Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study

THERAPEUTICS DOI 10.1111/j .1365-2133.2006.07316.x

Infliximab for severe, treatment-resistant psoriasis:a prospective, open-label studyC.H. Smith, K. Jackson, S.J. Bashir, A. Perez, A.L. Chew, A.M. Powell, M. Wain and J.N.W.N. Barker

Skin Therapy Research Unit, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, U.K.

CorrespondenceCatherine Smith.

E-mail: [email protected];

[email protected]

Accepted for publication15 December 2005

Key wordsbiologics, infliximab, psoriasis

Conflicts of interestJNWN is a consultant for Centor and Schering

Plough.

Summary

Background Infliximab, a mouse–human chimeric monoclonal antibody directedagainst tumour necrosis factor-a, has been shown to be effective for moderate tosevere psoriasis, but there are few data published on its use in recalcitrant, treat-ment-resistant disease or in combination with other antipsoriatic therapies.Objectives To report our experience with infliximab in the treatment of patientsattending a tertiary referral service with severe recalcitrant disease.Methods All patients attending a tertiary referral service for severe psoriasis whowere treated with infliximab between 2002 and July 2005 were entered into aprospective, open-label study. Details on disease phenotype, clinical course andadverse events were recorded together with measures of disease severity [Psori-asis Area and Severity Index (PASI), Dermatology Life Quality Index, clinical pho-tography] at baseline, weeks 2 and 6, and then at 2-monthly intervalsthroughout the treatment period.Results Twenty-three patients were treated with infliximab during the study; onepatient had pustular psoriasis and was therefore excluded from statistical analysis.All had severe disease (baseline PASI 26Æ5 ± 6Æ7, mean ± SD, n ¼ 22) and hadreceived at least two systemic therapies for psoriasis in the past; 16 were takingone or more concomitant therapies at the time of treatment initiation. At week10, 95% had achieved a 50% or greater improvement in baseline PASI (PASI50), and 77% had achieved a 75% or greater improvement (PASI 75). Efficacywas sustained in the longer term, with eight of 10 patients on treatment formore than 11 months maintaining at least a PASI 50. Only one patient had treat-ment withdrawn due to lack of efficacy, two suffered severe systemic infectionsincluding extrapulmonary tuberculosis (splenic abscess) and cellulitis, and sixhave discontinued due to adverse effects including infusion reactions (two),severe thrombocytopenia (one), hepatitis (one) and malignancy (two).Conclusions Data from this open-label study suggest that infliximab is a rapidlyeffective treatment for patients with severe, treatment-resistant disease, althoughapproximately 25% of patients had to discontinue therapy due to the develop-ment of serious adverse effects. Long-term follow-up, continued pharmacovigi-lance, and further controlled comparative studies will be required to evaluatefully the risks associated with infliximab in the context of this already difficult totreat population.

Patients with severe psoriasis constitute approximately 20–

30% of all patients with psoriasis, and represent a major

economic burden to the health service.1 Standard systemic

therapies are associated with a risk of toxicity with long-term

use, many are relatively expensive, and a proportion of

patients is resistant to treatment.1 Widespread dissatisfaction

among patients with commonly used therapies also

contributes to the already substantial morbidity and impaired

quality of life associated with severe disease.2–6

Infliximab (Remicade�; Schering-Plough, Welwyn Garden

City, Herts, U.K.) is a mouse–human chimeric IgG1 mono-

clonal antibody that has high specificity, affinity and avidity

for tumour necrosis factor (TNF)-a. It binds both soluble and

transmembrane TNF-a and inhibits TNF-a from binding to

160 � 2006 British Association of Dermatologists • British Journal of Dermatology 2006 155, pp160–169

the p55 and p75 receptors. Two randomized, placebo-

controlled trials7,8 have shown infliximab to be highly effect-

ive in the treatment of stable, moderate to severe chronic

plaque psoriasis with 90% of patients becoming clear, or min-

imally affected at 10 weeks following a standard induction

course of therapy. The larger of these two studies included

patients who had received at least one systemic therapy prior

to study entry.8 However, relatively little is known about the

efficacy or safety of infliximab in the long term, in recalcitrant

disease or in combination with other immunosuppressant

therapies. We report our experience with infliximab in the

treatment of patients attending a tertiary referral service with

severe recalcitrant disease.

Patients and methods

Patient selection

Patients attending the Special Psoriasis Clinic at St John’s Insti-

tute of Dermatology were considered for treatment with in-

fliximab in the following clinical situations: those who had

developed, or were at significant risk of developing, clinically

important drug-related toxicity and where no alternatives

existed; those intolerant of or unresponsive to available systemic

treatments; those requiring repeated inpatient management and

those with significant, coexistent, unrelated comorbidity which

precluded use of alternative systemic agents (including ciclo-

sporin, methotrexate, fumaric acid esters, hydroxycarbamide).

Funding was applied for on an individual basis to relevant pri-

mary care trusts, and where successful, treatment initiated either

in our daycare intravenous (IV) suite, or as inpatients.

Pretreatment assessment

All patients underwent a full history with particular reference to

infection (including risk factors for tuberculosis), demyelinating

disease, cardiac disease or malignancy. Clinical examination

included verification of bacille Calmette-Guerin (BCG) scar in

those vaccinated, and assessments of disease severity and quality

of life (see below). Baseline investigations were performed as

follows: full blood count (FBC), renal and liver function,

C-reactive protein, erythrocyte sedimentation rate, antinuclear

antibodies (ANA), and specific screening for hepatitis B and

human immunodeficiency virus infection in those identified to

be at risk; clinical photography; chest X-ray (CXR).

Intervention

Following informed, written consent, infliximab (Remi-

cade�) 5 mg kg)1 was given by IV infusion over 2 h ini-

tially at weeks 0, 2 and 6. Patients were monitored for 2 h

postinfusion and then allowed home. A maintenance dose

was subsequently given at 8–10, week intervals, and varied

between 3 and 5 mg kg)1 depending on individual response

to treatment. In view of the severity of disease in this

patient cohort, any concomitant systemic therapies were

continued until adequate disease control was achieved and

then reduced or stopped over subsequent months as clinic-

ally indicated.

All patients fulfilling the treatment criteria outlined above

who received at least one infusion are included in the analysis.

Monitoring

Clinical assessments

Prior to each infusion, patients were reviewed by both a der-

matology nurse specialist and a dermatologist. Disease severity

assessments comprised Psoriasis Area and Severity Index (PASI)

(or physicians’ global evaluation score where the PASI could

not be used, i.e. in pustular psoriasis) and Dermatology Life

Quality Index (DLQI) and were completed at baseline, and at

weeks 2 and 6 and subsequently 2-monthly intervals, prior to

each further infusion. Clinical photography was performed at

baseline, week 6 and then at 2-monthly intervals.

Laboratory investigations

Monitoring investigations (FBC, renal and liver profiles, ANA)

were repeated at approximately 2-monthly intervals, prior to

infliximab infusions, together with additional investigations as

clinically indicated.

Statistical analysis

Statistical comparisons were performed with the paired t-test

using SigmaStat (SPSS, Inc., Chicago, IL, U.S.A.). Pearson’s

coefficient of correlation was performed to determine the rela-

tionship between DLQI and PASI.

Results

Patients

Since 2002, 23 patients have been treated with infliximab

therapy: 18 men, five women; age 43Æ4 ± 11Æ9 (mean ± SD)

years. All had recalcitrant disease and had received therapy

with at least two systemic therapies prior to treatment with

infliximab (Table 1). Twenty-two of the 23 patients treated

had chronic plaque psoriasis. The disease course was compli-

cated by repeated episodes of erythroderma in five patients,

and generalized pustular psoriasis during pregnancy in one.

One patient had generalized pustular psoriasis only. Associated

significant psoriatic arthritis requiring specific rheumatological

input was present in eight.

Efficacy

Of 23 patients treated, 16 remain on therapy to date (July

2005) with satisfactory disease control (Fig. 1). Only one

patient has had treatment withdrawn due to lack of efficacy

and six have been discontinued due to adverse effects.

� 2006 British Association of Dermatologists • British Journal of Dermatology 2006 155, pp160–169

Infliximab for severe, treatment-resistant psoriasis, C.H. Smith et al. 161

Short-term efficacy

Of the 23 patients initiated on therapy, one patient had gener-

alized pustular psoriasis and is therefore not included in the

analysis that follows. Of the remaining 22, at 6 weeks (i.e.

just prior to the third infusion), 90% had achieved a 50%

improvement in baseline PASI (PASI 50) and 32% a 75%

improvement in baseline PASI (PASI 75); at week 10, 95%

had achieved PASI 50 and 77% PASI 75. The PASI fell from

26Æ5 ± 6Æ7 (mean ± SD) at baseline, to 3Æ9 ± 3Æ7 at week 10

(P < 0Æ001) (Fig. 1).

Long-term efficacy

Ten patients have completed treatment for 11 months or more

(Fig. 3); eight of these continue on therapy maintaining at least

PASI 50 throughout, and four, a PASI 75. For the remaining two

patients, one (patient 4, Fig. 3) had excellent disease control

Table 1 Summary of previous treatments used in patients entered into study. Experimental therapy includes clinical trials, most recently thoseevaluating alefacept

Patient

no.

Age(years)/

sex Arthritis

Inpatient

treatment PUVA Ciclosporin Methotrexate Acitretin

Hydroxy-

carbamide

Mycophenolate

mofetil

Fumaric

acid esters

Combination

treatment Experimental

1 48/M d d d d d d d d

2 19/M d d d d d d


4 46/M d d d d d d d d d d d


6 37/M d d d d d

7 38/M d d d

8 28/M d d d d d d

9 39/M d d d d

10 51/F d d d d d d d d

11 45/M d d d d d d d d

12 33/M d d d d d d d d

13 59/M d d d d d d d

14 46/M d d d d d d d

15 48/M d d d d d d d

16 39/M d d d d d d

17 24/M d d d d d d

18 56/M d d d d d d d

19 48/M d d d d d d d d d

20 71/M d d d d

21 44/M d d d d d d

22 43/F d d d d d d

23 38/F d d d d d

PUVA, psoralen plus ultraviolet A.

0

5

10

15

20

25

30

35

40

45

Baseline Week 2 Week 6 3 m 5 m 7 m 9 m 11 m 13 m 15 m 17 m 19 m 21 m

21 19 14 12 10 9 7 34Time

Fig 1. Psoriasis Area and Severity Index (PASI)

and Dermatology Life Quality Index (DLQI)

scores during infliximab therapy. Blue bars

denote PASI scores, and purple bars, DLQI.

Mean values shown at baseline (week 0) and

up to 21 months post-first infusion. Error bars

denote SD. Numbers of patients reduce with

time due to variable length of follow-up

(shown beneath arrows).


162 Infliximab for severe, treatment-resistant psoriasis, C.H. Smith et al.

(PASI 75 response) for 13 months, but subsequently his psori-

asis deteriorated despite subsequent infusions and treatment was

withdrawn. He was then established on etanercept 50 mg twice

weekly and has completed 12 months of therapy with excellent

disease control. The second patient initially responded well to

therapy but at month 6, infliximab infusions became less effect-

ive and the PASI scores reverted to his preinfusion level (patient

1, Fig. 3). However, treatment has been maintained as it has

afforded disease stability, and the patient has required inpatient

admission on only one occasion. This contrasts with the clinical

situation prior to infliximab where he had required inpatient

management for severe, unstable disease four to six times per

year. Overall, the mean ± SD 11-month PASI was 8Æ2 ± 8Æ4,significantly lower than baseline (P < 0Æ001).

Quality of life

Objective measures of improvement in disease severity were

accompanied by improvements in patient-assessed quality of

life. DLQI scores fell from 14Æ9 ± 6Æ7 (mean ± SD) at base-

line, to 3Æ4 ± 3Æ4 at week 10 (mean ± SD, P < 0Æ001,Fig. 1). This improvement was sustained for most patients

throughout the treatment period with a mean DLQI of

4Æ3 ± 5Æ2 for those patients who had received 11 months

or more of treatment (P < 0Æ001). A strong correlation was

identified over time between DLQI and PASI (R2 ¼ 0Æ81)(Fig. 4). The inconvenience of attending for IV infusions

was outweighed by the benefits of better disease control

for the majority, although the postinfusion 2-h observation

period became burdensome for some with long-term

therapy.

Experience in generalized pustular psoriasis

This patient was a 38-year-old woman with a history of

pustular psoriasis since the age of 10 years. Initially, this

was confined to the palms and soles, but became more

generalized and was resistant to phototherapy and

Fig 2. Patient 2 at baseline (left) and

following 5 months’ treatment with

infliximab.

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

Case 8

Case 9

Case 10

0

5

10

15

20

25

30

35

40

45

Baseline Week 2 Week 6 3 m 5 m 7 m 9 m 11 m 13 m 15 m 17 m 19 m 21 m

Fig 3. Psoriasis Area and Severity Index

scores for patients treated with infliximab for

11 months or more (n ¼ 10).



combined systemic immunosuppression with ciclosporin

200 mg daily and methotrexate 30 mg weekly. An immedi-

ate improvement in her skin and quality of life was noted

following infliximab 5 mg kg)1 and her concomitant ci-

closporin was stopped (pretreatment DLQI ¼ 28, 10-week

DLQI ¼ 1, 12-month DLQI ¼ 1). Progressively, the metho-

trexate was reduced to 10 mg weekly and infliximab

reduced to 3 mg kg)1 by 12 months of treatment. At 24-

month follow-up, she had minimal disease, with a DLQI

of 6Æ0.

Nail disease

Efficacy of infliximab with respect to nail disease was not sys-

tematically assessed, but marked improvement was noted in

many patients (Fig. 5a,b).

Concomitant therapy

At initiation of infliximab, 16 patients were taking at least

one concomitant therapy, and five patients, two additional

therapies (Table 2). All patients were able either to stop or to

reduce the dose of concomitant treatment.

Treatment discontinuation and toxicity

Six patients have discontinued treatment due to adverse events

(Table 3).

Infusion reactions

In total, 171 infusions have been given to 23 patients over the

last 3 years and in general, treatment has been well tolerated.

0

2

4

6

8

10

12

14

16

18

0 5 10 15 20 25 30PASI

DL

QI

Fig 4. Mean Dermatology Life Quality Index

(DLQI) plotted against mean Psoriasis Area

and Severity Index (PASI) for all patients at all

time points, with a ‘best fit’ line. There was a

strong correlation demonstrated between

DLQI and PASI (Pearson’s correlation

coefficient R2 ¼ 0Æ81).

a

b

Fig 5. (a) Nails (patient 5) at baseline (left) and following 2 months’ treatment with infliximab. (b) Nails (patient 3) at baseline (left) and

following 7 months’ treatment with infliximab.



Clinically significant infusion reactions occurred in two patients

(patients 20 and 22). Both occurred within 15 min of the sec-

ond and fifth infusions, respectively, and were characterized by

abdominal pain, vomiting and high temperature. Symptomatic

treatment with antihistamines (chlorpheniramine IV), and also

hydrocortisone (IV 100 mg) in the second patient, led to com-

plete resolution of all symptoms by the following morning.

Infliximab therapy was discontinued, and both patients have

been successfully established on etanercept and adalimumab,

respectively, for over a year with no evidence of local injection

site reactions or other allergic phenomena.

Autoantibody formation

Of 22 patients who were ANA-negative prior to treatment, six

have become positive, with variable titres. A further patient

noted to have weakly positive ANA titres prior to therapy has

now completed 12 months of treatment and has developed

significant titres (IgM 1 : 320; IgG 1 : 320) and additional

positive antibodies to double-stranded DNA. However, with

the exception of one patient who developed an autoimmune

hepatitis (see below), no patients have any symptoms or signs

suggestive of lupus and treatment has been continued.

Infections

Ten episodes of infection were recorded in seven patients.

Two of these were classed as severe (i.e. requiring hospital

admission) and comprised a lower leg cellulitis (patient 20)

and tuberculous abscess (patient 16). None led directly to per-

manent treatment discontinuation, although treatment had

already been discontinued in the patient with tuberculosis due

to earlier development of severe thrombocytopenia (see under

Haematological toxicity below).

Upper respiratory tract infections occurred seven times in

four patients. No abnormalities were detected on physical

examination or investigation, although infliximab infusions

were delayed on four occasions until symptoms resolved.

Lower leg cellulitis complicated the treatment course of one

elderly patient (patient 20) on monotherapy. Onset occurred

1 week following his second infusion and eventually required

2 weeks of inpatient management. Relevant comorbidity com-

prised long-standing leg varicosities and ulceration, hyper-

splenism with associated leucopenia, anaemia and

thrombocytopenia, and liver cirrhosis secondary to methotrex-

ate.

One patient developed a furuncle of the eyelid which

resolved with topical antibiotics.

Tuberculous infection

One patient (39-year-old Indian man, patient 16) developed a

tuberculous splenic abscess. Prior to (and at initiation of)

treatment with infliximab, he had been on a combination of

methotrexate (10 mg weekly) and mycophenolate mofetil

(2 g daily) for at least 3 years. His baseline CXR was normal,

and he had a visible BCG scar but did travel frequently to

India. Following three infusions of infliximab his psoriasis

cleared but he was admitted to a local hospital with epistaxis

and a swinging fever 3 weeks after his third infusion. Investi-

gations revealed a profound thrombocytopenia (platelet count

3 · 10)6 L)1) which resolved within 1 month of treatment

Table 2 Number of patients on concomitant therapy prior to andfollowing infliximab

Concomitant therapyAt

initiation StoppedDose

reducedDose

maintained

Ciclosporin 5 5 (–) (–)

Methotrexate 12 0 7 5Tacrolimus 1 1 (–) (–)

Acitretin 1 (–) 1 (–)Mycophenolate mofetil 1 1 (–) (–)

Fumaric acid esters 1 1 (–) (–)Totala 16 8 8 5

aPatients on more than one therapy counted only once.

Table 3 Summary of treatmentdiscontinuations and outcome

Reason for discontinuationDuration of treatment(number of infusions)

Current psoriasis disease statusand treatment

Inefficacy 11 Almost clear on etanercept

Adverse eventsInfusion reaction 2 Almost clear on etanercept

Infusion reaction 5 Significant but stable disease onadalimumab

Hepatitis (resolved) 4 Almost clear on etanerceptThrombocytopenia (resolved) 3 Significant but stable disease

on topical treatment andmethotrexate

CD30+ CTCL (ongoing) 3 Stable on etanercept andmethotrexate

Renal cell carcinoma 5 Deceased

CTCL, cutaneous T-cell lymphoma.



with pooled IV immunoglobulin. Infliximab was permanently

discontinued due to the temporal relationship with the onset

of the thrombocytopenia (see below). Despite extensive inves-

tigation, no source of infection was identified to account for

the fever which appeared to improve with time while an inpa-

tient, and his psoriasis was managed conservatively. Six

months later he was admitted to our unit, with a history of

increasing malaise, joint pains and fever. Investigations

revealed a normal CXR and echocardiogram, but supraclavicu-

lar, mediastinal and hilar lymphadenopathy on computed

tomography (CT) scan. Mycobacterium tuberculosis was subse-

quently isolated from pus aspirated from a large splenic

abscess demonstrated on abdominal ultrasound. The patient

has just completed 6 months of quadruple therapy, and has

remained on methotrexate 10 mg weekly throughout.

Liver toxicity

Significant elevations (i.e. twice greater than upper limit of

normal) in liver function tests were seen in four patients and

led to treatment discontinuation in one (patient 21). Pretreat-

ment liver morbidity was present in all and followed either

long-term methotrexate and/or alcohol excess [fatty liver only

(two), Roenigk9 stage 2 hepatitic fibrosis (one) and cirrhosis

(one)]. In the patient in whom treatment with infliximab had

to be discontinued, liver function tests prior to therapy were

normal, although he was known to have fatty liver secondary

to methotrexate and alcohol. Following his fourth infusion he

developed raised liver enzymes (maximum levels: alanine ami-

notransferase 650 uL)1; aspartate aminotransferase 370 uL)1)

which settled within 2 months of stopping treatment. His

autoantibody profile was consistent with an autoimmune

hepatitis caused by infliximab (ANA IgG 1 : 80; IgM

1 : 1280; diffuse pattern; DNA binding antibody 51%, anti-

smooth muscle antibody-positive). Subsequent treatment with

etanercept has been well tolerated, and liver function tests

have remained normal.

Haematological toxicity

A profound, isolated, thrombocytopenia developed in one

patient (patient 16) following three infusions of infliximab,

which was presumed to be drug related. No information is

available as to whether this episode was associated with platelet

autoantibodies and there has been no recurrence since. Other-

wise, infliximab therapy was not associated with significant,

persistent haematological abnormalities, despite significant

concomitant immunosuppressive therapy in many patients.

Cardiac toxicity

Persistent hypertension developed in one patient with no spe-

cific risk factors following induction therapy and has required

treatment. Atrial fibrilliation, evidence of left atrial dilatation

and moderate left ventricular dysfunction on echocardiogram

was noted in a 44-year-old man (patient 21) 3 months after

discontinuing infliximab (due to the development of hepati-

tis). The causal relationship with infliximab is unclear, given

the time lapse, and known pretreatment risk factors including

alcohol intake and moderate obesity.

Mild chronic heart failure (NYHA Class II) noted in one

patient prior to therapy showed no evidence of deterioration

during the subsequent 2 years of infliximab treatment.

Malignancies

Skin cancer

Two lentigo malignas (face and chest) and a superficial basal

cell carcinoma (trunk) have all occurred in a single patient

following 6 months of infliximab treatment on a background

of prolonged treatment with ciclosporin and psoralen plus

ultraviolet A, a prior history of a facial lentigo maligna (com-

pletely excised) and multiple nonmelanoma skin cancers. The

infliximab has been continued, as it has afforded better disease

control and enabled cessation of ciclosporin. Acitretin has

been continued for skin cancer prophylaxis. A second patient

with a similar pretreatment history has not developed any fur-

ther skin cancers.

Other malignancies

Metastatic renal cell carcinoma presented in a 48-year-old man

(patient 19) following five infusions of infliximab. He had

previously received varying combinations of immunosuppres-

sant therapy over the previous 10 years including ciclosporin

and methotrexate for the majority of that time. A focus of

increased density noted posteriorly within the seventh left rib

on his baseline CXR was presumed to be benign following a

thoracic CT scan which reported a ‘probably benign’ 2-mm

pleural tumour that was too small to biopsy. However, by the

fifth infusion (i.e. approximately 5 months after initiating

therapy), he developed persistent nausea and progressive

weight loss; clinical examination revealed a supraclavicular

node and a palpable right kidney. Bilateral pleural plaques evi-

dent on CXR were subsequently biopsied and suggested the

diagnosis of a papillary cell carcinoma. A final diagnosis of

papillary renal cell carcinoma type 2, stage pT3b pN1 pM1

was made following a right nephrectomy (right renal tumour,

lung metastases, paraortic lymphadenopathy and invasion of

the inferior vena cava). He died 12 months later following

treatment with a-interferon and palliative care.

CD30+ lymphoproliferative disease was identified in one

patient (patient 18). This 56-year-old man with a 30-year

history of chronic plaque psoriasis had previously received

multiple immunosuppressive therapies (see Table 1). At the

point of treatment initiation, he had not received ciclosporin

for 13 months, alefacept for 10 months, methotrexate for

9 months or fumaric acid esters for 4 months. After three

infusions of infliximab 5 mg kg)1, a solitary nodule devel-

oped on his back. An initial diagnosis of CD30+ cutane-

ous anaplastic large cell lymphoma was made based on the



histological and immunocytochemical findings (i.e. a promin-

ent dermal infiltrate of medium- to large-sized lymphoid cells

with pleomorphism; diffuse positive immunocytochemical

staining for CD30, CD2 and CD4 and focal positive staining

for CD5 and CD7; anaplastic lymphoma kinase-1 and epithelial

membrane antigen were negative). There was no lymphadeno-

pathy and staging investigations were negative. Blood investi-

gations demonstrated normal lymphocyte subsets and normal

CD4 : CD8 ratio. Although IgG antibodies for Epstein–Barr

virus were positive, IgM antibodies were not detected, exclu-

ding recent infection. Human T-lymphotrophic virus antibod-

ies I and II were negative. T-cell receptor gene analysis on

tissue was equivocal for a clone using V gamma II consensus

primer and no clone was seen in blood. Approximately

6 weeks after the appearance of the original lesion, the patient

developed other similar papules on the chest, limbs, back and

neck. Histology from these lesions was more consistent with

lymphomatoid papulosis than with CD30+ anaplastic large cell

lymphoma. No further infusions of infliximab were given and

he was commenced on etanercept 25 mg subcutaneously

twice weekly to control the psoriasis and methotrexate

10 mg weekly to control the CD30+ lymphoproliferative dis-

ease. The patient remains well controlled 15 months after

diagnosis with occasional self-resolving papules and no sys-

temic manifestation of lymphoma.

Discussion

Patients with severe psoriasis can present major therapeutic

challenges and dilemmas. While standard systemic therapy is,

for the most part, effective in the short term, predictable tox-

icity and/or gradual decline in efficacy may complicate long-

term use. Rotating or combining different treatment modali-

ties mitigates against these problems, but for a significant

group of patients with severe disease adequate disease control

is impossible or achieved only with actual, or high risk of,

drug toxicity and consequent morbidity. Our experience with

infliximab suggests that this agent represents a major thera-

peutic advance for this group of patients in spite of the cost

and logistics of administration. The risk of adverse effects is

nevertheless significant as 25% of our patient cohort discon-

tinued therapy due to serious side-effects. Careful patient

selection, pretreatment assessment and monitoring during and

after completion of therapy remain essential.

In this report, we have shown infliximab to be rapidly

effective with the onset of improvement being evident after

the first or second infusion and over 75% of patients achiev-

ing a 75% improvement in PASI score at week 10. This level

of efficacy is comparable with that reported in the three rand-

omized, placebo-controlled trials examining efficacy of inflix-

imab in moderate to severe, stable chronic plaque psoriasis

published to date.7,8,10 Our patient cohort probably represents

a more severely affected, treatment-resistant group as evi-

denced by higher mean scores on measures of disease severity

(PASI and DLQI), multiplicity of previous therapies and the

fact that most patients were on concomitant therapy at the

initiation of infliximab. This response to therapy was main-

tained over time, with marked improvements in patients’

quality of life, avoidance of hospital inpatient management,

and reduction or cessation of other immunosuppressive ther-

apies.

Our patients received maintenance rather than episodic

therapy (i.e. retreatment on disease flare). This decision was

based partly on our own early observations11 and also data

from one study in psoriasis,12 suggesting that once significant

disease relapse has occurred, repeat infusions do not achieve

the same rate of disease clearance as that seen on initial induc-

tion. This possibility is further supported by findings in

Crohn’s disease, where the risk of developing treatment resist-

ance to infliximab is reduced with maintenance (rather than

as required) infusions.13,14 Nevertheless, the dramatic reduc-

tion in PASI scores we observed during the ‘induction’ phase

of therapy was not necessarily maintained with subsequent

infusions in all patients. Even allowing for the fact that mul-

tiple additional variables might have impacted on disease

activity aside from infliximab, particularly reduction in con-

comitant therapy, there is a suggestion that with time, in

some patients, there is a gradual loss of efficacy, particularly

in those continuing therapy for longer than a year. Data from

one other case series in recalcitrant disease15 suggested loss of

efficacy over time in selected patients although in that instance

treatment was given as required rather than regularly. A recent

phase III study investigating efficacy of infliximab in 378

patients with moderate to severe psoriasis over 50 weeks also

showed loss of efficacy in a small proportion of patients over

time.10 The mechanism underlying this observation is not

clear although maintenance of therapeutic response appeared

to correlate with achievement of stable serum infliximab lev-

els, and was more common in patients who were antibody-

negative for antibodies to inflixmab compared with those who

were antibody-positive.10 Notably, loss of response to inflix-

imab in our patient cohort did not preclude a response to

other anti-TNF agents, supporting a highly specific (i.e. im-

munologically mediated) mechanism.

The benefit of infliximab in combination with other agents

in psoriasis is not established, and all the trials to date have

used infliximab alone. In rheumatoid arthritis, the addition of

methotrexate appears to confer both therapeutic and safety

benefits, whereas this is not the case in Crohn’s disease, where

infliximab is routinely used as monotherapy. However, in

clinical practice, as evidenced in our case series, concomitant

therapy may need to be continued to avoid unacceptable

deterioration in quality of life and/or a potentially dangerous

flare in disease activity while waiting for the therapeutic

effects of infliximab. Wherever possible, concomitant therapy

was rationalized prior to inflximab treatment, and agents of

questionable or minimal benefit stopped. Once disease control

was achieved, doses of concomitant therapy were reduced or

stopped over relatively short periods of time and with no con-

sequent destabilizing of disease. There was no evidence of sig-

nificant, specific drug-related toxicity developing with the co-

administration of infliximab, although the additional burden



of ‘generic’ immunosuppression may have contributed to the

observed infections and possibly onset or dissemination of

malignancy.

The pattern and frequency of adverse events in our popula-

tion is similar to that reported in the literature. In approxi-

mately 25% of our patients, these led to treatment cessation.

This is a higher proportion than that reported in formal clin-

ical trials of infliximab in psoriasis and probably reflects the

longer-term follow-up, disease severity of our patient cohort,

comorbidity and burden of previous treatments.

ANA and, less commonly, antidouble-stranded DNA, are

known to develop in some patients during therapy but, as we also

observed, do not seem to be associated with symptoms or signs

of lupus in the majority8,10 and rates are lower in psoriasis than

in rheumatoid arthritis and Crohn’s disease.

Data from clinical trials in all diseases indicate that although

infections are common, overall the rates of infection associ-

ated with infliximab are no greater than with placebo.

However, tuberculosis is known to be particularly associated

with anti-TNF agents as TNF-a plays a key role in host defence

against mycobacterial infection, particularly in granuloma for-

mation (and hence containment of Mycobacterium) and inhibition

of bacterial dissemination.16 A postmarketing surveillance report

in 200117,18 identified 70 cases of tuberculosis after treatment

with infliximab for rheumatoid arthritis, other forms of arthritis

and Crohn’s disease of a total estimated 147 000 people treated.

Based on this report, the risk of tuberculosis with infliximab has

been estimated to be approximately six times that of untreated

patients. Our case study illustrates several of the features com-

mon to tuberculosis infection in association with anti-TNF

agents in that onset of infection tends to occur early in treat-

ment, most patients are also receiving one or more immuno-

suppressive agents, and extrapulmonary disease is common.

Atypical and extensive infection is thought to account for the

high morbidity associated with infliximab-associated tuberculo-

sis, and underlines the need to maintain a high index of suspi-

cion in all patients during and after therapy. Guidelines issued

recently by the British Thoracic Society19 aim to identify those

particularly at risk of latent tuberculosis and would have identi-

fied our patient as ‘high risk’ in view of his ethnicity and

frequent travel to India.

Other serious infections reported in association with anti-

TNF therapy include sepsis secondary to Listeria monocytogenes

and histoplasmosis.20–23 The vast majority of these cases have

occurred in association with infliximab treatment, and in most

instances, additional immunosuppressant therapy.

With the exception of the single case of hepatitis which

appeared to be clearly and specifically related to the infliximab,

hepatic toxicity was not a clinically significant problem in our

series despite pre-existing liver pathology in some patients.

Although elevations in liver function tests have been reported

only infrequently in clinical trials, one case series recorded

transaminitis (defined as 1Æ5 · upper limit of normal) in six of

16 patients treated with infliximab for recalcitrant refractory

arthritis that necessitated treatment cessation in three.

Long-term toxicity of infliximab is largely unknown and

legitimate concern exists particularly about risks of malig-

nancy. Five cases of cancer occurred in our series. The role of

infliximab in the patient with renal cell carcinoma is unclear,

although it may have contributed to the rapid dissemination

of malignancy. Risks of skin cancer and lymphoma are already

elevated in patients with psoriasis,24–27 particularly in severe

disease although the relative contribution of antipsoriatic

(often immunosuppressive) therapy to this risk is not known.

Actual and relative risks associated with infliximab, including

intermittent vs. continuous therapy, and biological therapies as

a whole, especially in the context of this already very difficult

to treat population, will become evident only with careful,

long-term follow-up and continued pharmacovigilance. Cen-

tral registration of all patients receiving infliximab (and other

therapies of the same class) should facilitate this process.

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Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study

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