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Keywords:

  • background characteristics;
  • classification of changes in severity;
  • long-term efficacy;
  • psoriasis vulgaris;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Various therapies have been tried for psoriasis. In Japan, biologics began to be used for psoriasis treatment in January 2010. Their clinical efficacy is well known, but biologics cannot be used in all psoriasis patients for reasons such as side-effects and cost. It is necessary to evaluate the effect of long-term psoriasis treatment, but there have been no reports evaluating long-term treatment. Therefore, the outcomes of patients who had been treated at the Tokai University Hospital for more than 5 years, before biological agents were released, were examined. Three categories, classified by initial severity, changes in severity by method of treatment and background characteristics, were investigated. In conclusion, cases of long-term treatment with a combination of topical corticosteroid and topical vitamin D3 analog or oral cyclosporin were found to be effective therapies. Patients with a history of diabetes mellitus or cardiovascular disease of psoriasis were likely to be treatment resistant.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

There are a variety of treatments for psoriasis, including topical, oral, phototherapy and biologics. Many options for psoriasis treatment are currently available. The treatment of psoriasis targets a Psoriasis Area and Severity Index (PASI) score of 0 when using biologics, but because biological agents are expensive and have side-effects, they cannot be used in all cases. The problem with psoriasis treatment until now has been that there has been no way to cure the condition, and treatment evaluation was short term. This study evaluated long-term outcomes, looking at the relationships between treatment outcomes and initial severity, type of treatment and background characteristics. Since the opening of Tokai University Hospital in 1975, a specialized outpatient clinic has been provided for the treatment of psoriatic patients. Thus, the subjects were patients with psoriasis vulgaris given non-biological treatments seen at Tokai University Hospital between the years 1975 and 2010.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subjects

Of the total 1862 patients who visited the outpatient clinic of the Department of Dermatology, Tokai University Hospital, Kanagawa, Japan, and diagnosed as having psoriasis from 1975–2010, 232 cases that had been followed up for at least 5 years were evaluated.

Evaluation of severity

Severity was evaluated based on the body surface area (BSA) involved: mild, BSA of less than 10%; moderate, BSA of 10–30%; and severe, of BSA more than 30%.

Study design examining changes in severity classified by initial severity

The treatment effect was examined and compared over various durations of long-term follow up. For example, in patients who were followed for 10 years, the changes in severity from baseline at 5 and 10 years were compared. Similarly, in patients who had been followed for 20 years, the changes in severity from baseline were compared at 20, 15, 10 and 5 years. Therefore, these changes were compared in patients with at least 10 years of follow up.

Statistics

Statistical analyses were conducted using the SPSS statistical package ver. 19.0. Background characteristics were compared using the sign test, and the Z-test was used to compare period of treatment. Values of P < 0.05 were considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Characteristics of patients

A total of 232 patients (167 males, 65 females) were studied. At the time of diagnosis, their ages ranged 8–80 years (mean age, 42.89 ± 16.38). The disease duration ranged 6–51 years (mean duration, 22.75 ± 10.74). The numbers of mild, moderate and severe cases were 121, 76 and 35, respectively.

Changes in severity by follow-up period

A total of 111 of 232 cases were followed for more than 5 years; at the time of diagnosis, there were 59 mild cases, 32 moderate cases and 20 severe cases. A total of 47 cases were followed for more than 10 years; at the time of diagnosis, there were 24 mild cases, 20 moderate cases and three severe cases. A total of 29 cases were followed for more than 15 years; at the time of diagnosis, there were 18 mild cases, seven moderate cases and four severe cases. A total of 20 cases were followed for more than 20 years; at the time of diagnosis, there were five mild cases, 10 moderate cases and two severe cases. A total of 23 cases were followed for more than 25 years; at the time of diagnosis, there were 14 mild cases, five moderate cases and four severe cases. A total of six patients was followed for more than 30 years; at the time of diagnosis, there were two mild cases, two moderate cases and two severe cases. A total of three cases were followed for more than 35 years; at the time of diagnosis, there was one mild case, one moderate case and one severe case (Table 1).

Table 1. Changes in severity over different follow-up periods
Follow-up durationSeverity at the first visit (%)Severity at the last visit (%)
5 yearsMild60.46Mild51.16
Moderate9.3
Severe0
Moderate22.48Mild11.62
Moderate10.85
Severe0
Severe17.82Mild6.97
Moderate10.07
Severe0.77
10 yearsMild42.64Mild36.76
Moderate5.88
Severe0
Moderate39.7Mild30.88
Moderate7.35
Severe1.47
Severe17.64Mild10.29
Moderate7.35
Severe0
15 yearsMild50Mild41.17
Moderate8.82
Severe0
Moderate38.23Mild20.58
Moderate14.7
Severe2.94
Severe11.76Mild11.76
Moderate0
Severe0
20 yearsMild36.36Mild36.36
Moderate0
Severe0
Moderate45.45Mild27.27
Moderate18.18
Severe0
Severe18.18Mild9.09
Moderate4.54
Severe4.54
25 yearsMild71.42Mild57.14
Moderate7.14
Severe7.14
Moderate14.28Mild14.28
Moderate0
Severe0
Severe14.28Mild0
Moderate14.28
Severe0
30 yearsMild40Mild40
Moderate0
Severe0
Moderate40Mild40
Moderate0
Severe0
Severe20Mild0.66
Moderate0.66
Severe0.66
35 yearsMild33.33Mild33.33
Moderate0
Severe0
Moderate33.33Mild33.33
Moderate0
Severe0
Severe33.33Mild33.33
Moderate0
Severe0

Changes in severity classified by initial severity

Severity was evaluated every 5 years and compared to the severity at the initial visit. From these results, it was found that symptoms were relieved by continuing treatment (Fig. 1).

image

Figure 1. Changes in severity classified by initial severity. Initial severity was classified as (a) severe, (b) moderate and (c) mild. The black bar shows severe cases, the gray bar moderate cases and the light gray bar mild cases.

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There were significant differences in exacerbations (P = 0.0079) and unchanged cases (P = 0.0382) between 5 and 10 years of follow up, but not in cases of improvement (P = 0.47); in other periods, there were no significant differences (Fig. 2; Table 2).

Table 2. Comparison of severity by follow-up period
Consultation period for comparisonImprovementUnchangedExacerbation
P-valueP-valueP-value
5 years10 years0.470.04<0.01
15 years0.980.440.2
20 years0.460.470.6
25 years0.350.090.12
30 years0.210.280.44
35 years0.260.29
10 years15 years0.560.320.28
20 years0.820.440.04
25 years0.610.650.78
30 years0.370.920.14
35 years0.330.54
15 years 20 years0.510.950.18
25 years0.390.280.64
30 years0.240.540.25
35 years0.270.4
20 years25 years0.780.340.11
30 years0.490.580.56
35 years0.380.41
25 years30 years0.670.830.18
35 years0.450.65
30 years35 years0.590.59
image

Figure 2. Comparison of different severities by follow up. The pink bar shows exacerbations, the green bar unchanged and the blue bar improvement.

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Changes in severity by method of treatment

Cases involving topical therapy alone were investigated, and oral therapy and phototherapy, regardless of the existence and type of external application, were also investigated (Table 3).

Table 3. Methods of treatment
 Total numberMales (n)Females (n)Average follow-up period (years)
  1. n, number of patients.

Topical corticosteroid50302013.76 ± 7.84
Combination of topical corticosteroid and vitamin D3 analog88612713.5 ± 8.10
Vitamin D3 analog4316 ± 0.81
Cyclosporin231857.17 ± 3.55
Etretinate119218.63 ± 10.31
Phototherapy2421316.45 ± 10.21

For external application, topical corticosteroid was applied alone in 50 patients (30 males, 20 females). At the time of diagnosis, there were 44 mild cases (88.0%), six moderate cases (12.0%) and no severe cases. The average follow up was 13.76 ± 7.84 years, with the longest follow up being 30 years. Combination therapy of topical corticosteroid and vitamin D3 analog was given to 88 patients (61 males, 27 females). At the time of diagnosis, there were 53 mild cases (60.2%), 30 moderate cases (34.09%) and five severe cases (5.68%). The average follow up was 13.5 ± 8.10 years. Patients treated with only vitamin D3 analog included four cases (three males, one female). At the time of diagnosis, there were three mild cases (75.0%), one moderate case (15.0%) and no severe cases. The average follow up was 6 ± 0.81 years, with 7 years as the longest follow up (Fig. 3).

image

Figure 3. Changes in severity by method of topical treatment. (a) Topical corticosteroid, (b) combination therapy with topical corticosteroid and vitamin D3 analog, and (c) vitamin D3 analog. The black bar shows severe cases, the gray bar moderate cases and the light gray bar mild cases.

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For oral administration, cyclosporin was given to 23 patients (18 males, five females). At the time of diagnosis, there were four mild cases (17.39%), 10 moderate cases (43.47%) and nine severe cases (39.13%). The longest follow up was 18 years. Etretinate was given to 11 patients (nine males, two females). At the time of diagnosis, there were five mild cases (45.45%), five moderate cases (45.45%) and one severe case (1.81%; Fig. 4). Methotrexate treatment was not investigated because it is not covered by health insurance for psoriasis in Japan.

image

Figure 4. Changes in severity by method of oral therapy and phototherapy treatment. (a) Cyclosporin, (b) etretinate and (c) phototherapy. The black bar shows severe cases, the gray bar moderate cases and the light gray bar mild cases.

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A total of 24 patients (21 males, three females) received phototherapy. At the time of diagnosis, 10 cases (41.60%) were mild, 12 were moderate (50.0%) and two were severe (8.33%). The average number of years of follow up was 16.45 ± 10.21 years (Fig. 4).

Changes in severity at the time of the final evaluation compared to the first visit by method of treatment

Of the topical corticosteroid alone cases, 8.0% showed improvement, 84.0% was unchanged and 8.0% showed exacerbation. In patients treated with vitamin D3 analog alone, 25.0% showed improvement, 75.0% were unchanged and none showed exacerbation. In patients treated with combination topical corticosteroid and topical vitamin D3 analog, 31.0% showed improvement, 62.0% were unchanged and 7.0% showed exacerbation. In cases of improvement, there was a significant difference between combination topical corticosteroid and topical vitamin D3 analog and topical corticosteroid alone (P = 0.0021). Of the oral cyclosporin-treated patients, 78.0% showed improvement, 22.0% were unchanged and none showed exacerbation. Of the etretinate-treated patients, 55.0% showed improvement, 36.0% were unchanged and 9.0% showed exacerbation. No significant difference was observed between the two oral drugs in patients with improvement. Of the 8-methoxypsoralen ultraviolet A (PUVA)-treated patients, 40% showed improvement, 33.3% were unchanged and 26.6% showed exacerbation. Of the patients receiving both PUVA and ultraviolet (UV)-B, 80.0% showed improvement and 20.0% were unchanged. Of the patients receiving only UV-B, 100% showed improvement. Of the patients treated by narrowband ultraviolet UV-B (NB-UVB), 50.0% showed improvement and 50.0% were unchanged (Fig. 5).

image

Figure 5. Changes in severity at the time of the final evaluation compared to the first visit by method of treatment. (a) Topical treatment, (b) oral therapy and (c) phototherapy. The pink bar shows exacerbations, the green bar unchanged and the blue bar improvement. NB, narrowband; PUVA, psoralen plus ultraviolet A therapy; UVB, ultraviolet B.

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Background characteristics

To determine whether there were significant differences between the background characteristics and changes in severity, the following background characteristics were examined: sex, age of onset, family history, past history, concomitant symptoms, complications and blood test results. Psoriasis patients with a history of diabetes mellitus (P = 0.01) or cardiovascular disorders (P = 0.05) were treatment resistant (Table 4).

Table 4. Changes in background factors and severityThumbnail image of

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

It has been reported that 39% of cases achieved complete remission in a large study.[1] It has also been known that, during periods of long-term care, spontaneous disappearance is not rare. However, the majority of cases require long-term treatment. The methods of psoriasis treatment include topical corticosteroid, vitamin D3 analogs, cyclosporin, etretinate and phototherapy. Biological agents, such as tumor necrosis factor-α inhibitor, since 2010, and anti-interleukin-12/23p40 antibody, since 2011, are also available in Japan. Given that these new methods of treatment have recently become available, it appears to be a good time to re-evaluate earlier treatments. In this study, patients who had been followed up for more than 5 years were evaluated at 5-year intervals to determine the outcomes of psoriasis treatment.

According to a paper that examined the prognosis of 211 patients with psoriasis, there was a cure of cutaneous findings in 8%, improvement in psoriasis in 58%, 12% were unchanged and 7% showed exacerbation.[2] There were significant differences between 10 and 5 years of follow up in severity, especially in cases of deterioration and unchanged. Motivation of the patient to continue therapy is important to obtain good long-term results. For patients to continue treatment, it is necessary to stabilize the symptoms. Therefore, changes in severity with different treatment methods were examined. Cases that underwent systemic therapy at two or more visits during the period were excluded from the study.

The first part of the study dealt with topical therapy. Significantly more mild cases were treated with a combination of topical corticosteroid and topical vitamin D3 analog than with topical corticosteroid alone. The effect of topical corticosteroid treatment appears early, but the problems with topical corticosteroid treatment include early relapse, suppression of adrenal function, skin atrophy and tachyphylaxis. On the other hand, the therapeutic effect of vitamin D3 analog appears slowly, and the side-effects include an increase in blood calcium levels and stimulation.[3] Stimulation by vitamin D3 analog is relieved by combination treatment with topical corticosteroid.[4] Approximately 70–90% of patients use topical therapy.[5-7] With the large number of cases and the long follow-up period in the present study, a better effect was found with the combination of topical corticosteroid and topical vitamin D3 analog than with topical corticosteroid alone. Another problem with most topical therapies is that patient motivation is low because of the time needed for symptomatic improvement. It is important to develop ways to maintain patient motivation during topical therapy.

The second part of the study focused on oral therapy. Etretinate was studied, excluding re-PUVA or re-NB-UVB. The present results show that cyclosporin had a better therapeutic effect than etretinate. However, BSA was used in this evaluation, which does not independently evaluate erythema, thickening and scaling. Etretinate takes longer to relieve erythema than scale or thickening. On the other hand, cyclosporin provides faster improvement of erythema. This may explain why cyclosporin appeared better than etretinate. The problems with long-term oral cyclosporin are impairment of renal function and carcinogenesis.[8] Outside of Japan, 1 or 2 years of oral cyclosporin is considered the maximal duration of therapy,[9-11] and it is expected that a time limit for oral administration will also be adopted in Japan in the future. Griffiths et al. suggested that rotation therapy is effective, because patients cannot be maintained on long-term oral cyclosporin.[10]

For phototherapy, a 20-year cohort study of psoriasis patients who underwent PUVA therapy concluded that remission was achieved in approximately 10% of patients, and improvement was seen in approximately 40%.[12] The present results for PUVA therapy showed improvement in 41.6% of cases, matching the previous reports. In addition, trends in severity over time were also investigated by type of phototherapy. The present results showed that broadband UV-B (BB-UVB) and NB-UVB were better than PUVA. Archier et al. reported that the clearance rate of psoriasis was approximately 80% with PUVA versus 70% with NB-UVB.[13] The difference between the present result and that of Archier et al. may be due to the difference in the follow-up period, and the number of cases in the present study was less than in the study by Archier et al.[13]

Finally, the relationships between background characteristics and treatment outcomes were examined, referring to the items listed in the registration cards of the Japanese Society for Psoriasis Research. There appears to be a relationship between a family history of juvenile onset psoriasis and severity.[14] There has been a report about psoriasis patients and their background characteristics, examining metabolic syndrome, which includes diabetes insulin resistance, dyslipidemia and hypertension.[15] Based on the results of the present study, patients with diabetes mellitus or cardiovascular disorders were considered likely to be treatment resistant. In recent years, there have been many reports dealing with psoriasis and cardiovascular disorders. It has been found that patients with both are resistant to treatment. To our knowledge, no evidence has been reported in the English-language published work previously.

In summary, it is necessary to continue long-term treatment of psoriasis, and the present study showed that a combination of topical corticosteroid and topical vitamin D3 analog was better than corticosteroid alone, and oral cyclosporin was more effective than etretinate. Patients with diabetes mellitus or cardiovascular disorders were found likely to be resistant to treatment of any kind. A quantitative analysis could not be performed in this study because BSA was used instead of the PASI. Future studies will need to use the PASI score to obtain more accurate results. Furthermore, instead of considering the follow-up period and the method of treatment separately, they should be considered together, and a multicenter study is needed. Psoriasis treatment prior to the introduction of biological agents was reviewed. Instead of blindly using biological products together with the traditional psoriasis treatment, it is necessary to review previous treatment.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This work was supported by the Torii/Teikoku 2011 research award from the Japanese Society for Psoriasis Research.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  • 1
    Griffiths CEM, Camp RDR, Barker JNWN. Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths C eds. Rook's Textbook of Dermatology, 7th edn. Massachusetts: Blackwell Science, 2004; 35: 2021.
  • 2
    Ohtsubo H, Kohda H. A statistical study of psoriasis at Saga Medical School Hospital during 1981–1991. Nishinihon J Dermatol 1993; 55: 8691.
  • 3
    Van de Kerkhof PC, Barker J, Griffiths CE et al. Psoriasis: consensus on topical therapies. J Eur Acad Dermatol Venereol 2007; 22: 859870.
  • 4
    Van de Kerkhof PC, Vissers WHPM. Established treatment of psoriasis. Current drug-targets. Inflamm Allergey 2004; 3: 145146.
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    Pearce DJ, Spencer L, Hu J et al. Psoriasis and phototherapy. J Dermatol Treat 2004; 15: 235238.
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    Kawada A, Tezuka T, Nakamizo Y et al. A survey of psoriasis patients in Japan from 1982 to 2001. J Dermatol Sci 2003; 31: 5964.
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    Takahashi H, Nakamura K, Kaneko F et al. Analysis of psoriasis patients registered with th Japanese Society for Psoriasis Research from 2002-2008. J Dermatol 2011; 38: 11251129.
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    Paul CF, Ho VC, McGeoum C et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol 2003; 120: 211216.
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    Menter A, Korman NJ, Elmets CA et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009; 61: 451485.
  • 10
    Griffiths CE, Dubertret L, Ellis CN et al. Ciclosporin in psoriasis clinical practice: an international consensus statement. Br J Dermatol 2004; 150(Suppl 67): 1123.
  • 11
    Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23(Suppl 2): 570.
  • 12
    Nijsten T, Looman CWN, Stern SR. Clinical severity of psoriasis in last 20 years of PUVA study. Arch Dermatol 2007; 143: 11131121.
  • 13
    Archier E, Devauz S, Castela E et al. Efficacy of psoralen UV-A therapy vs. Narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol 2012; 26(Suppl 3): 1121.
  • 14
    Stuart P, Malick F, Nair RP et al. Analysis of phenotype variation in psoriasis as a function of age at onset and family history. Arch Dermatol Res 2002; 294: 207213.
  • 15
    Takahashi H, Iizuka H. Psoriasis and metabolic. J Dermatol 2012; 39: 212218.