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2.1. Indication

Systemic treatments are indicated when psoriasis makes a significant impact on the quality of life and topical treatments are not sufficiently effective or too boring or restrictive. As such, their indication is most often a request of the patient, always quite important to well understand. However, topical treatments could remain quite useful at this stage when combined with systemic treatments: either temporarily to gain time, or to achieve better results on a few limited, resistant regions; or to cope with a psoriasis attack and thus avoid having to increase systemic treatment doses; or even to boost the effectiveness of weak and well- tolerated doses of a systemic treatment.
The main systemic treatments are phototherapy, retinoids, methotrexate, cyclosporine, in some countries fumaric acid, or exceptionally azothioprine, mycophenolate mofetil, hydroxyurea, extracorporeal photophoresis. In case of resistance, intolerance or contraindication of two systemic treatments, recombinant proteins showing specific activities targeted against T cell’s activation or TNF ?are of great help.

[|This may be unimportant, but in general I would prefere not to place phototherapy other than PUVA among systemic treatments.|auteur196]

2.2. Phototherapies and light-activated chemotherapy

[|I was likewise interested in the discussion on phototherapy (light treatment). While Narrow Band has become commonplace in Europe, it is far less commonly utilized by dermatologists in clinical practice in the USA, with a concern that phototherapy as a treatment modality for psoriasis may slowly be “losing ground” to systemic therapy. Is this a question of accessibility with the pace of modern day lives being such that 2-3 visits a week to the dermatology clinic is difficult to accomplish, or is this driven by cost-related issues, ie the high cost of the 311 nanometer bulbs, or even reimbursement issues? Also, what is the role of the new Laser units for localized disease.|auteur215]

Psoriasis phototherapies consist of using the biological properties of ultraviolets for therapeutic purposes. Ultraviolet B’s induce DNA lesions, inactivate proteins and oxidize liquids and hence produce anti-mitotic, anti-inflammatory and immunosuppressive actions. It is possible to use a broad spectrum UVB lamp but narrow band UVB TL01 are more effective.

Ultraviolet A’s have no antipsoriatic activity. On the other hand, they can be absorbed by a drug applied or ingested prior to radiation. This drug, once activated by UVA, will develop different pharmacological properties: anti-mitotic activity by direct interaction with the DNA, photoinactivation of proteins, immunosuppression. Thus, it is not a phototherapy but a photoactivated chemotherapy. The drugs used most often in photoactivated chemotherapy of psoriasis are the psoralens, which are hydrophobic molecules, intercalated in DNA, highly photomutagenic, and photocarcinogenic in animals. Once intercalated in the hydrophobic DNA sites, the psoralen molecule will produce a covalent link with a DNA strand by absorbing the energy from an initial photon to form a mono-addition product. Some of these mono-addition products will be able to absorb a second photon to form a DNA cross-link. The produced cross-links form an intracellular lesion as powerful as those brought about by adriamycine. These cross-links are very difficult to repair and are responsible for the photomutagenic and photocarcinogenic properties of the psoralens. Alongside these interactions with the DNA, the photoactivated psoralens are capable of modifying proteins and lipids, and of inactivating enzymes and membrane receptors, as well as the complement fractions. Of all their properties, it is not known which are responsible for their antipsoriatic effectiveness.

New psoralens, forming only mono-additions with DNA (mono-additions that are much easier to repair and much less mutagenic) have been synthesized. Some of them are more effective and much better tolerated than the bifunctional psoralens currently in use. Unfortunately, the cost of producing them has prevented them from being developed by the pharmaceutical industry (photos 70, 71,72 and 73).

2.2.1. UVB phototherapy

UVB phototherapy has been used since the beginning of the 20th century. Their use derives from the observation of the solar radiation’s effectiveness, known to show improvement in 70% of psoriasis cases.

Their use, in conjunction with tars in England and with dithranol in the USA in the form of three to four-week cures, has been the benchmark treatment for extensive psoriasis for more than 60 years. The initial dose depends on the phototype, the rate of dosage increase depends on the rate of induced tanning. In biological terms, UVB is much lessphotomutagenic than PUVA therapy and the lesions made in the DNA are much easier to repair than those caused by psoralens. Subjects risking UVB photocarcinogenesis are probably the same as those put at risk by sun exposure. For the time being, they remain poorly identified, but progress should be made in the years to come.

UVB phototherapy may be used in the clearing phase and, for some people, in maintenance therapy (photos 74 and 75). For the time being, it is not known whether there exists a maximum cumulative dose beyond which this therapy should definitively be stopped. It is also unknown whether UVB phototherapy can still be offered to patients who have reached the maximum cumulative dose for PUVA therapy. However, sun exposure is never forbidden to psoriatic patients alongside with advices adapted to each individual situation (phototype, lentigines, actinic keratoses …). It seems reasonable to proceed in similar way for UVB usage.

Photo 74.

Photo 75.

UVB phototherapy can be produced by two types of lamps. Classic lamps emit broad-spectrum UVB, but are the less efficient. Philips TL01 lamps emit narrow-band UVB, centring around [313 nanometres|The peak is actually at 312nm.|auteur192]. The narrow-spectrum phototherapy tends to become widespread because of its effectiveness, which is close to that of PUVA therapy. The percentages of patients with skin clearing (PASI 90%) at the end of the clearing phase are 60% with broad-spectrum UVB and 70% with UVB TL01.

The doses dispensed at each session depend, in the case of the initial dose, on the patient’s phototype and, in the case of dosage increases, on his or her ability to tan. Actually, it is important to dispense always the same efficacious dose to the base cells of the epidermis. Having said that, tanning and especially the progressive thickening of the stratum corneum brought about by UVB gradually reduce this penetration.

The side effects
The acute side effects are identical to sunburns. The carcinogenic effect over time has been deemed weak, even negligible judging by many American authors; although no rigorous epidemiological study has been able to assess this risk with precision. Nothing is known of the genotoxic risks entailed by phototherapy using TL01 tubes as compared with using broad-spectrum UVB. Certainly, it would be useful - for UVB phototherapy alone or combined with retinoids - to deploy the same effort on epidemiological cancerology as that expended 25 years ago on PUVA therapy.

[|Early follow-up data in 1908 patients with a median follow-up duration of 4 years (range 0.04–13), a median cumulative number of 23 (1–199) TL-01 treatments and a median dose of 13.337 (30–284.415) mJ/cm² revealed no increased incidence of SCC or MM was observed. A small but significant increase of BCC was noted. (I. Man, I.K. Crombie,* R.S. Dawe, S.H. Ibbotson and J. Ferguson. The photocarcinogenic risk of narrowband UVB (TL-01) phototherapy: early follow-up data. Br J Dermatol 2005 152: 755–757)|auteur192]

Therapeutic combinations
UVB phototherapy may be combined in an altogether effective manner with topically administered vitamin D derivatives as well as topical retinoids. In these two instances, topical treatment must be applied the evening after the phototherapy. The combination of UVB and systemic retinoids in the clearing phase and during the maintenance phase is especially helpful: the number of sessions needed for clearance has been cut by one third and the percentage of patients reporting clearance increased from 15 to 20%.

2.2.2 Photoactivated Chemotherapy or PUVA

The photoactivation of psoralens (P) in skin cells by UVA (PUVA) has been a major therapeutic advance for many chronic extensive dermatosis and, more particularly, for psoriasis.

PUVA therapy protocols are different for each dermatosis treated. In the case of psoriasis, the basic protocol is perfectly standardized: when using 8-methoxypsoralen ([|Oxsoralen®|auteur192]Meladinine®), a dose just lower than the 0.7 mg/kg needs to be taken two hours before UVA sessions, knowing that the tablets are of 10 mg. The tablets must be taken with food in order to promote absorption. Glasses to filter out UVA must be worn as soon as the tablets have been taken until nighttime of the day of UVA sessions. This is essential to prevent against the occurrence or avoid rapid aggravation of a cataract by photofixation of the psoralens on the crystalline lens proteins. The used glasses may be high-capacity UVA filtration sunglasses or, clear Orma UVX glasses from Essilor, though a much more costly alternative. Photoprotection of the face before and during treatment and of genitals during treatment is necessary.

[|Despite data from animal studies, which indicate a risk of premature cataract formation, clinical evaluation shows no increase in lens opacities, even in patients who neglected careful eye protection. Several studies have shown no indication that psoralen-induced cataracts occur in patients undergoing long-term photochemotherapy. The majority of prospective studies did not report an increased incidence of lens opacities in patients who used eye protection following psoralen ingestion. (Stern RS: Ocular lens findings in patients treated with PUVA. Photochemotherapy Follow-Up Study. J Invest Dermatol 103:534, 1994)|auteur192]

If the patient suffers from nausea, the 8-methoxypsoralen may be replaced with 5-methoxypsoralen ([|Geralen®|auteur192]Psoraderm V®). The dose will then be 1.2 mg/kg and tablets should be taken three hours before treatment. Apart from the decrease in nausea observed with 5-methoxypsoralen, the two drugs 8-MOP and 5-MOP have the same acute and chronic side effects.

Radiation sessions are begun with an UVA dose calculated on the basis of the phototype; if in doubt, one starts at the dose immediately below.

[|In many European therapy centres dosimetry relies on Minimal Phototoxicity Dose (MPD) determination. The MPD is defined as the minimal dose of UVA that produces a barely perceptible, but well-defined, erythema when template areas of the skin are exposed to increasing doses of UVA. Erythema readings are performed 72 to 120 h after testing, at which time the psoralen phototoxicity reaction usually reaches its peak. The MPD test should be performed on previously nonexposed skin (e.g., buttocks). Although the MPD test is more time-consuming than phototyping, it allows for more accurate and higher UVA doses during initial treatment.|auteur192]

Here again, the aim is to have always the same dose of UVA at the basal cell layer of the epidermis, whatever the thickening of the stratum corneum and the tanning induced by the treatment. A PUVA therapy cure involves three sessions a week for two months, then one session a week for one or two months. Contrary to UVB, where the question remains open, it is essential not to carry out any chronic treatment in order to decrease the cumulative toxicity of this treatment. PUVA therapy in psoriasis is therefore used for the clearing phase only, and the eventual need for another maintenance treatment must be considered from the same moment it is prescribed. On completion of the clearing phase, PASI 90% is accomplished in 80% of patients (photos 76 and 77). Prolonged remissions, greater than a year, are observed in 30% of patients.

[|PUVA Maintenance therapy is recommended in the European regimen. It consists of 4 weeks of twice-weekly treatments at the last UVA dose used for clearing, followed by four once-weekly exposures. According to the recommendation of the British Photodermatology Group, maintenance treatment should be considered only if relapses are rapidly following clearance. An own prospective intrapatient left-right comparison study in patients with chronic relapsing plaque type psoriasis using a short-term maintenance protocol a significant delay in relapse of psoriasis was observed in only 8.8% patients. In the remaining patients (91.2%) maintenance treatment had no effect on the length of remission. This indicates that limited maintenance treatment is largely ineffective in preventing early relapse of psoriasis and should be avoided in order to reduce unnecessary UV burden. To clarify the impact of maintenance therapy more studies are required. (Tanew A, Radakovic-Fijan S, Seeber A, Hönigsmann H PUVA maintenance treatment for psoriasis. J Am Acad Derm, in press)|auteur192]

Photo 76.

Photo 77.

The side effects

PUVA therapy can cause acute and chronic side effects.

The acute side effects are phototoxic accidents, occurring two or three days after excessive radiation (photo 78). This phototoxic incident has nothing to do with sunburn then. It is much more belated and much longer lasting.

Photo 78.

Alongside with these phototoxic accidents and without any clear link to an overdose, unforeseeable modifications in the nerve plexus of the superficial dermis are observed, which sometimes translates into tingling, associated more or less with pruritus, and at other times into violent shooting pains very much like those observed in shingles. This pain may affect large areas of skin and is extremely unpleasant and sleep depriving. As a rule, this pain heals in five weeks and, needless to say, calls for a complete halt on treatment. Wearing tight undergarments to avoid brushing the skin and taking codeine may be a great help. If this treatment is inadequate, Rivotril will have to be used, starting with one drop in the evening and increasing very progressively to a maximum dose of five drops, depending on tolerability and efficacy. Gabapentin may also be useful. Major analgesics may sometimes be necessary.

The chronic side effects are ageing of the skin, accelerated particularly in the facial area. While in the cubicle, it is essential to protect the face with a cloth [|(except when the face shows lesions)|auteur192] and, as soon as the tablets have been taken, to prescribe the application of a high-index UVA/UVB filter and/or screen in order to avoid additional photo-aggression brought about by natural UVA in the facial area, before and after sessions. The most severe chronic side effects are cutaneous spinocellular carcinomas (photo 79), particularly in subjects who have already been treated chronically using UVB, methotrexate (photos 80 and 81) or arsenic. The risk is greater still, of course, in patients who have already had basal or spine cell cancer. It should be noted that this carcinogenic risk is particularly important in the male genital regions; it is therefore standard practice to protect them with some item of clothing during sessions.

[|I disagree with this statement as this could not be verified in a large patient cohort from France comprising 5400 patients treated between 1978 and 1998. No case of genital skin cancer was found, despite the fact that the genital area had not been protected during UVA exposure and this makes it unlikely that genital shielding may be indeed absolutely necessary. (Aubin F et al: Genital squamous cell carcinoma in men treated by photochemotherapy. A cancer registry-based study from 1978 to 1998. Br J Dermatol 144:1204, 2001.)|auteur192]

Finally, it has been recently observed in patients having undergone strong doses of PUVA therapy, that a large number of spinocellular carcinomas have appeared shortly after being put on cyclosporine. This illustrates the very long-term persistence (practically life-long) of the damage caused by PUVA as well as the importance of immunomonitoring in the rejection of incipient cancers. Reported cases are rare but sufficiently serious to avoid prescribing cyclosporine to patients who have had strong doses of PUVA therapy.

[|I agree but would like to stress that cyclosporine in combination with or after PUVA is absolutely contraindicated.|auteur192]

Photo 79.

Photo 80.

Photo 81.

Given the cumulative toxicity linked with the photomutagenic and photocarcinogenic nature of photoactivated psoralens, PUVA therapy can only be used to a limited extent during a lifetime. Therefore, for type-1 or 2 skin, a cumulative dose of 1,000 joules must not be exceeded; for type-3 skin, 1,500 joules; and for type-4 or 5 skin, 2,000 joules.
These data are approximate and tests should be available soon to help make a quantitative assessment of the degree to which PUVA therapy has impaired skin cell DNA repair capabilities. Finally, the appearance of lentigo, very frequent in Asian skin, must definitely bring any PUVA therapy to a halt, even though the risk associated with its appearance is not known.

[|I am in agreement with Rob Stern that the cumulative number of treatments rather than the total UVA doses should be used to determine whether PUVA should be stopped in a particular patient.|auteur192]

PUVA therapy, following general administration of psoralens, causes a cataract in laboratory animals. In humans, it has also been possible to demonstrate that psoralens bond covalently with the proteins of the crystalline lens following UVA radiation. However, a cataract produced by psoralens has never been described in patients who use effective eye protection as soon as they have taken the tablets and until nighttime. Ophthalmologic monitoring is only useful then for verifying that there is no cataract before treatment and, if a cataract does exist, for verifying that it does not get worse during treatment.

Finally, psoralens are practically not hepatotoxic, and a liver test seems unnecessary prior to treatment. However, drinking alcohol with psoralens has the effect of profoundly altering their pharmacokinetics, with a skin peak from the 30th minute followed by a rapid fall-off in epidermal concentration.

Unlike UVB, PUVA therapy must be therefore confined to crisis treatment or to first intention general treatment in patients who have only undergone topical treatment to date. PUVA therapy has just as much chance of working effectively as the sun. Patients achieving rapid clearance with PUVA therapy (by 18 sessions) have more chance of a prolonged remission than patients relatively resistant to treatment. This underlines the importance of a good therapeutic strategy, as the most common mistake is an insufficient dose of psoralens and a too mild increase in radiation doses with the commendable hope of avoiding acute side effects, but with the consequence of unresponsiveness to treatment due to tanning and thickening of the stratum corneum.

[|In the discussion on PUVA treatment, no mention was made in the chronic side effect profile of malignant melanoma. While the European consensus is that PUVA therapy does not trigger malignant melanoma, there has been great debate in the US literature, driven mainly by Professor Robert Stern from Harvard, utilizing his cohort of over 1,000 patients, followed for over 25 years since PUVA’s introduction. In addition to inevitable photoaging with long-term chronic use of PUVA therapy, the issue of PUVA lentigines, so commonly seen in patients, eg on buttocks and hips, may give further credence to Professor Stern’s argument.|auteur215]

How to reduce the side-effects of PUVA therapy

Thanks to a number of major advances, the side effects of PUVA therapy have decreased:

  • Balneo-PUVA therapy

With this technique, instead of ingesting psoralens, the patient takes a bath in water at 37°C, containing a solution of 8-methoxypsoralen.
After ten minutes in this bath, the concentration of psoralen is the same in the bathtub and in the epidermis, with a virtual absence of systemic crossover. The face and eyes contain no psoralen. Immediately after the bath, the patient is radiated by UVA. The concentration of psoralen in the epidermis decreases with great rapidity. It is essential, therefore, to perform the phototherapy immediately after getting out of the bath.
The technique is as follows:

  • 8-MOP, 360 mg for 100 litres of water
  • Water temperature: 37°C
  • Duration of bath: 10 minutes.
  • UVA radiation immediately after getting out of the bath

This technique, which is very widespread in the north of Europe, allows all ophthalmologic risks and hepatic crossover to be avoided, as well as eliminating all the digestive side effects of psoralens. Nonetheless, photomutagenesis at epidermal level remains the same and the carcinogenic risks remain identical.

[|I disagree with this statement, because Scandinavian studies have clearly shown that Bath PUVA appears to bear no relevant risk of carcinogenesis. (Hannuksela-Svahn A et al: Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis. Br J Dermatol 141:497, 1999. Hannuksela-Svahn A et al: Cancer incidence among Finnish psoriasis patients treated with 8-methoxypsoralen bath PUVA. J Am Acad Dermatol 40:694, 1999)|auteur192]

  • Therapeutic combinations

Different therapeutic combinations can be used to increase the effectiveness of PUVA therapy and reduce the number of sessions needed to get rid of the lesions quite significantly. The first technique is to take retinoids orally, at a dose lower than 1/2 mg/kg/j. This treatment is begun a fortnight before the PUVA therapy. The retinoids potentiate the phototherapy through their antipsoriatic activity and by preventing photoprotective thickening of the stratum corneum. The number of sessions needed for clearance is reduced by a third and the percentage of patients achieving clearance increases by 15%. Once the patient has experienced clearance and the PUVA therapy has stopped, some dermatologists discontinue the retinoids, but continuing on them at the highest well tolerated dose is very often a warranty in terms of delaying relapses.
It is interesting to note that the patients who remain clear on retinoids are those who experience rapid clearing while on PUVA.
Other treatments can potentiate the effectiveness of PUVA therapy. They are applied every evening and never directly before the session. These are vitamin D derivatives and topical retinoids, used particularly to speed up clearance in recalcitrant areas.

  • Therapeutic hopes

An easy way to proceed topical treatment can be made by combining psoralen with certain sun filters, applied to all affected areas of the body (not only the plaques) two hours before sessions. The presence of sun filters brings about an approximately tenfold reduction in the acute effects of psoralens without impairing their effectiveness and reduces psoralen photomutagenesis by a factor of more than 100. This technique should enable PUVA therapy indications to be broadened, thanks to the possibility of treating topicalized psoriasis and the reduction in acute and chronic toxicity.

[|This sounds nice but is barely practical in the usual treatment settings|auteur192]
[|I agree but the cumulated UV doses are of less interest. The total number of PUVA treatments should not exceed 200. Bath PUVA seems less carcinogenic than oral PUVA.|auteur193]

2.2.3 Laser phototherapy

Phototherapy by laser radiation has recently been suggested, particularly for plaques limited in size. Two types of laser radiation have been used: the first is an excimer xenon laser with an emission at 308 nanometres in the UVB range. This treatment offers some effectiveness but nothing is known about the consequences of the damage it causes to the DNA of the melanocytes and keratinocytes.

Much more interesting are pulsed dye lasers, which allow the microcirculation of the psoriasis plaques to be selectively destroyed. Under ideal radiation conditions (Dr Mazer), 30% of patients have seen their treated plaques disappear completely, 50% have observed some very substantial improvement, 10% some slight improvement and 10% failure. Patients with partial clearance have seen their plaques relapse very progressively in two to six months. In half of cases, relapse was not complete. Among patients with complete clearance, a third remained clear after four years, the others having relapsed very slowly between 4 and 14 months after the last session. These results are particularly interesting because they highlight the importance of microcirculatory troubles in the maintenance of psoriasis plaques. Moreover, these wavelengths present no genotoxic risk. What we have here is then something of real therapeutic “novelty value” with particular potential for treating fixed, bastion plaques and hence highly recalcitrant areas.

[|I agree with the prolonged remissions following successful treatment with pulsed dye laser. We had similar observations of prolonged remissions following pulsed dye laser. This treatment is indicated in particular for circumscribed recalcitrant chronic plaques.|auteur197]

2.3. Retinoids

The antipsoriatic activity of aromatic retinoids (etretinate and its principal metabolite acitretin) was discovered by chance when these substances were being developed with the aim to produce anticancer agents. With varying affinity from one substance to another, retinoids bind to nuclear receptors (alpha, beta and gamma RAR) though there is no way of currently establishing a correlation between the receptors involved and their antipsoriatic activity. It is known, however, that retinoids are capable of modifying the terminal differentiation of the epidermis. High doses are able to severely impair the skin barrier fonction. They are also known to have strong anti-inflammatory activity and, more specifically, are able to inhibit migration of the neutrophilic polynuclears from the capillaries of the superficial dermis towards the epidermis (photos 82 and 83). Finally, retinoids are capable of inhibiting antigen presentation by acting quite simultaneously on the Langerhans cells and T lymphocytes, though this immunosuppressive activity is far less than that of cyclosporine.

Photo 82.

Photo 83.

Aromatic retinoids are hydrophobic molecules (etretinate far more so than acitretin) that accumulate progressively in the adipose tissue. Their elimination is slow, the half-life being 120 days for etretinate and 2 days for acitretin. These two substances, like all retinoids, are powerfully teratogenic. In the presence of alcohol it is possible to induce inverse metabolism and thus transform acitretin into etretinate, hence the need for two years’ contraception after stopping treatment with acitretin as well as etretinate.

When psoriasis requires systemic treatment, acitretin and etretinate are the best long-term treatment, when efficient and well tolerated. Unfortunately they are contraindicated in any woman contemplating motherhood, due to the need for contraception throughout the duration of the treatment, but also during the two years following withdrawal of treatment.

[|For women of child-bearing age, the use of isotretinoin (Accutane®/Roaccutane®) can be considered because contraception is necessary for only 2 months after discontinuation of therapy. Isotretinoin in combination with PUVA or UVB is as effective as the aromatic retinoids.|auteur192]

The generally administered retinoids are etretinate (Tigason®) and acitretin (Neotigason®/Soriatane®). Acitretin is the principal metabolite of etretinate. Etretinate and acitretin have the same therapeutic profile during the first months of treatment but do not have the same side effects in the long term. Furthermore, some patients are more sensitive to one substance or the other. It is particularly detrimental, therefore, that these two substances are no longer available to patients in all countries.

The therapeutic effectiveness of retinoids shows up slowly, whereas their side effects for any given dosage appear within the first fortnight of the treatment. When the dose is reduced due to the side effects, the latter disappear within a fortnight after adjusting the dose. Therapeutic studies have shown that the maximum dose well tolerated by a patient was the dose most effective for that patient. In fact, with a high dose (0.5 to 1mg/kg/j), the percentage of patients showing clearance (PASI 90%) was only 25%, whereas starting at a low-dose with progressive increase up to the maximum dose well tolerated, the percentage of clear patients was 40%. (ROCHE, unpublished report of a one-year double blind study).

Retinoids are thus the only family of drugs currently in existence in the pharmacopoeia whose posology is chosen on the strength not of their efficacy but of their tolerability and hence of the patient’s quality of life. Effectively, the side effects are basically harmless, albeit highly uncomfortable at times due to the weakening of the epithelium and integumentary system brought about by these agents.

2.3.1. Prescription strategy

The rules for prescription are particularly simple, then. Usually, start off on 10 mg/j with meals, then increase the doses by increments of 5 or 10 mg, either fortnightly or monthly, until the maximum tolerated dose is found, i.e. most commonly, the dose entailing tolerable cheilitis. If this dose is exceeded, have the patient reduce the posology until the maximum well-tolerated dose is again found. Efficacy is judged by the improvement in the skin observed three months after reaching the maximum dose that is perfectly well tolerated.

It needs to be stressed that for each patient, retinoid activity goes through three phases, according to dosage. At very weak doses, there is no therapeutic effect. Then, if it exists, the therapeutic efficacy dose is reached. If this dose is exceeded, the retinoids may weaken the skin to the point where aggravation of the psoriasis is caused by Köebner’s phenomenon. The dose variation between inefficacy and intolerability may be as low as 5 mg. Given their long half-life, it is always possible to adjust treatment with retinoids in increments of 5 mg, varying the number of 10 mg tablets taken on even and uneven days, for example.

2.3.2. Side effects
The side effects of retinoids are dose-dependent. However, the maximum well tolerated dose is extremely variable from one patient to another, potentially ranging from less than 10 mg a day up to more than 75 mg a day. The reasons for these variations are not well known and are likely to couple sizable variations in retinoid absorption capacity with highly variable individual sensitivity to these drugs. This great variability explains why it is preferable to start off with very small doses, given that the drug is not prescribed for emergency situations. If this individual sensitivity cannot be predicted, it must be stressed that the weakening of the skin by the retinoids will increase with age and it is often severe in atopic subjects.

The clinical side effects essentially result from a weakening of the epithelia and their products, nails and hair, by the retinoids. The earliest side effect is generally cheilitis (photos 84-90). Dryness of the eyes is frequent and contact lenses are contraindicated. Rhinitis sicca, sometimes with epistaxis, is not uncommon. Fragility of the skin can be accompanied by pruritus, particularly in all rubbing or friction zones. Retinoids can frequently trigger senile pruritus, sometimes fierce. At strong doses, retinoids generate hair cycle synchronization, with hair loss of sometimes spectacular proportions.

Photo 84.

Photo 85.

Photo 86.

Photo 87.

Photo 88.

Photo 89.

Regrowth is usual on discontinuing the treatment but may be incomplete. Conversely, retinoids may modify the texture of the hair, making it look more or less curly, sometimes unmanageable. Nail growth may be disturbed, sometimes producing Köebner’s phenomenon at this level, entailing the development of ungual psoriasis, sometimes severe. The peri-ungual skin may be weakened, promoting the development of granulation tissue, particularly on the feet.

Apart from such epithelial fragility, numerous other side effects may be observed: a reduction in night vision that may be dangerous in the case of long-distance lorry drivers, moodswings capable of leading up to depression and libido decrease, as well as a faster appearance of muscle aches contraindicating the use of retinoids in elite sportsmen and sportswomen. Headaches can be invalidating.

Numerous other side effects may be observed. They may be unpleasant but are quite harmless. The patient must be informed that in the event of any nuisance ascribed to retinoids, the more simple is to stop the treatment for a fortnight; actually, there is no rebound phenomenon on discontinuing retinoids. If the trouble disappears and then reappears when the treatment is resumed, it is because it is connected with retinoids. On the basis of his quality of life and the therapeutic results, it is then up to the patient to choose whether or not to continue with retinoids.

The main side effect of retinoids is their teratogenicity. Provisions must be made for absolutely effective contraception throughout treatment and for the two years after halting treatment. In practice, this restriction prevents retinoids being prescribed to fertile women. What should be done in the event of onset of pregnancy during the two years following discontinuation of the treatment? For virtually all patients, acitretin is completely eliminated one month after treatment stops, and there is therefore no longer any teratogenic risk. To verify this, it is possible to determine the quantity of retinoids in the blood; to do this, approach the Roche Laboratories, who are always willing to help out in a difficult situation like this.

2.3.3. Biomonitoring

Biological monitoring (biomonitoring) is quite simple, as it will suffice to make a quantitative determination of transaminases, cholesterol and triglycerides before treatment, at the end of one month’s treatment and then every three months. Acitretin increases more often triglycerides, whereas etretinate increases more often cholesterol. Lipid problems will be more frequent if the patient is obese, diabetic or abuses alcohol; all situations are associated with hepatic steatosis. Only a hefty increase in triglycerides is a contraindication to starting treatment: in fact, acitretin may provoke a sudden increase in triglycerides in this case, with a risk of acute pancreatitis. There again, a moderate increase in triglycerides or cholesterol will simply provide an incentive to monitor the lipid balance every month and implement a diet. In the event of a progressive increase in cholesterol, the decision will be relative to the therapeutic improvement obtained: diet only, a lipid-lowering drug or discontinuation of retinoids.

Acitretin is only exceptionally hepatotoxic, but may bring about quite often, particularly in patients with hepatic steatosis, an increase in transaminases two or three times the norm. In these situations it is important to intensify biomonitoring (monthly monitoring), to ask patients to cut out alcohol and excess sugar and fat. Prescribing polyunsaturated omega-3 fatty acids (MaxEPA®) seems to be able to improve this situation and reduce the cutaneous side effects of the retinoids; however, this has still to be demonstrated and does not eliminate the need for dieting anyway. Cirrhosis or hepatitis C is not a contraindication to retinoids but an indication for monthly monitoring and a proper joint effort with the hepatologist.

2.3.4. Bone monitoring
Bone monitoring is useful in two different contexts: in the child and in the adult. In the child, retinoids are remarkably effective, but must always be monitored in liaison with the GP or paediatrician to make certain that there is no deterioration in the growth curve. In adults, the risk is of calcification of the tendon insertions. The presence of hyperostosis is more common in psoriatics than in normal subjects, but in some subjects it is clear that retinoids may favour the development of, sometimes spectacular, hyperostosis. Given the rarity of this side effect, systematic monitoring would seem to offer a very poor cost/benefit ratio. Conversely, if painful areas appear (a calcaneal spur, for example), it seems fair enough to perform bone scintigraphy and X-rays targeting any areas of hyperfixation. In the event of hyperostosis, it is then possible to monitor its development every two or three years. The indication for subsequently stopping retinoids is highly controversial and each case must be considered on its own according to the therapeutic benefits observed by the patient. Some patients presenting non-painful hyperostosis, clearly linked to the treatment, refuse to stop it due to the therapeutic benefits observed.

Some few patients have been on retinoids for more than 25 years now, raising the problem of potential side effects over a very long period. Vigilance remains the keyword for these patients. Some of them present atrophy of the dermis, albeit difficult to interpret, as these patients also make occasional use of a little topical corticotherapy. These observations have led to a study conducted for over five years to investigate the occurrence of osteoporosis in subjects on retinoid therapy. During this time, no significant variation has been observed. For treatments over a very long time, it seems reasonable to do bone densitometry to verify that the latter falls within the norm relatively to the patient’s age.

2.3.5. Strong doses
Retinoids can be given in strong doses of almost 1 mg/kg/j in two circumstances:

  • Firstly, pustular psoriasis. High doses are given during 7 to 10 days and thereafter reduced to tolerated doses. In this indication, acitretin or etretinate may be replaced with 13-cis-retinoic acid (Roaccutane) in fertile women wishing to contemplate pregnancy. In fact, the anti-inflammatory effect sought—inhibition of neutrophilic polynuclear migration—is the same with 13-cis retinoic acid as with acitretin, and contraception can be stopped one month after discontinuing the treatment.
  • Secondly, psoriatic rheumatism. High-dose retinoids, approaching 1 mg/kg/j, bring about a clear improvement in some two thirds of cases, the downside being substantial cutaneous or mucous side effects. Methotrexate’s efficacy/side-effect ratio is generally more favourable in this indication, where retinoids are rarely used.

2.3.6 Retinoids for Children
Children must not be given retinoids at a dose higher than 1/2 mg/kg/j. More often than adults, children will sustain discreet cerebral edema with cephalalgia and irritability of a nature that should bring treatment to a halt, and be resumed at much weaker doses or even contraindicated.

2.3.7 Retinoids and psoriasis erythroderma
In psoriatic erythroderma, retinoids may be a good treatment, but only in very low doses: 10 or a maximum of 20 mg a day. At higher doses there is a risk of causing Köebner’s with oozing erythroderma, capable of rapidly jeopardizing vital prognosis.

2.3.8. Combination therapies
Retinoids combine successfully with all topical treatments, but do heighten the irritant nature of some (vitamin D derivatives and, of course, topical retinoids). They potentiate the effectiveness of phototherapy and are increasingly being used in tandem with broad-spectrum UVB, TL01 UVB and PUVA. They provide faster and more frequent (+15% excellent results) clearance of lesions. They can even be useful in patients resistant to retinoids alone, as they potentiate phototherapy by countering the photoprotective thickening of the stratum corneum caused by the latter. They can be combined with methotrexate provided that a weekly or bi-monthly monitoring of liver enzymes is done. The potential interest of combining them with cyclosporine has never been clearly assessed.
The combination acitretin/Raptiva? or acitretine/TNF?inhibitors has never been studied. The association acitretin/Raptiva? should be quite useful because Raptiva? inhibits T cells’ migration and acitretin neutrophils’ migration

Finally, the combination of retinoids and tetracyclines is contraindicated, as it entails a risk of cerebral oedema.

Retinoids are the best maintenance therapy over a very long time for psoriasis in patients in whom they are efficacious. Their efficacy peaks after one year of treatment, so it will often be necessary to combine them with some quickly clearing therapy from the outset, thereby allowing the patient’s state to improve more quickly.

[|I want to underline that that we consider retinoids as an excellent long term maintenance therapy for the treatment of palmoplantar psoriasis (dose of 0.25 - 0.5 mg/kg/day). A combination therapy with photo(chemo)therapy may be of benefit to accelerate the initial treatment response.|auteur194]

2.4. Methotrexate

Methotrexate remains the benchmark therapy for severe psoriasis and/or psoriasis associated with articular involvement. It is the treatment that offers the best efficacy/tolerability/convenience/cost ratio for psoriasis.

Despite having been used in psoriasis for more than 40 years, the reasons for its effectiveness remain poorly known. In fact, its antifolic effect (it is a structural analogue of folic acid, a powerful inhibitor of dihydrofolate reductase) is undoubtedly insufficient to explain its effectiveness at weak doses used just once a week. Methotrexate has many pharmacological properties, each of which may contribute to its antipsoriatic activity: cytokine inhibition (IL1, IL6, TNF alpha), inhibition of LTB4, PGE2, PAF and histamine production; inhibition of adhesion and of intratissular migration of macrophages and neutrophilic polynuclears, induction of apoptosis (programmed cell death) in phase-S cells, inactivation of activated T lymphocytes at weak doses. The main constraint on its use is its hepatic toxicity, clearly overestimated. It is a teratogenic drug that persists in the tissues for several weeks after stopping treatment. It is partly linked to plasma proteins, and its free form is the active one. It is eliminated through the kidneys.

2.4.1. Pre-treatment testing
The pre-treatment testing is strictly structured: a general clinical examination and a biological checkup must be done to start with. It must include a blood count in order to ensure the absence of any haematological anomaly and above all the absence of macrocytosis. A quantitative creatininaemia analysis will be needed to ensure that there is no renal insufficiency, and liver enzymes must be checked for the absence of hepatopathy. A systematic investigation for hepatitis B and C seems useful. HIV testing could be proposed. An effective contraception must be prescribed before treatment and will last throughout the treatment and for the three months following its discontinuation, in men as well as in women.

2.4.2. Strategy for use
[The first dose of methotrexate will be 5 mg, in order to detect any phenomenon of intolerability or idiosyncrasy, and then it will be raised to a dose somewhere between 15 and 25 mg once a week|I don’t practice this way unless the patient is old or belongs to a riskgroup. Using an introductory low test dose is recommended by the American guidelines, although no data are presented showing hypersensitivity to the drug when starting therapy in patients outside risk groups. The latter should be ruled out before therapy is given. Since methotrexate does not work fast, starting low before the right dose has been reached and accomplished its result, the patient and occasionally also the physician may wrongly have reached the conclusion that the drug does not work.|auteur196], on a precise day chosen alongside with the patient and noted on the prescription. [In order to improve methotrexate tolerance, 5 mg of folic acid will be taken every evening, except the day on which methotrexate is taken.|I don’t recommend such a high dose of folic acid. Without doubt it may improve tolerance, but at the same time it will reduce efficacy of methotrexate. This has already been shown and published by rheumatologists in randomly controlled studies (Arthr Rheum 2005;52:3030-8) and similar data will be under way by dermatologists. My experience is that 5mg twice weekly can be used.|auteur196] [In order to avoid therapeutic error wherever possible and to start treatment under the best conditions for bioavailability and digestive tolerance, it is preferable to start treatment by intramuscular or subcutaneous injection for the first six months.|I understand the idea, but don’t practise this way, because it is my opinion that the majority of patients prefer oral treatment, and only few need switching to intramuscular injections due to digestive intolerance, when using the 5mg folic acid twice weekly or 30mg metoclopramid on a day of nausea. If this does not work, I will switch.|auteur196] Once sure that the patient is properly trained and treatment is effective, of course, it will be far more convenient to switch from injections to tablets (Novatrex®/Rheumatrex®). The tablets are often taken in three lots, once a week: that is, for example, on Friday evenings at 8 pm, Saturday mornings at 8 am and Saturday evenings at 8 pm. It is quite possible to administer the weekly dose in two goes. Taking the weekly dose in one go decreases the absorption, increases the risk of digestive disturbances and of turning the treatment into a boring routine, thereby making compliance less strict. It is not uncommon to observe a relapse during the changeover from intramuscular administration to taking tablets, the oral method often being less effective, due certainly to an initial hepatic passage and less favourable bioavailability.

With methotrexate, a number of drugs need to be avoided, and these must be listed on the prescription. These are antifolics such as Bactrim, sulphamides, sulphones, drugs that reduce renal elimination, like probenecid, or drugs that displace methotrexate from its plasma bonds, like strong doses of aspirin or non-steroidal anti-inflammatories. It is, of course, quite possible to start methotrexate treatment while patients are taking small doses of aspirin or non-steroidal anti-inflammatories for psoriatic arthritis, for instance.

2.4.3. Side effects and monitoring
The side effects are the occurrence of digestive disturbances during the two or three days following injection, a feeling of a sometimes incapacitating fatigue during the same period. The occurrence of sometimes-severe mucitis is particularly observable in the aged or in patiens with folate or B12 deficiencies. [Taking folic acid 5 mg/day excepting the injection day reduces greatly these side effects without decreasing therapeutic efficacy.|The latter is not my experience, see also my comment stated above.|auteur196] The appearance of macrocytosis and its progressive aggravation should alert to check for a folate deficiency or alcohol abuse, and to lower the doses. In case of appearance of hepatic cytolysis three times above the highest normal values, the treatment must be stopped and the advice of a hepatologist must be asked.

The immunosuppression caused by methotrexate is weak at the doses used in psoriasis in the absence of combination with any other immunosuppressants, but vigilance is still called for.

Contraception is essential, of course, in fertile women during treatment and for three months following its discontinuation, due to this teratogenic drug with prolonged tissue persistence. The same duration of contraception is also advisable in men, as methotrexate reduces spermatogenesis. On the other hand, contrary to what used to be suggested, there seems to be no point in storing and preserving sperm before undergoing treatment because inhibition of spermatogenesis is reversible at antipsoriatic doses.

Methotrexate is not mutagenic and is not considered contraindicated in a patient who has had cancer. However, this drug does contribute to reducing immune defenses and rare cases of EBV lymphomas have been described in psoriatics on methotrexate.

[Biomonitoring is simple. A blood count every week for two months, then every month, will suffice, and a dose of transaminases every month.|I should like to recommend adding gammaglutamyltransferase ocasionally for additional information.|auteur196] This biomonitoring must be conducted during the two days prior to taking methotrexate, as there is often a transient cytolysis, of no significance, during the days immediately following treatment.

The major problem is monitoring the liver. Cirrhosis may develop with biological liver tests showing normal results for a long time, and the liver biopsy puncture is an examination entailing non negligible morbidity and mortality. The old guidelines were to perform a liver biopsy puncture every time a cumulative dose of 1.50 g of methotrexate has been exceeded. French hepatologists consider this strategy to be quite excessive, causing patients to take needless risks. They also consider that there is no evidence to believe that methotrexate entails hepatic risks in patients who have no progressive hepatopathy and consume few alcohol. Finally, the scales used by anatomical pathologists, liver specialists, to measure hepatic fibrosis do not seem suitable to monitor hepatic fibrosis on methotrexate, which explains without doubt the disparities observed in the literature with the rate of cirrhosis ranging from 0 to 7.4%. It is important, then, to work with a team of hepatologists trained to monitor this drug. Finally, it should not be forgotten that the existence of hepatic fibrosis is more common in psoriatics than in non-psoriatics, without knowing with any certainty if such thing as a psoriatic liver exists or if psoriatics tend to be consumers of alcohol more than non-psoriatics.

[|One of the most controversial issues that today still divides dermatologists and rheumatologists is the vexed issue of methotrexate-induced hepatotoxicity. Thus, guidelines in the USA for dermatologists utilizing methotrexate in psoriasis is very different from those established by the American College of Rheumatology for methotrexate’s use in rheumatoid arthritis. Thus, liver biopsies are seldom required for rheumatoid arthritis patients, but are considered necessary in the USA once a total dose of approximately 1.5gms of methotrexate has been attained. These guidelines are currently undergoing revision in the USA under the American Academy of Dermatology with myself as Chair. Certainly, the discussion relating to procollagen IIIA is of vital importance with this test being readily available in Europe but not yet in general use in the United States. I find three specific issues of importance:

1. The relative obesity in psoriasis and the inevitable development of steatohepatitis in a significant proportion of these patients. In the United States today, steatohepatitis is a more common cause of liver “disease” than hepatitis C. Could this issue be the driving force behind the response of the psoriatic liver to methotrexate vis-à-vis the rheumatoid arthritis patient, recognizing that in our classification of methotrexate-induced hepatotoxicity, Grade I toxicity is fatty infiltration!
2. Would I take methotrexate personally? Our guidelines in the US state “alcohol absenteeism”. Is this “the real world” and does a glass of wine each night potentially worsen methotrexate-induce hepatotoxicity, both in the short term and in the long term?? Again, no studies have evaluated mild-moderate alcohol intake. I believe our new updated guidelines under development in the USA will moderate this strict view.
3. The third pertinent issue is, if we continue to use a rotational approach in systemic therapy for psoriasis, as popularized originally by Jerry Weinstein from California, can we utilize methotrexate for 2-3 years, ie 1.5gms total dose, rotate patients to an alternate systemic therapy, and then re-activate methotrexate therapy a year or two later and start counting the cumulative dose from 0?? It is well know that the majority of Grade II and Grade III methotrexate-induced liver biopsies will revert to a Grade I or Grade II after discontinuation of methotrexate. No studies are obviously available to date to answer this important question.|auteur215]

A series of follow-up studies extending up to 10 years suggests that the risk of hepatic fibrosis occurring while on methotrexate is extremely faint, if not none, in patients whose serum type III procollagen rate (increased when there is collagen synthesis) is normal and remains normal when monitored systematically every three months. It seems useful, therefore, to dose type III procollagen in patients on methotrexate every three months. A liver biopsy is useless in patients whose type III procollagen rate stays within normal limits.

Conversely, it must be recalled that the increase in type III procollagen is absolutely not specific to any hepatic involvement whatsoever and that the only consequence of its increase is to eliminate an item of information that would have given the green light for abstaining from liver biopsy. There remains a need to carry out a wide-ranging study comparing patients on methotrexate who drink no alcohol whatsoever with others who drink occasionally, in order to find out whether or not total abstention from alcohol might help avoid hepatic biopsy puncture.

Fortunately, the association of biological test (Fibrotest) with a new non-invasive technique (Fibroscan) allows a very sensitive evaluation of hepatic fibrosis and suppress the need of liver biopsies.

The pulmonary toxicity of methotrexate crops up in two different contexts:

  • The first is a hypersensitivity syndrome with 39-40°C fever, coughing, dyspnoea, appearance of major eosinophilia and of a non-systematized pulmonary infiltrate. Needless to say, treatment must be stopped urgently and never resumed. Systemic corticosteroid treatment can be necessary. This illness is exceptional.
  • The second problem is that of pulmonary fibrosis while on methotrexate. Used for over 40 years in dermatology without this side effect ever being noted, our colleagues from rheumatology have remarked the appearance of pulmonary fibrosis in some patients two or three years after starting using methotrexate in the treatment of rheumatoid polyarthritis,. By contrast, they never practise liver biopsy puncture. This illustrates that the side effects of a drug are not the same according to the pathology treated. It should also prompt dermatologists to be heedful of dyspnoea occurring in psoriatics, because even if this side effect is exceptional in the treatment of psoriasis, it nevertheless needs to be borne in mind.

2.4.4. Combination therapies
Methotrexate may be combined with all topical treatments. If combined with phototherapy, methotrexate needs to be injected on the Friday evening following the last session in order to avoid photoactivation. Methotrexate is not a photosensitizer but is phototransformed into a highly photosensitizing photo-product, [2,4-diamino-6-pteridinyl] carboxaldehyde (photos 80 and 81). Methotrexate may be combined with retinoids, provided tighter hepatic monitoring, and with cyclosporine in exceptional cases. It is commonly combined with infliximab in order to decrease the production of anti-infliximab antibodies. Its association with efalizumab and adalimumab should be quite interesting to evaluate.

[|I agree concerning Mtx|auteur193]

2.5. Cyclosporine

The history of treating psoriasis with cyclosporine is particularly interesting. Cyclosporine was isolated from a fungus found in a sample of soil on a high-lying plateau in south Norway in 1969. At the time, the Sandoz laboratories were looking for new antibiotic substances. Cyclosporine proved to be a second-rate antibiotic. Its weak toxicity provided an incentive to pursue pharmacological studies, and in 1972 the laboratory of J.F. Borel discovered its immunosuppressive properties. In 1978, the first organ transplant succeeded thanks to cyclosporine, and in 1979 the substance’s antipsoriatic powers were fortuitously recorded in patients suffering from psoriasis arthritis.

The use of cyclosporine in psoriasis developed in two stages, with12 years apart. First, cyclosporine was used in psoriasis in patients resistant to all other treatments (photos 91 and 92).

Photo 90.

Photo 92.

Under these conditions, it was a treatment of last resort administered over a long period of time; and especially beyond the first year of treatment it was usual to observe a reduction in glomerular filtration often signalled, though not always, by an increase in creatininaemia. This renal insufficiency, the upshot of irreversible renal fibrosis, left no choice but to stop the treatment once and for all. A second side effect, not always reversible after stopping treatment, was the appearance of hypertension, a frequent cause for halting the treatment. These two side effects, potentially serious and not completely reversible once the treatment stopped, initially prompted dermatologists to cut down on the indications for this drug, as it could only resolve particularly difficult situations for a limited time.

Twelve years after cyclosporine has started to be used in psoriasis, it was suggested using cyclosporine as a systemic treatment of first intention, but during short cures so to try avoiding renal toxicity and hypertension. It was then ascertained that these short cures, nearly always very well tolerated, could bring about prolonged remissions in some 30% of patients. Today cyclosporine has thus become a treatment of first intention, usually reserved for short cures. This 3 or 4-month prescription is designed to cope with urgent situations or seasonal psychological intolerance to the illness. Though particularly appealing to sufferers, it remains to be proved that this new strategy will help avoid cumulative toxicity.

2.5.1. The pre-treatment check-up
The pre-cyclosporine therapy check-up is quite standardized. It calls for:

  • ­ a complete clinical examination to make sure that there is no progressive disease;
  • a complete blood count (CBC) and an inflammation test to check that there is no major biological anomaly;
  • creatininaemia determination three days in a row to calculate the average creatininaemia that will enable treatment dosage to be adjusted in relation to renal tolerability;
  • monitoring of lipid levels, as cyclosporine can induce hypertriglyceridaemia during the initial months of treatment;
  • a gynaecological check-up in women to ensure the absence of any papilloma virus lesion of the cervix. HPV proliferation might be aggravated by the immunosuppression produced by the cyclosporine;
  • a dental examination to verify the absence of para-odontopathy, which must be treated prior to treatment in order to reduce the risk of gingival hypertrophy triggered by the cyclosporine;
  • finally, one must check for the absence of chronic viral diseases, hepatitis C or HIV and also that the patient has not been on strong doses of PUVA, which would contraindicate cyclosporine.

Tolerance to the treatment may be partly predicted beforehand, given that treatment cessation due to side effects is more frequent with advancing age, patient obesity, diastolic pressure bordering on the norm and average creatininaemia close to the upper limits of the norm. One major advantage of cyclosporine is that it requires no contraception for women and all pregnancies on cyclosporine have passed off without fetal problems. The ideal profile for benefiting from cyclosporine is therefore that of a young, slim, hypotensive woman.

2.5.2. Monitoring
Monitoring is simple. Creatininaemia has to be determined every month (mornings, on an empty stomach and with no previous muscular exertion). If the creatininaemia increases by more than 30% by comparison with the patient’s base value, and not with the norm, we must then check the dosage - which is highly variable - and, if the increase is confirmed, lower the cyclosporine dosage.
Arterial pressure must be measured every month.
Triglycerides must be monitored every month for the first three months of treatment.
The gynaecological examination must be repeated every year for women.
Whenever the cumulative duration of cyclosporine treatment has reached one year, a measurement of the glomerular filtration rate must be done. This will provide a complete sense of security when it comes to renal tolerability. This is an inexpensive and non-invasive examination.

2.5.3. The side effects
The main side effects, around which all clinical and biological monitoring is arranged, are nephrotoxicity and hyperarterial pressure. Moreover, these are the two prime causes of discontinuing cyclosporine. It must be remembered here that renal insufficiency brought about by cyclosporine may appear with creatininaemia remaining normal for a very long time. That is why regular renal functional explorations are necessary when monitoring this treatment. Hyperarterial pressure brought about by cyclosporine is all the more frequent when diastolic is high before treatment. It is not always reversible. In the event of hyperarterial pressure appearing while on cyclosporine, a salt-free diet must be begun; if that is not enough, resort must then be done to calcium inhibitors. Of these, it is necessary to avoid Nifedipine (Adalat®), which promotes gingival hyperplasia and give preference to the family of dihydropyrimidines, like nicardipine (Loxen®). If the latter are not effective, cyclosporine will have to be stopped. Side effects leading to the discontinuation of treatment increase with the duration of treatment, with the age of the patients, with base creatininaemia, with pre-treatment diastolic and, undoubtedly, with the presence of obesity.

Other less severe side effects are observed on cyclosporine: an increase in facial hairiness, reversible on discontinuation of treatment, a slight increase in skin infections: folliculitis, verrucas, herpes and shingles. The only cancers to increase in incidence under cyclosporine are the cutaneous squamous cells carcinomas, especially in patients who have had some PUVA and more than two years of cyclosporine treatment. No increase has been noted in the incidence of lymphomas, but this eventuality remains possible. EBV lymphomas have been caused by the combination of cyclosporine and systemic corticotherapy.

Other side effects are gastrointestinal disturbances, gingival hyperplasia, the appearance of paraesthesia at the beginning of treatment, fatigue, headaches and, exceptionally, convulsions. Finally, cyclosporine reduces the absorption of calcium and vitamin D3.

2.5.4. Strategy for use
Cyclosporine treatment is started at a dose somewhere between 2 and 3 mg/kg/j. The maximum dose prescribed in psoriasis is 5 mg/kg/j. At the very outset of cyclosporine use in psoriasis treatment, it has been suggested starting therapy at high doses (5mg/kg/j), clearing the patient rapidly, then progressively reducing doses until a relapse is observed , in order to find the effective minimum dose. This strategy was very soon dropped, as it was more aggressive to the kidneys and, above all, less well received by the patient. In fact, the patient experiences a rapid alleviation combined with a psychological questioning associated to the sudden disappearance of a chronic illness, and then he witnesses with an equivalent unrest the disease relapse. The strategy that has won acceptance is to start off with small doses in order to obtain progressive improvement of the illness, while keeping as a fallback, should this improvement be insufficient, the possibility of progressively increasing the cyclosporine doses without ever exceeding 5mg/kg/j. The patient then benefits from a progressive improvement in his quality of life until the dose is found that will restore to him a satisfying quality of life, even if it does not achieve complete clearance. Even with this strategy, however, the number of patients having to break off cyclosporine due to its side effects increases with time, and after five years of treatment there are only about 5% of patients who are able to continue on this treatment without complications.

The association of magnesium (100 mg/day) to cyclosporine seems able to protect the kidneys but its practical usefulness remains to be proved.

In order to avoid overdosage on obese patients, the daily dose of cyclosporine must be calculated according to the theoretical weight.

Due to its renal toxicity in prolonged therapy, it was suggested to use cyclosporine for a short cure of three to five months, either as an emergency treatment or “to turn a corner”, or to give maintenance therapy, prescribed as a relay measure, the time to act. Some patients use cyclosporine for four or five months every year, for example, in order to spend the summer enjoying normal social and living conditions.

This new therapeutic approach has led to cyclosporine being put forward as a systemic treatment of first intention. In these conditions, it has been observed that 30% of patients remained clear for six months after breaking off a short cyclosporine cure. In order to increase the chances of obtaining prolonged remission, it is important not to stop cyclosporine suddenly but to decrease doses gradually over two months. These observations have profoundly changed the way this drug is used. It is now suggested as a systemic treatment of first intention for young subjects in order to perform short cures not exceeding four months, followed by two months of dose reductions.

The change in the pharmacokinetics of cyclosporine brought about by other drugs is so frequent that it is important for psoriatics being treated with it to report always this treatment to their GP, so that if a prescription is needed for some other disorder, the GP can bear the drug interactions in mind.

2.5.5. Combination therapies
In order to potentiate the effects of cyclosporine, topical treatments, particularly Vitamin D derivatives, seem particularly interesting. Combining with phototherapy is contraindicated, due to the immunosuppressant role of cyclosporine, which may favour the development of squamous cells carcinomas. The sudden appearance of multiple squamous cells carcinomas has been observed in some few patients on cyclosporine who have had powerful cumulative doses of PUVA therapy, sometimes a great number of years before the cyclosporine treatment. Intensive and prolonged PUVA therapy therefore contraindicates the use of cyclosporine. Cyclosporine may be combined with retinoids, though the potential interest of this combination has not yet been validated. The most interesting strategy is, without doubt, the use of retinoids as a relay of cyclosporine to reduce the speed and intensity of a relapse on cessation of this potent therapy. At weak doses, the cyclosporine/methotrexate combination is effective, but exceptional, as no test is available to measure the importance of the immunosuppression produced by combining these two treatments.

[|I agree concerning cyclosporine.|auteur193]

[|I enjoyed the section on ciclosporin usage. Why are there such major regional differences around the world in the use of ciclosporin? Professor Dubertret does put forward the use of ciclosporin as the “treatment of first intention”. My questions to Professor Dubertret is: If we utilize this form of therapy as short-term “Interventional” therapy, ie 4-5 months per year, with remissions in 50% of patients being far less than six months, what do we do when these patients inevitably have return of psoriasis? To me, the single most worrisome aspect for psoriasis patients is to be given hope, ie clearance of their disease and then be allowed to relapse with no alternate form of therapy readily available. Thus, I do believe every single patient needs to be maintained in the optimal state of clearance for as long as possible, and in the safest way possible. This is partially discussed in the following chapter, under “Combination Therapies”.|auteur215]

2.6. Fumaric acid esters

In 1959 a German chemist, Schweckendiek, a victim himself of psoriasis, laid down the theory that psoriasis could be correlated with a disturbance in the citrate cycle and that, for this reason, fumaric acid might have some therapeutic power. He tested a number of fumaric acid salts on himself and noted that the esters were better absorbed and more effective than the fumaric acid itself. After this discovery, the use of fumaric acid followed a clandestine and empirical path for some years. Then some open studies attracted attention. Subsequently, patients’ associations have called upon dermatologists to carry out the required clinical and biological studies needed for marketing. What is available now is an assessed product, one that is officially authorized, commercially available in Germany and the Netherlands, and one that should have shortly European authorization. In 1999 the rules governing the use of fumaric acid esters for treating severe psoriasis were laid down during a consensus conference published in the British Journal of Dermatology.

2.6.1. Pharmacokinetics
Dimethylfumarate (half-life 12 minutes) is rapidly hydrolyzed in monomethylfumarate (half-life 36 hours), which is the most active metabolite. Through the citrate cycle the latter is metabolized into water and carbon dioxide. The drug is, therefore, essentially excreted through the airways and very little through the urine and stools. Fumaric acid esters are not mutagenic and are not teratogenic in animals.

2.6.2. Mechanisms of action
Fumaric acid esters have a number of biological activities that are still poorly understood. They increase secretion of various Th2-type cytokines, particularly IL4, IL5 and IL10. They inhibit lymphocytic proliferation. They significantly reduce T lymphocytes, with a 90% reduction in circulating CD8 and 53% reduction in circulating CD4 cells after one year of treatment. At non-toxic doses they inhibit the proliferation of keratinocytes, with rapid liberation of intracellular calcium. They inhibit in a dose-dependently way the expression of the adhesion molecules, more particularly of ICAM-1, in the cellular membrane and especially in the endothelial cells.
They inhibit oxidative explosion in activated neutrophilic polynuclears but stimulate their chemotaxis. Consequently, the fumaric acid esters’ mechanism of action is complex, not fully understood and aimed essentially at the T lymphocytes and keratinocytes.

2.6.3. Efficacy
Using Fumaderm, the derivative currently authorized and commercially available, allows an 80% improvement in the PASI after four months of treatment. 10 to 15% of patients must stop treatment because of the side effects.

2.6.4. Side effects
The most frequent side effects are digestive and occur in two thirds of patients. These involve stomach pains, an increase in the frequency of the stools, meteorism (flatulence) and diarrhoea. These side effects are most frequent between the fourth and twelfth weeks.

Flushing of the face occurs in about a third of patients. These flushes are accompanied by a sensation of heat. They can last from several minutes to several hours. Headaches may be associated. These flushes are more frequent at the outset of treatment and progressively diminish with time. These digestive side effects and flushes result in the withdrawal of the treatment in some 7% of patients.

A sizable decrease in the number of blood lymphocytes is observed in practically all patients. In 10% of patients a decrease of more than 50% is observed by comparison with base values. The number of T lymphocytes as well as that of B lymphocytes is reduced by this treatment. This decrease is reversible on cessation of the treatment.

An increase in blood eosinophils is observed in about half of patients, the maximum rate occurring between the fourth and eighth weeks. This increase may reach 40% of the white cells.

Nephrotoxicity, sometimes recorded in oldest observations, is no longer being observed under the recommended strategy for use.

In a study relating to patients nursed for more than three years, an increase in liver enzymes has been observed in 40% of patients, an increase in cholesterol in 17% of patients, triglycerides in 8%, serum potassium in 15% and creatininaemia in 4%. Proteinuria has been observed in 11% of patients. These anomalies have not been replicated in other studies.

No risk of infectious diseases or cancer has ever been observed.

2.6.5. Strategy for use
This treatment is used only in patients aged at least 18 suffering from severe psoriasis resistant to common therapeutics. It has sometimes been effective in pustular psoriasis and psoriatic rheumatism.

This treatment is contraindicated in patients suffering from a serious illness, patients with digestive or chronic renal illness and patients at risk of leukopaenia from some other illness or treatment. Pregnant or lactating women must not be treated, nor patients who have or have had cancer. The scope for using this treatment on children has not been documented.

The increase in dosage takes place very progressively to diminish the risk of side effects. Low- concentration tablets are available, as are high-concentration tablets.

  • First week: a low-concentration tablet in the morning
  • Second and third weeks: a low-concentration tablet mornings and evenings
  • Fourth week: a high-concentration in the mornings
  • Fifth week: a high-concentration tablet mornings and evenings
  • Sixth week: a high-concentration tablet mornings, noon and evenings
  • Seventh week: a high-concentration tablet mornings, noon and evenings
  • Eighth week: two high-concentration tablets in the morning, one at noon and two in the evening
  • Ninth week: two high-concentration tablets mornings, noon and evenings.

Once the therapeutic result has been obtained, we attempt to reduce dosage very progressively in order to find the minimal effective dose.

Treatment can be continued in patients suffering from very severe psoriasis over a quite lengthy period - more than two years. Another strategy consists of treating until the lesions disappear, then stopping treatment and only renewing it in the event of a relapse. Stopping treatment does not result in any rebound effect from the illness.

2.6.6. Monitoring
In addition to regular clinical monitoring, it is necessary to determine creatininaemia, urea, liver enzymes and CBC, and screen for dipstick proteinuria every month for six months and then every two months.

Doses will need to be lowered if white cells drop below 3106/ml, if lymphocytes drop below 0.5106/ml and in the event of persistent eosinophilia > 25%. Dosage will also have to be lowered if creatininaemia increases by more than 30% in relation to its base value and if proteinuria appears. If lowering doses does not eliminate these side effects or the situation deteriorates again, treatment will need to be stopped.

Treatment must be stopped, of course, if ineffective or in the event of overly painful side effects, pregnancy or cancer. Treatment may be discontinued suddenly without any risk of rebound.

2.6.7. Combination therapies
All topical treatments can be combined with fumaric acid esters. It is preferred not to combine phototherapy with them since this is already immunosuppressive therapy. Nor does it seem reasonable to combine it with other immunosuppressive or nephrotoxic drugs.

Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. U. Mrowietz, E. Christophers & P. Altmeyer, for the German Fumaric Acid Ester Consensus Conference. British Journal of Dermatology, 1999;141:424-429.

2.7. Azathioprine ([Imurel®|Imurek®|auteur192]), hydroxyurea (Hydrea®), mycophenolate mofetil, extracorporeal photophoresis

Some patients resistant to all treatments may benefit from systemic treatment whose efficacy has never been rigorously studied due to the rarity of their indication. For each of these drugs, the benefit/risk ratio must be discussed at length. They can only be prescribed in patients agreeing to submit to regular monitoring.

2.7.1 Azathioprine ([Imurel®|Imurek®|auteur192])
It acts by inhibiting synthesis of the normal nucleotides. It is potentially mutagenic, and teratogenic in animals, but causes no fetal aberrations in women exposed to the drug during pregnancy. Nonetheless, discontinuation during pregnancy and contraception during treatment are advisable. Haematological tolerance will depend on thiopurine methyltransferase (TPMT) activity.

Stop treatment if ineffective after three months of use at the optimal dose.

Daily dose
Depends on TPMT activity:

  • 0.5 mg/kg/j for homozygotic subjects for the low-activity allele.
  • 1.5 mg/kg/j for heterozygotic subjects.
  • 2.5 mg/kg/j for subjects without a deficiency.
  • If the enzymatic activity dose is not possible, start with the weakest dose and increase dosage every month while monitoring the haemogramme. The same applies to the renally or hepatically insufficient and to the elderly.
  • Take with meals to reduce digestive side effects.

Side effects

  • Dose-dependent medullary depression.
  • Gastrointestinal problems.
  • Cholestasis, rare.
  • Alopecia, rare.
  • Very rare hypersensitivity syndrome with fever, myalgia and multi-organ involvement. This dictates a definitive end to treatment.

Monitoring
Platelet count every week for the first month or until the optimal dose is found, then every two weeks for two months, then every month.

Combinations
With allopurinol, reduce the Imurel dose to 1/4 of the dose, paying attention to any cytostatics that may have been combined or taken recently, notify the drug in the event of general anaesthesia and avoid live attenuated vaccines.

Long-term risks
Those of immunosuppression: however, no increase in risk of cancer has been documented apart from an associated immunosuppressive drug.

2.7.2. Hydroxyurea (Hydrea®)
It inhibits the reduction of ribonucleics into desoxyribonucleics and hence DNA synthesis. It is mutagenic through the production of free radicals. It is used over long periods in the treatment of chronic myeloid leukemia, thrombocythemia and sickle cell anaemia. (No marketing authorization for psoriasis.)

Daily dose
Between 1 and 1.5 grammes, taken in one go, then progressive reduction of dose following clearance. Start at 0.5 grammes in elderly individuals or if renal function is impaired.
Requires effective contraception for men and women, but no fetal malformation was observed during treatment. Give preference to intermittent treatment.

Efficacy
Clearance in 60% of cases after 2 months of treatment, in psoriasis vulgaris only.
Relapse in the two months after cessation of treatment; rare rebounds.
No effect on psoriatic rheumatism.

Side effects
Haematological values relative to dose: anaemia, leucopaenia, and reversible thrombocytopaenia. Macrocytosis is constantly observed.

  • Diffuse pigmentation or limited to plaques.
  • Hepatic: increase in alkaline phosphatases and/or transaminases.
  • Alopecia.
  • Gastrointestinal disturbances.
  • Exceptional interstitial nephropathy.
  • Köebner in photo-exposed areas.
  • Oedema of the legs.
  • Hyperalgesic leg ulcers.
  • Explosion of pre-epitheliomatous keratosis and spinocellular carcinoma.
  • Lichenoid dermatosis.
  • Stomatitis, aphthae.
  • Drowsiness, disorientation, depression.
  • Amenorrhea, azoospermia.
  • Induced lupus.

Monitoring:
CBC liver enzymes, electrolytes and creatininaemia: every week for one month, then every month.
In the event of treatment lasting more than 6 months: creatinine clearance, uricaemia and screening for autoantibodies, folates, B12 and serum iron every 6 months.
No medication prohibited except for other myelosuppressants.
Slight carcinogenic risk.

2.7.3. Mycophenolate mofetil
Prodrug of mycophenolic acid already being used to combat psoriasis; it is an inhibitor of active purine synthesis, particularly on B and T lymphocytes. Non-mutagenic. Not to be prescribed without effective contraception in women.

Daily dose:
1 g mornings and evenings.
(Out of marketing authorization in France)

Monitoring:
CBC, every week for the first month, then every month.

Side effects:

  • Gastrointestinal: nausea, vomiting, diarrhoea, rectal bleeding; dose dependent.
  • Urinary: burning sensation, sometimes sterile pyuria; spontaneous regression during the first year of treatment.
  • Haematological values: anaemia, leucopaenia, thrombocytopaenia. Rare, dose-dependent.
  • Fatigue, regressive under treatment
  • Carcinogenic risk lower than that of azathioprine.

Efficacy:
50% PASI improvement in 3 months in an open study.

2.7.4. Extracorporeal photophoresis
This therapeutic technique has only been used in isolated cases resistant to all treatments, sometimes showing improvement.

[|According to own experience extracorporeal photopheresis is not effective in psoriasis.|auteur192]

2.8. THE BIOLOGICAL TREATMENTS

The anti-psoriatic effectiveness of the classic systemic treatment was discovered by chance, and the reasons of their effectiveness are only partially understood. Their biological targets are indeed extremely numerous and we do not know those who are mainly responsible for the therapeutic effect and those mainly responsible for the side effects.

The "biological" treatments are called as such because they are proteins partially or totally humanized, synthesized by genetic engineering.

These proteins are designed for targeting very selectively a chosen molecule having an important pathogenic role in a given disease.
These targets can be molecules involved in the antigenic presentation for example, or cytokines involved in the development of the inflammatory reactions as the TNF?.

The biological treatments have in common a very high cost, that’s why they are reserved in Europe for the patients to whom the classic systemic treatments are contraindicated, ineffective or badly tolerated. The long-term side effects of biological treatments are badly known. They modify the immune system and modify a spate of molecular reactions whose role is still very poorly known in physiology. At the moment, to prescribe them, we thus apply, on principle, various precautions: we do not use them during pregnancy (they require thus contraception until their effects on pregnancy are better known) and lactation; we do not prescribe them to patients with recent history of cancers (except basal cell carcinomo). Finally, in case of surgical intervention or infectious disease we stop them all and we resume them only after the healing or the recovery are obtained. For the same reasons the use of living vaccines is also contraindicated.

2.8.1. The TNF? inhibitors
There are two types of TNF? inhibitors: soluble receptors able to scavenge the circulating TNF?, and anti-TNF antibodies able to deactivate the circulating TNF and the TNF? present on the cellular membrane. The TNF? inhibitors are effective on skin lesions and on arthritis. They obtained their first marketing authorization for rheumatoid arthritis. The TNF inhibitors have common side effects. The frequency of these side effects increases with the therapeutic effectiveness. These common side effects include the activation of chronic infections, for example in the teeth or the sinus, but also mycobacterial infections and tuberculosis. With anti-TNF?, we must be very alert before and throughout the treatment to the appearance and the development of a bacterial or myco-bacterial infection. They are also contraindicated to patients suffering from severe cardiac insufficiency and patients suffering from demyelinating or autoimmune diseases.
[The global pre-therapeutic clinical assessment common to all the TNF inhibitors includes a complete clinical examination, lung radiography, a scanner of the sinuses, a dental panorex|We do not practice these radiological examinations before treatment intiation; we never experienced a notable adverse event in relation with an ORL neoplasia/infection.|auteur194], a dosage of anti-nuclear antibodies, and an intradermic test with tuberculin 5U. In case of antecedent untreated tuberculosis or in case of an intradermic positive reaction with tuberculin 5U superior to 5 mm in diameter, it is necessary to prescribe an antituberculosis treatment. This precaution brings to a frequent prescription of double therapy, Rafampicine / Ethambutol (Rifinah®) - 2 capsules each morning during 3 months. This treatment has to begin 3 weeks before the beginning of anti- TNF?.

With anti-TNF we observe sometimes paradoxical flares of psoriasis, maybe due to an increase of interferon’s liberation. And more episodically, we observe the appearance of naevi under anti-TNF?. The increase of the risk of lymphoma and the number of actinic keratosis remains controversial. This underlines how much we have to learn and how much attentiveness remains necessary in the follow-up of these patients.

2.8.1.1. Etanercept (Enbrel®)
It is a human soluble recombinant receptor of the TNF alpha.
It acts by competitive inhibition of the TNF alpha, its affinity being 50 to 1000 times superior for the TNF alpha than the physiological soluble receptor.
Etanercept is indicated in rheumatoid arthritis, chronic juvenile arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis in case of failure or intolerance or contraindication of the classic systemic treatments.

Effectiveness
By the 12th week the PASI 75 is reached by 34 % of the patients with a subcutaneous dose of 25 mg twice a week and by 49 % of the patients with a subcutaneous dose of 50 mg twice a week. This improvement is significant from the second week and continues until the 24th week with the PASI 75 being reached by 44 % with 25 mg twice a week and by 59 % with 50 mg twice a week.
The improvement of the quality of life evolves in the same way. There is no rebound effect when stopping the treatment. The average relapse time is 3 months after stopping the treatment.
The effectiveness of the resumed treatment is similar to that of the initial treatment.
Enbrel® is effective not only on skin lesions but equally on the joints.

Side effects
Evaluations were conducted on a total of 400 000 patients / year, taking into account the totality of the indications.
The only side effect was a reaction on the injection site, more frequent under Enbrel® than placebo. This side effect decreases with the pursuit of the treatment.
There was no record of more infections under Enbrel® than under placebo, provided that the contraindications were respected.

Contraindications:

  • Infections
  • Untreated tuberculosis
  • Cardiac insufficiency
  • Cancer or lymphoma
  • Demyelinating disease of type multiple sclerosis
  • In women: absence of contraception, pregnancy or breast-feeding
  • Allergy or intolerance to one or some of the constituents of the injection
  • Living vaccines must be practiced before the beginning of the treatment
  • In case of surgery with septic risk, stop the treatment and resume it after healing.

Dosage and surveillance
The treatment is conducted by subcutaneous injections twice a week.
During the first 3 months of treatment the injections are made at 25 mg or 50 mg twice a week. The relay is then taken at 25 mg twice a week. It is clear that this rule will not be convenient for all patients, in particular for those who will relapse when decreasing from 50 mg twice a week to 25 mg twice a week. The treatment must be interrupted if the answer is insufficient after 12 weeks of treatment.
In case of relapse after stopping the treatment, the treatment is resumed at the subcutaneous dose of 25 mg twice a week, what once again will not be convenient for all patients, in particular severe patients.

To improve local tolerance, it is necessary to inject slowly the product in one minute and to warm it at the exit of the fridge.

The surveillance is only clinical.
In case of infection it is necessary to stop the treatment, to identify and to treat the infection.

There is no systematic biological surveillance. It must be made for the slightest doubt of infection or auto-immune disease.

Etanercept association with small doses of Methotrexate or Acitretine should be interesting to study for patients insufficiently relieved.

2.8.1.2. Adalimumab (Humira®)
Humira is a human monoclonal recombinant antibody anti-TNF?. It contains the same risks as the other anti-TNF? and shares the same contraindications. It is indicated as infliximab in the Crohn disease, rheumatoid arthritis, chronic juvenile arthritis, the psoriatic arthritis, ankylosing spondylitis and psoriasis.

Effectiveness
Its effectiveness is slightly below infliximab and clearly superior to etanercept. It is slightly more effective than Methotrexate. After 8 weeks the PASI 75 is reached for 54 to 62 % of the patients and after 16 weeks for 70 to 79 % of the patients, according to the studies.

The improvement of the quality of life evolves in the same way. There is no rebound when stopping the treatment. Humira® is effective not only on the skin, but also on the joints.

The effectiveness decreases on average from 6 to 10 % a year because of the very progressive formation of anti-Adalimumab antibodies.

Side effects
The side effects are the same as those of the other anti-TNF, though less frequent than those of infliximab and a slightly more frequent than those observed under Etanercept.

Contraindications

  • Infections
  • Untreated tuberculosis
  • Cardiac insufficiency
  • Cancer or lymphoma
  • A demyelynating disease of type multiple sclerosis
  • In women: absence of contraception, pregnancy or breast-feeding
  • Allergy, intolerance to one or some of the constituents of the injection
  • Living vaccines must be practiced before the beginning of the treatment
  • In case of surgery with septic risk, stop the treatment and resume it after healing.

Dosage and surveillance
Humira® is prescribed in subcutaneous injections. The first injection is of 80 mg, the following injections are of 40 mg. The usual plan is a subcutaneous injection every 15 days, what is particularly convenient. The treatment once a week is more effective and can be used in case of difficulty. Its effectiveness is very close to that of infliximab. Some patients are particularly sensitive to this treatment and we can then space out more the injections.

To improve local tolerance it is necessary to inject slowly the product in approximately one minute and to warm it at the exit of the fridge.

The surveillance is only clinical.

In case of signs of an infection, it is necessary to stop the treatment, to identify and to treat the infection.

There is no systematic biological surveillance.

The Humira®’s ratio effectiveness / tolerance/ convenience is particularly interesting.

2.8.1.3. Infliximab (Remicade)
It is a partially humanized antibody against the TNF?. It is indicated in the Crohn disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and psoriasis.

Effectiveness
It is the most effective biological medicine.
The improvement appears from the 2nd week with a maximum effectiveness in the 10th week. 87 % of the patients reach the PASI 75.

Side effects
They are essentially reactions to the perfusion; an increase of the infectious risk and the appearance of lupus-like autoimmune phenomena.

Anti-Infliximab antibodies can appear and end up in a poorer tolerance to the treatment and in a decrease of its effectiveness. Paradoxical skin reactions looking like psoriasis were observed as well as the appearance of auto-antibodies at a high rate, in particular anti-DNA, and clinical symptoms evoking lupus. Reactions to the perfusion are observed in 15 to 20 % of the patients and in 5 % of perfusions. These reactions do not reproduce systematically. These reactions are most often small or moderated with less than 1 % of severe reactions.

The most important infectious risk is that of tuberculosis. In 147 000 treated patients, 70 cases of tuberculosis were observed, more than half of which developed in the first months of the treatment. The other serious infections observed were listeriosis and histoplasmosis. This risk is even more important since there is an immunosuppressed ground, either because of the gravity of the disease, or because of the treatments associated to immunosuppressive drugs, or even because it is linked to a HIV infection. This infectious risk is common to all the anti-TNF?, but is more important with Infliximab than with Etanercep or Adalimumab.

A cardiac insufficiency can be aggravated by anti-TNF and in particular by Infliximab.
To the moment, no increased risk of cancer or lymphoma under anti-TNF was observed, but it is necessary to remain vigilant.

Infliximab is contraindicated in the demyelinating diseases as optic neuritis, or multiple sclerosis.

Finally, 35 cases of hepatitis chronic infection have been observed with infliximab, this accident occurring between 2 weeks and one year after the beginning of the treatment. A hepatic surveillance is thus necessary. We do not know the effect of anti-TNF on the chronic hepatitis B and C. In that case it is necessary to ask for the opinion of a hepatologist.

Contraindications

  • Antecedents of tuberculosis or chronic infection (dental, sinus ….)
  • In women: absence of contraception, pregnancy and breast-feeding
  • Hepatic disease
  • Cardiac insufficiency
  • Demyelinating disease
  • Allergy or intolerance in the product or in one of its constituents
  • Living vaccine must be performed before treatment
  • In case of surgery or of infectious disease, stop treatment and start again after healing.

Dosage and surveillance
Infliximab is administered by slow intravenous perfusion (at least 2 hours) at the dose of 5 mg/kg. The treatment is given in week 0, week 2 and week 6, then every 2 months.
A premedication is not systematic.
In case of reaction to the perfusion, the first measure is to slow down the debit of perfusion and if it is not sufficient, to stop the perfusion. The treatment of the reaction will be adapted to the nature and to the intensity of the reaction: paracetamol, antihistamines, corticoids …
The perfusion is made in a minimum of 2 hours, the patient staying under observation two hours after the end of the perfusion.

A clinical and biological follow-up is necessary before every treatment in search of an infection. We shall also watch the anti-nuclear antibodies, the liver enzymes, the radio of lungs, the CBC.

The prescription of Methotrexate in the dose of 10 mg once a week potentiates the action of Infliximab and delays the appearance of anti-Infliximab antibodies.

In case of intolerance or inefficiency of Infliximab, clinical isolated reports suggest that adalimumab or etanercept could be an effective relay.

[|I have to underline an important point in this
context: most infusion reactions are supposed to be non-immune mediated and regress spontaneously after reduction of
the infusion rate or a transitory
treatment interruption. This adverse event should not contraindicate
treatment continuation and a premedication should eventually be considered in
some patients (paracetamol, antihistaminics, steroids). Only few of the
infusion reactions are immune-mediated (type 1 hypersensitivity reaction) that
will require a treatment interruption. Those patients may be treated by other
TNF-a antagonists in the future (etanercept,
adalimumab).|auteur194]

2.8.2. The T cell activation inhibitors

[|In addition, the two T-cell agents, alefacept (Biogen Idec) and efalizumab (Genentech and Serono), should be discussed. While clinical responsiveness with these two agents is not as early and as dramatic as with the TNF-? agents, the use over the past five years has shown that these agents are exceptionally safe in comparison to our traditional systemic agents. Hopefully, pharmacogenomics measures in the future will allow us the opportunity to use these drugs in appropriate patients, as a small percentage of patients do obtain long remission, ie 6-9 months, with courses of alefacept. Likewise, the safety database of efalizumab is the largest of all the biologic agents in purely psoriasis treatment with publication in 2008 of 36 months of continuous therapy. However, this begs the question: Can we utilize safety data in rheumatoid arthritis and Crohn’s disease, where over 1 million patients have been treated with the anti-TNF-? agents, for our psoriasis population?|auteur215]

2.8.2.1. Efalizumab (Raptiva®)
Raptiva® is a humanized monoclonal antibody which targets CD11a. In doing so, it inhibits the migration of the lymphocytes from the blood towards the tissues. It also inhibits the expression of CD11a, the proliferation of T cells and the lymphocytes, the expression of the IL-2 receptors.
Receptors CD11a exist in the brain. Their functions are unknown.

Effectiveness
29% of the patients reach the PASI 75 after 12 weeks of treatment. The improvement is shown from the 2nd week of treatment.
44% of the patients reach PASI 75 after 24 weeks. For a certain number of patients, this improvement under treatment continues for a few more weeks.
Efalizumab is not effective on psoriatic arthritis.

Side effects
By mid-2005, tolerance to efalizumab has been estimated on 6500 patient/year. During the first 3 injections 40 % of the patients note a cytokinic reaction with headaches, myalgia, nausea and fever appearing within 48 hours following the injection. These symptoms disappear after the 3rd injection. Other observed side effects are as frequent under efaluzimab as under placebo. However, a slight increase of the ALAT and the alcaline phosphatases is possible, what incites a more particular follow-up of the patients having a hepatic disease. A lymphocytosis is usually observed, it is the result of the molecule’s mode of action.

An autoimmune thrombocytopenia lower than 50 000 platelets was observed in 0, 3 % of the patients. 4 cases of autoimmune hemolytic anemia were described There is no increase of the infectious risk under efalizumab but we can observe the worsening of a pre-existent infection or the aggravation of an infection’s resistance to antibiotics.
No increased risk of cancers has been noticed until now.

Cutaneous side effects

Treatment-responsive patients

*a) The appearance of new plaques in non-affected skin area, whilst the affected zones improve. This paradoxical reaction spontaneously disappears under treatment.

*b) A papular rash with neutrophilic infiltrate on histology is observed in 0,1 % and disappears spontaneously under treatment. These two types of reaction can disappear more quickly with the help of a local treatment.

After stopping treatment, it is possible to observe a rebound. To avoid this, it is necessary to resume very quickly the treatment with efalizumab to responsive patients from the beginning of the relapse.

[|The rebound phenomenon is more frequently observed
in non-responders compared to the incidence in responders. I want to underline
that retreatement with efalizumab should not be considered in patients that are
non-responsive and that experience a rebound phenomenon. In case of a severe
rebound phenomenon in non-responsive patients, the first choice treatment
attitude should be a short cycle of cyclosporine A. As a second choice, I
recommend intensive topical treatment (steroids, VitD derivates). Methotrexate
and retinoids seem to be less effective. I experienced a severe rebound
phenomenon that was refractory to infliximab and methotrexate.|auteur194]

Treatment-non-responsive patients

On non-responding patients, a very severe flare of the disease, leading sometimes to erythroderma, may happen after 6 to 10 weeks of treatment. Thus, in case of no response after 4 weeks, it is necessary to shift to another treatment.
As such, induction of psoriasis arthritis by efalizumab is possible.

Contraindications

  • Hypersensitivity to efalizumab or to its excipient
  • History of cancer
  • Patients suffering from a severe infection or from tuberculosis
  • Guttate psoriasis , pustular psoriasis, erythroderma, psoriatic arthritis
  • For women: absence of contraception, pregnancy, or breast-feeding

Dosage and surveillance
The efalizumab is administered by subcutaneous injection once a week.
The first injection is made at the dose of 0,7 mg/kg, the following injections at 1 mg/kg.
The follow-up consists of a CBC, every month during 3 months, then every 3 months.
A monthly surveillance of liver enzymes is necessary for patients presenting a hepatic or renal insufficiency.

No case of anaphylactic shock has been observed under efalizumab.
Efalizumab is especially indicated for chronic stable psoriasis. We do not know if its effectiveness is good to control psoriasis flare.

We do not know either if it is useful to associate it to small doses of acitretine, Methotrexate or with Etanercept.

2.8.2.2. Alefacept (Amevive)

(At present unavailable in most European countries)

Amevive is a fusion associating: a) an extra cellular part linking to the receptor CD2 (found particularly lymphocytes T’s surface) of the surface molecule LFA3 (found, in particular, on cells presenting antigens) and b) the terminal fragment Fc of human IgG1.
Alefacept then blocks the connection of co-stimulation LFA3-CD2 and decreases this way the activation of T cells.
But its effectiveness seems especially linked to the connection it allows between CD2 and Fc receptor on the surface of NK cells. This connection provokes the activation of NK cells, the liberation of granzymes and the lysis of T cells. This lysis affects preferentially the memory T cell CD45Ro +. There is a clear correlation between the decrease of the memory T cell CD45Ro + after a month of treatment and the therapeutic answer.

Effectiveness
After 12 weeks of treatments at the rate of 15mgr IM once a week, 21 % of the patients reach the PASI 75.
A marked improvement is noticed in responsive patients, from the second month of treatment. The average duration of this improvement after stopping treatment is of two months. A second series of 12 injections performed on responsive patients 3 months later allows to obtain an even better result.
On some patients, a very prolonged bleaching, superior to 10 months after the last injection is obtained.
We do not observe a rebound after sopping the treatment.
Alefacept seems to be a very efficient treatment with long lasting results for around 10 to 20 % of the patients.

Side effects
Alefacept is an immunosuppressant and can induce a lymphopenia below 250 CD4/ml. This was observed in 28 % of the patients during the clinical studies. This lymphopenia led to stop the treatment for 4 % of the patients. A Hyperplasia of lymphocytes B in lymph nodes and spleen and a case of lymphoma B were observed in monkeys during the pre-clinical studies. Attentiveness is thus required with regards to treated patients.
In spite of the absence of teratogenic effect in monkeys, this drug is not recommended to be taken during pregnancy and lactation.
Alefacept can be used beyond 65 years. On the other hand, its effectiveness and its tolerance on children were not studied.
Alafacept can provoke urticaria and angio-œdema, bringing to stop at once the treatment.
Hepatic cytolysis and hepatic steatosis are rarely observed (9 cases in the clinical studies). It is necessary to be vigilant with patients suffering from hepatic abnormalities and to survey liver function. Alefacept does not increase the risk of infection.

Contraindications

  • Lymphopenia
  • Cancer, lymphoma (or history of)
  • Infection
  • Pregnancy and lactation
  • Severe hepatic disease
  • Living vaccine (to be made before treatment)
  • Other immunosuppressive treatment
  • Hypersensitivity to Amevive.

Dosage and surveillance
The most convenient and the most effective dosage is 15 mg IM once a week (the other possibility is 7,5 mg IV in bolus).
The duration of the treatment is of 12 weeks. A second series of injection can be practiced 12 weeks after stopping the first one if there is no lymphopenia.
It is necessary to measure CD4 T cells before treatment and every week under treatment. The treatment must be suspended if the rate of CD4 is lower than 250 cells/ml. The treatment must be stopped if this lymphopenia persists one month later.

Amevive is not indicated in children. It must be stopped in case of severe infection, of cancer, of lymphoma or of hepatic abnormalities.

This molecule is at present in development in transplantation.

Conclusion

The biological treatments offer a range of new therapeutic possibilities for people suffering from psoriasis and in therapeutic failure. Numerous studies remain to be done in order to understand the optimal use of each of them, the possibility to associate them to classical systemic treatments, and the most effective and the least risky therapeutic alternations.
In the current state of knowledge, it seems that we can note the following tendencies: Remicade® is the most effective biological treatment but the one which contains the most side effects. Its effectiveness is equal or superior to that of the cyclosporine, given according to an optimal protocol. This treatment is reserved in situations of urgency or total therapeutic deadlock. Remicade? is quite useful for severe patients incapable of a good observance. It is very helpful in case of psoriasis arthritis. Enbrel® is very interesting because of its convenience of use, its easy follow-up despite its medium effectiveness. Humira® has a very interesting effectiveness, doubtlessly superior to that of Methotrexate. Its subcutaneous administration every 15 days is very convenient. The tolerance is excellent. Humira® is more effective than Enbrel? and better tolerated than Remicade®.
Raptiva® has a similar effectiveness to that of Enbrel®, it is more delicate to handle but it is very interesting because it often greatly improves the quality of life. It is the drug of choice for chronic stable psoriasis. Amevive® is the least effective of biological treatments. However, it can be of great help for responsive patients. For many of them, prolonged remission of their disease after stopping the treatment is observed.

The therapeutic associations are very badly known. Methotrexate seems quite interesting in association with anti-TNF?. The strategies of alternation between treatments are not assessed yet.

The association of the biological treatments with weak doses of Acitretine or Methotrexate should be better studied. The Raptiva/Enbrel association would be very logical because we would inhibit at the same time the activation of the lymphocytes and the neutrophiles.

Other studies need to be performed in order to better assess the medical interest brought by these different treatments. Their effectiveness is known, but their usefulness, meaning their best place in the strategy of treatment of the psoriasis, remains to be defined.

A particularly careful clinical and sometimes biological patient’s surveillanc is necessary, because their long-term safety remains partially unknown.

[|I agree.|auteur193]

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