titolo breve: CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE primo autore: ALTOMARE Rivista: GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIACod Rivista: G ITAL DERMATOL VENEREOL e additional copies G ITAL DERMATOL VENEREOL 2014;149:607-25 or personal or commercial use is , electronic mailing or an It is not per.
aming techniques to enclose an Consensus on the use of cyclosporine
The production of repr in dermatological practice
ticle through online inter e only one file and prv Cyclosporine A (CsA) efficacy and safety have been proven
IRCCS Galeazzi, University of Milan, Milan, Italy in various dermatoses both in adults and in children even
as long-term treatment. Over the last 25 years, Italian der-
matologists have gathered relevant experience about CsA
University of Naples Federico II, Naples, Italy treatment for psoriasis and atopic dermatitis. This paper has
been developed by an Italian Consensus Conference and it
is aimed at providing recommendations based on real-world
University of Bologna, Bologna, Italy The creation of der clinical experience in adult patients, consistent with efficacy
4Novartis Farma, Italy, Origgio, Varese, Italy and safety data arising from the scientific literature. The pa-
ute the electronic cop per is mainly focused on the analysis of the optimal thera-
peutic schemes for psoriasis and atopic dermatitis, in terms
of doses and treatment duration, according to individual
characteristics and to the severity of the disease. Moreover, it
University of Siena, Siena, Italy VA MEDICA
overviews ideal management, taking into account pharmaco-
logical interactions, influence of comorbidities, and the most
common adverse events related to CsA treatment.
Key words: Cyclosporine - Skin diseases - Psoriasis - Derma-
It is not per.
ight notices or ter titis, atopic.
y Commercial Use is not per Genoa, Italy 11Private Practitioner, Bari and Barletta, Italy Cyclosporine (cyclosporine A, CsA), was first iso- lated from the soil fungus Tolypocladium infla‑ tum in 1970.1 Its antifungal activity was demonstrat- ed to be poor, whereas a potent immunosuppressive Despite the increased availability of new thera- effect was found in 1976.1 For this reason, two years peutic options, CsA is still one of the most widely later, CsA was successfully used in preventing kid- No additional reproduction is author used and effective systemic drugs for the treatment ney transplant rejection 2 and, in 1979, it was proven of psoriasis and atopic dermatitis, worldwide.4-6 In effective in the treatment of rheumatoid arthritis and Italy, it has been found to be the most frequently psoriasis.3 The original orally administered formula- used systemic antipsoriatic therapy.7 inted or electronic) of the Ar The use of all or an tion of CsA (Sandimmun, Novartis) was approved in It is noteworthy that the Italian experience in CsA 1983 by the Food and Drug Administration (FDA) is broad, and often long lasting, for most of its thera- for the prevention of transplant rejection.
peutic indications, starting from transplant with 25- year experience. Moreover, several indications for Corresponding author: Giampiero Girolomoni, Clinica Dermatologi- CsA have originated from clinical trials conducted ca, Università di Verona, Piazzale A. Stefani 1, 37126 Verona. mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an Upon these grounds, an Italian Consensus Confer- Table I.—Drugs and foods that inhibit the cytochrome P450 sys‑ ence was held to provide recommendations based on tem, leading to a higher concentration of cyclosporine.5 It is not per.
real-world clinical experience.
aming techniques to enclose an – Antifungals (fluconazole, itraconazole, ketoconazole and – Bromocriptine The production of repr – Calcium channel blockers (diltiazem, nicardipine, verapamil CsA is a cyclic endecapeptide, 8 able to act directly – Ciprofloxacin on cells of the immune system, primarily on T cells, because of its inhibitory effects on calcineurine. It targets the major T cell-driven pathways of immune- – Gentamicin and tobramycin mediated response and inflammation. These effects – Grapefruit juice It is not per.
explain its efficacy both in prevention of transplant – Macrolide antibiotics (erythromycin, clarithromycin and rejections and in immune-mediated dermatoses.9 – Methylprednisolone CsA absorption occurs within 30 minutes and the – Metoclopramide peak serum concentration (Cmax) is observed 2-4 – Oral contraceptives and androgen steroids ticle through online inter – Protease inhibitors e only one file and prv hours after the administration.10-15 – Ranitidine and cimetidine Due to its lipophilicity, CsA is widely distributed – Statins (especially atorvastatin and simvastatin) throughout the body. In plasma, it is mostly bound to – Thiazide diuretics lipoproteins (≥90%) and easily transferred between different lipoproteins, and to or from albumin as well.5 It has a first-pass effect of 27% in the liver.15 CsA metabolism is highly dependent on cyto- The creation of der chrome P450 isoenzymes 3A4 (CYP3A4) and 3A5 Table II.—Drugs that stimulate the cytochrome P450 system, leading to a lower cyclosporine level.5 ute the electronic copib (CYP3A5) in the liver and small intestine, and de- pendent on the efflux p-glycoprotein pump (PGP) – Anticonvulsants (carbamazepine, phenobarbitone, phenytoin encoded by the multidrug resistance-1 gene (MDR1) in the gastrointestinal tract and liver.5 The metabo- VA MEDICA
lites of CsA are mainly excreted in the bile; another 6% is eliminated in the urine, of which 0.1% remains It is not per.
ight notices or ter A higher CsA serum concentration reflects higher y Commercial Use is not per clinical efficacy and is obtained if the drug is admin- – Selective serotonin reuptake inhibitors (sertraline) istered before food intake.5,16 – St John's Wort (Hypericum perforatum) CsA dosage is established on a weight-per-weight – Sulfinpyrazone basis (mg/kg/day, see below for further details).
Table III.—Drugs that may impair renal function during cyclo‑ No additional reproduction is author By virtue of its almost complete hepatic metabo- lism by cytochrome P450 IIIA, the plasmatic levels – Aminoglycosides (gentamycin and tobramycin) of CsA are increased or decreased by drugs that in- – Amphotericin B – Cimetidine and ranitidine hibit or stimulate cytochrome P450 activity, respec- – Ciprofloxacin inted or electronic) of the Ar The use of all or an tively (Tables I-III).5 The consequent change in CsA – Clotrimazole and ketoconazole bioavailability results in adverse effects that are po- tentially exerted on target-organ toxicity.17 Among patients with dermatoses, the use of some – Nonsteroidal antiinflammatory drugs systemic antibiotics as well as of NSAIDS could be – Trimethoprim with sulfamethoxazole critical due to pharmacological interactions, leading mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an to higher CsA concentration and, consequently, tox- The clinical benefit of CsA therapy is related not only to the clinical response, but also to the effects It is not per.
CsA may reduce the clearance of some HMG-CoA on psychological distress, which are a common ex- aming techniques to enclose an reductase inhibitors. Thus, statins should be used perience in patients with psoriasis (see below).29, 30 with caution because of the risk of rhabdomyolysis.5 Many studies indicate a clear dose-dependent re- It is important to underline that heavy alcohol in- sponse, with higher doses producing higher rates of The production of repr take increases CsA levels.18 remission.6, 31-35 Grapefruit juice avoidance must be recommended To identify patients who may benefit from system- during CsA treatment, since it inhibits the metabo- ic treatments including CsA, the "rule of tens" has lism of CsA by suppressing cytochrome P450 en- been proposed: a body surface area affected >10% zyme activity.5, 18 or a Psoriasis Area Severity Index (PASI) >10 or a Dermatology Life Quality Index (DLQI) >10.36 It is not per.
Dose-finding studies and current consensus guide- Systemic CsA in dermatoses
lines have identified 2.5 mg/kg/day CsA as ideal start- ing dose, to be gradually increased up to 5 mg/kg/ CsA has been proven an effective therapeutic op- day by 0.5-1 mg/kg/day at 2-4 weeks intervals.4, 21-32 ticle through online inter e only one file and prv tion for several dermatoses.4-6 Its systemic use is au- Tachyphylaxis did not occur if regimens with pro- thorized in Italy for psoriasis and atopic dermatitis.19 gressive increases were prescribed.31 In patients who are unresponsive, or who respond inadequately after 3 months (PASI 50 not achieved), CsA withdrawal is recommended.4 Drug reduction should be performed Among the available systemic treatments for pso- stepwise (0.5-1.0 mg/kg/day at 2 weeks intervals).4 riasis, CsA has a particularly favorable profile, due Based on long-term clinical experience, six thera- The creation of der to the rapid clinical response (4 weeks for the relief peutic strategies are currently used to treat moderate- ute the electronic copib of symptoms, 10-16 weeks for a PASI 75 response) to-severe psoriasis with systemic CsA (I=induction; even in patients unresponsive to other therapies.4, 20- M=maintenance; definition and treatment regimens are illustrated in Table V): 1) intermittent short- CsA has been proven effective in all variants of term therapy (I); 2) rescue therapy (I); 3) long-term VA MEDICA
psoriasis (Table IV), where different schemes in continuous therapy (I+M); 4) combination therapy terms of doses and treatment duration have been (I+M); 5) rotational therapy (I+M); and 6) week-end therapy (M).4, 6, 37, 38 It is not per.
ight notices or teryr y Commercial Use is not per Table IV.—CsA in psoriasis variants. Lebwohl M et al. J Am Acad Dermatol 1998;39:464-75.23 Erythrodermic psoriasis Fradin MS et al. Br J Dermatol 1990;122(Suppl 36):21-5.24 Palmoplantar pustular psoriasis Erkko P et al. Br J Dermatol 1998;139:997-1004.25 Generalized pustular psoriasis Ozawa A et al. J Dermatol 1999;26:141-9.26 Farber EM. Cutis 1993;51:29-32.27 Witkamp L et al. J Eur Acad Derm Vener 1996;7:49-58.28 No additional reproduction is author Table V.—Systemic cyclosporine treatment schedules. Intermittent short-term therapy – Short course (12-16 weeks) until significant improvement is achieved, after which treatment – If relapse occurs, treatment is reinstituted at the previously effective dose inted or electronic) of the Ar The use of all or an – Used in severe flares of disease until an alternative maintenance treatment is instituted Long-term continuous therapy – Clinical improvement maintained with the lowest effective dose Combination therapy – Cyclosporin can be combined with topical therapies, such as corticosteroids, anthralin, or vitamin D3 analogues, and other systemic treatments, such as methotrexate, fumaric acid esters and mycophenolate mofetil Rotational therapy – Treatment with cyclosporine can be rotated with other systemic agents (see text) – Maintain remission (5mg/kg/day) for 2 consecutive days a week for 24 weeks mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an Moreover, CsA due to its fast therapeutic action, is the possibility to minimize toxicity due to the dose represents an appropriate "bridging" therapy, which reduction,4 even if the possibility of adverse effects It is not per.
is useful if associated with a new long term biologi- arising from pharmacological interactions has to be aming techniques to enclose an cal treatment which needs a certain time lapse to be taken into account.6 A recent Italian study reported a clinical response (therapeutic success or complete clinical remission) The production of repr in 80% of patients with moderate-severe plaque pso- Intermittent short-term therapy riasis who received CsA plus systemic methotrexate The most common systemic CsA regimen is or retinoids, or plus topical treatment and/or photo- represented by a short course (12-16 weeks) ad- therapy.59 ministration, followed by the withdrawal when a significant improvement (PASI 75) or remission Rotational therapy It is not per.
(PASI≥90) is achieved. In case of relapse, a short- term course may be repeated at the previously ef- CsA treatment of psoriasis is not associated with fective dose.4, 21, 23, 39-43 tachyphylaxis,4, 20, 51, 60, 61 allowing rotational thera- In patients with severe psoriasis, a 1-year remis- py, whose rational is similar to that of combination ticle through online inter e only one file and prv sion is obtained in 80% of cases with 2 courses of therapy, characterized by the sequential use of the therapy, the remission after the first course lasting 4 above mentioned systemic agents.20, 61, 62 months in 45% of cases.41, 42 A slight advantage in An Italian study has proven, in patients with se- terms of remission duration was observed with dose vere psoriasis, the superiority of the sequential thera- py with CsA (3 mg/kg/day for 4 weeks) and narrow- band UVB phototherapy compared to narrow-band UVB phototherapy alone.63 The creation of der ute the electronic copib The rapid onset of effect with short-term CsA is Week-end therapy and pulse therapy useful to control severe flares, particularly in severe psoriasis variants.4 A starting dose of 5 mg/kg/day is An additional therapeutic maintenance schedule recommended, followed by a gradual dose decreas- was proposed and evaluated by PREWENT (Pso- VA MEDICA
ing after remission.13,14,17 riasis Relapse Evaluation with Week-End Neoral® Treatment) study, a 24-week, double-blind placebo- controlled trial, carried out in 22 Italian hospitals or Long-term therapy It is not per.
ight notices or ter university Dermatology units. CsA microemulsion y Commercial Use is not per Long-term continuous therapy with CsA is a less was used in patients with chronic plaque psoriasis common approach for severe psoriasis and is pre- who had achieved clinical remission after continu- scribed to obtain a significant clinical improvement ous CsA therapy, and then randomized to receive with the lowest effective dose rather than a complete oral CsA 5 mg/kg/day or placebo for two consecutive control.15, 44-47 Its duration is limited to 2 years in Eu- days/week for 24 weeks. Time to first relapse (adopt- rope 9, 20, 21 with the possibility of a further prolongation ing PASI as diagnostic criterion) was significantly in selected cases, and to 1 year in the United States.48 longer with CsA and PASI was significantly lower The typical maintenance dose is 3-3.5 mg/kg/day.49 at weeks 4-16 in CsA recipients. The incidence of No additional reproduction is author adverse events was similar in both groups.37 Similar results have been reported by another Combination therapy Italian study, in which patients with severe chron- The effects of systemic CsA associated with ic plaque psoriasis were assigned to a continuous inted or electronic) of the Ar The use of all or an various topical treatments, as corticosteroids,50-52 schedule or 4-day therapy per week, administered anthralin,53 vitamin D3 analogues,54 or systemic for 6 months. PASI score and severity of itching treatments, as methotrexate,55 fumaric acid esters,56 were efficiently controlled in both groups. Moreover, acitretin,57 or mycophenolate mofetil 58 have been the safety profile was shown more favourable in the evaluated only in small case series and single case- group with intermittent 4 days per week administra- reports.4 The main advantage of combination therapy tion.64 mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an Consensus Conference Statements
— To establish the optimal dose, the clinical severity has to be taken into account: for PASI aming techniques to enclose an — There is consensus on the indications re-
higher than 20 and especially in cases with a ported by literature for the treatment of psoriasis relevant inflammatory component, an induction variants, in particular for the doses and the dura- dose of 5 mg/kg may be appropriate; a dose of The production of repr 2.5 mg/kg/day, although reported in clinical tri- — However, in clinical practice, indications als, has to be considered suboptimal in severe to start CsA treatment are less strict. It may be used in the following cases with PASI<10: — Based on our experience, a satisfactory − resistance to topical drugs (experience control of itching is generally obtained in few suggests that resistance may occur even weeks, generally earlier than the control of skin − certain clinical characteristics, e.g. the — The clinical response has to be assessed site of the disease (palmoplantar pso- after the first month, when both the profiles of ef- riasis, genital psoriasis); ficacy and safety (see the section Management of ticle through online inter e only one file and pr − characteristics of the patients, including patients) should be assessed. The treatment has sex, age, personal or social relationship to be carried out for at least 3 months, evaluating and employment. In fact, the impact of psoriasis on a patient's quality of life — After clinical remission is achieved, mul- (QoL) may be disproportionate to the tiple possibilities can be evaluated about which clinical severity, due to his/her self- the Consensus doesn't express a unanimous rec- perception and his/her expectations ommendation, rather the advice to make a choice The creation of der about the treatment. Due to the young according the individual patient's characteristics, ute the electronic cop average age of psoriatic patients, the clinical history, and needs: consequences of the psychological and − tapering after 3 months of treatment or emotional stress are particular relevant − tapering once PASI 0 has been reached in terms of their impact on social and VA MEDICA
sexual life leading to low self-esteem, − once PASI 0 has been reached, mainte- high anxiety, and sexual dysfunction nance therapy for 1 month/for at least — In limited extent psoriasis, e.g. nail pso- 1 month due to the high risk of relapse ight notices or ter riasis where PASI and NAPSI (NAil Psoriasis — When a relapse occurs:
y Commercial Use is not per Severity Index) may result quite low: CsA may − during the tapering, then the full dose be considered even if it is not the first-line treat- regimen is recommended followed by ment. The indication has to be established on the continuous therapy for 6 months basis of the patient's characteristics (e.g. per- − immediately after/close to the treat- sonal relationship and employment). In clinical ment completion (unlikely possibility), experience,65,66 CsA has proven effective when the rotational therapy may be an option the ungueal variant was associated to general- − few months after the treatment comple- — A weight-per-weight dose, based on the
tion, the treatment can be repeated, ac- No additional reproduction is author.
ideal body weight is recommended. Adopting as cording to the disease extension and the a reference the actual body weight, overweight severity of the relapse or obese patients may be exposed to high doses, — CsA high doses (5 mg/kg/day) may be
inted or electronic) of the Ar The use of all or an even double that those of normal weight patients, used also to control severe flares
with an increased risk of toxicity (see below for — The recommended dose for induction is
further details). In order to obtain a better com- pliance with the therapy, a fixed dose (200 mg/ — The recommended dose for long-term
day) may be used in such patients therapy is 3 mg/kg/day
mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an — The aim of long-term therapy is to
mg/kg/day for 3 doses per week is equivalent to the achieve more prolonged clearance and improve administration of 3 mg/kg/day for 5 doses per week. aming techniques to enclose an the balance between effectiveness and safety. However, it is largely safer in terms of potential ne- Our large experience of a good safety profile phrotoxicity, since the more prolonged discontinu- supports a prolonged duration of treatment at the ation decreases vasoconstriction, a well described The production of repr minimal effective doses in selected cases functional adverse effect — Lifestyle modifications, including an ap- propriate diet, have a role in achieving a good control of the disease, as indicated by a recent Atopic dermatitis Italian study where weight loss has been able to improve the response to low-dose CsA in obese Atopic dermatitis is one of the most common patients with moderate-severe chronic plaque chronic relapsing childhood dermatoses which af- fects up to 30% of children in most cases before the — Clinical experience suggests the use of age of 5 years, but persists into adulthood in more combination regimens in selected cases ("dif-
cases than reported by the literature (up to 3%). ticle through online inter e only one file and pr ficult cases" in terms of poor responsiveness or Moreover, its onset may be observed in adult age, clinical complexity). Combination therapy pro- even in elderly patients. Overall, clinical experience vides the opportunity to facilitate decreases in suggests that atopic dermatitis is by far more frequent the dose of each single drug and reduction of po- than expected according to diagnostic criteria.68, 69 tential adverse effects In the diagnosis of atopic dermatitis several crite- — In Italian clinical practice, the association ria have been established,68-71 but there is no labora- tory biomarker.
The creation of der − fumaric acid esters is not registered in Current management of atopic dermatitis has not ute the electronic cop curative targets, while it is focused on symptoms re- − acitretin or methotrexate is uncommon − narrow band UVB is not infrequent CsA is the only immunosuppressant agent ap- − topical corticosteroids or vitamin D/vi- proved in Europe for the short-term treatment of VA MEDICA
tamin D analogues is very common severe atopic dermatitis that cannot be controlled — The rational basis of rotational therapy
with topical therapy.4 It has not been formally ap- is reducing the exposure to a single agent in a proved by FDA for this indication, but it has been ight notices or ter chronic (incurable) disease, improving both ef- recommended by American Academy of Dermatol- y Commercial Use is not per ficacy and safety profile ogy (AAD).68, 72 There is no statement indicating the — Clinical experience suggests CsA use in recommended dose in atopic dermatitis, although the cases of inadequate/incomplete responsiveness therapeutic dosage used in psoriasis is convention- (not cured patients who need a continuous thera- ally administered.
py). Notably, individual clinical history has to be The data of a systematic review clearly demon- taken into account strated the efficacy of CsA in atopic dermatitis. Body — Italian clinical research was relevant in the surface area, erythema, sleep loss and corticosteroid development of week-end therapy, a schedule
use were reduced in the CsA group.73 related to CsA effectiveness in a "real-life" clini- No additional reproduction is author A 47% improvement in itching has been described cal setting. Week-end therapy is able to provide a within 2 weeks in patients treated with high dose of longer maintenance of the remission and/or to re- duce relapses in patients with moderate psoriasis. The PREWENT Study schedule consists in the ad- inted or electronic) of the Ar The use of all or an.
ministration of systemic CsA 2 days/week, but a
Short-term therapy schedule of 3 days/week provides a better clini-
cal response. The choice should be based on the
According to the European guidelines, an initial characteristics of the patient or of the disease 37 dose of 5 mg/kg/day for 2 weeks has to be gradually — It is noteworthy that the administration of 5 tapered to a dose of 1.5 mg/kg/day over 3 months, based on the individual clinical response.9,75-78 mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an A meta-analysis by Schmitt 47 demonstrated the QoL scores should be used in conjunction with ob- effectiveness of short-term continuous CsA treat- jective measures of severity as an assessment tool. ment (50% reduction in severity after 6-8 weeks of aming techniques to enclose an Because of the rapid onset of action and marked ef- therapy). Patients treated with an initial dose of 4-5 ficacy, CsA is particularly useful in the treatment of mg/kg/day showed a more rapid response at 2 weeks atopic dermatitis (40% decrease in severity) in comparison to patients The production of repr — Atopic dermatitis is often associated to severe treated with a lower initial dose of 2.5-3 mg/kg/day itching, whose significant improvement is generally (22% decrease in severity). Nevertheless, after a 6-8 obtained in 1-2 weeks with CsA week follow-up, no difference was observed between — In the management of atopic dermatitis skin the two doses in terms of responses.
care, cleansing and bathing, lifestyle, diet restric- According to results of a recent double-blind rand- tion with avoidance strategies are important factors. omized, multicentre trial, CsA is superior to prednisolo- Patients have to be informed and instructed in order It is not per.
ne in inducing a stable remission of severe eczema.79 to actively and effectively collaborate — With short-term therapy, a high initial dose
(4-5 mg/kg/day) is recommended to obtain a more Long-term therapy rapid and sustained improvement ticle through online inter e only one file and prv On the basis of the above mentioned results, the — With long-term therapy, the minimum ef-
lowest effective dose is recommended if a mainte- fective dose of CsA to achieve substantial improve- nance therapy is needed.6, 78 ment in disease severity is appropriate Two randomized controlled studies reported the — The duration of treatment able to obtain a satisfactory clinical response (4-6 months) is lon- effect of CsA long-term therapy to control severe ger than that indicated in clinical guidelines (2-3 atopic dermatitis.80, 81 In a pediatric population (2- 16 years), intermittent short-term therapy (5 mg/kg/ The creation of der day) for 12 weeks was compared to a continuous ute the electronic copib 1-year course (5 mg/kg/day), the latter being associ- ated to better outcomes in terms of short-term and Impact of CsA on QoL
sustained clinical response and patients' QoL.80 The second study,81 which was performed in pa- Dermatoses cause as much disability as that of VA MEDICA
tients with severe atopic dermatitis, compared two other major medical conditions. For instance, dis- long-term CsA regimens: an initial dose of 5 mg/kg/ ability from psoriasis is comparable to that from ar- day tapered to 3 mg/kg/day as tolerated vs 3 mg/kg/ thritis, hypertension and diabetes;82 while QoL from It is not per.
ight notices or ter day increased to 5 mg/kg/day as needed, both main- atopic dermatitis is impaired to a similar extent as is y Commercial Use is not per tained the optimal dose for the following 10 months. seen in other common childhood diseases, such as After 1 year, patients in the treatment group who asthma and diabetes.83 started with 5 mg/kg/day showed slightly better re- The impact on patient's QoL of dermatoses such sults in terms of disease control (59.8% vs. 51.7%), as psoriasis and atopic dermatitis is relevant 82-85 and similar adverse events.
and has been shown able to affect the adherence to Considering relapse and worsening after CsA, medication.84 Consequently, QoL assessment tools data reported is highly variable, in terms of rates and have been specifically developed for dermatologic time of occurrence.4 However, there is no evidence conditions (e.g. the Dermatology Life Quality Index, No additional reproduction is author of a rebound phenomenon on this drug withdrawal.47 DLQI, the Psoriasis Disability Index, PDI, the Ecze- ma Disability Index, EDI, and the Psoriasis Index of Quality of Life, PSORIQoL). In addition, the updat- Consensus Conference Statements
ed "rule of tens" used to select patients with severe inted or electronic) of the Ar The use of all or an (recommendations for adult
psoriasis who could benefit from systemic treatment patients with atopic dermatitis)
includes QoL parameters.9 The impact of a dermatological condition on QoL — When treating atopic dermatitis, a crucial doesn't show a clear relationship with the clinical se- point is the relevant impact of the disease on QoL.
verity of the disease, as assessed with PASI and de- pends more on patient's self-reported morbidity.85, 86 mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an In patients with dermatoses, CsA has been shown The adherence to dental hygiene has to be recom- able to improve QoL. Considering psoriasis, data of mended and checked at 6-months periodic examina- It is not per.
a 1-year substudy from PISCES (Psoriasis Intermit- tions.5, 6 aming techniques to enclose an tent Short Course of Efficacy of Sandimmun Neoral) Laboratory tests have to be performed both at has demonstrated an improvement in QoL (P<0.001) baseline and during the treatment. They include se- and a reduction in itching and disease extent ⁄sever- rum creatinine, potassium, magnesium, bilirubin, The production of repr ity (P<0.001 for both).87 Similar results have been liver enzymes, uric acid, fasting lipids, urea nitrogen, observed for atopic dermatitis both in adults 74, 88 and blood cell count, and urine analysis.21, 61 According to the international guidelines, the tests have to be Considering the common experience of psycholog- repeated during CsA treatment at definite intervals ical distress in patients with psoriasis, generally with (every 2 weeks during the first 2 months of treat- a higher burden in female patients, the PSYCHAE ment).6, 20-22 It is not per.
study, a large observational study performed in 39 The physical examination should include blood Italian dermatology centers on more than 1500 pa- pressure measurement, at least in two separate oc- tients, has shown that, differently to methotrexate casions basally, and continuous monthly monitoring and topical corticosteroids treatment, CsA treatment during the treatment.5 ticle through online inter e only one file and prv is able to control the risk of psychological distress Due to a variety of pharmacological interactions assesses using the General Health Questionnaire (Tables II-IV), it is crucial to investigate the use of (GHQ) and the Brief Symptoms Inventory (BSI).29, any systemic drug (over-the-counter drugs included) 30 It is interesting to note that only 16% of physicians before initiating a treatment with CsA, and to reiter- in the PSYCHAE trial declared that they considered ate the investigation at each visit, eventually men- a patient's psychological status when choosing a sys- tioning the specific class of medication.
temic therapy for psoriasis.30 Notably, evidence suggests that CsA is able to The creation of der inhibit in vitro HCV replication. Some data con- ute the electronic copib firm this property in vivo, in patients who under- Management of patients treated with systemic CsA went liver transplantation or with chronic active CsA is the most commonly used drug by Italian der- hepatitis.90, 91 The Italian experience on patients matologists for the treatment of moderate-severe pso- with concomitant rheumatologic disorders and VA MEDICA
riasis and atopic dermatitis unresponsive to conven- HCV infection indicates that CsA is effective and tional therapy.7 However, due to its narrow therapeutic safe, and may contribute to better outcomes.92, 93 window, clinicians have to take into account the mul- Moreover, the short-term therapeutic association It is not per.
ight notices or ter tiple pharmacological interactions, and the relevant in- of CsA and anti-TNF shows a satisfactory safety y Commercial Use is not per fluence of comorbidities on therapeutic strategy.89 profile (Table VI).91-93 Consensus Conference Statements
Before starting CsA treatment, a careful clinical evaluation has to be carried out (history, examina- — CsA is endowed with a relevant manage- tion, baseline laboratory examinations).
ability, with the possibility to dose changes (ta- Among comorbidities, previous or concurrent ma- pering or increasing according to either clinical No additional reproduction is author lignancies, hypertension, renal impairment, current response or adverse effect onset) infections, or a history of previous PUVA photother- — There is a general consensus with the apy have to be investigated.5, 61 Skin surface should guidelines about baseline assessment and mon- be inspected in order to identify the presence of can- itoring, with some differences, already dis- inted or electronic) of the Ar The use of all or an cerous or actinic lesions. In case of active herpes simplex infection or viral warts the treatment should — In contrast to guidelines recommenda- be postponed after healing.5, 61 tions, the screening for malignancies is exclu- Hepatitis profiles including anti-HAV, HBsAg, sively based on clinical history anti-HBs, anti-HBc,  anti-HCV and also  anti-HIV — The screening of infectious diseases is should be checked in patients treated with CsA.61 mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an Table VI.—Laboratory examinations during cyclosporine treatment. It is not per.
aming techniques to enclose an Full blood count leukocytes, platelets) The production of repr Liver function tests (transaminases, alkaline phosphatase, gamma- glutamyl transferase, Electrolytes (sodium, It is not per.
Urine analysis and ticle through online inter e only one file and prv Further specific test may be required according to clinical signs, risks and exposure based on the patient's individual history. The Consensus Conference Statements
measurement of blood infective markers is not The creation of der mandatory, unless a high clinical suspicion is — There is consensus on the following abso- lute contraindications: ute the electronic copibtr — The first time point for laboratory test is
− poorly controlled hypertension, scheduled at the first month, later than what stated
− severe infections, by guidelines (2 weeks) − malignancies (ongoing disease or pre- VA MEDICA
vious history; particular caution with haematological malignancies and der- matological malignancies, with the ex- ception of basal cell carcinomas) It is not per.
ight notices or ter CsA is contraindicated in uncontrolled hyperten- — There is consensus on the following rela- y Commercial Use is not per sion, renal disease, serious infections, and in patients tive contraindications: with a previous history of malignancy (excluding ba- − liver impairment, sal cell carcinoma).5, 20-23, 78 − concomitant administration of drugs Moreover, the drug should be avoided in patients able to pharmacologically interact with previously treated with a high cumulative dose of psoralen and ultraviolet A light phototherapy − concomitant PUVA (also previous (PUVA), due to the risk of carcinogenicity.
PUVA treatment at dose >1000 J/cm², Skin infections superimposed to atopic eczema − pregnancy and lactation (for more de- No additional reproduction is author do not represent an absolute contraindication, but an tails, see below), adequate antibiotic therapy is needed before CsA.78 − antihypertensive treatment with a com- A careful evaluation of the benefit/harm balance bination regimen of two or more agents is requested in patients with epilepsy, severe hepatic inted or electronic) of the Ar The use of all or an dysfunction, immunodeficiency disorders, diabetes, obesity, premalignant conditions. Elderly patients Management of adverse effects (≥65 years), patients with a history of drug or alco- hol abuse, poor compliant patients are at higher risk The concern about adverse effects of CsA has lim- to develop adverse events.
ited its use also in dermatology, although the doses For CsA use in pregnancy and lactation, see below. used to treat skin diseases are largely beneath those mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an considered at risk. To reduce the risk of side effects whose dose-dependency is definitely proven,5, 18, 20, tients, with the exception of female and pediatric recommendations of current guidelines in terms patients, and is reversible aming techniques to enclose an of dosage and monitoring have to be strictly fol- — Serious adverse effects are reported with limited frequency, but need careful and appro- The risk of gingival hyperplasia is generally con- priate management The production of repr trolled by an adequate hygiene or antiseptic thera- py. More severe cases may be cured by a CsA dose reduction or azithromycin administration for 3-5 Renal impairment Major concerns are related to renal impairment, Renal dysfunction associated to CsA therapy may hypertension, and hyperlipidemia, which are the be functional or structural. Its occurrence and char- It is not per.
most relevant even if not the most common adverse acteristics are largely dose-dependent, damage being effects associated to CsA treatment. They may rep- more frequent and more likely to become structural resent the reason why dermatologists show a certain with prolonged therapy (over 2 years) or doses (high- resistance to embrace CsA use in their clinical prac- er than 5 mg/kg/day which is considered the highest ticle through online inter e only one file and prv recommended dermatological dose, i.e. up to 8-8.5 mg/kg/day which were used in the past in transplant recipients).5, 94-96 Consensus Conference Statements
Kidney impairment, based on either vascular or tubular alterations, may lead to a decrease in renal — Patients must be adequately informed glomerular filtration rate (GFR) and in renal blood about the possibility of adverse effects and in- flow (as reflected by a decreased creatinine clearance) The creation of der structed on their management, thus reducing leading to hypomagnesaemia, decreased bicarbonate ute the electronic copib their anxiety or distress and, indirectly, their concentration, hyperuricemia, and hyperkalemia.97 negative perception At lower doses, as those administered with inter- — Side effects are dose-dependent in terms mittent short-term therapy, nephrotoxicity causes of incidence and severity, related to the dura- functional changes and is reversible on drug with- VA MEDICA
tion of the therapy and reversible on discon- Long-term and/or high dose CsA therapy is a risk — In clinical practice, mild neurological/neu- factor for tubular interstitial fibrosis 95, 96, 98 which is It is not per.
ight notices or ter romuscular side effects are reported (probably mediated by an in increase in Transforming Growth y Commercial Use is not per underreported and/or underdiagnosed): periph- Factor-beta (TGF-β) 99 and is facilitated by older eral paraesthesias, limbs burning sensation. They age, concurrent hypertension or obesity.
do not usually result in treatment discontinua- Recommendations about prevention, monitoring tion, since they tend to improve or disappear in and management of renal nephrotoxicity following the first week(s) of treatment. However, if they the S3-European guidelines 20 and an international are severe and/or persistent, treatment discon- statement consensus 34 are reported in Figure 1. The tinuation is suggested best predictive factor of nephrotoxicity is the per- — Fatigue and gastrointestinal side effects centage of serum creatinine increase over baseline No additional reproduction is author (nausea, diarrhoea, discomfort, pain) are rather common, particularly in female patients. Gas- Factors likely to increase the risk of nephrotoxic- trointestinal effects may be controlled with ad- ity (e.g., advanced age, diabetes, nephrotoxic drugs, ministration after the meals obesity) should also be evaluated, and medication inted or electronic) of the Ar The use of all or an — Oral hygiene is likely to reduce the risk of charts should be carefully reviewed for potential gingival hyperplasia, actually becoming an un- drug interactions.
common adverse event. It has to be treated with A difference is apparent between US and Euro- azithromycin, 500 mg/day for 3-5 days pean guidelines with respect to the duration of con- — Hypertrichosis is underreported by pa- tinuous treatment to prevent chronic nephrotoxicity: a maximum of 1 year is recommended by the Ameri- mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an It is not per.
aming techniques to enclose an The production of repr It is not per.
ticle through online inter e only one file and prv The creation of der ute the electronic copibtr VA MEDICA
It is not per.
ight notices or teryr y Commercial Use is not per Figure 1.—Management of nephrotoxicity.22 can Academy of Dermatology, while the British are the laboratory tests of reference. Following Association of Dermatology and the European As- this flow chart, i.e. decreasing the CsA dose by sociation of Dermatology and Venereology recom- 25% if creatinine rises 30% over baseline and mend 2 years.5, 18, 20-22, 96 These strict limitations are by 50% if the rise is ≥50%, the incidence of CsA somewhat inconsistent with the long-term experi- No additional reproduction is author.
nephrotoxicity is rather low and reversible. Es- ence gathered with transplanted patients who have timated glomerular filtration rate (eGFR, to be undergone lifelong treatment with CsA.
estimated using Cockroft Gault) is not a routine laboratory measure and may be evaluated when inted or electronic) of the Ar The use of all or an serum creatinine is increased Consensus Conference Statements
— Among agents able to increase nephro- — There is consensus on the flow chart pro- toxicity, aminoglycosides, amphotericin B, cip- posed by the international guidelines (Figure 3).
rofloxacin, vancomycin, lovastatin, cimetidine, — Serum creatinine and blood urea nitrogen acyclovir, and NSAIDs have to be mentioned mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an Table VII.—Magnesium‑rich foods.101 The incidence of new-onset hypertension with CsA It is not per.
aming techniques to enclose an treatment ranges from 0% to 57%, being higher with a long-term treatment and lower with short-course thera- pies and reversible after dose reduction and/or withdraw- Whole wheat flour The production of repr al or with the use of antihypertensive drugs.5, 20, 41, 61, 76 However, some studies show the lack of a clear relation- ship between CsA dose and frequency of hypertension occurrence,5, 61, 100 thus suggesting a role for an individual variability in the sensitivity to CsA hypertensive effect.5, This hypothesis supports the use of antihypertensive drugs rather than a reduction of the dose to manage the — The onset of hypomagnesaemia, which onset of hypertension.100 occurs earlier than that of hyperkalaemia, is a good even if poor predictor of renal impair- The differences observed between patients with atopic ment. Several conditions (e.g. administration dermatitis (lower incidence) and with psoriasis (higher ticle through online inter e only one file and prv of diuretics and aminoglycosides or alcohol incidence) may be explained by their younger age and consumption) are able to induce hypomag- the increased association of obesity, respectively.5, 102, 103 nesaemia, which favours nephrotoxicity. The A regular monitoring of blood pressure is crucial in pa- daily recommended intake of magnesium is tients with psoriasis, as they are known to be at increased 400-420 mg. A list of magnesium rich foods is risk of cardiovascular morbidity and mortality.104 presented in Table VII A flow-chart reporting the recommendations from cur- rent guidelines about the management of hypertension The creation of der ute the electronic copibtr VA MEDICA
It is not per.
ight notices or teryr y Commercial Use is not per No additional reproduction is author.
inted or electronic) of the Ar The use of all or an Figure 2.—Management of hypertension.22, 61 mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an associated to CsA treatment is reported in Figure 2. The choice of the antihypertensive drug is of particular interest contraindicated if already included in the sched- It is not per.
and somewhat controversial both in literature and in clini- ule. Considering the broad range of positions on aming techniques to enclose an cal practice. Calcium channel blockers are the first choice this clinical question, it is highly recommended thanks to their vasodilating effect, conferring some pro- to seek the advice of a specialist consultant for a tection against nephropathy, although nifedipine should decision on any individual case The production of repr be avoided because of an increased risk of gingival hyper- plasia. The calcium channel blockers of the dihydropyrid- ine class, i.e. isradipine and amlodipine represent a good Hyperlipidemia choice, since they do not modify CsA levels and exert a Hyperlipidemia has to be carefully monitored and vasodilating effect on the afferent arteriole, which confers controlled with diet or medications (Figure 3).20, 61 protection against nephropathy.104-106 Beta-blockers may However, caution is needed with the co-administra- It is not per.
also be used, taking into account the possibility of the tion of CsA and statins to detect myopathy (rhab- disease worsening, while thiazide diuretics are contrain- domyolysis) at an early stage. Cases of muscle toxic- dicated because of a potential increase in nephrotoxicity. ity have been reported with pravastatin, atorvastatin Angiotensin-converting enzyme inhibitors and potassium- ticle through online inter and lovastatin. Fluvastatin is the most studied and e only one file and prv sparing diuretics should be avoided as they may cause hy- recommended lipid-lowering drug.20, 61 perkalemia and a decrease in GFR.5, 22, 61 The monitoring and control of hypertension, as well as of hyperlipidemia (see below) is crucial in Consensus Conference Statements
patients with psoriasis because of their increased risk of cardiovascular morbidity and mortality.103 — The absolute increase in lipid levels is The creation of der moderate, generally higher in cholesterol levels than in triglycerides levels ute the electronic copib Consensus Conference Statements
— Dietary intervention is mandatory — There is consensus about fluvastatin as first — There is consensus on the flow chart pro- choice therapy, due to its peculiar mechanism of posed by the international guidelines,20, 22 al- action, different to that of other statins.107, 108 VA MEDICA
though a closer monitoring is considered more Moreover, pravastatin has a somewhat peculiar appropriate, particularly at the beginning of the metabolism, being only partially catalyzed by treatment (daily monitoring during the first week cytochrome P-450 isoenzymes and, differently It is not per.
ight notices or teryr or with blood pressure levels ≥140/90 mmHg) from other statins, competing less with CsA for y Commercial Use is not per — To manage hypertension, there is con- uptake by hepatocytes 109 sensus on calcium channel blockers as the first choice (excluding nifedipine for the increased risk of gingival hyperplasia; preferring israd- ipine and amlodipine because they don't alter CsA levels). In clinical practice thiazide diuretics An increased risk of malignancy after long-term (even if contraindicated in renal impairment) are CsA treatment has been described in patients who prescribed for short courses. Angiotensin-con- underwent organ transplantation.111, 112 A large re- No additional reproduction is author verting enzyme inhibitors (risk of hyperkalemia view, investigating the incidence of malignancy in although associated to a protective vasodilating patients treated with CsA for up to 5 years for severe effect) and potassium-sparing diuretics (risk of psoriasis, showed that the incidence of extracutane- hyperkalemia) are contraindicated ous malignancy was not higher than that reported in inted or electronic) of the Ar The use of all or an If blood pressure levels are under control with the general population.112 a previously defined antihypertensive sched- CsA enhances the induction of skin tumours by ule, there is controversy about the need of any therapeutical change. In particular, angiotensin- Actually, the risk of cutaneous squamous cell converting enzyme inhibitors are not absolutely carcinoma (SCC) increases with longer duration of therapy, only in patients with a previous history mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an It is not per.
aming techniques to enclose an The production of repr It is not per.
ticle through online inter e only one file and prv The creation of der ute the electronic copibtr VA MEDICA
ight notices or ter Figure 3.—Management of hyperlipidemia.20, 61 y Commercial Use is not per of PUVA or immunosuppressant agents.112, 114-116 cases 117 failed to show an increase in their incidence In fact, duration of exposure to CsA, psoralen and in patients treated for psoriasis.112, 115 UVA, exposure to methotrexate, and to immunosup- pressants has a significant impact on the incidence of non-melanoma skin cancers.112 As a consequences current guidelines suggest to CsA administration may increase the general risk avoid association of CsA and PUVA or immunosup- of bacterial, parasitic, viral, and fungal infections, as No additional reproduction is author pressants and/or to be cautious in case of an indi- well as the risk of infection with opportunistic patho- vidual history of a high cumulative dose of PUVA gens, but the actual incidence of infective complica- or a previous history of SCC or melanoma.20, 22, 23 tions when treating psoriasis is low.5, 20, 117 Manage- Again, it has to be pointed out that this association is ment of infection depends on appropriate and prompt inted or electronic) of the Ar The use of all or an routinely prescribed in transplant recipients.
antibiotic therapy (for the choice of drugs, see drug An increased risk of lymphoma has been shown in interactions). In case of herpes simplex infections, transplant recipients, while in patients with autoim- CsA therapy should be deferred until resolutions.5, mune dermatoses data are controversial and confined to isolated cases reports.5 As far as solid tumours Vaccinations given concomitantly with CsA may are concerned, comprehensive studies and single be less effective. Studies in patients with transplan- mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an tation taking CsA have shown inconsistent effective- ness of the influenza vaccine. Live vaccines are con- Consensus Conference Statements
It is not per.
traindicated and should be avoided.20, 61 aming techniques to enclose an — When starting CsA, a baseline pregnancy test is not mandatory Pregnancy and lactation — CsA is contraindicated during pregnancy The production of repr Because of the state of immunologic tolerance of Drug discontinuation is recommended when pregnancy, several patients with autoimmune derma- planning an intended gestation or when an un- toses report an improvement during gestation.
planned gestation is ascertained The need for contraception should be discussed — Clinical experience demonstrates a good with women of child-bearing age taking into account safety profile for CsA:5 that CsA can reduce the efficacy of oral contracep- − cases of administration in neonatal or It is not per.
pediatric age without the evidence of CsA has been classified in category C drug by the FDA Pregnancy Labeling Task Force 118 (studies on − approximately 700 pregnancies without animals have shown an adverse effect on the foetus, negative adverse events in women who ticle through online inter e only one file and prv and there are no adequate and well controlled studies previously underwent organ transplan- in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). − there is no evidence of adverse events CsA passively crosses the placental blood barrier to in pregnant women who did not discon- achieve 10-50% of the maternal plasma concentra- tinue CsA treatment during pregnancy tion.119 Its levels decrease with pregnancy due to the − there is no evidence of teratogenicity increased volume distribution and metabolism.120 — Since no teratogenicity has been proven, The creation of der CsA is excreted in breast milk and its levels show a CsA is of choice when a systemic drug is needed ute the electronic copib broad variability in terms of milk-to maternal serum — Cases of premature delivery have been re- concentration ratio, depending on the time of sam- pling and maternal dose.121 — CsA safety profile is better than that of al- Most safety data on humans are derived from anal- ternative agents (e.g. etretinate administration has VA MEDICA
yses of pregnancy outcomes in transplant recipients to be avoided for 2 years prior the conception) and suggest that there is no evidence of teratogenici- — At present there are no adequate and well ty.20, 61, 122, 123 A limited number of observations up to controlled studies in pregnant women and, there- It is not per.
ight notices or ter an age of approximately 7 years in children exposed fore, CsA should not be used during pregnancy y Commercial Use is not per to CsA in utero show preserved renal function and unless the potential benefit to the mother justifies normal blood pressure levels.10, 11 the potential risk to the fetus Among the oral medications approved for pso- Therapeutic abortion is not an absolute indi- riasis, CsA is considered the safest and it has been cation in case of exposure to CsA of a pregnant suggested as the best choice for pregnant women.61 patient. The choice has to be made on the basis A certain number of cases of prematurity and/or de- of an acceptable risk-to-benefit balance, provid- velopmental delay is reported in children born to ing the patient with the opportunity to make an mothers with solid-organ transplantations.5 Pregnant informed decision and taking into account her No additional reproduction is author women receiving immunosuppressive therapies af- individual needs and preferences ter transplantation, including CsA or CsA contain- ing regimens, are at risk of premature delivery (<37 Pediatric use inted or electronic) of the Ar The use of all or an Breastfeeding is contraindicated in mothers tak- Children are less susceptible to CsA toxicity be- ing CsA, mainly because of concerns about im- cause of a reduction in drug bioavailability and a lower munosuppression in the neonate.20-22, 36, 124 There predisposition to nephrotoxicity.5 CsA has been used is evidence, even from small studies, of no adverse at high doses in pediatric transplant recipients and in events associated to breastfeeding during CsA treat- children with atopic dermatitis or psoriasis with no se- ment.121, 125, 126 rious adverse effects.5, 40, 81, 128, 129 Theoretically, pedi- mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an atric patients better tolerate higher CsA doses, due to Niven AA et al. Influence of biliary T-tube clamping on CsA phar- macokinetics in liver recipients. Transplant Proc 1988;20:512-5.
a different pharmakocinetics with clearance rates up to 14. Halloran PF, Helms LM, Kung L, Noujaim J. The temporal profile It is not per.
four times those of adults, this meaning lower blood of calcineurin inhibition by cyclosporine in vivo. Transplantation aming techniques to enclose an concentrations for the same dose.130-132 15. Vine W, Bowers LD. Cyclosporine: structure, pharmacokinet- ics, and therapeutic drug monitoring. Crit Rev Clin Lab Sci The production of repr 16. Umezawa Y, Mabuchi T, Ozawa A. Preprandial vs. postprandial pharmacokinetics of cyclosporine in patients with psoriasis. Int J Consensus Conference Statements
17. Colombo D, Egan CG. Bioavailability of Sandimmun® versus — CsA has been used starting from the first SAndimmun Neoral®: a meta-analysis of published studies. Int J Immunopathol Pharmacol 2010;23:1177-83.
year of life and cases of high dose treatment in 18. Paul MD, Parfrey PS, Smart M, Gault H. The effect of ethanol on pediatric patients who underwent organ trans- serum cyclosporine A levels in renal transplant recipients. Am J It is not per.
plantation are described. However, caution is Kidney Dis 1987;10:133-5.
19. Legge 23 dicembre 1996, n. 648 [Internet]. Available from: http:// needed, when changes in standard schedules or guidelines are adopted — CsA management in pediatric patients ceRedazionale=096G0680&elenco30giorni=false [cited 2014, Apr ticle through online inter 3]. Elenco farmaci erogabili a totale carico del S.S.N. ai sensi della e only one file and prv (usually to treat atopic dermatitis) needs specific legge 648/96 e relative indicazioni terapeutiche (aggiornamento ad considerations and caution, even if better toler- aprile 2013). Available from: 20. Pathirana D, Ormerod AD, Saiag P, Smith, C, Spuls, PI, Nast et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009;23(Suppl 2):5-70.
21. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gor- don KB et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the manage- The creation of der 1. Borel JF, Feuer C, Gubler HU. Biological effects of cyclosporine ment and treatment of psoriasis with traditional systemic agents. J A: a new anti-lymphocyte agent. Agents Act 1976;6:468-75.
ute the electronic cop Am Acad Dermatol 2009;61:451-85.
2. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC 22. Griffiths CE, Dubertret L, Ellis CN, Ellis CN, Finlay AY, Finzi AF et al. Cyclosporin A in patients receiving renal allografts from ca- et al. Ciclosporin in psoriasis clinical practice: an international daver donors. Lancet 1978;2:1323-7.
consensus statement. Br J Dermatol 2004;150(Suppl 67):11-23.
3. Mueller W, Hermann B. Cyclosporin A for psoriasis. N Engl J Med 23. Lebwohl M, Ellis C, Gottlieb A, Koo J, Krueger G, Linden K VA MEDICA
Shupack J et al. Cyclosporine consensus conference: with empha- 4. Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatol- sis on the treatment of psoriasis. J Am Acad Dermatol 1998;39:464- ogy. Part I. J Am Acad Dermatol 2010;63:925-46.
5. Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatol- 24. Fradin MS, Ellis CN, Voorhees JJ. Efficacy of cyclosporin A in ogy. Part II. J Am Acad Dermatol 2010;63:949-72.
psoriasis: a summary of the United States' experience. Br J Derma- It is not per.
ight notices or ter 6. Capella GL, Della Casa-Alberighi O, Finzi A. Therapeutic con- tol 1990;122(Suppl 36):21-5.
y Commercial Use is not per cepts in clinical dermatology: cyclosporine A in immunomediated 25. Erkko P, Granlund H, Remitz A, Rosen K, Mobacken H, Lindeloef and other dermatoses. Int J Dermatol 2001;40:551-61.
B et al. Double-blind placebo-controlled study of long-term low- 7. Naldi L, Griffiths CE. Traditional therapies in the management of dose cyclosporin in the treatment of palmoplantar pustulosis. Br J moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol 2005;152:597-615.
26. Ozawa A, Ohkido M, Haruki Y, Kobayashi H, Ohkawara A, Ohno 8. Brunton L, Chabner BA, Knollman B. In: Goodman & Gilman's. Y et al. Treatments of generalized pustular psoriasis: a multicenter The pharmacological basis of therapeutics. New York: McGraw- study in Japan. J Dermatol 1999;26:141-9.
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27. Farber EM, Nall L. Pustular psoriasis. Cutis 1993;51:29-32.
9. Griffiths CE, Katsambas A, Dijkmans BA, Finlay AY, Ho VC, 28. Witkamp L, Meinardi MMHM, Bossuyt PMM, Van de Kerkhof Johnston A et al. Update on the use of ciclosporin in immune-me- PCM, Arnold WP, De Hoop D et al. A multicentre evaluation of the diated dermatoses. Br J Dermatol 2006;155:1-16.
guidelines for the use of cyclosporin A in severe psoriasis. J Eur No additional reproduction is author 10. Novartis Pharmaceuticals Corporation. Neoral (cyclosporine) soft Acad Derm Vener 1996;7:49-58.
gelatin capsules, oral solution: full US prescribing information. 29. Colombo D, Caputo A, Finzi A, Andreassi L, Chimenti S, Vena GA 2009 [Internet]. Available from:
et al. for the PSYCHAE Study group. Evolution of and risk factors com/product/pi/pdf/neoral.pdf [cited 2014, Apr 3].
of distress in patients with psoriasis: the PSYCHAE Study. Int J 11. Novartis Pharmaceuticals UK Ltd. Neoral (ciclosporin) soft gelatin Immunopathol Pharmacol 2010;23:297-306.
inted or electronic) of the Ar The use of all or an capsules, oral solution: summary of product characteristics. 2011 30. Finzi A, Colombo D, Caputo Andreassi L, Chimenti S, Vena GA et [Internet]. Available from: al. for the the PSYCHAE Study Group- Psychological distress and coping strategies in patients with psoriasis: the PSYCHAE Study. J Oral1Solution/ [cited 2014, Apr 3].
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12. Kahan BD. Individualization of cyclosporine therapy using phar- 31. Timonen P, Friend D, Abeywickrama K, Laburte C, Von Graffen- macokinetic and pharmacodynamic parameters. Transplantation ried B, Feutren G. Efficacy of low-dose cyclosporine A in psoria- sis: results of dose-finding studies. Br J Dermatol 1990;122:33- 13. Tredger JM, Naoumov NV, Steward CM, O'Grady JG, Grevel J, mation of the Pub w access to the Ar adically or systematically GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE e additional copies or personal or commercial use is , electronic mailing or an 32. Faerber L, Braeutigam M, Weidinger G, Mrowietz U, Christophers 51. Griffiths CEM, Powles AV, McFadden J, Baker BS, Valdimars- E, Schulze HJ et al. Cyclosporine in severe psoriasis: results of a son H, Fry L. Long term cyclosporine for psoriasis. Br J Dermatol meta-analysis in 579 patients. Am J Clin Dermatol 2001;2:41-7.
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33. Christophers E, Mrowietz U, Henneick HH, Farber L, Welzel D. 52. Vena GA, Galluccio A, Pezza M, Vestita M, Cassano N. Combined aming techniques to enclose an Cyclosporine in psoriasis: a multicenter dose-finding study in se- treatment with low-dose cyclosporine and calcipotriol/betametha- vere plaque psoriasis. J Am Acad Dermatol 1992;26:86-90.
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honoraria and/or research funding from Abbvie, Novartis and Leo Phar- 117. Behnam SM, Behnam SE, Koo JY. Review of cyclosporine im- ma; F. Ayala has received advisory/speaker honoraria and/or research munosuppressive safety data in dermatology patients after two de- funding from Abbvie, Janssen, MSD, Novartis and Pfizer; F. Bardazzi cades of use. J Drug Dermatol 2005;4:189-94.
has received advisory/speaker honoraria and/or research funding from The creation of der 118. Pregnancy and lactation labeling [Internet]. Available from: http:// Abbvie, Janssen, Novartis, Schering-Plough and Pfizer; G. Bella is an employee of Novartis Farma Italy; D Colombo is a part-time em- ute the electronic cop tResources/Labeling/ucm093307.htm [cited 2014, Apr 3].
ployee of Novartis Farma Italy and received grants from Allergan and 119. Petri M. Immunosuppressive drug use in pregnancy. Autoimmunity Aventis; S. Chimenti has received advisory/speaker honoraria and/or research funding from Abbvie, MSD, Novartis and Pfizer; M. L. Flori 120. Armenti VT, Ahlswede KM, Ahlswede BA, Cater JR, Jarrell BE, has received advisory/speaker honoraria and/or research funding from Mortiz MJ et al. Variables affecting birthweight and graft survival Novartis; G. Girolomoni has received advisory/speaker honoraria and/ VA MEDICA
in 197 pregnancies in cyclosporine-treated female kidney trans- or research funding from Abbott, Almirall, Boehringer Ingelheim, Cel- plant recipients. Transplantation 1995;59:476-9.
gene, Dompè, Eli-Lilly, Galderma, GSK, Janssen, Leo Pharma, Otsuka, 121. Moretti ME, Sgro M, Johnson DW, Sauve RS, Woolgar MJ, Taddio Merck-Serono, Maruho, MSD, Novartis and Pfizer; G. Micali has re- A et al. Cyclosporine excretion into breast milk. Transplantation ceived advisory/speaker honoraria and/or research funding from Abbvie, It is not per.
ight notices or ter Almirall, Leo Pharma, Novartis and Pfizer; A. Parodi has received advi- 122. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome y Commercial Use is not per sory/speaker honoraria and/or research funding from Abbvie, Almirall, after cyclosporine therapy during pregnancy: a meta-analysis. Galderma, Leo Pharma, MSD, Novartis, Pfizer and Shire; K. Peris has received advisory/speaker honoraria and/or research funding from Ab- 123. Lamarque V, Leleu MF, Monka C, Krupp P. Analysis of 629 preg- bott, Galderma, GlaxoSmithKline, Hofmann La Roche, Janssen, Leo nancy outcomes in transplant recipients treated with Sandimmun. Pharma, Meda, MSD and Novartis; G. A. Vena has received advisory/ Transplant Proc 1997;29:2480-1.
speaker honoraria from Abbvie, Almirall, Astellas, Galderma, Leo Phar- 124. American Academy of Pediatrics Committee on Drugs. Trans- ma, Merck-Serono, MSD, Novartis, Pfizer and UCB.
fer of drugs and other chemicals into human milk. Pediatrics Received on December 6, 2013.
125. Nyberg G, Haljamae U, Frisenette-Fich C, Wennergren M, Kjellm- Accepted for publication on January 3, 2014.
No additional reproduction is author.
inted or electronic) of the Ar The use of all or an mation of the Pub w access to the Ar adically or systematically Vol. 149 - No. 5 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA This document is protected b


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HACIA UN PROCESO CIVIL MÁS EFICIENTE: COMUNICACIONES TELEMÁTICAS. EL SISTEMA "LEXNET" MONTSERRAT DE HOYOS SANCHO Profesora Titular de Derecho Procesal. Universidad de Valladolid1 I. INTRODUCCIÓN Los actos procesales de comunicación -cuya trascendencia no siempre es considerada en toda su dimensión2- constituyen la "correa de transmisión" que permite el correcto funcionamiento del sistema que nos conducirá al dictado de la resolución que dará respuesta a la pretensión de tutela judicial efectiva. Sin embargo esta funcionalidad, con su indudable relevancia, no alude expresamente a su trascendencia más allá del acto procesal, o concatenación de actos procesales preordenados a la obtención de la resolución final; debemos tener presente también que de su correcta ejecución y puntual eficacia depende la plena vigencia de derechos y garantías que forman parte del más amplio derecho fundamental al debido proceso o al proceso con todas las garantías: los derechos de defensa, audiencia y contradicción, con observancia además del derecho a un proceso sin dilaciones indebidas. Recordemos además que no son pocas las nulidades declaradas por nuestros tribunales, precisamente por notificaciones practicadas con vulneración de garantías esenciales del procedimiento que han provocado indefensión –art. 238 LOPJ, vid. LEC-.

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