nfliximab in psoriasis: Highly effective for both skin and nails

[Guest guest]

nfliximab in psoriasis: Highly effective for both skin and nails



Oct 14, 2005



Zosia Chustecka

Göttingen, Germany - Results from a phase 3 trial of infliximab

(Remicade, Centocor & Schering-Pough) in moderate to severe psoriasis

show that monotherapy is " highly effective in the treatment of skin

and nail disease . . ., with a rapid onset of action and a sustained

effect in most patients. " The results of the company-sponsored trial

(known as EXPRESS), which lasted a year and involved 378 patients,

are reported by Dr Kristian Reich (Georg-August University,

Göttingen, Germany) and colleagues in the Oct 15-21, 2005 issue of

the Lancet [1].

Infliximab, already marketed for a number of indications, including

psoriatic arthritis, rheumatoid arthritis (RA), and Crohn's disease,

is not yet approved for psoriasis, but likely will be on the basis of

this trial. When these data are added to earlier smaller studies,

they provide " a new level of evidence " and confirm the results of

studies of infliximab for psoriatic arthritis, comments an

accompanying editorial [2].

Another TNF blocker, etanercept (Enbrel, Immunex & Wyeth), is already

approved for use in psoriasis, and a third product, adalimumab

(Humira, Abbott), is under development for this indication. The past

few years have also seen the launch of several new biologics

developed specifically for psoriasis, including alefacept (Amevive,

Biogen) and efalizumab (Raptiva, Genentech/Xoma). All of these drugs

are administered parenterally—etanercept, adalimumab, and efalizumab

by subcutaneous injection, alefacept by intramuscular or intravenous

injection, and infliximab by intravenous infusion.

Response compares favorably with other biologics

The EXPRESS results show that infliximab compares favorably with

efalizumab and etanercept, the researchers comment. Efficacy was

assessed on the psoriasis area and severity index (PASI), and the

primary efficacy end point was PASI 75 at week 10 (the end of the

induction period); this was achieved by 80% of patients on

infliximab. Using a per-protocol approach to assess maintenance of

response, 86% of infliximab patients achieved PASI 75 at six months,

and 71% were at this level after a year. Put another way, an analysis

of responders based on prespecified data-handling rules shows that

89% of patients who achieved PASI 75 at week 10 maintained this

response at six months, and 65% maintained this response at one year.

In previous trials with efalizumab and etanercept, about 77% of

patients responding with PASI 75 at week 12 maintained this response

at week 24.

" No dose escalation or concomitant treatment was allowed in our

study, apart from very-low-potency topical corticosteroids on the

face or groin after week 10, " the researchers add. " To our knowledge,

no data spanning a year of treatment without the use of concomitant

therapy or dose escalation have been published for other biological

treatments. "

Nail psoriasis also responded. Seen in around 20% to 50% of psoriasis

patients, these nail changes are often a sign of treatment-resistant

disease, the authors comment. Significant improvements were seen by

week 10, and by week 24 there was an average response of 56%, which

was maintained through to the end of the trial. " These results

warrant further investigation, " the researchers comment.

In an interview with rheumawire, senior author Professor

Griffiths (Dermatology Center, Hope Hospital, Salford, Manchester,

UK) commented that his group tested all of the new systemic therapies

for psoriasis, and says infliximab is the " most effective I've seen

so far. " It has the most rapid onset of action (with some patients

responding within a week); for patients with very severe and very

rapidly spreading psoriasis, he says he would use this product. It's

the only product that is administered by infusion, but this doesn't

necessarily pose a problem, he says, because most dermatologists work

in a hospital and can tap into the infrastructure that already exists

for administering infliximab to patients with Crohn's disease and RA.

Patients themselves don't object to regimen because an infusion once

every two months keeps their skin clear and eliminates the need for

topical preparations, he adds.

In an accompanying commentary [2], Dr Schöen (University of

Wurzburg, Germany) writes that the psoriasis in people taking

infliximab showed a " profound improvement, " which was " maintained in

many patients over a long period. This remarkably good response was

accompanied by good tolerability of the drug. "

" Each of these novel drugs has its strengths and weaknesses, " Schöen

tells rheumawire. Infliximab shows the best response rates, he says,

but is associated with a higher risk of infection and has to be

administered intravenously. Efalizumab and etanercept can be self-

administered by patients. Efalizumab has the lowest rate of unwanted

side effects, but there is a rather high proportion of patients who

do not respond sufficiently to treatment. Both infliximab and

etanercept are efficacious in psoriatic arthritis, but efalizumab is

not. Unfortunately, he adds, alefacept is not approved for psoriasis

in Europe.

Dose for psoriasis higher than that for RA

The dose of infliximab used for psoriasis in the EXPRESS trial was 5

mg/kg, administered at zero, two, and six weeks, and thereafter every

eight weeks. This is higher than the dose for RA, which is 3 mg/kg,

but the administration schedule is the same. The dose of etanercept

used for psoriasis, 50 mg subcutaneously, is double that used for RA.

These higher doses mean that the use of TNF inhibitors for psoriasis

is even more expensive that it is for RA, which is already

prohibitive in many countries.

Why is a higher dose necessary? Griffiths says this is unclear, but

earlier trials of infliximab in psoriasis were carried out with both

3 mg/kg and 5 mg/kg, and the higher dose was " clearly more

effective. " Although the higher dose was used, the adverse reactions

reported were in line with those seen in other trials of infliximab

for other indications, he noted, and the emergence of autoantibodies

to the chimeric protein was seen in a similar proportion of patients.

This is despite the fact that infliximab is used as monotherapy for

psoriasis, whereas for RA it is used in conjunction with methotrexate

(one of the reasons for using methotrexate is to dampen autoantibody

responses to the protein). Griffiths commented that many patients

with severe psoriasis have already tried and failed with

methotrexate, and that psoriasis patients seem to be more likely to

have liver problems, one of the potential side effects of this drug.

Liver-enzyme elevations have also been seen with TNF inhibitors, and

psoriasis patients may be predisposed to this, the authors suggest in

the paper. They note that in the EXPRESS trial, infliximab was

associated with generally asymptomatic but markedly abnormal

increases in alanine aminotransferase and aspartate aminotransferase

(usually less than three times the upper level of normal), seen in 6%

and 2% of the drug-treated patients, respectively, and in none of the

placebo group. Increases in these liver enzymes have also been

reported in trials of infliximab in psoriatic arthritis, the authors

note. In contrast, previous trials of RA patients showed increases in

alanine aminotransferase at least two times the upper level of

normal, but the frequency was similar in both the infliximab and

placebo groups.

" As psoriasis is a chronic disease that usually needs long-term

treatment, understanding why some patients lost response from week 30

to one year is important, " the researchers write in the paper. They

found that those who were less likely to maintain a response had

undetectable levels of serum infliximab (<0.1 g/mL) just before the

next infusion, and some had developed neutralizing antibodies. It may

be that a subgroup of patients requires more frequent administration

to maintain a response, they comment, adding that variable dosing

frequency is currently being addressed in another study.

Biologics should be considered first line

" Biological treatments for psoriasis are now well beyond their

infancy, " Schöen writes in the commentary. " Collectively, biologics

have been evaluated in thousands of psoriasis patients and might,

because of their favorable safety and tolerability profiles, offer

advantages over conventional treatments. " The major advantage of

these drugs might be their low risk for end-organ toxicity and drug-

drug interactions; however, potential side effects, such as the risk

of infection observed with TNF blockers in particular, have to be

considered. These are indicated in the rather restrictive European

label for biologics as " second-line treatments, " he adds.

Schöen tells rheumawire that a recent consensus recommendation

authored by a panel of experts and published last year in the British

Journal of Dermatology [3] says that biologics as a new class of drug

should be given equal consideration among first-line treatment

options for patients with moderate to severe psoriasis. " Personally,

I largely agree with this assessment, although one has to bear in

mind that long-term safety data are (of course) not yet available, "

and this is probably part of the reason for the European labeling.

Also, he adds, there are no valid comparative data for biologics vs

conventional psoriasis treatments, and there is a danger that " overly

high expectations for new drugs might not be met. " Earlier this year,

the US FDA objected to a television advertisement about etanercept

for psoriasis, as reported by rheumawire, because it felt that the ad

encouraged unrealistic expectations by showing individuals with

completely clear and unblemished skin.







Sources



Reich K, Nestle FO, Papp KO, et al. Infliximab induction and

maintenance therapy for moderate-to-severe psoriasis: a phase 3,

multicenter, double-blind trial. Lancet 2005; 366:1367-1374.

Schöen MP. Advances in psoriasis treatment. Lancet 2005;

366:1333-1335.

Sterry W, Barker J, Boehncke WH, et al. Biological therapies in the

systemic management of psoriasis: International Consensus Conference.

Br J Dermatol 2004; 151 (Suppl 69):3-17. 

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