**3.5 Efficacy of infliximab**

Clinical response is often excellent. Primary response must be distinguished from more long-term response. Primary response is immediate efficacy, generally deemed at 10 weeks for infliximab. The more long-term response is the persistence of efficacy, without relapse; there is no defined timeframe for measuring this. We will therefore talk about a 1-year or 2 year response, etc. For this study, we analyzed the long-term response according to the clinical practice at the time of file analysis, so 1 to 4 years after the beginning of treatment.

Fig. 2. W0, baseline

A review of the literature indicates excellent clinical response rates to infliximab after 10 weeks: around 80% at PASI 75 (Chaudhari et al., 2001). In other words: four patients out of five achieve a three-quarter response at minimum (reduce their initial PASI by 75% minimum). In our series, this was true for 31 out of 41 assessable patients, so 76%. 19 patients (46%) had a complete response (total clearance of lesions) (table 1). 6 patients achieved a PASI reduction of between 90 and 99%. 6 others reduced their PASI by a

Infliximab Therapy for Plaque Psoriasis: The UCL Experience 279

Response evolution Stable Partial loss Complete relapse Initial responders 100% (19) 9 (47%) 6 (32%) 4 (21%)

Our series shows more relapses than the literature initially reported, but the latter was often based on short observation time periods, or a more frequent combination with methotrexate. However, the most recent publications are in line with our observations. Thus, a Brazilian series demonstrates numbers similar to ours: 32% maintain efficacy, 44% partially recur, 17% completely relapse, and another 6% of patients had a relapse corrected by infusion every six weeks (Duarte et al., 2011). In a series of 120 patients, 93% of patients had an initial response achieving at least PASI 90, however 87% required a higher frequency of treatment

In our series, complete relapses occurred most commonly after between 8 and 12 months of treatment; partial relapses could appear up to three years after the start. The responders are highly satisfied and intend to continue treatment, with an improvement in quality of life consistently nearing 100%. We should note that 9 out of 35 patients (26%) maintain a

50-99% (16) 5 (31%) 3 (19%) 8 (50%) *Total (35 pat.) 14 (40%) 9 (26%) 12 (34%)* 

than the normal regimen of 5 mg/kg every 8 weeks (Kamili et al., 2011).

**Clinical response upon completion (after 1 to 4 years)** 

Fig. 4. W46, partial relapse

Table 2. Clinical response at long-term

complete clinical response throughout!

Initial responders

percentage between 75 and 89%. Just 4 remained with an improvement of 'only' between 50 and 74%. 6 patients are considered to have a primary resistance to treatment as they have never obtained a 50% reduction in their initial severity. These six patients cannot be distinguished from the others on the basis of age, sex, comorbidity, or prior treatments received. No characteristics predictive of response emerged from our series.

Fig. 3. W10, complete response


Table 1. Clinical response at 10-12 weeks

Although the initial clinical response is therefore very good, there are concerns about its persistence in the medium and long term. Indeed, in our series there were numerous relapses: of the 35 responders, 12 (34%) experimented complete relapse, and 9 partial losses of efficacy (26%) (table 2). By relapse, we mean relatively rapid or gradual return to initial clinical severity. Each case must be confirmed in time in order to exclude spontaneous fluctuations of the illness. True relapses rarely pose diagnostic problems, and justify treatment abandonment. In contrast, for partial loss of efficacy, the absence of external factors must first be verified. In our series, several patients experienced periods of aggravation, which should be seen in relation to increased alcohol consumption; hygienic, dietary, and psychosomatic care improved several cases. The use of contributory drugs should also be systematically researched.

### Fig. 4. W46, partial relapse

278 Psoriasis

percentage between 75 and 89%. Just 4 remained with an improvement of 'only' between 50 and 74%. 6 patients are considered to have a primary resistance to treatment as they have never obtained a 50% reduction in their initial severity. These six patients cannot be distinguished from the others on the basis of age, sex, comorbidity, or prior treatments

**Initial clinical response** 

PASI improvement **100% 90-99% 75-89% 50-74% < 50%**  Number of patients 19 6 6 4 6 %, of patients (46%) (15%) (15%) (10%) (15%)

Although the initial clinical response is therefore very good, there are concerns about its persistence in the medium and long term. Indeed, in our series there were numerous relapses: of the 35 responders, 12 (34%) experimented complete relapse, and 9 partial losses of efficacy (26%) (table 2). By relapse, we mean relatively rapid or gradual return to initial clinical severity. Each case must be confirmed in time in order to exclude spontaneous fluctuations of the illness. True relapses rarely pose diagnostic problems, and justify treatment abandonment. In contrast, for partial loss of efficacy, the absence of external factors must first be verified. In our series, several patients experienced periods of aggravation, which should be seen in relation to increased alcohol consumption; hygienic, dietary, and psychosomatic care improved several cases. The use of contributory drugs

received. No characteristics predictive of response emerged from our series.

Fig. 3. W10, complete response

Table 1. Clinical response at 10-12 weeks

should also be systematically researched.


Table 2. Clinical response at long-term

Our series shows more relapses than the literature initially reported, but the latter was often based on short observation time periods, or a more frequent combination with methotrexate. However, the most recent publications are in line with our observations. Thus, a Brazilian series demonstrates numbers similar to ours: 32% maintain efficacy, 44% partially recur, 17% completely relapse, and another 6% of patients had a relapse corrected by infusion every six weeks (Duarte et al., 2011). In a series of 120 patients, 93% of patients had an initial response achieving at least PASI 90, however 87% required a higher frequency of treatment than the normal regimen of 5 mg/kg every 8 weeks (Kamili et al., 2011).

In our series, complete relapses occurred most commonly after between 8 and 12 months of treatment; partial relapses could appear up to three years after the start. The responders are highly satisfied and intend to continue treatment, with an improvement in quality of life consistently nearing 100%. We should note that 9 out of 35 patients (26%) maintain a complete clinical response throughout!

Infliximab Therapy for Plaque Psoriasis: The UCL Experience 281

respond to the loss of efficacy observed. For two of them, response improved temporarily, however the dosage frequency would have had to be increased more, which was not possible. In contrast, for 5 patients, the dose had to be reduced; the clinical response had been complete and stable for 18 months, and these patients questioned the usefulness of continuing the treatment, at least at the initial dosage. Four patients out of the five thus continued their treatment at a reduced dose, without loss of efficacy. In practice, a reduction

The medical follow-up we propose follows English guidelines (Smith et al., 2009): essentially clinical and anamnestic, it is also based on a blood sampling every six months and particular monitoring for tuberculosis risk. For our patients, we have not observed a tendency for

One death by suicide, of a 30 year old man. The patient had been depressed for a long time, with a first suicide attempt long before the infliximab treatment. The psychological followup was good, but the patient was unable to cope with a failed love affair. The doctor considered this suicide as unrelated to the infliximab treatment. Similarly, a 67 year old patient reported an aggravated impotence problem since the first infliximab infusions. He decide to stop the treatment, which left the effect on erectile function unclear. He had reported the same problem during methotrexate treatment, with recovery after

Overall, we did not observe any significant infection. Specifically, we did not note any opportunistic infection or any tuberculosis. There were no severe infections to justify a deferral of the infliximab infusion, and anti-infective treatment did not need to be increased

One patient suspended their treatment during cardiac surgery on the mitral valve (condition

The two cases of induced lupus were severe and required hospitalization. Remission was slow. The first patient had already been treated with infliximab, with an excellent initial clinical response but a relapse after one year. The treatment was stopped for 9 months, but the administration of adalimumab was not conclusive, and the patient wished to try infliximab again. Ten days after the first re-introduced infusion, the patient experienced joint pain and swelling, with rapidly-progressive functional disability leading to an incapacity to move, and hospitalization. The second patient, on methotrexate from the start, developed signs of articular lupus from the 9th month of infliximab treatment, with seroconversion. After the 11-month infusion, the seizure was acute, incapacitating, requiring hospitalization and the use of corticosteroids, and then even thalidomide. It was possible to

For six patients, the obligation to discontinue treatment was more acute (see table 3).

to 4, and then 3 mg/kg was suggested to them.

weight gain or loss, nor change in blood pressure.

Few adverse events were observed, but these were occasionally severe.

discontinuation. Urological examination results were normal.

**4.1 Medical follow-up** 

**4.2 Adverse events** 

in any case.

pre-existing the infliximab treatment).

discontinue the latter after six months.

An interesting observation is the difference for the long-term result between complete and partial initial responders. Among complete initial responders, half patients maintain the response, and 21% have a complete relapse. In comparison, among partial initial responders, 31% have a stable efficacy, and 50% have a complete relapse.

#### **3.6 Infliximab and methotrexate**

We commonly propose infliximab in monotherapy. It is the most common method for treating plaque psoriasis, in contrast to other indications, where combination with methotrexate is systematic. The aim is therefore both to increase treatment efficacy, and to prevent the formation of neutralizing anti-drug antibodies (Poulhalon etal., 2007). The question of more frequently combining infliximab and methotrexate in dermatology has already been raised but never resolved. In our series, 4 patients take methotrexate in parallel with infliximab; they began it after around four months on infliximab, to compensate for insufficient efficacy. 1 other patient began infliximab immediately in parallel with methotrexate.

#### **3.7 Practical attitude in case of relapse**

In case of partial relapse, after removing the aggravating factors mentioned above, we usually suggest continuing treatment, this time in combination with methotrexate. The dosage of the latter is in line with usual regulations, adapted to the patient's weight (between 55 and 135 kg, for the present four patients). The medical practice is initially to diminish the dosage relative to methotrexate taken alone, but the clinical facts then dictate the procedure to follow. Tolerance posed no particular problems for three patients. The fourth patient experiences biological perturbations in the liver, which require frequent dose reductions; gastroenterology results are reassuring and allow treatment to be continued, which is furthermore essential due to the severity of the psoriasis and its impact on the patient's life.

We did not try to combine infliximab with other treatments for psoriasis.

Another option would have been to adapt the dosage of infliximab; an increase in frequency has demonstrated success (an infusion every 6 weeks instead of every 8) (Duarte et al., 2011). In Belgium, this is impossible in common practice due to Social Security reimbursement regulations.

If relapse is complete, a combination with methotrexate is not sufficient and the continuation of infliximab is not justified. It could even be deleterious, by analogy with other observations (Korswagen et al., 2011). Among patients with relapse (complete or partial, severe and resistant), 16 were treated with ustekinumab: after a minimum of 10 months, 5 responses at 100%, 7 satisfactory responses (50-99%), and 4 failures were observed. Please note: a naive patient of biological therapy for whom infliximab has never produced a significant improvement (primary non-responder), has then responded optimally to adalimumab.

#### **4. Adaptation of dosage**

The official dosage is 5 mg/kg, every eight weeks, after the induction phase. We adapted it in 8 cases. For 3 patients, we increased the frequency of infusions to 1x/6 weeks to try and respond to the loss of efficacy observed. For two of them, response improved temporarily, however the dosage frequency would have had to be increased more, which was not possible. In contrast, for 5 patients, the dose had to be reduced; the clinical response had been complete and stable for 18 months, and these patients questioned the usefulness of continuing the treatment, at least at the initial dosage. Four patients out of the five thus continued their treatment at a reduced dose, without loss of efficacy. In practice, a reduction to 4, and then 3 mg/kg was suggested to them.
