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Print version ISSN 0365-0596
On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.79 no.3 Rio de Janeiro May/June 2004
CONTINUING MEDICAL EDUCATION
Systemic treatment of psoriasis - Part I: methotrexate and acitretin*
Gladys Aires MartinsI; Lucia ArrudaII
ISpecialist in Dermatology, M.Sc.
Dermatology. Volunteer Professor at the School of Medicine, UnB. Coordinator
of the Psoriasis Ambulatory, Brasília Teaching Hospital
IISpecialist in Dermatology, M.Sc. Dermatology. Professor of Dermatology - School of Medicine; Head of the Dermatology Service and Coordinator of the Psoriasis Ambulatory, Hospital and Maternity Celso Pierro - PUC-Campinas
The physiopathology of psoriasis has not yet
been thoroughly clarified. Although there has been undeniable progress in the
last decade, doubts remain about the nature of the antigens, which lead to activation
of T lymphocytes, and about the regulation of the inflammatory mechanisms.
Besides the development of new therapies, the improved management of classical systemic treatments has contributed to reduce the morbidity rate of the disease and has achieved a positive impact on the patients' quality of life. Underscoring the importance of this, the EMC-D article focuses on a review of using Methotrexate and Acitretin in the treatment of psoriasis. The use of biological therapies and other immunomodulators will be discussed in a future chapter.
Key-words: acitretin; methotrexate; psoriasis.
Psoriasis is a chronic inflammatory disease of the skin, that affects from one to 3% of the world population, and presents great polymorphism in its clinical expression. Despite all the investment in the research of new medicines, most with an immunological base (immunopharmacology), there are gaps which have yet to be fully explained. A group of genetic, immunological and environmental factors is necessary for the development of the disease. Heredity plays an important role in psoriasis, with parents transmitting genes to their children that are susceptible to developing the disease. However, psoriasis is only expressed clinically if an immunological reaction induced by T lymphocytes develops in the patients' skin. The "antigens of psoriasis" are still not known, but the role of bacterial infections in the development of childhood psoriasis suggests that environmental antigens can induce an immune response capable of generating psoriatic lesions. Stress in its widest sense (psychological, physical and surgical) is a well known aggravating or triggering factor, as well as certain medicines (lithium, interferon-a, b-blockers).1
The disease is associated to a genetic predisposition, but its transmission does not obey the mendelian pattern as it has a multifactorial inheritance mode, and is not explained solely by an association to histocompatibility antigens (HLA) and in particular the CW6 haplotype. Molecular biology techniques are enabling the search for susceptibility genes of psoriasis (Psors), and in the near future patients will probably benefit from gene or antisense therapies.
T Lymphocytes play an important role in the triggering and maintenance of the inflammation. The immunosuppressants that block the functions of T lymphocytes, such as cyclosporin, tacrolimus, or CD4 antibodies, are effective in the treatment of psoriasis. Most of the inflammatory dermatoses mediated by T cells can be classified, according to the cytokine profile, into Th1 mediated and Th2 mediated. In psoriasis, there is a superexpression of the pro-inflammatory Th1 cytokines (IL-2, interferon d and tumor necrosis factor-alpha - TNFa) with a relative deficiency of Th2 cytokines (IL-4, IL-5, IL-6 and IL-10).1,2 Therefore, psoriasis is characterized as disease immunomodulated by type 1 response, and research has pointed to immunomodulatory therapeutics with new molecules that enable a selective modulation of the action of various cytokines implicated in the development and maintenance of psoriatic lesions or to inhibit the activation of T lymphocytes.
On the other hand, great therapeutic progress has been obtained in the treatment of psoriasis through a better use of classic treatments.
The future should point to studies that allow conclusions regarding the degree of effectiveness of the new medications in relation to the classic treatments and which are the best strategies for their use with a proven positive impact in the short, medium and long term on the quality of the patients' life.2,3
Although available since 1948, MTX was only introduced as an antipsoriatic agent in 1958 and has been approved by the FDA (Food and Drug Administration) for this indication since 1971.1
MTX is an antimetabolite structurally similar to folic acid (Figure 1), that inhibits in a competitive manner the activity of dihydrofolate-reductase enzyme, and is considered a specific chemotherapeutic for phase S (synthesis) of the cellular cycle.4,5 Its action is more marked on cellular populations in the exponential growth phase, which explains its selective effect on tumoral cells and action on tissue in proliferation. It was used originally in psoriasis due to its effect on the keratinocytes undergoing fast division. It is known today, however, that the most outstanding effect of MTX is anti-inflammatory, reducing the chemotaxis of the polymorphonuclear cells, inhibiting the C5a induced cutaneous inflammation, reducing the B4-induced chemotaxis and the number of positive OK-T6 cells in the epidermis.6 Finally, the effectiveness of MTX in psoriasis is also due to its immunomodulating properties, braking the production of IL-1 and reducing the density of Langerhans' cells in the epidermis, and also appears to have an effect on the antigen-presenting cells.4,5,6,7
Administered orally, it is absorbed quickly and reaches peak serum levels in one or two hours. After intramuscular injection, the plasmatic peaks are detected within approximately half of that time. Dairy foods and non absorbable antibiotics, such as Neomycin, can reduce its bioavailability.4 MTX is diffused and accumulates in the red globules. In the serum, about 50% of the medication binds in a reversible manner to albumin, which means that the concomitant use of other medicines that also bind to proteins can increase its hematological toxicity (Table 1). Once absorbed, the levels of MTX in the plasma have a triphasic reduction - the rapid distribution phase is followed by a second phase after two to four hours that reflects the renal excretion; the third phase represents the terminal half-life from 10 to 27 hours and is secondary to the enterohepatic circulation. This terminal half-life, if unduly prolonged as a consequence of renal insufficiency, may be responsible for the main poisonous effects of the drug on bone marrow and on the gastrointestinal tract (G.I. tract). Between 50 and 90% of MTX is eliminated through renal path, by glomerular filtration and, to a lesser extent, by tubular secretion, which is reduced in the presence of nonsteroidal anti-inflammatory drugs (NSAID) or sulfonamides. As it is a weak organic acid, it is excreted predominantly by the kidney, the concomitant use of other weak organic acids should be avoided, such as salicylates and probenecid, that reduce the renal tubular transport and can prolong the excretion of MTX (Table I). Furthermore, MTX has an age-dependent pharmacokinetic, with greater distribution and elimination of the drug in the young; and care must be taken with geriatric patients, due to a possible reduction in renal function.5,8,9
In Brazil, MTX is available in tablets of 2.5 mg and in glass ampoules of 25, 50 and 500 mg (Methrexato®, Biometrox®, Metrotex®). Three means of administration are used and their equivalent: deep intramuscular injection or rapid intravenous in a single weekly dose; orally in a single weekly dose; and orally, divided into three doses at 12-hour intervals. In dermatology, the latter regimen is considered to be ideal, due to the cellular kinetics of the psoriatic epithelium and there are indications of a better pharmacological effect as it reaches a larger proportion of cells in the reproductive cycle, together with a lower incidence of side effects.4,5 The mean weekly oral dose varies from 7.5 to 30 mg, and most of the authors have recommended that this should begin with a low dosage, from five to 7.5 mg/week (taking into account the patient's weight and age) as a form of preventing myelotoxic activity; following a repeated blood count without alterations, the dose is adjusted from 15 to 30 mg. Clinical improvement is usually evident from the third week, and the maximum therapeutic result occurs at the end of two months, with an over 75% improvement in the lesions.4 Having obtained the desired therapeutic result, the decrease in dosage should be slow, with monthly reductions from 2.5 to 5 mg, aiming at a maintenance with the lowest possible effective dose.
In theory, MTX is indicated for psoriatic arthritis, in the erythroderma, generalized pustular or palmoplantar forms and in patients unresponsive to topical treatments and phototherapy. Patients should be careful selected, taking into account the risk/benefit ratio. Compliance with the treatment is paramount, and the patients should be warned of the risks involved with pregnancy and abuse of alcohol. Having defined the option for MTX, the patient should be submitted to laboratory exams, that should be repeated regularly.
The pre-methotrexate evaluation includes: complete blood count with platelet count, biochemistry of the blood and enzymes (urea, glucose, creatinine, glutamic-oxaloacetic transaminase - GOT, glutamic-pyruvic transaminase - GPT, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, proteinogram), urine summary, serology for hepatitis B and C, and chest X-ray. Depending on the history and physical exam, a complementary evaluation may be necessary with anti-HIV serology and creatinine clearance. In the first month, when possible, the blood count should be repeated on a weekly basis, once myelotoxicity is the most serious side effect in the short term. Following this, control exams (blood count and biochemistry) should be monthly and then quarterly, depending on the signs and symptoms presented by each patient. Since the values of the hepatic enzymes tend to be altered in the first two days after administration of MTX, the blood collection should be performed six or seven days after the last dose.8 There can occasionally be a temporary increase in the dosages of GOT and GPT. If the increase is significant (over double the normal rates), the treatment should be interrupted for a period of one or two weeks and then the battery of tests should be repeated, usually they return to normal; but if the values persist for two or more collections, the treatment should be discontinued, and hepatic biopsy considered.8,9,10
In case of acute hematological toxicity or accidental overdose with MTX, it is necessary to immediately prescribe its antidote intravenously, namely folinic acid, citrovorum factor or leucovorin (Leucovorin Cálcio®) at a similar dose to that of the MTX.4,5,8
In the long term, the most common side effect is cumulative toxicity, and various hepatic studies have demonstrated a high frequency of fibrosis (1 to 50%) and cirrhosis (zero to 20%).12 Blood biochemistry and other noninvasive methods, such as ultrasound and hepatic scintigraphy are not predictive, and biopsy remains the most reliable diagnostic test.4,8,9,10,11,12 All the guides and international norms for use of MTX recommend performing hepatic biopsy if the cumulative dose reaches one to 1.5 g in patients without risk factors (abuse of alcohol, personal or family history of hepatic disease, persistently high hepatic enzymes, diabetes mellitus, obesity and a history of exposure to hepatotoxic drugs). In patients with the above mentioned risk factors, the biopsy should be performed at the beginning of treatment.4,9,10 The histopathological findings from the biopsies are standardized into five levels: I - normal; II - moderate or serious steatosis, nuclear variation, inflammation; IIIA - mild fibrosis; IIIB - moderate to serious fibrose; and IV - cirrhosis. Regarding the interpretation of the results, it is recommended that patients with level I or II can continue the treatment; while for those with level IIA alternative therapeutics should be considered or to maintain MTX for six months and then repeat the biopsy; those with level IIIB or IV should interrupt MTX therapy.8,9 table 2 shows the ideal time schedule for performing biopsies in prolonged therapies with MTX.10 However, considering that the complication rate of hepatic biopsies vary from 0.01 to 10% and that such a procedure is contraindicated for patients with comorbidity, such as blood dyscrasia, cardiac insufficiency and advanced age, less invasive methods are being sought to evaluate fibrosis and hepatic cirrhosis, the most promising being dynamic hepatic scintography and measuring serum type III procollagen.11,12,13 The blood dosage of type III procollagen, an amino-terminal propeptide, every three months, according to some authors, could significantly reduce the number of biopsies, because persistently normal rates indicate a minimal risk of developing hepatic fibrosis.3,12,13
With the current tendency to use rotating treatments, in which MTX enters as one of the medications to be used for periods of one year at the most in alternation with other medications or procedures, and the advent of biological therapies, it is probable that in the future these discussions on cumulative hepatotoxicity will be reconsidered.11,12
In the dosages used to treat psoriasis, the main adverse reactions described include, besides leukopenia, thrombocytopenia and megaloblastic anemia, migraine, general indisposition, vertigo, concentration difficulty, digestive disturbances (anorexia, metallic taste, nausea, vomits, diarrhea and peptic ulcer), ulceration of the oral mucous membrane or stomatitis, alopecia, photosensitivity, urticaria, acral erythema, candidiasis, folliculitis, fever and depression.4 There have been reports of lymphomas and cutaneous carcinomas in patients treated with MTX.4,10 In some cases, the lymphomas receded when the medication was discontinued, suggesting a strong causal relationship. Nephrotoxicity is rare and practically null, since in the pre-therapeutics evaluation correct renal function is demanded and the patient is advised to avoid associations with drugs that are nephrotoxic or that interact with MTX. Secondary pulmonary toxicity to MTX is not common and the physiopathology is still poorly understood, but could be of two types: acute pneumopathy, with unpredictable hypersensitivity; and secondly obstructive chronic type, due to progressive diffuse interstitial fibrosis. Regarding reproduction, it is an abortive and teratogenic drug, mainly during the first quarter of pregnancy (category X) and, in the male gender, it can cause transitory oligospermia with a long-term mutagenic effect, and is therefore formally contraindicated for men and women who wish to have children during the entire treatment and for three months after discharge.9 The administration of folic acid at a dose of one to 5 mg/day improves the digestive symptoms and prevents megaloblastic anemia.10,14
Cutaneous toxicity with epidermal necrosis of psoriasis plaques is another side effect that has been described in a few cases, usually among elderly patients.15,16,17 In the reported cases, all the patients were aged 55 years or older, and many presented some degree of renal insufficiency. Therefore, for patients in this age group, it is advisable that more attention is taken over the renal function (creatinine clearance, if necessary) and with medicamentosus interactions that could be part of the pathogenic mechanism of the ulceration in the plaques and in the mucous membranes, and that are indicative of precocious myelotoxicity.
Absolute contraindications for the use of MTX are: pregnancy and breast feeding, seropositivity for HIV, clinical or biological immunodeficiency, active infectious disease, renal insufficiency, active or recent hepatitis, cirrhosis, consumption of alcoholic drinks greater than 100g of alcohol a day, active gastroduodenal ulcer, hemoglobin below 10g/dl, leukopenia below 3,000/mm3 or platelets below 100,000/mm3. Appart from exceptional cases, MTX should not be prescribed for children.4,8,9
Concomitant topical therapy should be stimulated as a form of increasing the effectiveness and to reduce the dose of MTX. Although serious side effects can occur when MTX is associated to other systemic treatments, in recalcitrant cases, good results are obtained with a combined or sequential use of MTX and PUVA therapy or UVB phototherapy, or acitretin, for short periods and with appropriate monitoring.8,9 Association with cyclosporin should be reserved for exceptional cases, since the elimination of the two is decreased, thereby elevating their blood levels, with an increased risk of serious side effects.18 With the arrival of biological therapies, in psoriatic arthritis there are reports of the combined use of MTX and anti-TNF drugs, that do not present interaction.2
In conclusion, MTX still represents a treatment option with good efficacy/cost/tolerance relationship, especially in poorer countries, such as Brazil. The final decision of the therapeutic choice for patient with psoriasis should be based on their needs and preferences, but also on the clinical and economic consequences of the therapeutic strategy adopted, and some studies have confirmed a longer remission time and lower cost in rotating treatments with the use of MTX.19
Acitretin (Neotigason®) is a second generation synthetic retinoid and monoaromatic agent that has substituted etretinate (Tigason®) in the treatment of psoriasis. It presents also an action in disturbs of keratinization, in certain dermatoses (lichen planus, lupus erythematosus, lichen nitidus, lichen sclerosus et atrophicus, amyloid lichen, subcorneal pustular dermatosis, angiolymphoid hyperplasia with eosinophilia, eosinophilic folliculitis), in cutaneous lymphomas and in the chemoprevention and treatment of cutaneous cancer in genodermatoses (xeroderma pigmentosum, basal cell nevus syndrome, epidermodysplasia verruciformis) and in conditions induced by Puva and cyclosporin.20,21,22,23
It is known that retinoids bind to nuclear receptors, altering the expression of a variety of genes, but the mechanism of action of acitretin in psoriasis has yet to be fully explained, given that it has immunomodulatory and anti-inflammatory effects, besides acting on the growth and epidermal cellular differentiation.21,23,24 While in the epidermis it reduces the proliferation of keratinocytes and stimulates cellular differentiation, in the dermis it inhibits the migration of neutrophiles to the epidermis and reduces the CD25 T lymphocytes in the lesion by 50 to 65%, thereby interfering in the actions induced by various cytokines.2,24 However, in contrast to other antipsoriatic medications, it is neither cytotoxic nor immunosuppressive.
Etretinate is the prodrug of acitretin, which is its active metabolite, presenting under the isomeric form with trans and cis interconvertible metabolites (Figure 2), both teratogenic.20,21 Although it has a better pharmacokinetic profile (only slightly lipophilic and with a half-life from two to four days), small amounts of acitretin can be converted into etretinate, which is 50 times more lipophilic and has a slower elimination half-life (from 80 to 175 days).20,21 The conversion is increased by the consumption of alcohol.10,21,25,26 Therefore, the warnings valid for etretinate are also applicable to acitretin, the latter being formally contraindicated in pregnancy (category X), and for fertile women, contraception is mandatory for an additional period of three years after discharge. Ingestion of alcohol should also be prohibited during the treatment and then for another two months, as it is believed that, in the absence of ethanol, the acitretin is totally eliminated by the end of two months.25,26 It should be emphasized that ethanol may be present in certain medicated syrups, medicines and alimentary seasonings.10
After oral administration, its absorption may vary between individuals (from 36 to 95%).21 The bioavailability is significantly improved with the ingestion of foods. Due to its high degree of protein connection, it penetrates the corporal tissues quickly, crossing the placental barrier and is secreted in maternal milk.20,21,23 Acitretin is metabolized through isomerization by the isomeric 13-cis-acitretin by glycuronidation and by rupture of the lateral chain.20,21 Elimination occurs by hepatic and renal paths, hence the substance should be used with caution in patients with renal insufficiency.
Although acitretin presents few drug interactions, there have been reports of possible interaction with oral contraceptives in microdoses of progesterone, such that this type of pill is contraindicated during treatment with acitretin. 20,21 It is recommended that patients using phenytoin should have their doses adjusted, because acitretin reduces the connection of phenytoin to plasmatic proteins and there are reports of a decrease in the effectiveness of the acitretin during concomitant treatment with carbamazepine and primidone.21,22,26,27 It has also been suggest that acitretin increases sensitivity to endogenous insulin, a reason for which diabetic patients should undergo rigid control of glycemia. As occurs with isotretinoin, vitamin A and cyclines potentialize the risk of intracranial hypertension and are prohibited during treatment with acitretin.
In Brazil, acitretin is available in capsules of 10 and 25 mg (Neotigason®). It is included in the list of high-cost medicines of the Ministry of Health, and could be made available to poor patients enrolled in the health services of various states. In psoriasis, acitretin is suitable in the pustular, erythrodermal and palmoplantar forms as well as in plaque with involvement of more than 20% of the body surface. In psoriatic arthritis, it seems to be less effective than MTX and cyclosporin, however it is underscored that there are no controlled studies for this indication.21 In childhood, it is indicated for serious cases that do not respond to topical treatment, provided the potential for bone toxicity is monitored, which is detected mostly in prolonged therapies.20,22,23 Pustular and erythrodermal are the forms with best responses to acitretin as a monotherapy (Figure 3). In the plaque forms, the response can be improved by the combination of the retinoid with calcipotriol, calcitriol, or phototherapy (reverse-UVB, re-Puva).21,22,28,29 Geiger and Czarnetzki performed a meta-analysis of 12 studies and found good to excellent results (total remission or improvement of at least 80%) reaching 100% in the pustular forms, 83% in the erythrodermal and 76.5% in the plaque forms.21,27 Most of the time, the lesions can be controlled with doses of 0.5 to 0.6 mg/kg/day or 25 to 30 mg/day, in bolus during or immediately after the main meal of the day. During the clinical course, the dose should be readjusted according to the response and tolerance. The maximum dose recommended for adults is 75 mg/day. Some studies have suggested that the best strategy for using retinoids is a regimen with an initial low dose (10 mg) followed by a progressive increase every two to four weeks, until reaching the maximum well-tolerated dose.3,21 The retinoids are the only medicines for which the dose adjustment is done in function of the clinical tolerance rather than the effectiveness.3 This strategy of low initial doses, reduces the intensity of mucocutaneous side effects and raises compliance to treatment by the patient, resulting in 40% clearance of the lesions and 60% improvement.3 When used in combination with other medicines, the recommended dose is smaller (0.3 to 0.5 mg/kg/day) and in children 0.4 to 0.5 mg/kg/day, with a maximum recommended dose of 35 mg/day. The combined use of acitretin with ultraviolet light (reverse-Puva or reverse-UVB) maximizes the effect and reduces the potential acute side effects and cumulative toxicity of the two treatments.2,21,22,26,29 Controlled studies have demonstrated a reduction of up to 42% in the total dose of irradiation, which means less carcinogenesis.29 This is indicated for patients with moderate to serious psoriasis in plaque that is refractive to isolated treatments with UVB, Puva, acitretin and also in those unresponsive or which demand a limited use due to the side effects from MTX and cyclosporin.29 The treatment protocols with reverse-Puva and reverse-UVB recommend therapy to be initiated with retinoid two weeks before the first phototherapy session (10 mg/day and 25 mg/day for patients with weight below and above 70 kg, respectively), to reduce the thickness of the corneal layer and of the epidermis, in order to render them more susceptible to the effects of the UV rays; if acitretin is added after initiating phototherapy, the UV dose should be reduced by half.28,29
In serious and recalcitrant forms, acitretin can be used in a sequential regimen with cyclosporin, since they are compatible drugs, their metabolites depend on different hepatic isoenzymes, and the profile of side effects is different, except for a greater possibility of elevation in the serum levels of cholesterol and triglycerides.22 The monitoring should, therefore, be more careful. In the first phase, cyclosporin is introduced, as it is a suppressive medication and presents a rapid onset of action. In the second phase, acitretin is initiated and the cyclosporin is gradually withdrawn, while at the same time adjusting the dose of acitretin, until the third maintenance phase is reached with acitretin alone. If, during the maintenance phase, acitretin proves to be ineffective in the control of the lesions, Puva or UVB can be added to reinforce its therapeutic effect.22 The association with MTX is dangerous due to a greater potential for toxicity. In rotating treatments that alternate UVB and Puva phototherapy, MTX, cyclosporin and acitretin, the latter should be placed preferentially in the final sequence, since there are studies suggesting a role for acitretin in the chemoprophylaxis of cutaneous cancer and treatment of lesions induced by cyclosporin and Puva.10,30,31
In the evaluation prior to therapeutics, it is mandatory to dose hepatic enzymes (GOT, GPT, alkaline phosphatase, bilirubin, gamma-glutamyl transferase), total cholesterol and triglycerides, besides glucose, urea, creatinine, complete blood count and urine summary.10,21 When intending to initiate long-term therapy, the bone status evaluation is suggested and, in children and adolescents, bone age and growth parameters. These procedures should be repeated annually, although there is consensus regarding which exams are more predictive.10,21,23 The dosage of hepatic enzymes and the lipid profile should be repeated at the end of two weeks of treatment, then monthly for the following three months and after this, at every three months. Women who could potentially become pregnant should sign a consent term and be counseled to use a contraceptive method for three years after discharge. It is mandatory to perform a pregnancy test (b- HCG) prior to treatment and then on a monthly basis. Neither women nor men using acitretin should donate blood during the treatment and for a further three years afterwards.
Among the side effects, teratogenicity is the most serious. Acitretin is an embryotoxic and teratogenic drug (category X), the main malformations are: congenital anomalies of the CNS (hydrocephaly and microcephaly); ocular malformations (microcephaly); small or absent ears; facial dysmorphism; cleft palate; bone alterations with defects in the members; cardiovascular anomalies; thymic defects; parathyroid hormone deficiency; and mental retardation.21,23,32 Compared to isotretinoin, acitretin causes less heart defects and more alterations in the acral skeleton. In men, acitretin does not alter the spermatogenesis. Mucocutaneous effects are the most frequent, but are treatable, dose-dependent and reversible with a decrease in the dose or suspension of the treatment. They include: cheilitis (82 to 96%), dry mouth, dry nose, epistaxis, dry eyes, intolerance to contact lenses, blepharoconjunctivitis, xerosis, pruritus, photosensitivity, palmoplantar desquamation and also of the digital pulps, cutaneous desquamation, cutaneous fragility, adherent skin, difficulty in cicatrization, colonization of the skin by S. aureus, fragile nails, ungual dystrophy, pyogenic periungual granulomas, alopecia, alteration of the hair texture, vaginitis, urethritis and rectal bleeding.21,23,26 When compared to isotretinoin, it causes more palmoplantar desquamation, more ungual alterations, more cutaneous fragility and more alopecia.23 Non-randomized studies have suggested that vitamin E supplementation, at a daily dose of 800 IU, can relieve some of the mucocutaneous effects of the retinoids.10 Other effects that have been reported are: asthenia, hyperhidrosis, migraine, dysesthesia, arthralgia, myalgia, blurred vision, night blindness, and otitis. To date, only one case of intracranial hypertension has been reported in a patient receiving concomitant cyclines.21,23,26
The most important laboratorial alterations are rises of the GOT and GPT hepatic enzymes (from five to 33%), hypertriglyceridemia (from 14 to 66%) and hypercholesterolemia (from nine to 33%).21,23,32 In most of the reported cases, the alterations reverted following a reduction in the dosage, combined with dietary alterations or treatment with hypolipemiant drugs. The triglyceride levels should not exceed 800 mg/dl due to the risk of pancreatitis and eruptive xanthoma.21,23 Cases of hepatitis due to acitretin have already been described, but serious hepatotoxicity is rare. Long-term therapy did not cause significant hepatic histological alterations in a group of patients pre-selected for potential hepatotoxicity and followed-up prospectively for three years.21 Therefore, hepatic biopsy is not recommended for patients on long-term treatment with acitretin, unlike when using MTX.
Retinoids can cause bone lesions similar to the bone findings of hypervitaminosis A: hyperostosis, calcification of ligaments, premature closing of epiphyses and possible osteoporosis. In children that need long-term therapy (more common in disturbances of keratinization and genodermatosis), it is recommended that the maintenance dose is the lowest possible, as a mean of preventing skeletal toxicity.21,23,26 In adults, the association of osteoporosis to chronic treatment of psoriasis with acitretin has yet to be fully clarified; the data are conflicting, and prospective studies have questioned the results of previous retrospective studies, in which the levels of osteoporosis detected might have been caused by the aging process itself.22,26 Thus, in patients with a perspective of long-term treatment, the bone status should be evaluated beforehand.26
There are absolute contraindications to the use of the acitretin: gestation or desire to become pregnant within the next several years, serious hepatic and renal insufficiency and allergy to the parabeno contained in the capsules. Hyperlipidemia, diabetes mellitus and osteoporosis are relative contraindications. Among diabetics, those that are obese, consumers of alcohol or have hereditary hyperlipidemia, should use acitretin with caution, due to the increased potential of hepatotoxicity and pancreatitis.
Women in fertile age and who need treatment with systemic retinoids can use isotretinoin as an alternative, since it has a faster elimination, albeit with less action against psoriasis than acne. When associated to calcipotriol, it has proven to be moderately effective for psoriasis in plaque; in high doses (one to 1.5 mg/kg/day) or associated to phototherapy, and was highly effective in pustular psoriasis.21,29,32,33
In summary, excluded the possibility of pregnancy, and with appropriate patient selection and proper monitoring, acitretin therapy is not usually followed by major side effects, increasing the period of remission in relation to MTX and cyclosporin.34,35 Hyperlipidemia and hepatic toxicity are controllable with the monitoring of exams and adjustment of the dosages. As it is not an immunosuppressant drug, the use of acitretin reduces the occurrence of cutaneous cancers in patients that have previously been treated with carcinogenic therapies and, as acitretin is not associated to cumulative toxicity, it represents an excellent option for long-term maintenance therapy and for elderly patients.3,32,33,34,35
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Received in April, 15th of 2004.
Approved by the Editorial Council and accepted for publication in April 23rd of 2004.
* Work done at University Hospital of Brasilia.
Questões e Resultados das Questões
1. As afirmações abaixo estão corretas, EXCETO:
a) A psoríase está associada a predisposição genética, com modo de herança multifatorial.
b) A psoríase é imunomodulada por resposta tipo 2.
c) Interferon-d e TNFa são citocinas implicadas na imunopatogênese da psoríase.
d) Tacrolimus inibe a ativação de linfócitos e a síntese e expressão de citocinas.
e) CW6 provavelmente é um marcador para o gen determinante de susceptibilidade à psoríase.
2. Assinale a afirmativa correta:
a) MTX freia a produção de IL-8 e aumenta a renovação das células epidérmicas.
b) Alimentos leitosos podem diminuir a biodisponibilidade do MTX.
c) MTX é um ácido orgânico fraco excretado predominantemente pelo fígado.
d) MTX aumenta a quimiotaxia dos neutrófilos na epiderme psoriásica.
e) Alimentos leitosos podem melhorar a biodisponibilidade do MTX.
3. Os seguintes medicamentos interagem com o MTX, provocando diminuição da eliminação renal:
a) Ciclosporina e dipiridamol.
b) Penicilina e probenecid.
c) Probenecid e dipiridamol.
d) Dipiridamol e retinóides.
e) Salicilatos e tetraciclina.
4. A curto prazo, o efeito colateral do MTX mais grave é:
c) Pneumopatia de hipersensibilidade.
5. A longo prazo, o efeito colateral do MTX mais comum é:
a) Necrose cutânea.
d) Insuficiência renal
e) Anemia megaloblástica.
6. Entre as afirmações abaixo, assinale a única que não está correta:
a) Gravidez e aleitamento são contra-indicações para tratamento com MTX.
b) Os níveis de AST e ALT podem estar elevados quando o sangue é colhido um a dois dias após a tomada do MTX.
c) Na monitorização do tratamento com MTX, durante o primeiro mês, o hemograma deverá ser feito semanalmente.
d) Em caso de mielotoxicidade aguda, deve-se suspender o tratamento e aplicar imediatamente Heparina via parenteral.
e) O resultado terapêutico máximo costuma ocorrer ao final de dois meses.
7. A administração de ácido fólico:
a) Previne reações de hipersensibilidade ao MTX.
b) Diminui o risco de anemia megaloblástica.
c) Previne lesão renal.
d) Só é eficaz se utilizada via endovenosa.
e) Deve ser preconizada como forma de evitar fibrose e cirrose hepáticas.
8. A ACITRETINA:
a) É retinóide sintético de terceira geração.
b) É indicada exclusivamente no tratamento de formas graves de psoríase e em ictioses.
c) É pró-droga do etretinato.
d) Não é citotóxica nem imunossupressora.
e) Tem meia-vida de eliminação mais lenta do que o etretinato.
9. As formas que melhor respondem à MONOTERAPIA com Acitretina são:
a) Gutata e eritrodérmica.
b) Palmoplantar e ungueal.
c) Pustulosa e eritrodérmica.
d) Pustulosa generalizada e em grandes placas.
e) Em placas e pustulosa palmoplantar.
10. São contra-indicações ABSOLUTAS à terapia com acitretina:
a) Insuficiência renal grave.
b) Insuficiência hepática grave.
c) Em mulheres: gestação e desejo de engravidar nos próximos anos.
d) Alergia a parabem.
e) Todas acima.
11. Em comparação à isotretinoína, a ACITRETINA...
a) Causa menos alopecia.
b) Causa menos malformações cardiovasculares.
c) Causa menos descamação palmoplantar.
d) Causa menos alterações ungueais.
e) Causa menos fragilidade cutânea.
12. Na monitorização da acitretina, a seguinte alteração laboratorial deve chamar atenção do médico para risco de PANCREATITE:
a) Glicose acima de 180mg/dl.
b) Colesterol acima de 280mg/dl.
c) Colesterol acima de 359mg/dl.
d) AST e ALT acima de 100UI.
e) Triglicerídeos acima de 800mg/dl.
13. O tratamento com ACITRETINA na psoríase INFANTIL:
a) Está totalmente contra-indicado.
b) Não deve ultrapassar três meses.
c) Exige monitorizaão da idade óssea.
d) É a melhor opção para psoríase em placas e artrite.
e) Tem indicação nos casos graves, não responsivos à Puva.
14. Os seguintes medicamentos/procedimentos podem ser combinados à acitretina, permitindo menos toxicidade cumulativa, menos tempo de terapia e maior tempo de remissão:
a) UVB (re-UVB).
b) Puva (re-Puva).
d) Vitamina E oral.
e) a, b e c estão corretas.
15. A "melhor estratégia" de uso da ACITRETINA é:
a) Regime de baixa dose inicial.
b) Não ultrapassar a dose diária de 0,3mg/kg.
c) Regime de alta dose inicial.
d) Terapia seqüencial com ciclosporina.
e) Doses fracionadas ao longo dos dias, longe das refeições.
16. Na avaliação pré-tratamento do MTX é OBRIGATÓRIO:
a) Sorologia anti-HIV
b) Clearance de creatinina
c) Lipidograma completo
d) Beta-HCG para mulheres em idade fértil
e) Biópsia hepática
17. Considera-se contra-indicação ABSOLUTA o uso de MTX:
a) leucopenia abaixo de 4.000/mm3
b) plaquetopenia abaixo de 100.000/mm3
c) passado de úlcera gastro-duodenal
d) idade acima de 60 anos
18. A ACITRETINA:
a) Não é excretada pelo leite materno
b) Tem ação citotóxica e imunossupressora
c) É eliminada exclusivamente por via renal
d) Está associada à toxicidade cumulativa
e) Pode reduzir a ocorrência de cânceres cutâneos em pacientes previamente tratados com PUVA e ciclosporina
19. Comparando-se o MTX à ACITRETINA, podemos concluir:
a) Ambos são teratogênicos
b) Ambos são contra indicados na infância
c) O MTX causa menos transtornos digestivos que a Acitretina
d) Ambos necessitam de receituário especial e assinatura de termo de consentimento
e) A acitretina leva à plaquetopenia enquanto que o MTX à leucopenia
20. Assinale o CORRETO:
a) A ciclosporina leva a tempo de remissão mais prolongado que a Acitretina
b) O MTX leva a tempo de remissão mais prolongado que a Acitretina
c) A Acitretina leva a tempo de remissão mais prolongado que a Ciclosporina
d) A fototerapia UVB associada a MTX leva a maior período de remissão que a re-PUVA
e) O MTX não deve ser associado à fototerapia