Journal of Dermatological Treatment
ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20
Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis Ali Soliman, Eman Nofal, Ahmad Nofal, Fatma El desouky & Maha Asal To cite this article: Ali Soliman, Eman Nofal, Ahmad Nofal, Fatma El desouky & Maha Asal (2015) Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis, Journal of Dermatological Treatment, 26:6, 528-534, DOI: 10.3109/09546634.2015.1034069 To link to this article: http://dx.doi.org/10.3109/09546634.2015.1034069
Published online: 24 Apr 2015.
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Date: 27 September 2017, At: 06:33
http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, 2015; 26(6): 528–534 ! 2015 Informa UK Ltd. DOI: 10.3109/09546634.2015.1034069
ORIGINAL ARTICLE
Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis Ali Soliman, Eman Nofal, Ahmad Nofal, Fatma El desouky, and Maha Asal
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Department of Dermatology and Venereology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Abstract
Keywords
Background: The efficacy of methotrexate (MTX) plus narrowband ultraviolet B (NBUVB) phototherapy in treatment of chronic plaque psoriasis has been rarely assessed. Objectives: The objective of this study is to compare the efficacy of MTX/NBUVB phototherapy versus MTX monotherapy in treatment of chronic plaque psoriasis. Methods: Forty patients with psoriasis were enrolled into the study and classified into group A receiving oral MTX and group B receiving oral MTX plus NBUVB. Onset of improvement was 70% of baseline PASI. End point clearance was 90 % reduction in PASI or up to 6 months. Side effects were reported. Follow up for 12 weeks for assessment of relapse was done. Results: Of 40 patients, 35 completed the study. A higher clearance rate was achieved in patients of group B versus group A (100% versus 83%). A significant difference was reported regarding the onset of improvement and the duration required for clearance (p50.001) in favor of the MTX/NBUVB group. Patients in group B had a highly significant lower cumulative dose of MTX than the monotherapy group (p50.05). No significant difference as regard side effects and relapse was reported. Conclusion: MTX remains the mainstay in the treatment of psoriasis in developing countries and its combination with NBUVB offers a cheap and a beneficial therapeutic option.
Endpoint clearance, methotrexate, narrowband ultraviolet B, psoriasis
Introduction Various and numerous topical and systemic therapies are available for the treatment of psoriasis. The treatment modalities are chosen on the basis of disease severity, efficacy of the drug, individual patient response, and patient preference, including cost and convenience (1). In some cases, monotherapy (with either systemic agents or phototherapy) adequately controls moderate to severe disease. For many reasons, however, including loss of efficacy, adverse effects, or cumulative or acute toxicity and especially the inability to clear resistant lesions, a single modality will not be adequate. Using two or more therapies is, thus, the rule rather than the exception for most patients with moderate-to-severe psoriasis, but picking a combination that serves to balance safety and efficacy needs careful consideration, especially since no evidence-based treatment guidelines exist (2). Methotrexate (MTX) is a traditional systemic drug that has proven a great efficacy as a mono-therapeutic option in the treatment of psoriasis despite its potential side effects and toxicity that is related to its cumulative dose. In developing countries, retinoids, cyclosporine, and biologics are often times prohibitively expensive. MTX is, thus, the mainstay when costs are taken into consideration. MTX could be combined with many anti-psoriatic
Correspondence: Eman Abdelgawad Nofal, Department of Dermatology and Venereology, Faculty of Medicine, Zagazig University, Postal code: 44516, Zagazig, Egypt. Tel: +20 1115393902. E-mail: [email protected]
History Received 21 December 2014 Revised 10 March 2015 Accepted 11 March 2015 Published online 24 April 2015
agents either topical or systemic to maximize its effectiveness in the treatment of psoriasis (3). Phototherapy is a relatively safe and very effective treatment modality. However, several weeks are often required to achieve satisfactory clearing of lesions. Combination of MTX with NBUVB could clear psoriasis in a significant less time and with a lower cumulative dose of both MTX and UVB (4). The aim of the present study is to compare the efficacy of MTX/ NBUVB phototherapy as a combination therapy versus MTX monotherapy in the treatment of chronic plaque psoriasis.
Patients and methods Patients The study included 40 patients of both sexes with chronic plaque psoriasis. The patients were randomly selected from the outpatient clinics of Dermatology and Venereology Department, Zagazig University Hospitals from January 2011 to March 2012 after approval of the Institutional Review Board (IRB). Inclusion criteria: patients with chronic plaque psoriasis having more than 20% of body surface area involvement were included in the study. They should discontinue any systemic treatment including PUVA in the last 4 weeks and topical antipsoriatic treatment in the last 2 weeks before initiations of therapy. Male and female patients of reproductive age group were advised to take contraceptive precautions while on oral methotrexate and also not to conceive within 3 month of stopping oral medications
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DOI: 10.3109/09546634.2015.1034069
Combination therapy of methotrexate plus NBUVB phototherapy
Exclusion criteria: patients with severe hepatic, renal, hematological diseases, peptic ulcer, diabetes mellitus, immunosuppressive states, pregnant, and lactating females were excluded. Patients with known history of methotrexate intolerance or have reached previously the maximum total cumulative dose of MTX (1.5 g) were also excluded.
Table 1. The clinical data of the patients in both groups.
Methods
Age (years) Range Mean Duration Range Mean PASI Score Range Mean
An informed and written consent was obtained from all patients. All patients were subjected to detailed history taking, including history of previous medications. Psoriasis area and severity index (PASI) score was calculated for every patient. Patients then were randomly assigned into two groups: group A and group B, 20 patients in each (see Appendix). Patients of group A received oral MTX (2.5 mg/tablet) that started by 7.5 mg once weekly in three divided doses as a test dose and gradually increasing the dose by 5 mg in the successive weeks till reaching the individual effective therapeutic dose with maximum of 30 mg/week. Patients of group B received oral methotrexate in a regimen similar to that of patients in group A in addition to NB-UVB phototherapy twice weekly on non-consecutive days at the end of 3 week run-in period on the next day of oral medication. Before starting phototherapy, minimal erythema dose (MED) was determined in all patients. As most of the Egyptian patients are of skin types IV and V, we started the phototherapy by 0.574 J/cm2 as an initial dose, which was increased 20% in the following session if no reactions developed from previous setting, 10% if minimal reactions occurred and no increment if erythema developed and lasting longer than 24 h. If moderate erythema (grade 2, welldefined asymptomatic erythema) developed, topical corticosteroids were used and postponed treatment until the erythema fade then reduced by 20–50% of the last dose. If the erythema was severe (grade 3, painful and persistent erythema for more than 24 h after the last session), no further treatment was given and topical corticosteroid was used. Dose increment of NB-UVB was continued with a maximum of 4.5 J/cm2. In both groups, all patients were subjected to CBC, liver & renal function tests, and pregnancy test prior to initiation of therapy. A daily dose of 5 mg folic acid tablet was given to all patients except the day when methotrexate was administered. Treatment was continued till 90% reductions in original PASI score or until 24 weeks period. CBC was repeated every week for the first 2 weeks and then once every 4 weeks. Renal and liver functions tests were done every 2 weeks for the first month then repeated every 4 weeks. Evaluation All patients were evaluated every 2 weeks. Onset of improvement was considered when original PASI score is reduced by 30%. Change in PASI score was recorded till the patient achieved 90% reduction in PASI scores (end point clearance) or up to 24 weeks, after which methotrexate was slowly tapered (2.5 mg per week to avoid relapse) and NBUVB radiation was discontinued. Follow up was done for further 12 weeks for assessment of relapse (PASI returns to 30% of the original score). Statistical analysis Data were checked, entered, and analyzed by using SPSS program version 15 (SPSS Inc., Chicago, IL). Data were expressed as mean ± standard deviation (SD) for quantitative variables, number, and percentage for categorical variables. T-test was used for comparison of two means and ANOVA F test for several means. Chi-square test was used when appropriate. Correlation coefficient (r) was used to find the relation between quantitative variables.
Character Female Male
Group A N (%) 8 (40) 12 (60)
Group B N (%) 7 (35) 13 (65)
529
Value ( 2)
p
0.1
NS
T
P
16–59 41.3 ± 12.1
17–57 36.6 ± 11.4
1.2
NS
0.5–10 years 5.2 ± 3.0 y
1–12 years 5.2 ± 3.5 y
0.00
NS
18.6–45.8 26.6 ± 8.9
11.4–45.4 31 ± 11.7
1.3
NS
Group A, oral methotrexate; Group B, oral methotrexate + NBUVB. NS, non-significant.
Results The clinical data of both groups are illustrated in Table 1. Both groups were matched as regards sex, age, duration of the disease, and baseline PASI score. Therapeutic response (1) Onset of improvement (reduction of baseline PASI score by 30%): Table 2, Group A: all patients showed improvement in 2–7 weeks with a mean of 4.2 ± 1.6 weeks. Group B: two patients were excluded due to exacerbation of the disease at the start of the treatment. The other 18 patients showed improvement in 1–5 weeks with a mean of 2.05 ± 1.0 weeks. A highly significant statistical difference in the onset of improvement was found between the studied groups in favor of group B (p50.001). (2) End point clearance (reduction of baseline PASI score by 90%): Table 3, Group A: two patients were lost after the onset of improvement and did not complete the treatment period (24 weeks). Eighteen patients completed the treatment period. Fifteen of them (83.3%) reached the end point clearance in a duration ranged from 8 to 14 weeks with a mean of 10.4 ± 1.8 weeks. Group B: one patient was lost after the onset of improvement and did not complete the treatment period. Seventeen patients completed the treatment period and all of them (100%) reached the end point clearance in a duration ranged from 4 to 14 weeks with a mean of 7.4 ± 2.6 weeks. Statistically, there was a highly significant difference between both groups as regards the duration of treatment (p50.001) and a significant difference (50.05) as regards the percentage of patients achieving clearance in favor of group B. Total cumulative dose of MTX and NBUVB On one hand, the mean total cumulative dose of methotrexate was 165.5 ± 61.3 (range: 65–255 mg) in group A with the most frequently used doses between 100 and 150 mg (Figure 1). On the other hand, the mean total cumulative dose in group B was 89.8 ± 65.6 with a range of 60–255 mg with the most frequently used doses between 50 and 100 mg (Figure 2). The statistical analysis showed a significant lower dose in group B than in group A (p50.05). The total cumulative dose of NB-UVB in group B was 34.13 ± 20.9 J/cm2 with a range of 6.9–73.3 J/cm2, and the number of settings ranged from 6 to 30 with a mean of 15.8 ± 6.1 setting, Table 3 and Figure 3.
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Table 2. Onsets of improvement (reduction of baseline PASI score by 30%) in both groups. Weeks Onset
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00
Total
Group A
Group B
2
p
Count (%) 0 (0.0%) 0 (0.0%) 19.5 50.001 Count (%) 0 (0.0%) 5 (25.0%) HS Count (%) 4 (20.0%) 10 (50.0%) Count (%) 3 (15.0%) 1 (5.0%) Count (%) 5 (25.0%) 1 (5.0%) Count (%) 2 (10.0%) 1 (5.0%) Count (%) 4 (20.0%) 0 (0.0%) Count (%) 2 (10.0%) 0 (0.0%) Count 20 18 % within group 100.0 90
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HS, highly significant. NB, two patients in group B were excluded due to disease exacerbation.
Table 3. End point clearance and TCD of methotrexate in both groups.
Clearance (PASI510%) Weeks until clearance Mean Range TCD of MTX (mg) Mean Range
Group A N%
Group B N%
15 /18 (83%) Group A
17/17 (100%) Group B
3.09 50.05 T P
10.4 ± 1.8 7–14
7.4 ± 2.6 4–14
3.6
50.001
165.5 ± 61.3 65–255
89.8 ± 65.6 60–255
3.4
50.05
2
p
NB, two patients in group A and one patient in group B did not complete the study.
Correlation among age, dose, time until clearance, and baseline PASI in both groups In group A, there was a highly significant positive correlation among age, baseline PASI, and dose, the older ages of patients correlate with higher baseline PASI and higher doses of methotrexate. In group B, the time until clearance has a significant positive correlation with the dose of methotrexate. Side effects Gastritis and abdominal pain were reported in 38.8% of patients in group A and in 17.6% in group B. Erythema was reported in 29.4%, severe itching in 23.5%, and mild anemia in 5% of patients in group B only. There was no significant statistical difference between both groups as regards the occurrence of side effects. However, it is considerable to note that the percentage of patients with side effects related to methotrexate was markedly less in group B (17.6%) than in group A (38.8%). Relapse of the disease As regards relapse, eight patients (44.4%) in group A and four (23.5%) patients in group B relapsed before the end of the 12 weeks period. There was no significant statistical difference between both groups. There were no significant predictors for the occurrence of side effects and relapse of disease in group (B). The most important predictors for the occurrence of side effects and relapse of disease during the treatment with methotrexate alone (group A) are the age of the patient and the cumulative dose of methotrexate (Table 4)
Discussion Methotrexate is a traditional drug that has been in use for many decades. It can be combined with many topical and systemic agents for the treatment of psoriasis. Combination of MTX with NBUVB could produce rapid clearance of lesions (5). Efficacy of such combination in the treatment of psoriasis has been rarely assessed. To the best of our knowledge, this is the first study that compared the efficacy of MTX as a monotherapy versus its combination with NBUVB in the treatment of chronic plaque psoriasis. The results of our study showed a superior efficacy of combination therapy (MTX plus NB-UVB) compared with MTX monotherapy. The efficacy is evaluated not only by the clearance of lesions but also by the duration and the TCD of MTX needed to achieve that clearance. All patients in group B (100%) achieved the end point clearance (PASI 10% of the original one) versus 83% of patients in group A (p50.05). The difference in the duration of treatment and the TCD between the studied groups was statistically significant in favor of group B (p50.001; p50.05, respectively). Our results do agree with those of Kumar et al. (7) who have treated 197 psoriatic patients with weekly oral MTX at a fully therapeutic dose (0.3–0.5 mg/kg/week). They reported marked improvement in 84.3% of patients after 11.8 ± 7.4 weeks with a mean TCD of 709.3 ± 369.2 mg. However, the TCD of methotrexate was much higher than ours; this could be due to the use of a fully therapeutic dose of methotrexate (least effective therapeutic dose was used in our study) and the large sample size of their study. In our study, we avoided the full dosage of MTX to avoid any potentiality of hepatic toxicity in a developing country, with a high prevalence of hepatic diseases, like Egypt. In group B, psoriatic patients received a pretreatment of 3-week course of MTX followed by combined therapy of MTX and NBUVB phototherapy. Our philosophy is to clear psoriasis in a significant less time and with a lower cumulative dose of both MTX and UVB. Both MTX and NBUVB have an anti-mitotic and anti-proliferative action on infiltrating T lymphocytes, and both possess significant anti-inflammatory properties. Moreover, methotrexate leads to reduction in the scaling and infiltration of the lesions; thereby, enabling deeper penetration of NBUVB in the dermis with greater effectiveness in depleting the dermal T lymphocytes. This explains why we used a 3-week course of MTX before initiation of NBUVB (4). It may be worthy to note that 50% of patients receiving combined therapy showed improvement after only 2 weeks while 25% of patients on monotherapy showed improvement after a period of 4 weeks, so the onset of improvement (reduction of PASI by 30%) showed a highly significant statistical difference between both groups (p50.001). The early onset of improvement in group B helped the assurance of patients in this group, improved their psychological aspect and increased their confidence in the modality of the treatment. The concept of combining MTX with UVB phototherapy has been relatively less exercised. Some previous studies reported the success of such a combination. The first study was reported by Paul et al. (8) who tried the combination of MTX and broadband (BB) UVB. They stated that the number of phototherapy sessions and the dose of UVB used in this combination were less than half when BBUVB alone was used. Two studies (4,5) have compared MTX/NBUVB combination versus placebo/NBUVB in the treatment of chronic plaque psoriasis. The study of Asawanonda and Nateetongrungsak (5) showed that about 90.9% of patients on combination of MTX and NBUVB achieved clearance after a median time of 4 weeks compared with only 38.4% in the placebo/NBUVB group.
DOI: 10.3109/09546634.2015.1034069
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Figure 1. The most frequently used doses of MTX in group A.
Figure 2. The most frequently used doses of MTX in group B.
Combination therapy of methotrexate plus NBUVB phototherapy
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Figure 3. TCD of MTX, TCD of NBUVB, and no. of NBUVB sessions.
Table 4. Predictors for occurrence of side effects and relapse in both groups. Independent factors Dose and relapse Group A Group B Dose and side effect Group A Group B Baseline PASI and relapse Group A Group B Baseline PASI and side effect Group A Group B AGE and side effect Group A Group B AGE and relapse Group A Group B NB setting and relapse Group B NB setting and side effect Group B
F-test
p Value
9.1 0.015
50.05 S NS
5.8 0.06
50.05 S NS
3.8 0.5
NS NS
4.3 0.5
NS NS
25 1.1
50.001 HS NS
7.2 0.5 0.8 0.009
50.05 S NS NS NS
The mean cumulative MTX dose received was 114.0 ± 24.7 mg. The mean cumulative dose of NBUVB in MTX/NBUVB group was 26.92 ± 15.54 J/cm2. When compared to our results, we achieved clearance of lesions in all patients (100%) with lower TCD of MTX. The previous authors attributed the lower clearance rate to the fact that their institution is a referral center where patients seen with psoriasis are relatively more recalcitrant to treatment. The higher TCD of MTX may be also attributed to the same cause, i.e. the recalcitrant type of psoriasis. Our result were also in agreement with those of Mahajan et al. (4) who have reported a significant statistical difference in the percentage of patients who achieved clearance (100% in the MTX/NBUVB group versus 77.7% in the placebo/NBUVB group), and in the time required to achieve such clearance (7.57 ± 3.09 weeks versus 11.42 ± 4.98 weeks) in favor of the
MTX/NBUVB group. The TCD of MTX was 200 ± 81.0 mg. The TCD of NBUVB in the group receiving MTX/NBUVB was 9.14 ± 5.39 J/cm2 versus 25.99 ± 18.55 J/cm2 in the placebo/ NBUVB group. The total cumulative dose of NBUVB obtained in our study was higher than that obtained in the MTX/NBUVB group in the two previous studies but still lower than that in the group receiving monotherapy of NBUVB. This might be due to the fact that most of our patients were of dark colored skin, skin phototypes IV and V, for which higher fluencies are often necessary to clear the disease. On the other hand, TCD of MTX was markedly less in group B of our study which might be due to the use of the least effective dose of MTX versus the fully therapeutic dose used by the previous authors. Some studies (9–11) evaluated the efficacy of combined MTX and PUVA in the treatment of psoriasis. They concluded that concomitant use of MTX and PUVA can reduce the disease clearance time in plaque type psoriasis than either MTX or PUVA as a monotherapy. They demonstrated that MTX plus PUVA combination can yield an efficacy comparable with MTX plus NBUVB. The main disadvantage of this regimen is the additive carcinogenesis, especially an increased risk of squamous cell carcinoma. Additionally, the regimen may have limited long term utility in patients previously unresponsive to PUVA treatment. After treatment, considerable percentage of the formerly PUVAresistant patients had experienced flare-ups or needed relatively high maintenance doses of UVA (2) In patients with moderate-to-severe psoriasis, remission can be difficult to be achieved and sustained. No optimal information is found about the average length of remission (12). As regards the number of patients who relapsed during the follow-up period (12 weeks), no significant statistical difference was found between both groups. Similar results were reported in previous studies (4,5). As regards side effects, both groups reported occurrence of minimal and short-term side effects in the form of gastritis and abdominal pain. In group B, some patients suffered from erythema, itching, and mild anemia plus the gastrointestinal side effects of methotrexate. However, no significant statistical difference was found between both groups. Similar results were reported in the previous studies (4,5). However, Asawanonda and Nateetongrungsak (5) reported generalized hyper pigmentation in
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DOI: 10.3109/09546634.2015.1034069
Combination therapy of methotrexate plus NBUVB phototherapy
all patients and erythroderma in some patients that we have not detected in our patients. There were no significant predictors for the occurrence of side effects and relapse of the disease in group B. In group A, the most important predictors for the occurrence of side effects and relapse are the age of the patient and the cumulative dose of MTX. The risk of increased incidence of non-melanoma skin cancer remains the limiting factor for the use of MTX/NBUVB combination therapy. But up till now, this remains largely theoretical because both MTX and NBUVB have not been conclusively linked to increased incidence of cutaneous and noncutaneous malignancies (4,13,14). The present study supported the concept that the combination of MTX and NBUVB phototherapy is a useful, effective, and relatively safe treatment for chronic plaque psoriasis. This combination leads to marked improvement in psoriatic lesions in a significant less time and a significant lower dose of MTX. MTX remains the mainstay in the treatment of psoriasis in developing countries because of its cheapness. Its combination with other agents offers a cheap and clinically beneficial therapeutic option. Clinical and investigational studies to increase the efficacy of MTX, to decrease its cumulative dose and consequently its side effects should be encouraged. Future research on other combination regimens and larger number of patients is recommended to establish how these therapies will expand and/or support the established psoriasis treatment protocols.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Lebwohl M, Ali S. Treatment of psoriasis. Part 2: systemic therapies. J Am Acad Dermatol. 2001;45:649–61.
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2. Lebwohl M, Mentcr A, Koo J, Feldman SR. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol. 2004;50: 416–30. 3. Dubertret L, Climenti S, Christophers E, et al. The lives of four patients with psoriasis and the therapeutic approaches of eight European experts. Br J Dermatol. 2009;161:1–30. 4. Mahajan R, Kaur I, Kanwar AJ. Methotrexate /narrowband UVB phototherapy combination vs. narrowband UVB phototherapy in the treatment of chronic plaque-type psoriasis – a randomized singleblinded placebo-controlled study. JEADV. 2010;24:595–600. 5. Asawanonda P, Nateetongrungsak Y. Methotrexate plus narrowband UVB phototherapy versus narrowband UVB phototherapy alone in the treatment of plaque-type psoriasis: a randomized, placebocontrolled study. J Am Acad Dermatol. 2006;54:1013–18. 6. Saporito FC, Menter MA. Methotrexate and psoriasis in the era of new biologic agents. J Am Acad Dermatol. 2004;50:301–9. 7. Kumar B, Saraswat A, Kaur I. Short-term methotrexate therapy in psoriasis: a study of 197 patients. Int J Dermatol. 2002;41:444–8. 8. Paul BS, Momtaz K, Stern RS, et al. Combined methotrexateultraviolet B therapy in the treatment of psoriasis. J Am Acad Dermatol. 1982;7:758–62. 9. Morison WI, Momtaz K, Parrish JA, Fitzpatrick TB. Combined methotrexate-PUVA therapy in the treatment of psoriasis. J Am Acad Dermatol. 1982;6:46–51. 10. Shehzad T, Dar NR, Zakria M. Efficacy of concomitant use of PUVA and methotrexate in disease clearance time in plaque type psoriasis. J Pak Med Assoc. 2004;54:453–5. 11. Laxmisha C, Kumar PV, Thappa DM. Modified combined methotrexate PUVA therapy in the treatment of recalcitrant psoriasis: a preliminary report. Indian J Dermatol Venereol. 2006;72:153–5. 12. Van Dooren-Greebe RJ, Kuijpers ALA, Buijs WCAM, et al. The value of dynamic hepatic scintigraphy and serum aminoterminal propeptide of type III procollagen for early detection of methotrexate induced liver damage in psoriasis patients. Br J Dermatol. 1996; 134:481–7. 13. Weischer M, Blum A, Eberhard F, et al. No evidence for increased skin cancer risk in psoriasis patients treated with broadband or narrowband UVB phototherapy: a first retrospective study. Acta Derm Venereol. 2004;84:370–4. 14. Pasker-de Jong PC, Wielink G, van der Valk PG, van der Wilt GJ. Treatment with UVB for psoriasis and non melanoma skin cancer: a systematic review of the literature. Arch Dermatol. 1999;135: 834–40.
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Appendix The CONSORT diagram:
Assessed for eligibility (n=55)
Excluded (n=15 ) • Not meeting inclusion criteria (n=11) • Declined to participate (n=4)
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Randomized (n=40)
Allocated to intervention (n=20) • started allocated intervention (n=20) • completed allocated intervention (n=18) • Did not complete intervention (n= 2 patients were lost and excluded from the study)
Allocated to intervention (n=20) • started allocated intervention (n=20) • completed allocated intervention(n=17) • Did not complete allocated intervention (n=3) due to disease exacerbation in 2 patients and I patient was lost and excluded from the study)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n= 0)
Analysed (n=18) • Excluded from analysis (n=0 )
Analysed (n=17) • Excluded from analysis (n= 0)
ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20
Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis Ali Soliman, Eman Nofal, Ahmad Nofal, Fatma El desouky & Maha Asal To cite this article: Ali Soliman, Eman Nofal, Ahmad Nofal, Fatma El desouky & Maha Asal (2015) Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis, Journal of Dermatological Treatment, 26:6, 528-534, DOI: 10.3109/09546634.2015.1034069 To link to this article: http://dx.doi.org/10.3109/09546634.2015.1034069
Published online: 24 Apr 2015.
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Date: 27 September 2017, At: 06:33
http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, 2015; 26(6): 528–534 ! 2015 Informa UK Ltd. DOI: 10.3109/09546634.2015.1034069
ORIGINAL ARTICLE
Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis Ali Soliman, Eman Nofal, Ahmad Nofal, Fatma El desouky, and Maha Asal
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Department of Dermatology and Venereology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Abstract
Keywords
Background: The efficacy of methotrexate (MTX) plus narrowband ultraviolet B (NBUVB) phototherapy in treatment of chronic plaque psoriasis has been rarely assessed. Objectives: The objective of this study is to compare the efficacy of MTX/NBUVB phototherapy versus MTX monotherapy in treatment of chronic plaque psoriasis. Methods: Forty patients with psoriasis were enrolled into the study and classified into group A receiving oral MTX and group B receiving oral MTX plus NBUVB. Onset of improvement was 70% of baseline PASI. End point clearance was 90 % reduction in PASI or up to 6 months. Side effects were reported. Follow up for 12 weeks for assessment of relapse was done. Results: Of 40 patients, 35 completed the study. A higher clearance rate was achieved in patients of group B versus group A (100% versus 83%). A significant difference was reported regarding the onset of improvement and the duration required for clearance (p50.001) in favor of the MTX/NBUVB group. Patients in group B had a highly significant lower cumulative dose of MTX than the monotherapy group (p50.05). No significant difference as regard side effects and relapse was reported. Conclusion: MTX remains the mainstay in the treatment of psoriasis in developing countries and its combination with NBUVB offers a cheap and a beneficial therapeutic option.
Endpoint clearance, methotrexate, narrowband ultraviolet B, psoriasis
Introduction Various and numerous topical and systemic therapies are available for the treatment of psoriasis. The treatment modalities are chosen on the basis of disease severity, efficacy of the drug, individual patient response, and patient preference, including cost and convenience (1). In some cases, monotherapy (with either systemic agents or phototherapy) adequately controls moderate to severe disease. For many reasons, however, including loss of efficacy, adverse effects, or cumulative or acute toxicity and especially the inability to clear resistant lesions, a single modality will not be adequate. Using two or more therapies is, thus, the rule rather than the exception for most patients with moderate-to-severe psoriasis, but picking a combination that serves to balance safety and efficacy needs careful consideration, especially since no evidence-based treatment guidelines exist (2). Methotrexate (MTX) is a traditional systemic drug that has proven a great efficacy as a mono-therapeutic option in the treatment of psoriasis despite its potential side effects and toxicity that is related to its cumulative dose. In developing countries, retinoids, cyclosporine, and biologics are often times prohibitively expensive. MTX is, thus, the mainstay when costs are taken into consideration. MTX could be combined with many anti-psoriatic
Correspondence: Eman Abdelgawad Nofal, Department of Dermatology and Venereology, Faculty of Medicine, Zagazig University, Postal code: 44516, Zagazig, Egypt. Tel: +20 1115393902. E-mail: [email protected]
History Received 21 December 2014 Revised 10 March 2015 Accepted 11 March 2015 Published online 24 April 2015
agents either topical or systemic to maximize its effectiveness in the treatment of psoriasis (3). Phototherapy is a relatively safe and very effective treatment modality. However, several weeks are often required to achieve satisfactory clearing of lesions. Combination of MTX with NBUVB could clear psoriasis in a significant less time and with a lower cumulative dose of both MTX and UVB (4). The aim of the present study is to compare the efficacy of MTX/ NBUVB phototherapy as a combination therapy versus MTX monotherapy in the treatment of chronic plaque psoriasis.
Patients and methods Patients The study included 40 patients of both sexes with chronic plaque psoriasis. The patients were randomly selected from the outpatient clinics of Dermatology and Venereology Department, Zagazig University Hospitals from January 2011 to March 2012 after approval of the Institutional Review Board (IRB). Inclusion criteria: patients with chronic plaque psoriasis having more than 20% of body surface area involvement were included in the study. They should discontinue any systemic treatment including PUVA in the last 4 weeks and topical antipsoriatic treatment in the last 2 weeks before initiations of therapy. Male and female patients of reproductive age group were advised to take contraceptive precautions while on oral methotrexate and also not to conceive within 3 month of stopping oral medications
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Combination therapy of methotrexate plus NBUVB phototherapy
Exclusion criteria: patients with severe hepatic, renal, hematological diseases, peptic ulcer, diabetes mellitus, immunosuppressive states, pregnant, and lactating females were excluded. Patients with known history of methotrexate intolerance or have reached previously the maximum total cumulative dose of MTX (1.5 g) were also excluded.
Table 1. The clinical data of the patients in both groups.
Methods
Age (years) Range Mean Duration Range Mean PASI Score Range Mean
An informed and written consent was obtained from all patients. All patients were subjected to detailed history taking, including history of previous medications. Psoriasis area and severity index (PASI) score was calculated for every patient. Patients then were randomly assigned into two groups: group A and group B, 20 patients in each (see Appendix). Patients of group A received oral MTX (2.5 mg/tablet) that started by 7.5 mg once weekly in three divided doses as a test dose and gradually increasing the dose by 5 mg in the successive weeks till reaching the individual effective therapeutic dose with maximum of 30 mg/week. Patients of group B received oral methotrexate in a regimen similar to that of patients in group A in addition to NB-UVB phototherapy twice weekly on non-consecutive days at the end of 3 week run-in period on the next day of oral medication. Before starting phototherapy, minimal erythema dose (MED) was determined in all patients. As most of the Egyptian patients are of skin types IV and V, we started the phototherapy by 0.574 J/cm2 as an initial dose, which was increased 20% in the following session if no reactions developed from previous setting, 10% if minimal reactions occurred and no increment if erythema developed and lasting longer than 24 h. If moderate erythema (grade 2, welldefined asymptomatic erythema) developed, topical corticosteroids were used and postponed treatment until the erythema fade then reduced by 20–50% of the last dose. If the erythema was severe (grade 3, painful and persistent erythema for more than 24 h after the last session), no further treatment was given and topical corticosteroid was used. Dose increment of NB-UVB was continued with a maximum of 4.5 J/cm2. In both groups, all patients were subjected to CBC, liver & renal function tests, and pregnancy test prior to initiation of therapy. A daily dose of 5 mg folic acid tablet was given to all patients except the day when methotrexate was administered. Treatment was continued till 90% reductions in original PASI score or until 24 weeks period. CBC was repeated every week for the first 2 weeks and then once every 4 weeks. Renal and liver functions tests were done every 2 weeks for the first month then repeated every 4 weeks. Evaluation All patients were evaluated every 2 weeks. Onset of improvement was considered when original PASI score is reduced by 30%. Change in PASI score was recorded till the patient achieved 90% reduction in PASI scores (end point clearance) or up to 24 weeks, after which methotrexate was slowly tapered (2.5 mg per week to avoid relapse) and NBUVB radiation was discontinued. Follow up was done for further 12 weeks for assessment of relapse (PASI returns to 30% of the original score). Statistical analysis Data were checked, entered, and analyzed by using SPSS program version 15 (SPSS Inc., Chicago, IL). Data were expressed as mean ± standard deviation (SD) for quantitative variables, number, and percentage for categorical variables. T-test was used for comparison of two means and ANOVA F test for several means. Chi-square test was used when appropriate. Correlation coefficient (r) was used to find the relation between quantitative variables.
Character Female Male
Group A N (%) 8 (40) 12 (60)
Group B N (%) 7 (35) 13 (65)
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Value ( 2)
p
0.1
NS
T
P
16–59 41.3 ± 12.1
17–57 36.6 ± 11.4
1.2
NS
0.5–10 years 5.2 ± 3.0 y
1–12 years 5.2 ± 3.5 y
0.00
NS
18.6–45.8 26.6 ± 8.9
11.4–45.4 31 ± 11.7
1.3
NS
Group A, oral methotrexate; Group B, oral methotrexate + NBUVB. NS, non-significant.
Results The clinical data of both groups are illustrated in Table 1. Both groups were matched as regards sex, age, duration of the disease, and baseline PASI score. Therapeutic response (1) Onset of improvement (reduction of baseline PASI score by 30%): Table 2, Group A: all patients showed improvement in 2–7 weeks with a mean of 4.2 ± 1.6 weeks. Group B: two patients were excluded due to exacerbation of the disease at the start of the treatment. The other 18 patients showed improvement in 1–5 weeks with a mean of 2.05 ± 1.0 weeks. A highly significant statistical difference in the onset of improvement was found between the studied groups in favor of group B (p50.001). (2) End point clearance (reduction of baseline PASI score by 90%): Table 3, Group A: two patients were lost after the onset of improvement and did not complete the treatment period (24 weeks). Eighteen patients completed the treatment period. Fifteen of them (83.3%) reached the end point clearance in a duration ranged from 8 to 14 weeks with a mean of 10.4 ± 1.8 weeks. Group B: one patient was lost after the onset of improvement and did not complete the treatment period. Seventeen patients completed the treatment period and all of them (100%) reached the end point clearance in a duration ranged from 4 to 14 weeks with a mean of 7.4 ± 2.6 weeks. Statistically, there was a highly significant difference between both groups as regards the duration of treatment (p50.001) and a significant difference (50.05) as regards the percentage of patients achieving clearance in favor of group B. Total cumulative dose of MTX and NBUVB On one hand, the mean total cumulative dose of methotrexate was 165.5 ± 61.3 (range: 65–255 mg) in group A with the most frequently used doses between 100 and 150 mg (Figure 1). On the other hand, the mean total cumulative dose in group B was 89.8 ± 65.6 with a range of 60–255 mg with the most frequently used doses between 50 and 100 mg (Figure 2). The statistical analysis showed a significant lower dose in group B than in group A (p50.05). The total cumulative dose of NB-UVB in group B was 34.13 ± 20.9 J/cm2 with a range of 6.9–73.3 J/cm2, and the number of settings ranged from 6 to 30 with a mean of 15.8 ± 6.1 setting, Table 3 and Figure 3.
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Table 2. Onsets of improvement (reduction of baseline PASI score by 30%) in both groups. Weeks Onset
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00
Total
Group A
Group B
2
p
Count (%) 0 (0.0%) 0 (0.0%) 19.5 50.001 Count (%) 0 (0.0%) 5 (25.0%) HS Count (%) 4 (20.0%) 10 (50.0%) Count (%) 3 (15.0%) 1 (5.0%) Count (%) 5 (25.0%) 1 (5.0%) Count (%) 2 (10.0%) 1 (5.0%) Count (%) 4 (20.0%) 0 (0.0%) Count (%) 2 (10.0%) 0 (0.0%) Count 20 18 % within group 100.0 90
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HS, highly significant. NB, two patients in group B were excluded due to disease exacerbation.
Table 3. End point clearance and TCD of methotrexate in both groups.
Clearance (PASI510%) Weeks until clearance Mean Range TCD of MTX (mg) Mean Range
Group A N%
Group B N%
15 /18 (83%) Group A
17/17 (100%) Group B
3.09 50.05 T P
10.4 ± 1.8 7–14
7.4 ± 2.6 4–14
3.6
50.001
165.5 ± 61.3 65–255
89.8 ± 65.6 60–255
3.4
50.05
2
p
NB, two patients in group A and one patient in group B did not complete the study.
Correlation among age, dose, time until clearance, and baseline PASI in both groups In group A, there was a highly significant positive correlation among age, baseline PASI, and dose, the older ages of patients correlate with higher baseline PASI and higher doses of methotrexate. In group B, the time until clearance has a significant positive correlation with the dose of methotrexate. Side effects Gastritis and abdominal pain were reported in 38.8% of patients in group A and in 17.6% in group B. Erythema was reported in 29.4%, severe itching in 23.5%, and mild anemia in 5% of patients in group B only. There was no significant statistical difference between both groups as regards the occurrence of side effects. However, it is considerable to note that the percentage of patients with side effects related to methotrexate was markedly less in group B (17.6%) than in group A (38.8%). Relapse of the disease As regards relapse, eight patients (44.4%) in group A and four (23.5%) patients in group B relapsed before the end of the 12 weeks period. There was no significant statistical difference between both groups. There were no significant predictors for the occurrence of side effects and relapse of disease in group (B). The most important predictors for the occurrence of side effects and relapse of disease during the treatment with methotrexate alone (group A) are the age of the patient and the cumulative dose of methotrexate (Table 4)
Discussion Methotrexate is a traditional drug that has been in use for many decades. It can be combined with many topical and systemic agents for the treatment of psoriasis. Combination of MTX with NBUVB could produce rapid clearance of lesions (5). Efficacy of such combination in the treatment of psoriasis has been rarely assessed. To the best of our knowledge, this is the first study that compared the efficacy of MTX as a monotherapy versus its combination with NBUVB in the treatment of chronic plaque psoriasis. The results of our study showed a superior efficacy of combination therapy (MTX plus NB-UVB) compared with MTX monotherapy. The efficacy is evaluated not only by the clearance of lesions but also by the duration and the TCD of MTX needed to achieve that clearance. All patients in group B (100%) achieved the end point clearance (PASI 10% of the original one) versus 83% of patients in group A (p50.05). The difference in the duration of treatment and the TCD between the studied groups was statistically significant in favor of group B (p50.001; p50.05, respectively). Our results do agree with those of Kumar et al. (7) who have treated 197 psoriatic patients with weekly oral MTX at a fully therapeutic dose (0.3–0.5 mg/kg/week). They reported marked improvement in 84.3% of patients after 11.8 ± 7.4 weeks with a mean TCD of 709.3 ± 369.2 mg. However, the TCD of methotrexate was much higher than ours; this could be due to the use of a fully therapeutic dose of methotrexate (least effective therapeutic dose was used in our study) and the large sample size of their study. In our study, we avoided the full dosage of MTX to avoid any potentiality of hepatic toxicity in a developing country, with a high prevalence of hepatic diseases, like Egypt. In group B, psoriatic patients received a pretreatment of 3-week course of MTX followed by combined therapy of MTX and NBUVB phototherapy. Our philosophy is to clear psoriasis in a significant less time and with a lower cumulative dose of both MTX and UVB. Both MTX and NBUVB have an anti-mitotic and anti-proliferative action on infiltrating T lymphocytes, and both possess significant anti-inflammatory properties. Moreover, methotrexate leads to reduction in the scaling and infiltration of the lesions; thereby, enabling deeper penetration of NBUVB in the dermis with greater effectiveness in depleting the dermal T lymphocytes. This explains why we used a 3-week course of MTX before initiation of NBUVB (4). It may be worthy to note that 50% of patients receiving combined therapy showed improvement after only 2 weeks while 25% of patients on monotherapy showed improvement after a period of 4 weeks, so the onset of improvement (reduction of PASI by 30%) showed a highly significant statistical difference between both groups (p50.001). The early onset of improvement in group B helped the assurance of patients in this group, improved their psychological aspect and increased their confidence in the modality of the treatment. The concept of combining MTX with UVB phototherapy has been relatively less exercised. Some previous studies reported the success of such a combination. The first study was reported by Paul et al. (8) who tried the combination of MTX and broadband (BB) UVB. They stated that the number of phototherapy sessions and the dose of UVB used in this combination were less than half when BBUVB alone was used. Two studies (4,5) have compared MTX/NBUVB combination versus placebo/NBUVB in the treatment of chronic plaque psoriasis. The study of Asawanonda and Nateetongrungsak (5) showed that about 90.9% of patients on combination of MTX and NBUVB achieved clearance after a median time of 4 weeks compared with only 38.4% in the placebo/NBUVB group.
DOI: 10.3109/09546634.2015.1034069
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Figure 1. The most frequently used doses of MTX in group A.
Figure 2. The most frequently used doses of MTX in group B.
Combination therapy of methotrexate plus NBUVB phototherapy
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Figure 3. TCD of MTX, TCD of NBUVB, and no. of NBUVB sessions.
Table 4. Predictors for occurrence of side effects and relapse in both groups. Independent factors Dose and relapse Group A Group B Dose and side effect Group A Group B Baseline PASI and relapse Group A Group B Baseline PASI and side effect Group A Group B AGE and side effect Group A Group B AGE and relapse Group A Group B NB setting and relapse Group B NB setting and side effect Group B
F-test
p Value
9.1 0.015
50.05 S NS
5.8 0.06
50.05 S NS
3.8 0.5
NS NS
4.3 0.5
NS NS
25 1.1
50.001 HS NS
7.2 0.5 0.8 0.009
50.05 S NS NS NS
The mean cumulative MTX dose received was 114.0 ± 24.7 mg. The mean cumulative dose of NBUVB in MTX/NBUVB group was 26.92 ± 15.54 J/cm2. When compared to our results, we achieved clearance of lesions in all patients (100%) with lower TCD of MTX. The previous authors attributed the lower clearance rate to the fact that their institution is a referral center where patients seen with psoriasis are relatively more recalcitrant to treatment. The higher TCD of MTX may be also attributed to the same cause, i.e. the recalcitrant type of psoriasis. Our result were also in agreement with those of Mahajan et al. (4) who have reported a significant statistical difference in the percentage of patients who achieved clearance (100% in the MTX/NBUVB group versus 77.7% in the placebo/NBUVB group), and in the time required to achieve such clearance (7.57 ± 3.09 weeks versus 11.42 ± 4.98 weeks) in favor of the
MTX/NBUVB group. The TCD of MTX was 200 ± 81.0 mg. The TCD of NBUVB in the group receiving MTX/NBUVB was 9.14 ± 5.39 J/cm2 versus 25.99 ± 18.55 J/cm2 in the placebo/ NBUVB group. The total cumulative dose of NBUVB obtained in our study was higher than that obtained in the MTX/NBUVB group in the two previous studies but still lower than that in the group receiving monotherapy of NBUVB. This might be due to the fact that most of our patients were of dark colored skin, skin phototypes IV and V, for which higher fluencies are often necessary to clear the disease. On the other hand, TCD of MTX was markedly less in group B of our study which might be due to the use of the least effective dose of MTX versus the fully therapeutic dose used by the previous authors. Some studies (9–11) evaluated the efficacy of combined MTX and PUVA in the treatment of psoriasis. They concluded that concomitant use of MTX and PUVA can reduce the disease clearance time in plaque type psoriasis than either MTX or PUVA as a monotherapy. They demonstrated that MTX plus PUVA combination can yield an efficacy comparable with MTX plus NBUVB. The main disadvantage of this regimen is the additive carcinogenesis, especially an increased risk of squamous cell carcinoma. Additionally, the regimen may have limited long term utility in patients previously unresponsive to PUVA treatment. After treatment, considerable percentage of the formerly PUVAresistant patients had experienced flare-ups or needed relatively high maintenance doses of UVA (2) In patients with moderate-to-severe psoriasis, remission can be difficult to be achieved and sustained. No optimal information is found about the average length of remission (12). As regards the number of patients who relapsed during the follow-up period (12 weeks), no significant statistical difference was found between both groups. Similar results were reported in previous studies (4,5). As regards side effects, both groups reported occurrence of minimal and short-term side effects in the form of gastritis and abdominal pain. In group B, some patients suffered from erythema, itching, and mild anemia plus the gastrointestinal side effects of methotrexate. However, no significant statistical difference was found between both groups. Similar results were reported in the previous studies (4,5). However, Asawanonda and Nateetongrungsak (5) reported generalized hyper pigmentation in
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DOI: 10.3109/09546634.2015.1034069
Combination therapy of methotrexate plus NBUVB phototherapy
all patients and erythroderma in some patients that we have not detected in our patients. There were no significant predictors for the occurrence of side effects and relapse of the disease in group B. In group A, the most important predictors for the occurrence of side effects and relapse are the age of the patient and the cumulative dose of MTX. The risk of increased incidence of non-melanoma skin cancer remains the limiting factor for the use of MTX/NBUVB combination therapy. But up till now, this remains largely theoretical because both MTX and NBUVB have not been conclusively linked to increased incidence of cutaneous and noncutaneous malignancies (4,13,14). The present study supported the concept that the combination of MTX and NBUVB phototherapy is a useful, effective, and relatively safe treatment for chronic plaque psoriasis. This combination leads to marked improvement in psoriatic lesions in a significant less time and a significant lower dose of MTX. MTX remains the mainstay in the treatment of psoriasis in developing countries because of its cheapness. Its combination with other agents offers a cheap and clinically beneficial therapeutic option. Clinical and investigational studies to increase the efficacy of MTX, to decrease its cumulative dose and consequently its side effects should be encouraged. Future research on other combination regimens and larger number of patients is recommended to establish how these therapies will expand and/or support the established psoriasis treatment protocols.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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Appendix The CONSORT diagram:
Assessed for eligibility (n=55)
Excluded (n=15 ) • Not meeting inclusion criteria (n=11) • Declined to participate (n=4)
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Randomized (n=40)
Allocated to intervention (n=20) • started allocated intervention (n=20) • completed allocated intervention (n=18) • Did not complete intervention (n= 2 patients were lost and excluded from the study)
Allocated to intervention (n=20) • started allocated intervention (n=20) • completed allocated intervention(n=17) • Did not complete allocated intervention (n=3) due to disease exacerbation in 2 patients and I patient was lost and excluded from the study)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n= 0)
Analysed (n=18) • Excluded from analysis (n=0 )
Analysed (n=17) • Excluded from analysis (n= 0)
