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Efficacy and safety of leflunomide in psoriatic arthritis.

Byline: ATM Asaduzzaman Akramullah Sikder Md. Mostaque Mahmud Harashit Kumar Paul and Md. Nazrul Islam

Abstract

Objective To compare the effectiveness and safety of leflunomide with methotrexate (MTX) in the treatment of psoriatic arthritis.

Methods An open randomized clinical trial was conducted in 32 patients of psoriatic arthritis at the department of Dermatology and Venereology and Rheumatology wing of Bangabandhu Sheikh Mujib Medical University Dhaka Bangladesh from June 2002 to December 2003. 17 patients of leflunomide group were treated with oral leflunomide l00 mg for first three days followed by 20 mg daily. 15 patients of MTX group were treated with methotrexate 10 mg weekly. Both groups were allowed to take ibuprofen maximum 1400 mg daily. For both groups hematological and biochemical tests were done at baseline and at every follow-up. All patients were assessed clinically for articular features psoriasis area and severity index (PASI) for effectiveness and for side effects of drugs was listed for safety measure.

Results Sixteen patients of leflunomide group and 14 of MTX group completed 24 weeks follow- up. Male: female ratio was 14:2 in leflunomide and 13:1 in MTX group. Significant improvement was observed in tender joint count swollen joint count joint tenderness index NSAIDs score and PASI score in both groups. Adverse effects in both groups were tolerable and did not require any withdrawal or dose reduction. Asthenia alopecia nausea and vomiting were common side effects noticed by patients but overall there was no significant difference in between two groups.

Conclusion Leflunomide appears to be as effective and safe as methotrexate in psoriatic arthritis.

Key words

Psoriasis psoriatic arthritis leflunomide methotrexate.

Introduction

Psoriatic arthritis (PsA) is a potentially disabling inflammatory condition that affects 5-30% of patients with psoriasis.1 It is associated with significant disability increased mortality and reduced quality of life.2 Pathophysiologically PsA is characterized by the presence of activated T cells particularly in joint fluids and synovial tissues. T cell activation has also been implicated in psoriasis and rheumatoid arthritis (RA) suggesting a common pathway linking these disorders.34 Effective treatment options for patients with PsA survey found that 25% of patients are dissatisfied with the treatment they receive for PsA.4 A number of disease modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis have been employed for PsA. Methotrexate (MTX) sulfasalazine cyclosporin intramuscular gold and few other DMADRs were tried for PsA with variable outcome and tolerability.5 High-dose parenteral MTX (1-3 mg/kg every 10 days) and sulfasalazine were found to be more effective than placebo.

Recently biologics are the main option of treatment in developed world. Infliximab and etanercept tumor necrosis factor (TNF) inhibitors have demonstrated significant efficacy in the treatment of PsA and psoriasis.78

Another biologic agent alefacept a lymphocyte function-associated antigen 3 fusion protein that blocks T cell activation is available for the treatment of psoriasis and may also be useful in PsA.

Leflunomide is a DMARD that inhibits de novo pyrimidine synthesis. Because activated lymphocytes require a large pyrimidine pool leflunomide preferentially inhibits T cell activation and proliferation and thus has the potential to address underlying pathophysiologic events in RA PsA and psoriasis.10 Leflunomide has been approved for the treatment of RA in the US countries of the European Union and numerous other countries for several years. In patients with RA controlled clinical trials have demonstrated that leflunomide reduces symptoms and radiographic progression.11

Follow-up studies indicate that safety and efficacy have been maintained for up to 5 years.

In developing countries like Bangladesh majority of the people are of poor socioeconomic condition. Available effective and cheap agents are essential for managing our patients. Both leflunomide and MTX are such agents. Leflunomide can be an effective alternative in the management of active psoriasis and psoriatic arthritis patients. To our knowledge no such study was undertaken to see the efficacy and safety of leflunomide compared with MTX in our active psoriasis and psoriatic arthritis patients.

Methods

This open randomized clinical trial was carried out with 32 cases of psoriatic arthritis at the Department of Dermatology and Venereology and Rheumatology wing of Bangabandhu Sheikh Mujib Medical University Dhaka Bangladesh from June 2002 to December 2003. Randomization was done with using a random number table. Sample size was calculated with the following formula n=Z PQ/d . Out of them 17 were in the leflunomide group and 15 in the MTX group. 32 patients of psoriatic arthritis were taken consecutively and grouped into two by card test.

Patient fulfilling the following criteria was selected for the study a) active psoriatic arthritis (=3 swollen and 3 tender joints); b) age =18 years; c) both sexes (females only if they agreed to practice appropriate contraceptive measure); d) patients should have serum ALT serum creatinine WBC count and platelet count within defined range: serum ALT: 0-40 U/L serum creatinine: less than 130 mol/L leucocyte count: =3.5A-10 /L platelet count: =150A-10 /L. Exclusion criteria were: a) axial joint involvement; b) compromised immune function including bone marrow dysplasia; c) severe uncontrolled infection; d) concurrent vaccination with live vaccine; and e) patients who received retinoids PUVA cyclosporin within last two weeks. Patients of leflunomide group were treated with leflunomide 100 mg daily orally for three days followed by 20mg daily for 6 months and MTX group treated with methotrexate 10 mg orally in two divided doses (12 hours apart) weekly for 6 months.

Both groups were allowed to take ibuprofen orally with a maximum allocated dose 1400 mg. A score of 10 was assigned to a daily dose of 1400 mg. A patient was withdrawn from the study; a) if WBC count less than 3.5A-10 /L or platelet count less than 150A-10 /L; b) serum ALT exceeded three times of the upper limit of normal in single measurement; c) serum creatinine greater than 160 mol/L. Clinical assessment was done at baseline after first month and then monthly for 5 months. Laboratory assessment was done at baseline after 2 weeks end of first month and then monthly for 5 months. Clinical assessment covered detail medical history physical examination measures of disease activity (arthritis and psoriasis).

Monitoring of adverse effects was done after two weeks at the end of first month and then monthly by query of symptoms of different systems physical examination and hematological and biochemical laboratory tests NSAID score and different measures of arthritis disease activity were assessed at one month and then monthly.

The measures of arthritis disease activity

1. Tender joint count (68 joints)

2. Joint tenderness index (0=none l= describe pain 2= grimace 3= withdrawal)

3. Swollen joint count (66 joints)

4. Joint swelling index (0= none l= mild (detectable synovial thickening with normal joint contour) 2= moderate (loss of normal joint contour) 3= severe (bulging synovial proliferation with cystic characteristics).

5. Duration of morning stiffness until maximum improvement (0= absent 1= up to 30 minutes 2= 30-60 minutes 3= more than 60 minutes).

6. Patient assessment of pain (visual analogue scale - graded on a scale of 1-10 cm).

7. Physician's global assessment of disease activity. On a scale of 1 to 5 (1= asymptomatic 2= mild 3= moderate 4= severe 5= very severe).

8. Patient's global assessment of disease activity on a scale of 1 to 5.

9. Health assessment questionnaire score.

10. NSAID score.

11. Psoriasis area and severity index (PASI)

The primary endpoint with respect to efficacy in psoriatic arthritis was the proportion of patients who met the psoriatic arthritis response criteria at 6 months.13 A secondary endpoint for the assessment of psoriatic arthritis was the proportion of patients meeting the American College of Rheumatology (ACR) preliminary criteria for improvement as ACR 20 ACR 50 and ACR 70.14

Results

Out of total 32 patients one patient from each group was excluded from analysis due to lack of follow-up. Sixteen in the leflunomide group and 14 in the MTX group completed 24 weeks follow-up.

Table 1 shows the comparative baseline characteristics of patients about personal information duration activity and laboratory investigations and Table 2 reflects the outcome of two groups after 24 weeks of therapy. Within each group there was significant improvement of disease activity; however the outcome of disease activity and laboratory reports between two groups was not different.

Adverse effects of drugs are listed with percent distribution in Table 3. Asthenia and alopecia

Table 1Baseline characteristics of patients (n=30).

Characteristics###Leflunomide group###Methotrexate group###pa

###(n=16)###(n=14)

Age (Years)###41.8113.43###37.939.34###0.372

Sex (Male/Female)###14/2###13/1###0.552

Duration of psoriasis(Years)###7.565.29###7.00 4.24###0.753

Duration of arthritis(Years)###3.222.43###2.82 2.22###0.645

Tender joint count###7.751.81###9.64 2.34###0.019

Swollen joint count###5.241.48###6.36 1.34###0.042

Joint tenderness index###11.503.08###14.64 3.23###0.011

Joint swelling index###6.723.19###8.29 2.97###0.186

Morning stiffness score###2.060.57###2.07 0.62###0.968

Patient's assessment of joint pain###5.060.68###4.93 0.27###0.496

Patient's global assessment of disease activity###3.060.25###3.00 0.00###0.359

Psoriasis area and severity index (PASI)###9.755.49###7.67 3.71###0.242

NSAID score###6.961.95###8.88 0.61###0.001

HAQ score###0.880.20###0.87 0.16###0.811

Physician's global assessment of disease activity###3.060.25###3.00 0.00###0.359

ESR (mm/1st Hour)###65.4418.95###66.36 13.28###0.880

Hemoglobin (gm/dl)###12.051.14###12.17 1.31###0.783

Platelet count (109/L)###277.2578.94###248.93 42.80###0.242

Serum ALT (U/L)###26.888.28###28.93 7.83###0.493

Serum creatinine (mol/L)###98.1914.90###99.29 10.31###0.819

Table 2 Comparison of outcome of treatment.

###Leflunomide group###Methotrexate group

Variables###pa

###(n=16)###(n=14)

Tender joint count###1.0 0.97###1.330.96###1

Swollen joint count###0.500.63###0.640.74###0.574

Joint tenderness index###1.000.97###1.000.96###1

Joint swelling index###0.50 0.63###0.640.74###0.574

Morning stiffness score###0.500.52###0.500.52###1

Patient's assessment of joint pain###1.001.03###0.930.83###0.886

Patient's global assessment of disease activity###2.000.00###2.000.00###1

Psoriasis area and severity index (PASI)###2.691.60###2.681.67###0.998

NSAIDS score###1.511.22###2.14 1.34###0.192

Physician's global assessment of disease activity 2.000.00###2.000.00###1

HAQ score###23.257.05###26.715.44###0.147

ESR (mm/Hr)###23.257.05###26.715.44###0.147

Hemoglobin (gm/dl)###11.812.34###12.34 1.06###0.442

Total count of WBC###7.731.56###8.211.24###0.361

Platelet count###232.6953.35###236.0029.75###0.838

Serum ALT (U/L)###31.636.26###31.075.64###0.802

Serum creatinine (mol/L)###102.5610.83###103.8611.80###0.756

was more in the leflunomide group but nausea and vomiting in MTX group (pgreater than 0.05).

Discussion

Disease modifying antirheumatic drugs such as

sulfasalazine gold penicillamine azathioprine MTX cyclosporine etc. are well studied in psoriatic arthritis. Safety efficacy and cost of these agents are erratic thus keeping dermatologists and rheumatologists in search of new safe as well as cost-effective treatment

Table 3 Psoriatic arthritis endpoints study.

###Group

###Difference###pa

###Leflunomide (n=16) MTX (n=14)

Primary endpoint-achieved at 6 months

PsARC###16 (100.00%)###14 (100.00%)###0%

Secondary endpoint- achieved at 6 months

ACR20###16 (100.00%)###14 (100.00%)###0%

ACR50###13 (81.30%)###12 (85.70%)###4.40%###0.342

ACR70###05 (31.30%)###02 (14.20%)###17.10%###0.004

Table 4 PASI improvement at 6 months.

PASI (Improvement)###Group

###Difference###pa

###Leflunomide (n=16)###MTX(n=14)

25%###16 (100.00%)###14 (100.00%)###0%

50%###11 (86.80%)###09 (64.30%)###4.50%###0.455

75%###06 (31.70%)###02 (28.60%)###3.10%###0.646

Table 5 Adverse effects of drugs.

###Leflunomide group (n=16)###Methotrexate group (n=14)

Adverse effects###pa

###N (%)###N (%)

Dyspepsia###9 (56.2)###9(64.30)###0.312

Asthenia###12 (75.0)###0 (0)###0.001

Alopecia###2 (12.5)###0 (0)###0.001

Nausea###1 (6.2)###11 (78.6)###0.001

Vomiting###0 (0)###5 (35.7)###0.001

Headache###1 (6.2)###1 (7.1)###0.774

Dizziness###0 (0)###1 (7.1)###0.007

option. Recent discovery of targeted molecules such as infliximab etanercept etc. has opened new avenues and hope in the management of this illness but cost remained big barrier of their use in 3 world.

Statistically significant improvement was observed in leflunomide group in all clinical parameters i.e. tender joint count swollen joint count joint swelling index joint tenderness index morning stiffness score patient's assessment of joint pain patient's global assessment of disease activity physician's global assessment of disease activity health assessment questionnaire score and ESR. The results were consistent with the findings of other study with leflunomide in rheumatoid arthritis.

In MTX group statistically significant improvement was noted in all clinical parameters including PASI and ESR. The results were also consistent with the results of other studies.1617 All patients of two groups achieved the primary end point but for secondary end point there was significant difference in ACR 70 in favour of leflunomide.

Common adverse effects were asthenia (75%) and dyspepsia (56.2%) in leflunomide group and other side effects were alopecia (12.5%) nausea (6.2%) and headache (6.2%). Similar pattern of adverse effects were reported by Schiff et al. in rheumatoid arthritis with leflunomide.15

The most common adverse effects in MTX group were nausea (78.6%) and dyspepsia (64.3%) and other side effects were vomiting (35.7%) headache (7.1%) and dizziness (7.1%).

Dyspepsia nausea headache were observed in both groups. Statistically significant differences were observed in adverse events of two groups except dyspepsia and headache (pgreater than 0.05). Adverse events were mild and improved with time that required no withdrawal or dose reduction of drugs.

Conclusion

Oral leflunomide is an effective and safe drug for psoriatic arthritis when compared with methotrexate. It has some adverse effects but they were well-tolerable and self-manageable. Chances of nausea and vomiting are less in leflunomide. In the light of our study we suggest leflunomide as a treatment option for psoriatic arthritis before trying any other conventional hazardous drug.

References

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2. National Psoriasis Foundation. New research shows 1 million U.S. adults suffer from psoriatic arthritis: others may be at risk but not know it. Portland (OR): NPF Press Releases; May 15 2002. URL:http://www.psoriasis.org/release2002.p sasurvey.htm.

3. Tassiulas I Duncan SR Centola M et al. Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis. Hum Immunol. 1999;60:479-91.

4. Costello PJ Winchester RJ Curran SA et al. Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions that appear antigen driven. J Immunol. 2001;166:28:78-86.

5. Jones G Crotty M Brooks P. Interventions for treating psoriatic arthritis (Cochrane Review). In: The Cochrane Library Issue 3. Oxford: Update Software; 2001.

6. Black RL O'Brien WM Van Scott EJ et al. Methotrexate therapy in psoriatic arthritis. JAMA. 1964;189:743-7.

7. Antoni C Dechant C Hanns-Martin Lorenz PD et al. Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation. Arthritis Care Res. 2002;47:506-12.

8. Mease PJ Goffe BS Metz J et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;356:385-90.

9. Kraan MC van Kuijk AW Dinant HJ et al. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum. 2002;46:2776-84.

10. Breedveld FC Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000;59:841-9.

11. Smolen JS Kalden JR Scott DL et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double- blind randomized multicentre trial. Lancet. 1999;353:259-66.

12. Strand V Cohen S Schiff M et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med. 1999;159:2542-50.

13. Clegg DO Reda DJ Mejias E et al. comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. Arthritis Rheum. 1996;39:2013-20.

14. Fredriksson T Petterson U. severe psoriasis- oral therapy with new retinoids. Acta Dermatologica. 1978;157:238-44.

15. Schiff MH Strand V Oed C Loew- Friendrich I. Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis. Drugs Today. 2000;36:383-94.

16. Spadaro A Riccieri VA Sili-scavalli et al. Comparison of cyclosporine A and methotrexate in the treatment of psoriatic arthritis: a one year prospective study. Clin Exp Rheumatol. 1995;13:589-93.

17. Zachariae H Zachariae E. Methotrexate: treatment of psoriatic arthritis. Acta Derm Venereol. 1987;67:270-3.
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Author:Asaduzzaman, A.T.M.; Sikder, Akramullah; Mahmud, Md. Mostaque; Paul, Harashit Kumar; Islam, Md. Nazr
Publication:Journal of Pakistan Association of Dermatologists
Article Type:Report
Geographic Code:9BANG
Date:Mar 31, 2014
Words:2928
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