Vitiligo is the most frequent depigmentation disorder of the skin, which is cosmetically and psychologically devastating . It affects approximately 1 to 2% of the world population and may occur at any age [2,3].
It is characterized by the appearance of white macules that may spread over the entire body skin. Depigmentation arises from the loss of functioning melanocytes . It is an acquired progressive disorder in which some or all of the melanocytes in the interfollicular epidermis, and occasionally those in the hair follicles, are selectively destroyed .
Vitiligo lesions may be localized or generalized, with the latter being more common than the former. Localized vitiligo is either segmental, where it is restricted to one general area with a dermatomal distribution, or focal vitiligo, where one or more isolated macules are present in one general anatomic area . Generalized vitiligo implies more than one general area of involvement. It is either in the form of scattered macules (vulgaris) or the macules are present on the face and extremities (acrofacial) or nearly total body involvement (universal) is observed .
The precise cause of vitiligo is not well understood. Several theories exist to explain the pathogenesis of vitiligo. The underlying pathogenesis of the pigment loss has, however, been clarified to some extent in recent years, offering the prospect of effective treatment, accurate prognosis, and rational preventative strategies. Vitiligo occurs when functioning melanocytes disappear from the epidermis. A single dominant pathway is unlikely to account for all cases of melanocyte loss in vitiligo; rather, it is the result of complex interactions of biochemical, environmental, and immunological events, in a permissive genetic milieu .
The frequent association of vitiligo with other autoimmune diseases such as thyroid disease, diabetes mellitus, pernicious anemia, and alopecia areata supports the immune hypothesis theory .In addition, the neural hypothesis theory, the self-destruction hypothesis , the genetic hypothesis , the apoptotic theory, and the convergence theory are also proposed .
Interleukin-2 (IL-2) is clearly connected with a variety of cellular actions on T and B lymphocytes, natural killer cells, macrophages, monocytes, oligodendrocytes, and fibroblasts . It is a lymphokine synthesized and secreted by T-helper lymphocytes. It stimulates the production of IL-2 receptor-α on the T-cell surfaces. It is then released to the serum as a measurable protein, soluble interleukin-2 receptor (sIL-2R) .
Today, vitiligo is a treatable condition, although treatment can take a period of 2 years or even longer to regain pigments, even though repigmentation may not be 100% . The response to therapy is highly variable and patients should be made aware of the risks associated with the therapy .
Narrow-band UVB (NB-UVB) phototherapy was developed and is widely used with good clinical results . NB-UVB microphototherapy is also used, which targets specific small lesions .
Systemic steroids have been used, although their prolonged use and toxicity are undesirable. Benefits and toxicity of this therapy must be weighed carefully. More research is necessary to establish the safety and effectiveness of this therapy for vitiligo .
Methotrexate, an immunosuppressive drug, has been successfully used for the treatment of psoriasis and other skin diseases . However, to the best of our knowledge, its role in treating patients with vitiligo has not been investigated before. This study aimed to compare the effectiveness of methotrexate, NB phototherapy, and corticosteroid as three different treatment modalities for vitiligo.
Patients and methods
This study is a prospective randomized open-label clinical trial study. It included 52 patients (26 men and 26 women) with nonsegmental vitiligo and 20 healthy participants who served as controls who were age and sex matched with the patients. All participants were recruited from the Dermatology Outpatient Clinic, National Research Center (Cairo, Egypt).
- (1) Patients who received any systemic medication, phototherapy for 4 weeks, or topical treatment for 2 weeks before sample collection;
- (2) Patients under 18 years of age;
- (3) Pregnant and lactating women;
- (4) Patients with history of any systemic or dermatological disease affecting the immune system, such as autoimmune diseases (e.g. alopecia areata, thyroid disease, pernicious anemia) and malignancy confirmed by investigating the complete blood picture, erythrocyte sedimentation rate, and thyroid-stimulating hormone.
Patients were randomly allocated to treatment groups using a simple random table:
- (1) Group 1: included patients who received NB phototherapy (NB-UVB) three times weekly (n=16);
- (2) Group 2: included patients who received methotrexate (12.5 mg) intramuscularly once weekly (n=19);
- (3) Group 3: patients who received corticosteroids in the form of triamcinolone acetonide intramuscularly injection (Kenacort, USA) every 3 weeks plus mometasone (Elocon, USA) cream once daily (n=17).
Informed consent was taken from all participants before their participation in this study. The study was approved by the Ethics Committee of the National Research Centre, Cairo, Egypt.
The patients were subjected to the following procedures:
Full history taking
- (1) Full general and dermatological examination for the site and distribution of the lesions was made;
- (2) For estimation of sIL-2R, venous blood sample was collected from each patient on the initial visit before receiving any type of treatment, as well as from the control group. Another blood sample (approximately 2 ml) was withdrawn from patients after 6 months of treatment. The blood samples were left to clot and the serum were separated by centrifugation and stored at −20°C. Determination of sIL-2R was by quantitative sandwich enzyme-linked immunoassay technique  and the kit supplied from R&D system (R&D system, Inc., 614 McKinely Place, Minneapolis, USA);
- (3) Liver and kidney function tests were conducted for those subjected to methotrexate therapy every month for 6 months, the period of evaluation of therapy;
- (4) Post treatment clinical evaluation after 6 months was conducted, including response to treatment and presence or absence of signs of improvement as erythema and perifollicular pigmentation.
SPSS statistical software package [version 15 (Chicago, IL, USA)] was used for data analysis. While comparing between two independent mean groups for parametric data, the Student's t-test was used. Comparison between the two independent groups for nonparametric data was carried out using the Mann–Whitney test. Analysis of variance was used for comparison between more than two patient groups for parametric data, followed by multiple comparisons using least significant difference to evaluate the significance between each of the two subgroups. To find the relation between two continuous variables, the Pearson's correlation test was used. A P value of less than 0.05 was taken as a significant level.
The study included 52 patients with vitiligo with mean age±standard deviation (35.6±15.7) and 20 healthy participants with mean age±standard deviation (31.8±8.7) who served as the control group. There was no statistically significant difference between cases and control regarding age and sex (P>0.05) as shown in Table 1. The table also shows that the serum level of sIL-2R was significantly higher among patients compared with controls before treatment, whereas no significant difference was detected after treatment.
Table 2 shows no statistically significant difference between the three studied groups of patients regarding age, sex, age of onset, disease duration, family history of vitiligo, and exposure to either stress or sun.
Table 3 shows a highly statistically significant lowering of serum level of serum sIL-2R among both NB and corticosteroid-treated patients, whereas the decrease was not statistically significant among those treated with methotrexate. However, while comparing the three treatment modalities before or after treatment, no significant difference was shown.
No statistically significant difference was detected between the three groups of patient regarding severity after treatment (Table 4).
Table 5 shows the degree of response to the three modalities among patient groups; there was no statistically significant difference between the three groups.
Table 6 shows the difference in degree of patient satisfaction to the three modalities of treatment; the difference was statistically significant. On comparing degree of patient satisfaction among different groups the following results were obtained:
- (1) NB versus methotrexate→significant;
- (2) NB versus corticosteroids→nonsignificant;
- (3) Methotrexate versus corticosteroids→significant.
Patients who received methotrexate significantly reported least satisfaction compared with the other groups.
Table 7 shows statistically significant negative correlation between patient satisfaction and serum level of sIL-2R after treatment.
Vitiligo is an asymptomatic skin disease characterized by well-circumscribed milky-white cutaneous macules devoid of identifiable functional melanocytes. Patients with this disease are usually burdened by its psychiatric morbidity, which is strongly associated with poorer quality of life .
The exact pathogenesis of vitiligo is not fully understood, but several theories exist to explain it. There is ample evidence of immunological phenomena in vitiligo, as both innate and adaptive arms of the immune system are involved, with a dominant role for T cells .
Several studies reported that sIL2-R levels are raised in patients with vitiligo as the lymphocytes were found to be directly involved in the destruction of the melanocytes .
NB-UVB phototherapy as well as both systemic and topical steroids are widely used with good clinical results .
In an attempt to investigate the therapeutic role of methotrexate in vitiligo, this study investigated the efficacy of methotrexate in treating different types of vitiligo and compared it with the other classical forms of vitiligo treatment such as steroids and NB. Moreover, comparison of the effectiveness of these three treatment modalities with sIL2-R before and after treatment was performed.
We were able to show in this study a highly significant increase in serum level of sIL-2R in vitiligo cases compared with the controls. This is in agreement with Honda et al. , Caixia et al. , and Yeo et al. , as they found that the overall levels of serum sIL-2R of the patients with vitiligo were significantly higher than those of the normal control group. Moreover, on comparing the three groups with each other regarding serum levels of sIL-2R, no statistically significant difference was detected.
Our results thus support the findings of Xu et al. , who pointed out that nonsegmental vitiligo is related to immunity, as the increase of sIL-2R level is a sign of T cell activation .
In this study, a highly statistically significant lowering of serum level of sIL-2R among both NB and corticosteroid-treated patients was noted, whereas the decrease was not statistically significant among those treated with methotrexate. This may be explained by the fact that many of the patients included in this study showed poor compliance to their follow-up visits. Moreover, we were unable to prolong the follow-up period of the study due to the expiry date of the kits used and the time limit of the project.
A difference in the degree of response to the three treatment modalities was noted but the difference was not statistically significant. On comparing response of treatment among different groups, the results showed that a nonsignificant difference was found between NB-UVB versus methotrexate, NB-UVB versus corticosteroids, and methotrexate versus corticosteroids. This, in our opinion, points the efficacy of all three treatment modalities in treating vitiligo. We, furthermore, tested the degree of patient satisfaction to the three treatment modalities and the difference was found to be statistically significant.On comparing degree of patient satisfaction among the different groups, NB-UVB versus methotrexate and methotrexate versus corticosteroids were found to be significant. However, NB-UVB versus corticosteroids was not significant. Patients receiving methotrexate significantly reported the least satisfaction compared with the other groups.
There is no evidence that the presently available systemic treatments are helpful and safe in the treatment of vitiligo. There is a need for further research into the causes of vitiligo, and into discovering better treatments  as some studies reported that targeted NB-UVB phototherapy plus topical tetrahydrocurcuminoid cream was slightly more effective than targeted NB-UVB monotherapy for vitiligo located in UV-sensitive areas; however, the differences in degrees of repigmentation did not reach statistically significant levels . Other studies reported that addition of topical tacrolimus increases the extent of overall repigmentation achieved with NB-UVB therapy in vitiligo and also reduces the cumulative NB-UVB dose needed to achieve a therapeutic benefit in affected patients . Hence, recent advances in the pathogenesis of vitiligo have contributed to find better treatments.
Furthermore, we recommend that methotrexate should be investigated on a larger scale of patients in a future study as it could possibly be beneficial for these patients.
1. Eleftheriadou V, Whitton ME, Gawkrodger DJ, Batchelor J, Corne J, Lamb B, et al. Future research into the treatment of vitiligo
: where should our priorities lie? Results of the vitiligo
priority setting partnership. Br J Dermatol. 2011;164:530–536
2. Nath SK, Majumder PP, Nordlund JJ. Genetic epidemiology of vitiligo
: multilocus recessivity cross-validated. Am J Hum Genet. 1994;55:981–990
3. Hann SKLotti T, Hercogova J. Clinical variants of vitiligo
: Problems and Solutions. 2004 New York, NY Marcel Dekker:159–173
4. Guerra L, Dellambra E, Brescia S, Raskovic D. Vitiligo
: pathogenetic hypotheses and targets for current therapies. Curr Drug Metab. 2010;11:451–467
5. Njoo MD, Vitiligo
WW. Pathogenesis and treatment. Am J Clin Dermatol. 2001;2:167–181
6. Hann SK, Nordlund JJHan SK, Nordlund JJ. Definition of vitiligo
. 2000 London Blackwell Science:3–5
7. Gottumukkala RV, Gavalas NG, Akhtar S, Metcalfe RA, Gawkrodger DJ, Haycock JW, et al. Function-blocking autoantibodies to the melanin-concentrating hormone receptor in vitiligo
patients. Lab Invest. 2006;86:781–789
8. Glassman SJ. Vitiligo
, reactive oxygen species and T-cells. Clin Sci (Lond). 2011;120:99–120
9. Jadali Z, Eslami MB, Sanati MH, Mansouri P, Mahmoudi M, Maghsoudi N, et al. Identification of peptides specific for antibodies in vitiligo
using a phage library. Clin Exp Dermatol. 2005;30:694–701
10. Souza Filho LGC, Rivitti EA, Miyauchi LM, Sotto MN, Maria DA, Puejo SST, et al. Comparative study of vitiligo
, halo nevus, and vitiligoid variant of lupus erythematosus by immunological, histological, and immunohistochemical methods. An Bras Dermatol. 2005;80:143–148
11. Aroni K, Grapsa A, Lazaris AC, Kavantzas N, Kordosis T, Patsouris ES. Tissue estimation of protein gene product 9.5 (PGP 9.5) expression and apoptosis in vitiligo
. Int J Dermatol. 2008;47:911–917
12. Manuel SR, Anabela MPBurtis CA, Ashwood ER, Bruns DE. Cytokines. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 2006.4th ed St. Louis, MO Elsevier Saunders:645–744
13. Honda Y, Okubo Y, Koga M. Relationship between levels of soluble interleukin-2 receptors
and the types and activity of vitiligo
. J Dermatol. 1997;24:561–563
14. Hann SKHann SK, Nordlund J. Clinical features of segmental vitiligo
: Monograph on the Basic and Clinical Science. 2000. Oxford, UK Blackwell Science:49–69
15. Menchini G, Lotti T, Tsoureli-Nikita ELotti T, Hercogova J. UV-B narrowband micro phototherapy. Vitiligo
: Problems and Solutions. 2004. New York, NY Marcel Dekker:323–334
16. Taneja A. Treatment of vitiligo
. J Dermatolog Treat. 2002;13:19–25
17. Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate
in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38:478–485
18. Alenius GM, Eriksson C, Rantapää Dahlqvist S. Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis? Clin Exp Rheumatol. 2009;27:120–123
19. Dell'anna ML, Picardo M. A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo
. Pigment Cell Res. 2006;19:406–411
20. Caixia T, Hongwen F, Xiran L. Levels of soluble interleukin-2 receptor in the sera and skin tissue fluids of patients with vitiligo
. J Dermatol Sci. 1999;21:59–62
21. Yeo UC, Yang YS, Park KB, Sung HT, Jung SY, Lee ES, et al. Serum concentration of the soluble interleukin-2 receptor in vitiligo
patients. J Dermatol Sci. 1999;19:182–188
22. Xu XK, Chen Z, He YZ. Observations on the clinical aspect, peripheral T lymphocyte subgroup and autoantibody in segmental and nonsegmental vitiligo
. Clin J Dermatol. 1991;20:178–185
23. Rubin LA, Nelson DL. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med. 1990;113:619–627
24. Gawkrodger DJ, Ormerod AD, Shaw L, Mauri-Sole I, Whitton ME, Watts MJ, et al. Vitiligo
: concise evidence based guidelines on diagnosis and management. Postgrad Med J. 2010;86:466–471
25. Asawanonda P, Klahan SO. Tetrahydrocurcuminoid cream plus targeted narrowband UVB phototherapy for vitiligo
: a preliminary randomized controlled study. Photomed Laser Surg. 2010;28:679–684
26. Majid I. Does topical tacrolimus ointment enhance the efficacy of narrowband ultraviolet B therapy in vitiligo
? A left-right comparison study. Photodermatol Photoimmunol Photomed. 2010;26:230–234