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USE OF INFLIXIMABE IN 25 LIBYAN PSORIASIS VULGARIS PATIENS

A Altrabulsy1, A.H.Griew2, E .M Elmangoush1, G.A.Duweb1

1 Dermatology Department, 2 Family& Community Department . Faculty of medicine,

Benghazi University, Benghazi-Libya

INTRODUCTION:

Psoriasis is a distressing, chronic immune mediated, inflammatory disease that affects skin and

joints. It is characterized by infiltration of the skin by activated T cells, abnormal keratinocyte

proliferation, cytokines, chemokines, and excessive production of tumor necrosis factor (TNF) in

the psoriatic lesion(1).

Estimates of the prevalence of psoriasis vary from 2% to 3%, with rates varying between

countries and races (2). Burd 2006 has been found that, a quarter of patients develop the disease

before the age of 20 years. A further peak in incidence is recorded in the fifth and sixth decades.

The age of onset seems to be genetically determined ( 3,4 ).

Clinically have been found that, around 80% of individuals present with chronic plaque psoriasis

characterized by well demarcated, red, thickened patches of skin which become elevated and

covered with an adherent, silvery scales ( 5,6).

Erythrodermic psoriasis denotes the involvement of the entire skin surface which is rare and it

can be life threatening with a risk of sepsis and thermoregulatory disruption. Pustular psoriasis

may be localized or generalized. In the generalized variant sheets of sterile pustules are found on

a background of red skin. Fever, arthralgia and malaise are common accompaniments(7).

Psoriatic arthritis affects between 5% and 30% of psoriasis patients and can be aggressive and

deforming. Both the axial and the peripheral joints may be involved with several overlapping

patterns: asymmetric, oligoarticular disease, predominant distal arthritis characterized by

involvement of the distal interphalangeal joints, arthritis mutilans, symmetric polyarthritis

(closely resembling rheumatoid arthritis) and axial involvement/spondolarthropathy

Enthesopathy and dactylitis are characteristic features.(8, 9)

2

Infliximab belongs to the class of biological response modifiers called Tumor Necrosis Factor

(TNF-α) blockers, with human constant regions and murine variable regions. It engineered from

human and mouse antibody molecules. It works by directly binding to both trans-membrane and

soluble TNF-α molecules in the blood and diseased tissue. with high affinity, specificity, and

avidity.(10 )

Infliximab helps to control angiogenesis, a key factor in the pro-inflammatory state of psoriasis,

by down-regulating angiopoietin, a growth factor critical for new blood vessel growth, and its

receptor. Complementary to its anti-inflammatory effect that is mediated through the

neutralization of TNF-α, infliximab normalizes keratinocyte differentiation (8, 9,10).

AIM OF THE STUDY

To assess the efficacy and tolerability of infliximab monotherapy in Libyan patients with severe

psoriasis vulgaris..

SUBJECTS AND METHODS

The study group included twenty five adult patients who had sever psoriasis vulgaris involving

more than 10% of the body surface area, over one year ( December 2010 to November 2011) at

dermatology department Al-Jamhoria hospital, Benghazi-Libya. All patients had signed written,

informed consent.

Each patient was exposed to detailed medical history, clinical and laboratory assessments

including complete blood count, chemistries, urine analysis, serum for human chorionic

gonadotrophin concentration, chest x- ray, tuberculin test to exclude tuberculosis, serological

examination including HIV, HBV and HCV.

INCLUSION CRITERIA

Adult, healthy patients by investigation and clinical examination has no evidence of any chronic

illness, or infections.

Patients had severe psoriasis vulgaris more than 10% of body surface area (BSA).

EXCLUSION CRITERIA

Moderate to sever CHD.

Pre-existing CNS disorder.

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Untreated chronic infection, such as TB or hepatitis.

Elderly patients and patients with kidney or liver failure.

Pregnancy and breast feeding.

Measures of psoriasis activity (Psoriasis Area Severity Index) (PASI) , as screening baseline and

before each dose. Each patient prepared by measuring the BP and pulse and given hyrocortisone

IV, antihistamine.

Each patient received infliximab IV infusion 5mg/kg in 250 ml normal saline, slowly over hours.

The treatment doses given at 0, 2, 6 Weeks and then every 8 weeks. Patient assessment was

based on measuring PASI score and observing any side effects and repeating the investigations at

each visit.

RESULTS

All patients were assigned infliximab 5 mg/kg. Two patients withdrew during the course of the

study. One patient was withdrawn at week 2, secondary to an infusion reaction and another

patient was withdrawn 7 days after her first infusion, because of hypotension. Figure 1

We determined the disease severity by PSORIASIS AREA SEVERITY INDEX (PASI) Score.

Most patients showed good improvement at 3rd dose, total improvement occurred mainly at 5th

and 6th dose. Mean total score of base line PASI for 25 patients was (32.88±10.871.

Among 25 patients were included in this study 15 (60%) were males and 10 (40%) were females

(Fig.2). The patient´s age was ranging from 25 to 51 years, patients aged (40-44) years had the

highest frequency 35%, followed by those who aged (30-34) years representing 30% of patients

(Fig. 3). Figure 4 showed that, patients who had the disease for a duration ranged between 10- 14

years represented the highest frequency ( 30 % )

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Efficacy

Therapeutic response was evaluated in accordance with PASI. About 17 of 23 (72.2%) patients

treated with the infliximab 5 mg/kg had at least 50% improvement in the PASI score, while (16)

of (23 ) (67% ) had at least 75% improvement in PASI score and 23 patients (100%) had at least

90% improvement in the PASI score (Fig.4). The mean PASI scores at baseline for infliximab

5mg/kg was (32.8 ). At week 2 and 6, the mean PASI scores were (16.2 ), (2.2 ) respectively,

and (0.5 ), (0.1) at week 16, 24 respectively(Fig.5).

The mean percentage improvements in PASI scores were higher 92% as early as 6th week of

therapy and reached maximum improvement 100% at 32 week as compared to initial time of

treatment. (Fig.6). Photographs illustrating shows the typical degree of improvement observed

from baseline PASI (Fig.7), at week 6th (Fig.8), at week 32th (Fig.9). Improvement in nail was

observed early at 6th week ,as shown in (Fig. 10,11)

Adverse events

There were no serious adverse events. UTI was the adverse event that occurred in a higher

proportion (10%). The acute adverse effect was infusion reactions were reported in one patient

during the initial first week, and hypotension for another one which occurred at week 2 this led

to discontinuation of the drug. Infections were occurred in 2 patients (8 %) developed UTI, two

at 2nd week and week 16th also another patient at week 6th developed URTI & UTI from week

0. All delayed adverse effects were followed up and treated without the drug having to be

interrupted. ( Fig.12 ).

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Figure.1: Summary of patients in the study.

25 patients with severe

psoriasis vulgaris were

screened.

Full medical history

and laboratory

assessments

25 patients assigned infliximab

5mg/kg

2 patients were dropped out

due to severe hypotension and

urticaria.

23 patients completed the course of

infliximab.

20 patients with out

complications

3 patients with

complications

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Figure 2: Sex distribution of the patients.

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Figure 3: Patients age groups

8

Figure 4: Duration categories of psoriasis cases in years

15

5

30

15

25

10

0

5

10

15

20

25

30

35

1-4 5-9 10-14 15-19 20-24 25 and

above

%

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Figure 5: Mean total score of PASI for each dose

32.8

16.2

0 0.1 0.5

2.2

0

5

10

15

20

25

30

35

First

dose

Second

dose

Third

dose

Fourth

dose

Fifth

dose

Sixth

dose

10

Figure 6: Mean percentage of PASI improvement

54.5

92.3

45.5

98.2 99.6 100

0

20

40

60

80

100

120

Base line Second week

Tenth week Sixteenth week

Twenty fourth week

Thirty two

week

Mean %

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Figure 7 : Extensive psoriasis at base line PASI.

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Figure 8 : Much improvement in psoriatic plaques at 6th week.

Figure 9: Total clearance at 32 week.

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Figure 10: Nail involvement at baseline PASI.

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Figure 11: Total improvement in nail lesion at 32 week.

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Figure 12: Adverse effect of Infliximab among

Psoriatic patients

76%

4%

4%

12%

4%

None

Infusion reaction

(IR)

Hypotension

Urinary tract

infection (UTI)

UTI & URTI

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DISCUSSION

Psoriasis is a distressing, chronic immune mediated, inflammatory disease that affects skin and

joints. It is characterized by infiltration of the skin by activated T cells, abnormal keratinocyte

proliferation, cytokines, chemokines, and excessive production of tumor necrosis factor (TNFα)

in the psoriatic lesion( 1).

The mean age of onset was (37.7year ±6.815) ranged from 25-51year which in contrast to study

by Duarte A.A 2011 with mean age 49.2year (11). The peak age group in our study was

observed in the 40-44year age group (35%), which disagreement with Sinniah B 2010 where the

peak age group was 40-60year (17.2%) (12).

About the mean duration of the disease was (14.90year ±8.25years) ranging from 2-27year,

(30%) of patients were between 10-14year which is in contrast to study by Natarajan V 2010

where the mean duration of the disease was found to be 9.63 years ranged from 1 month -49 year

(13). Patients with psoriasis are at significant risk of developing psoriatic arthritis. The frequency

of psoriatic arthritis appears to be strongly related to the degree of skin severity. A population

based study indicated that the prevalence of psoriatic arthritis in patients with ≤ 1% body surface

area, 1-2% BSA, 3-10% BSA and 10+% BSA was 6%, 14%, 18% and 56% respectively(14). In

our study 6 patients (30%) out of 20 had joint involvement.

Regarding PASI is considered by many to be the gold standard severity assessment tool and

consists an average measure of 4 parameters; redness, thickness and scaling of lesions and extent

of disease. Each parameter is graded as 0–4 with 0 equating to no disease and 4 severe

involvement. The body is divided into 4 areas (head, arms, trunk to groin, legs to top of

buttocks). The scores are summed, a percentage of the area covered by psoriasis estimated and a

multiplier applied to each area generating a final PASI. PASI ranges from 0 to 72 with PASI >

10 recognized as indicative of severe disease (15).

A 75% reduction in PASI from baseline (PASI 75) is commonly used as an indicator of disease

response, and in most clinical trials this is the primary efficacy endpoint. For individual patients

a smaller improvement in PASI can be clinically meaningful (16). This is reflected in clinical

trials which frequently report PASI 50 rates as well as PASI 75. The mean PASI score at

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baseline was 32.8 which show marked decrease at third dose (6th week) where it became 2.2 and

reached zero at sixth dose (32nd week), the mean percentage of PASI improvement at base line

was 45.5% and had shown marked improvement at third dose (6th week) and reached total

clearance at sixth dose (32nd week), as compared our study with finding by Chaudhari 2001, the

mean PASI at base line was 17.5 with marked decrease at (2nd week) (17).

50% improvement in PASI had been observed in 6 (33.3%) patients out of 18 after first dose

and 7 patients (38.8%) were show improvement in PASI after 2nd dose .75% improvement in

PASI was observed in one patient (5.5%) after first dose, 2 patients (11.1%) at second dose, 7

patients (38.8%) at third dose and 2 (11.1%) patients at fourth dose, as compared our study with

finding by Reich et al 2005 study of 378 patients with severe psoriasis vulgaris 75%

improvement in PASI occur after 10th week in 80% of patients(18).

90% improvement in PASI was observed at 2nd week by 2 patients (11.1%), 11 patients (61.1%)

at 6th week, 16 patients (88.8%) at week 16th and at 24th week all patients had 90%

improvement, as compared this finding with Reich et al 90% improvement occur in 57% of

patients (18).

Infliximab had been generally well tolerated and available for clinical use in adult. The acute

adverse effect was infusion reactions were reported in 1 (5%) of patients during the initial first

week of treatment and hypotension in one patient (5%), this lead to discontinuation of the drug

,as compared our study with Kipnis et al infusion reaction were reported in 20% of patients

receiving infliximab(19). UTI was the adverse event that occurred in a higher proportion (10%),

two at 2nd week and week 16th also another patient at week 6th developed URTI & UTI . All

delayed adverse effects were followed up and treated without the drug having to be interrupted.

CONCLUSION & RECOMMENDATION

Infliximab was found to be safe and effective for treatment of sever psoriasis vulgaris.

Infliximab has a rapid induction phase and 75% improvement was reported after 3rd dose (6

weeks ) in majority of the studied cases. Additional effect was observed, early improvement in

psoriatic arthritis and nail changes improvements including complete regrowth of destructed

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nails and return to normal. Mild adverse effects including hypotension, urticarial rash and

urinary tract infection has been reported and no serious side effects.

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