Actas supl def.indd

Actas Dermosifiliogr. 2008;99 Supl 4:30-5 CASE REPORTS
Efficacy of Treatment With Infliximab in Patients
With Moderate-Severe Psoriasis and High Needs of Therapy.
A Retrospective Study of 43 Patients
L. Puig
Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Abstract. Background. Much of the information on efficacy and safety of infliximab comes from clinical trials, but reports on clinical practice with patients with high therapeutic needs, for whom infliximab is approved according to the EMEA label, are scarce.
Objective. The evaluation of efficacy of infliximab treatment in patients with moderate-to-severe psoriasis and high therapeutic needs in daily practice at a reference Dermatology Department of a teaching hospital in Barcelona, Spain.
Methods. We reviewed the clinical records of 43 patients with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] > 10) with failure, contraindication or intolerance to other systemic treatments who started infliximab therapy between 2004 and 2007 and completed at least 2 infusions.
Results. We treated 43 patients (28 men and 15 women) with a mean baseline PASI of 23.7. Five patients received two courses of infliximab, therefore 48 courses of treatment were evaluated, with a mean number of infusions of 7.7 (range 3 to 25). Sixteen patients have been receiving continuous treatment for more than one year; PASI-75 and PASI-90 responses have been achieved by week 48 and maintained by 87.5 % and 68.8 % of those patients, respectively. We have observed loss of clinical efficacy (PASI < 50 of baseline) during the course of treatment in 9 patients (20.9 %). In 16 of the first courses of treatment (37.2 %) and 5 (100 %) of the second courses combination therapy with low doses of methotrexate, ciclosporin or acitretin was given to optimize the therapeutic result. The interval between infusions had to be shortened to 6 weeks in 7 patients receiving one course of treatment (16.3 %) and in 2 patients on their second course of treatment (40 %). Infusion reactions occurred in 9 patients (20.9 %). Nine successful therapeutic courses were stopped on patient’s decision; 6 of these patients (66.7 %) presented a relapse (loss of PASI-50 response) within 6 months. Treatment failures were seen in 7 patients (16.3 %) due to non-recoverable loss of efficacy (2 cases) severe acute infusion reaction alone (2 cases) or in association with loss of efficacy (relapse/rebound) (3 cases). Conclusions. Infliximab treatment was successful in 83.7 % of our patients; 16 of them (37 %) have been under continuous treatment for more than one year. Combination with systemic treatment and/or increase in the frequency of infusions contributed to attain an excellent response (PASI < 3) in most cases. Relapses within the first 6 months after treatment withdrawal were seen in 2/3 of patients, but second courses of treatment achieved the same degree of efficacy, even though it usually was delayed with respect to the first course of therapy and required concomitant administration of combined systemic therapy.
Key words: infliximab, psoriasis, clinical practice, non-trial.
Correspondence:Luis PuigServicio de DermatologíaHospital de la Santa Creu i Sant PauC/ Sant Antoni Maria Claret, 16708025 Barcelona, Spain Puig L. Efficacy of Treatment With Infliximab in Patients With Moderate-Severe Psoriasis and High Needs of Therapy. EFICACIA DEL TRATAMIENTO CON INFLIXIMAB EN PACIENTES CON PSORIASIS MO-
DERADA-GRAVE Y ALTAS NECESIDADES TERAPÉUTICAS. ESTUDIO RETROSPECTIVO DE
43 PACIENTES
Resumen. Antecedentes. Aunque existe información sobre la eficacia y seguridad de infliximab procedente de
ensayos clínicos, la experiencia clínica publicada en pacientes con psoriasis moderada-grave y con elevadas
necesidades terapéuticas es escasa.
Objetivo. Evaluar la eficacia y características del tratamiento con infliximab en estos pacientes de un Servicio de
Dermatología de un hospital universitario en Barcelona, España.
Métodos. Se han revisado las historias clínicas de 43 pacientes con psoriasis moderada-grave (Psoriasis Area and
Severity Index [PASI] > 10) con fracaso, contraindicación o intolerancia de uno o más tratamientos sistémicos
que iniciaron tratamiento con infliximab en los años 2004 a 2007, completando por lo menos 2 infusiones.
Resultados. Se trataron 43 pacientes (28 hombres y 15 mujeres), con un PASI basal promedio de 23,7. Cinco
pacientes recibieron dos series de infusiones, por lo que se evaluaron 48 cursos de tratamiento, con un promedio
de 7,7 infusiones (rango, 3 a 25). Dieciséis pacientes han estado recibiendo tratamiento continuado durante
más de un año, consiguiendo una respuesta PASI-75 en el 87,5 % y PASI-90 en el 68,8 % a las 48 semanas. En
el transcurso del tratamiento se ha observado pérdida de eficacia clínica (respuesta menor a PASI-50) en algún
momento en 9 pacientes (20,9 %). Con el fin de aumentar la eficacia terapéutica se administró, de forma con-
tinua o intermitente, tratamiento combinado con metotrexato, ciclosporina o acitretino a dosis bajas en 16 de
los primeros cursos de tratamiento (37,2 %), y en 5 de los segundos (100 %). En 7 de los primeros cursos
(16,3 %) y 2 de los segundos (40 %) fue eventualmente necesario acortar el intervalo entre infusiones a 6 sema-
nas para mantener la respuesta terapéutica.
Se produjeron reacciones a la infusión en 9 pacientes (20,9 %). Nueve cursos de tratamiento eficaces se inte-
rrumpieron por decisión del paciente, observándose una recaída (pérdida de la respuesta PASI-50) antes de
6 meses en 6 pacientes (66,7 %). El tratamiento fracasó en un total de 7 pacientes (16,3 %), por pérdida de efi-
cacia no recuperable (2 casos), reacción a la infusión aguda grave, aislada (2 casos) o asociada a pérdida de efi-
cacia (recaída/rebote) (3 casos).
Conclusiones. El tratamiento con infliximab resultó exitoso en más del 80 % de los pacientes de esta serie, de los
que 16 (37,2 %) han recibido tratamiento continuado durante más de un año. La administración concomitante
de tratamiento sistémico convencional y/o el aumento de la frecuencia de las infusiones contribuyó al mante-
nimiento de una respuesta excelente (PASI < 3) en la mayoría de los casos. Aunque se produjeron recaídas en
los primeros 6 meses siguientes a la retirada del tratamiento en dos tercios de los pacientes, puede conseguirse
la misma eficacia en un segundo curso de tratamiento, aunque a menudo la instauración es más lenta y requie-
re tratamiento sistémico combinado.
Palabras clave: infliximab, psoriasis, experiencia clínica.
Introduction
tentially serious adverse effects. Infliximab is a chimeric monoclonal antibody that has a high specificity and af- Psoriasis is a chronic immunologically mediated inflam- finity for tumor necrosis factor a. It was approved by matory skin condition that affects 1.4 % of the Spanish the European Medicines Agency (EMEA) in 2004 for population. 1 Topical therapy cannot be used in large the treatment of adult patients with moderate to severe number of patients given the extension, location, and plaque psoriasis for whom other systemic agents pro- disabling character of the disease, and all the systemic duce no response, are contraindicated, or lead to intol- agents that were available before the advent of the bio- erance. The efficacy of infliximab in inducing remission logics are associated with significant organ-specific tox- in patients with moderate to severe chronic plaque pso- icity. Such treatments are therefore contraindicated in riasis has been proven in several randomized place- many patients and cause, or are very likely to cause, po- bo-controlled clinical trials, 2-5 one of which enrolled Actas Dermosifiliogr. 2008;99 Supl 4:30-5 Puig L. Efficacy of Treatment With Infliximab in Patients With Moderate-Severe Psoriasis and High Needs of Therapy. patients previously treated with at least 1 systemic with differential, kidney and liver function, antinuclear agent. However, few published series report real clinical antibody testing, and serology testing for human immu- experience 6-10 in patients fulfilling the indications of the nodeficiency virus and chronic hepatitis (B and C). Pho- EMEA Summary of Product Charac ter istics and for tographs were taken and the PASI calculated at the start whom systemic therapy has failed or cannot be used at full doses due to the risk of toxicity, and who are there-fore defined as having “high therapeutic needs.” We must also remember that a clinical practice setting dif- fers from that of a clinical trial in terms of the need to optimize the response to treatment; therefore, recourse Infliximab (Remicade) was administered at 5 mg/kg/d by to combination therapy or dosage adjustments is justi- intravenous infusion (125 mL/h) in the day hospital at fied. The present retrospective study of 43 patients aims weeks 0, 2, 6 (induction phase), and every 8 weeks there- to evaluate the efficacy and special characteristics of after (maintenance phase). Patients were monitored treatment with infliximab in daily clinical practice in throughout the infusion and for 2 hours afterwards. De- the dermatology department of a teaching hospital in pending on the clinical response, the interval between Barcelona, Spain. The fact that ours is a reference de- infusions was reduced in some patients to 6 weeks (tem- partment means that patients tend to have more severe porarily or permanently) during the maintenance phase. and refractory forms of the disease, thus justifying the Previous systemic therapy was suspended in all patients attempt to develop an approach in which treatment is immediately before the first infusion, although in some cases combined systemic therapy (methotrexate, cy-closporine, or acitretin at doses corresponding to the re-spective efficacy thresholds) was administered depending Patients and Methods
on the circumstances (from the outset or from the start of a second course of treatment) to optimize efficacy or re- duce the immunogenicity of infliximab (methotrexate, 7.5-10 mg/wk, according to body weight). All patients We reviewed the medical records of 43 patients with mod- who had received at least 3 infusions were included in the erate to severe psoriasis—Psoriasis Area and Severity In- dex [PASI] > 10—for whom another systemic agent had failed, was contraindicated, or had led to intolerance and who started treatment with infliximab at the dermato logy department of Hospital de la Santa Creu i Sant Pau in Barcelona, Spain, between 2004 and 2007. All patients had At each follow-up visit, we recorded the response to treat- ment using the PASI as noted on the patient’s chart and according to photographs, as well as the adverse effects and results at the following points: baseline; weeks 0, 2, 6, and every 2 months thereafter; the day the infusion was administered; during the interval between 2 infusions; or In all patients with moderate to severe psoriasis for whom as needed according to the patient. A relapse was defined we considered administering a biologic agent, an exten- as a loss of response to treatment considered as a PASI sive medical history was taken to establish the following: > 50 % with respect to baseline—the criterion for failure of history of the disease, previous treatment for psoriasis, therapy at 12 weeks in clinical trials—at any time during presence of other diseases or comorbid conditions and concomitant therapy, and possible contraindications or special risk factors with biologic agents, specifically pres-ence of active infection, history of tuberculosis and pos- sible exposure thereto, demyelinating disease, heart failure, and cancer. All patients underwent a Mantoux A laboratory workup (complete blood count with dif- test with 2 tuberculin units of purified protein derivative- ferential, kidney and liver function, antinuclear antibody RT23 (repeated 10 days later for patients receiving po- titer) was performed at regular intervals (coinciding tentially immunosuppressive therapy), a chest radiograph, with the infusions) or when deemed necessary by the and a laboratory workup including complete blood count Actas Dermosifiliogr. 2008;99 Supl 4:30-5 Puig L. Efficacy of Treatment With Infliximab in Patients With Moderate-Severe Psoriasis and High Needs of Therapy. although in 3 of the 5 patients (60 %) a longer course of treatment was necessary than during the first series in or- We treated 43 patients (28 men and 15 women) with moderate to severe plaque psoriasis and high therapeutic A total of 9 patients (20.9 %) experienced infusion reac- needs. The average PASI at baseline was 23.7. Eight pa- tions. In 5, who received 5 infusions on average (range, tients (18.6 %) had psoriatic arthritis. The result of the tu- 2-7 infusions), the reaction—acute, moderate, or severe— berculin skin test (induration > 5 mm in diameter) was led to treatment discontinuation, and coincided with an positive in 5 patients (12.2 %), all of whom had received almost total loss of the response reached in 3 cases. In 9 months of chemoprophylaxis with isoniazid, which 2 women, the reactions recurred in 3 to 4 consecutive infu- had been started 1 month before the first infusion with sions, although prophylaxis and lower infusion rates ena- bled treatment to be continued. One patient presented a Five patients (11.6 %) received 2 series of infusions; delayed reaction that did not recur.
therefore, we evaluated 48 courses of treatment, with an Treatment failed in 7 patients (16.3 %), who completed average of 7.7 infusions (range, 3-25 infusions) per series. a mean of 7 infusions (range, 5-12 infusions), due to irre- A total of 373 infusions were administered during the versible loss of efficacy (PASI < 50 % of baseline, 2 cases) study period; the number of infusions per series (course) or isolated severe acute infusion reaction (2 cases) or loss was 8 or more (duration of treatment > 48 wk) in 16 cases of efficacy with relapse/rebound (3 cases).
(33.3 %), between 5 and 7 (duration of treatment ≥ 24 wk and < 48 wk) in 15 cases (31.3 %), between 3 and 4 (dura-tion of treatment ≥ 12 and < 24 wk) in 16 cases (33.3 %), Discussion
and 2 in 1 case (due to a severe acute infusion reaction that led to withdrawal of therapy, although the patient contin- In routine clinical practice, infliximab is the most effective biologic agent for patients with moderate to severe psoria- The Table shows the efficacy outcomes (PASI-50, PA- sis and high therapeutic needs—especially when a rapid SI-75, and PASI-90, or responses to treatment with an response is required—and enables continuous long-term improvement ≥ 50 %, 75 %, and 90 % over baseline, respec- management of the disease in a significant number of pa- tively) in patients who received at least 3, 5, and 8 infu- tients. Treatment with infliximab was successful in 83.7 % sions (weeks 12, 24, and ≥ 48 of treatment, respectively). of patients in this series: 16 (37.2 %) received continuous Sixteen patients were receiving treatment continuously for treatment for more than 1 year, and 87.5 % reached a PA- more than 1 year: 87.5 % reached a PASI-75, 68.8 % SI-75 and 68.8 % reached a PASI-90 at week 48 and reached a PASI-90 at 48 weeks, which later remained un- thereafter. These results are comparable to or even better than those of recently published series of patients with se- A loss of clinical efficacy (relapse defined as a vere, treatment-resistant psoriasis. 6-10 Infliximab has a PASI > 50 % over baseline, or loss of PASI-50 response) rapid, reproducible onset of effect, and can be used as res- was observed at some time during treatment in 9 patients cue therapy in patients with psoriasis that is refractory to systemic treatment and/or other biologics. 9 In order to improve efficacy, we combined treatment, We observed a loss of response (relapse, defined as a loss either continuously or intermittently, with methotrexate, of PASI-50 response) at some point during treatment in cyclosporine, or acitretin at low doses in 16 of the first 9 patients (20.9 %); this figure was lower than the 30 % courses of treatment (37.2 %) and in 5 of the second recently reported in a retrospective study, 8 and in 2 cases of (100 %). In 7 of the first courses (16.3 %) and 2 of the sec- our series the original response was recovered by increas- ond (40 %), it was eventually necessary to reduce the inter- ing the frequency of the infusions (every 6 weeks) and re- val between infusions to 6 weeks in order to maintain the introducing concomitant treatment (methotrexate and acitretin), which had been withdrawn.
We interrupted 9 efficacious courses of treatment (com- Although two-thirds of patients experienced relapses plete or almost complete clearance) at the request of the during the first 6 months after the withdrawal of treat- patient (satisfactory clearance and no wish to continue, ment, the same therapeutic efficacy was achieved in a wish to become pregnant, other reasons), and observed a second course of treatment; nevertheless, this efficacy relapse (loss of PASI-50 response) before 6 months in (reaching a therapeutic objective of PASI-75) began to be 6 patients. All those patients who underwent a second se- observed later and required combined systemic treatment. ries of infusions and who received concomitant treatment Despite the fact that treatment at fixed intervals is better with low-dose methotrexate presented a good response, than treatment as needed, both in terms of efficacy and in Actas Dermosifiliogr. 2008;99 Supl 4:30-5 Puig L. Efficacy of Treatment With Infliximab in Patients With Moderate-Severe Psoriasis and High Needs of Therapy. Table. Efficacy of Treatment with Infliximab in Patients With Moderate to Severe Psoriasis and High Therapeutic Needs.
Analysis of Patients Who Completed Each Treatment Period, Including Combination Therapy With Systemic Drugs and
Increased Frequency of Infusion (Every 6 Weeks)
Infusions Received (Weeks of Treatment) Abbreviation: PASI, Psoriasis Area and Severity Index.
terms of production of antibodies against infliximab, 11 we as long as efficacy is maintained or no infusion reactions found no information on the efficacy or safety of retreat- appear. Infliximab is particularly suitable for those patients ment with infliximab in patients with psoriasis; our expe- with almost continuously active psoriasis, greater depend- rience leads us to expect a favorable, albeit less rapid, ence on systemic treatment (with rapid relapses on discon- response in most patients who undergo a second course of tinuation), or the need for high doses (with the appearance treatment after an interruption not due to therapeutic fail- or likelihood of potentially severe adverse effects).
ure or infusion reaction. Concomitant administration of low-dose methotrexate could help reduce the immuno-genicity of infliximab in cases of repeated or intermittent treatment.
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infliximab for severe and recalcitrant psoriasis: evidence for Dr Puig has participated in clinical trials, given lectures, efficacy and high incidence of biological autoimmunity. Br J and participated in expert panels funded by Schering-Plough. He has also served as a consultant for Schering-Plough.
Actas Dermosifiliogr. 2008;99 Supl 4:30-5

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