Cyclophosphamide is a nitrogen mustard alkylating agent that was synthesized in 1958.²⁴ It is approved by the FDA for the treatment of mycosis fungoides; however, it is used to treat several dermatologic diseases. Its main characteristics are the fact that it is not specific to any phase of the cell division cycle; it suppresses B-lymphocytes more than it does T25 lymphocytes and, among the latter, it affects more intensely T suppressor cells (CD8) than auxiliary (CD4).

Mechanism of action and pharmacokinetics: The alkylating agent acts in the following manner: it crosses the nuclear membrane, binds to DNA and inhibits the synthesis of guanine, cytosine, and adenine, supplanting capacity of repair, with consequent cell apoptosis. The drug is extensively distributed in the body, including passage through the hematoencephalic barrier.²⁶ The oral bioavailability of the drug is 75%, achieving plasma peak levels one hour after administration. Its half-life is of 2 to 10 hours in the body. It is a prodrug: it needs to be metabolized by cytochrome P450 in the liver to be converted into its active form 4- hydroxycyclophosphamide. Despite the fact that only 13% of the drug is protein bound, approximately 50% of its metabolites are bound to proteins. The kidneys are responsible for half of the excretion of its inactive metabolites. Among them, acrolein is the one responsible for hemorrhagic cystitis and transitional cell carcinoma of the bladder.

Indications (as a monotherapy or corticosteroid sparer): Vasculitis (especially Wegener's granulomatosis); bullosis; neutrophilic dermatosis; collagenosis; infiltrative diseases, histiocytosis X. Absolute contraindications: Pregnancy and/or breastfeeding, hypersensitivity to cyclophosphamide; bone marrow depression. Relative contraindications: Hepatopathy, nephropathy.

Routine laboratory pretreatment procedures: Complete blood count (leukocytes > 5,000/mm3 and granulocytes >2,000/mm3); urea and creatinine; hepatography; abnormal elements and urine sediments; parasitological fecal test; serology tests (hepatitis, HIV infection); PPD; thoracic radiography; β-hCG.

Posology: The recommended oral dose is 1-5 mg/kg/day, which can be divided or administered in the morning in a single dose. It is available in tablet form containing 25 and 50 mg or ampoules of 200mg. It is essential that a great amount of liquid be ingested before and during administration of the drug to avoid the risks of hemorrhagic cystitis. To treat dermatologic diseases, the dose is rarely greater than 2-2.5mg/kg/day. Another important factor is that dosages greater than 200mg/day carry high risk of myelosuppression, and this effect is not necessary to achieve the desired immunosuppression. Cyclophosphamide can also be administered parenterally, by means of pulse therapy. In this case, monthly infusions are done until the sixth month. After that, infusions should be done every three months. The dose is increased until the third application: 1st infusion with 10mg/kg; 2nd infusion with 12.5mg/kg, and 3rd infusion with 15 mg/kg. The third dose should be maintained until the end of treatment. When pulse therapy is done, the recommended dose should be diluted in 500ml of GS5% infusing it in 3 to 4 hours. In addition, some recommendations are necessary: generous hydration (1000 ml of NaCl 0,9%), instruct the patient to keep a high urine flow and perform a blood count after the 14th day (nadir).

Another form of cyclophosphamide administration is pulse therapy associated with dexamethasone.²⁷ This combination regimen is indicated in cases of very severe pemphigus or those cases refractory to usual therapy. The cyclophosphamide-dexamethasone pulse therapy regimen would be implemented with intervals of 21 or 28 days. On the first day sequential cyclophosphamide-dexamethasone pulses are done. On the second and third days, only dexamethasone is used. Cyclophosphamide (1000mg or 10-15 mg/kg) is diluted in 500ml of GS5%, infusing it in 3 to 4 hours. Dexamethasone 100mg (2ml ampoule with 25 mg - 4 ampoules) is diluted in 250 ml of GS5%, infusing it in 3 to 4 hours. The main recommendations are to maintain intravenous hydration in the three days, to administer bromopride 10 mg and/or ondansetron in cases of nausea, and to evaluate vital signs at short intervals. If the patient is diabetic, a hemoglucotest should be performed every 6 hours and a regular insulin regimen should be prescribed. Corticosteroid should be reduced until the minimum dose. At least six cycles are necessary. These can be maintained for up to 2 years. If a significant response is obtained after the 6th cycle, cycles every 2 or 3 months should be attempted.

Our personal experience leads us to believe that pulse therapy with cyclophosphamide guarantees better results than daily doses of the drug, and it also reduces the occurrence of side effects.

Follow-up: Clinical evaluation (physical exam, preventive gynecological examination, and thoracic radiography) every six months; complete blood count, abnormal elements and urine sediments (weekly for 2 to 3 months; after that, every two weeks). After six months, if the patient is stable, they should be done every three months. Monthly TGO and TGP should be done in the first three months and after that every three months. During treatment, drug administration must be interrupted if the following occur: leukocytes < 4,000 cells/mm3; platelet count < 100.000mm3 or hematuria.

Drug interactions: Major drugs that can increase serum levels of cyclophosphamide are: cimetidine, allopurinol, and chloramphenicol. Chlorambucil and mechlorethamine have crossed reaction and may lead to hypersensitivity to cyclophosphamide.

Adverse reactions: The most common are hematologic reactions (leukemia, lymphoma, pancytopenia), gastrointestinal (hepatoxicity, nausea, vomiting) and genitourinary (bladder cancer, hemorrhagic cystitis²⁸). Other reactions: amenorrhea, azoospermia, seizures, peripheral neuropathy, pneumonia, opportunistic infections, cutaneous eruptions, anagen effluvium, and diffuse hyperpigmentation. Chronic use of low doses increases the risk of transitional cell carcinoma when compared with the administration of high doses for a short period of time. Moreover, the combined use of the drug with corticosteroid causes stronger immunosuppression.

CYCLOSPORINE

Introduction: The drug belongs to the family of calcineurin inhibitors and it was initially approved by the FDA in 1983 to reduce the risk of organ transplant rejection. Later, it was approved to treat rheumatoid arthritis and psoriasis.

Mechanism of action and pharmacokinetics: It is a prodrug - it is inactive until bound to its cytoplasmic receptor, known as cyclophilin. Inside T cells, the complex cyclosporine-cyclophilin inhibits the activity of phosphatase calcineurin responsible for the dephosphorylation of nuclear factors of active T lymphocytes. Dephosphorylation allows the translocation of the nuclear factor of active T cells from the cytoplasm to the nucleus, activating T cells and producing cytosines such as IL-2 and IFNγ. This explains why T cells are particularly sensitive to the inhibitory effects of cyclosporine. Some studies have shown that inhibition of calcineurin directly affects the proliferation of keratinocytes. Thus, cyclosporine inhibits the release of cytosines, the activation of lymphocytes, the release of mast cells mediators, and the proliferation and secretion of cytosines by keranocytes, in addition to having an important anti-inflammatory effect. Contrary to other immunosuppressive drugs with cytotoxic action, cyclosporine does not cause bone marrow suppression and teratogenic effects.²⁹

After administration, the bioavailability of the drug is 30-35%, with peak concentration levels varying from 2 to 4 hours. When the drug enters the blood circulation, it is metabolized in the liver by cytochrome P450 3A4, having as its main route of excretion the bile. Patients with hepatic insufficiency may have the half-life of the drug increased, thus needing dose adjustment.

Indications: Psoriasis (erythrodermic, arthropathic, pustular, recalcitrant, "social"); atopic dermatitis,³⁰ suppurative hydradenitis; Behcet's disease; collagenoses; lichen planus;³¹ Sweet's syndrome, alopecia areata;³² pyoderma gangrenosum.^33,34

Absolute contraindications: Arterial hypertension that is difficult to control; renal dysfunction; T cell lymphoma. Relative contraindications: controlled arterial hypertension; pregnancy and/or breastfeeding; active infection; combined use of other immunosuppressants; migraine. Patients at higher risk of adverse reactions: elderly, obese, diabetic, hypertensive, and alcohol users.

Routine laboratory pretreatment procedures: Complete blood count; sodium, potassium, calcium, magnesium, uric acid, glycemia, lipid profile, urea and creatinine (3 doses);³⁵ hepatography; serology tests (hepatitis, HIV infection, HTLV-1); βhCG; abnormal elements and urine sediments; urine spot sodium; creatinine clearance; parasitological fecal examination; thoracic radiography; renal USG; gynecological examination; PPD.

Posology: Cyclosporine is available in capsule form (10, 25, 50, and 100mg) and oral solution (100mg/ml). The latter is a good option for children and should be diluted in orange or apple juice or soft drinks, immediately before administration. Milk should be avoided.

The daily dose recommended is between 3-5 mg/kg/day, and it should be divided into two doses³⁶ taken with food. Therefore, a patient who wishes to get better faster may use higher doses, whereas those at risk for drug interactions may use lower doses.³⁷

A few considerations about the use of cyclosporine: the drug should preferably not be used continuously for more than 8-12 months; use the drug in the acute stage of dermatosis³⁸, perform rotational therapy with other drugs; slowly reduce the dose based on clinical improvement to avoid drug rebound effect (reduce 0.5mg/kg every 15 days), and perform maintenance with pulse therapy (when the patient reaches the low dose of 1.5-2mg/kg/day, administer accumulated dose of three days and do not administer the drug in the next two days).

Follow-up: Blood pressure measurement done in every appointment; dosage of creatinine every fifteen days in the first month; complete blood count, nitrogenous waste products measurement, abnormal elements and urine sediments, electrolytes, hepatography, uric acid, and monthly lipid profiles.

If there is an increase in blood pressure (diastolic > 90mmHg or systolic > 140mmHg), blood pressure measurement should be repeated after two weeks. If blood pressure remains elevated, the dose should be reduced by 25-50% and the administration of antihypertensive drugs should be considered. If creatinine levels are more than 30% greater than basal levels, the exam is repeated after two weeks. If levels remain high, the dose should be reduced by 1mg/kg. After one month of administration of the reduced dose, creatinine levels are reevaluated: 1) if they have returned to normal, cyclosporine therapy can be continued; 2) if they are still high, treatment should be interrupted. Another important consideration is to monitor the dosage of serum cyclosporine (request morning levels of blood cyclosporine before taking the next dose, that is, C zero levels, which will show levels of the drug in the last 12 hours). This exam should be requested when clinical improvement occurs faster than expected, in the absence of therapeutic response, if laboratory alteration occurs or in the likelihood of drug interaction.

Drug interactions: It is important to consider the use of drugs that interfere with the enzyme P450, which can either increase (diltiazem, verapamil, macrolides, fluoroquinolone, amiodarone, antifungal, cimetidine, fluoxetine) or reduce (rifanpicin, phenobarbital, carbamazepine, griseofulvin)39 plasma cyclosporine levels. Corticosteroids, together with furesomide and thiazide diuretics, increase cyclosporine levels.

Adverse reactions: The main adverse reactions are: arterial hypertension and nephrotoxicity. The latter can be acute, due to a dose-dependent functional alteration⁴⁰ (afferent arteriole constriction) or chronic, with structural alteration (obstructive microangiopathy and interstitial fibrosis associated with hypertension and drug toxicity). Chronic nephrotoxicity may occur in the absence of alterations in blood pressure or creatinine levels. It is confirmed by ultrasonography through observation of reduced echogenicity of the kidneys. Therefore, when cyclosporine is used for more than one year, an evaluation must be conducted by a nephrologist to investigate possible areas of fibrosis and, if necessary, to perform kidney biopsy. Some risk factors for kidney damage are: daily dose greater than 5mg/kg, creatinine level 30% greater than basal levels, blood pressure increase, and advanced age.

Other side effects: Oncogenicity, hypertrichosis, acne, keratosis pilaris, sebaceous hyperplasia, folliculitis, gingival hyperplasia (occurs mostly in individuals with poor mouth hygiene),⁴¹ fatigue, myalgia, arthralgia, headache, tremor, paresthesia, nausea, vomiting, diarrhea, hepatography alteration, hyperlipidemia⁴², hyperuricemia, calcium increase, and magnesium reduction. Some of these side effects may negatively influence adhesion to treatment.

MYCOPHENOLATE MOFETIL

Introduction: Mycophenolate mofetil is a mycophenolic acid prodrug. It was widely used in the 1970s to treat refractory psoriasis. Mycophenolate mofetil has more advantages when compared with mycophenolic acid because it has greater bioavailability, efficiency and tolerability.

Mechanism of action and pharmacokinetics: Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, an enzyme responsible for metabolizing purines. Since T and B-lymphocytes use this metabolic route, its inhibition causes suppression of lymphocytes proliferation, of formation of autoantibodies, of leukocyte recruitment, and of endothelial binding proteins glycosylation. Due to the selective inhibition of only one enzyme in the synthesis of purines, this drug is considered more selective when compared with azathioprine, which affects several cell lineages. This fact makes it possible for mycophenolate mofetil to be used in patients with deficiency of thiopurine methyltransferase. Another advantage in relation to azathioprine is that mycophenolate mofetil is less mutagenic.^43,44

The bioavailability of orally administered mycophenolate mofetil is 94% when compared with venous infusion.⁴⁵ It is mostly metabolized in the liver. Its half-life is of 16 to 18 hours and 87% of the administered dose are eliminated by the kidneys. An important characteristic of the drug is that 97% of its active form (mycophenolic acid) is bound to albumin. Any alteration in albumin serum levels due to renal or hepatic dysfunction or medication leads to increases in the levels of mycophenolic acid, thus making dose reduction necessary. In patients with renal alterations, mycophenolate mofetil dose should be carefully adjusted.

Mycophenolate mofetil has been approved by the FDA for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants; however, the drug is used "off-label" in Dermatology and Rheumatology to treat various autoimmune and inflammatory diseases.

Indications:

As a steroid sparing treatment^46,47: pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, atopic dermatitis⁴⁷; Based on our experiences, mycophenolate mofetil is the best steroid sparing drug to be used in the treatment of bullous diseases.

As monotherapy: bullosis (when corticosteroid use is restricted),^48,49 pyoderma gangrenosum.⁵⁰ Associated with other drugs: vasculitis, collagenoses.

Absolute contraindications: Pregnancy and/or breastfeeding; hypersensitivity to the drug. Relative contraindications: hepatopathy, nephropathy, and combined use with azathioprine.

Routine laboratory pretreatment procedures: Complete blood count; hepatography; urea and creatinine; glycemia, abnormal elements and urine sediment; serology tests (hepatitis, HIV infection, HTLV-1); βhCG; PPD; thoracic radiography.

Posology: Mycophenolate mofetil therapeutic regimen should be initiated with gradual dose increases, every 2-4 weeks, to avoid gastrointestinal effects. If necessary, dose adjustments should be made for nephropatic patients. The recommended dose is 35-45 mg/kg/day (up to 2g), administered every 12 hours with food. It is available for oral administration in capsules containing 500mg. Therapeutic effects occur within 6 to 8 weeks. Currently, another form of the drug, sodium mycophenolate, is available. This drug causes fewer adverse gastrointestinal reactions and is available in capsules containing 360mg (corresponds to 500mg of mycophenolate mofetil).

Follow-up: It is done through rigorous physical examination (to investigate lymphonodomegalia and cutaneous neoplasty) and gynecological examination every 6 months. Laboratory exams are executed in the following manner: complete blood count (weekly in the first month; every fifteen days in the second month, bimonthly in the third month), and serum biochemistry (monthly in the first two months and every two months thereafter).

Drug interactions:⁵¹ Among the drugs that interact with mycophenolate mofetil, those that elevate its level in the blood (salicylates, furosemide, probenecid) and those that reduce it (fluoroquinolone, metronidazole, corticosteroids, cyclosporine, antacid, cholestyramine, sevelamer, calcium, iron) deserve attention.

Adverse reactions: The main adverse reactions affect the gastrointestinal tract (nausea, vomiting, colic, diarrhea) and are dose-dependant with a tendency to improve with time, and the genitourinary system (urinary urgency, polyuria, dysuria, sterile pyuria). Other important side effects are hepatoxicity and myelosuppression (although the drug is less hepatotoxic and myelotoxic than azathioprine). Nethrophilic dysplasia may occur (deviation to the left and nuclear hypolobulation, which indicate subsequent neutropenia); constitutional symptoms (fever, myalgia, headache), peripheral edema, arterial hypertension, acne, urticary, and dyshidrosis. It is important to stress that there are no long-term studies about infections and malignancies (lower oncogenic potential because it does not interfere with DNA).

Due to little experience, few prospective studies about the long-term use of the drug, and possible risk of malignancy, mycophenolate mofetil dosage should be gradually reduced in proportion to a favorable treatment response, until it can be discontinued.

CONCLUSION

Immunosuppressive drugs are extremely valuable tools in the therapeutic arsenal of dermatologists that deal with more severe inflammatory diseases. When choosing to prescribe these drugs, physicians must be aware of their risks and benefits. They also must have detailed knowledge of their indications, previous laboratory exams required, clinical laboratory follow-up, drug interactions, and adverse reactions. In this way, patients can be offered better quality of life with fewer or attenuated risks.

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*

Trabalho realizado no Serviço de Dermatologia do Hospital Universitário Pedro Ernesto (RJ) - Brasil.

Publication Dates

• Publication in this collection
  06 May 2010
• Date of issue
  Feb 2010