http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–4 ! 2014 Informa UK Ltd. DOI: 10.3109/09546634.2014.933167
REVIEW ARTICLE
Cutaneous lichen planus: A systematic review of treatments Nasim Fazel
J Dermatolog Treat Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/14/14 For personal use only.
Department of Dermatology, University of California, Davis, Sacramento, CA, USA
Abstract
Keywords
Various treatment modalities are available for cutaneous lichen planus. Pubmed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database were searched for all the systematic reviews and randomized controlled trials related to cutaneous lichen planus. Two systematic reviews and nine relevant randomized controlled trials were identified. Acitretin, griseofulvin, hydroxychloroquine and narrow band ultraviolet B are demonstrated to be effective in the treatment of cutaneous lichen planus. Sulfasalazine is effective, but has an unfavorable safety profile. KH1060, a vitamin D analogue, is not beneficial in the management of cutaneous lichen planus. Evidence from large scale randomized trials demonstrating the safety and efficacy for many other treatment modalities used to treat cutaneous lichen planus is simply not available.
Cutaneous, lichen planus, randomized controlled trial, systematic review History Received 14 May 2014 Revised 26 May 2014 Accepted 27 May 2014 Published online 9 July 2014
Abbreviations: CLP: cutaneous lichen planus; LP: lichen planus; NBUVB: narrow band ultraviolet B; PUVA: psoralen plus ultraviolet A; RCT: randomized controlled trial
Introduction
Search strategy
Cutaneous lichen planus (CLP) is a chronic immunologic disease that involves the skin and its appendages including hair and nails. While a wide range of therapeutic modalities have been utilized in the management of cutaneous lichen planus, no single treatment has emerged as the standard of care. Therapies such as topical and systemic corticosteroids, retinoids, calcineurin inhibitors, immunosuppressive agents, phototherapy, and biologics are used to decrease the time to lesion resolution, alleviate patient discomfort, and enhance quality of life. However, high-quality scientific evidence for the effectiveness and safety of many treatment options is lacking. In this article, we systematically review the current literature and discuss all of the randomized controlled trials (RCTs) for CLP.
Terms ‘‘lichen’’ and ‘‘planus’’ were used to search the following databases: Pubmed (1950–1 November 2012), EMBASE (1980–1 September 2012), Cochrane Database of Systematic Reviews (Cochrane Reviews, Issue 8, August 2012), Cochrane Central Register of Controlled Trials (Clinical Trials, Issue 8, August 2012), Database of Abstracts of Reviews of Effects (Other Reviews, Issue 3, July 2012), and Health Technology Assessment Database (Technology Assessments, Issue 3, July 2012). The list of references for the included systematic reviews and RCTs was reviewed.
Materials and methods Eligibility criteria All systematic reviews and RCTs of any design that investigated the efficacy of any therapeutic modality for the treatment of lichen planus with skin, nail and/or hair involvement were considered. RCTs that compared at least one active treatment arm with a control arm, including a placebo, an alternative therapy, or no treatment were included. In all included RCTs, the diagnosis of CLP was confirmed clinically and histopathologically.
Correspondence: Nasim Fazel, MD, DDS, Associate Professor, Department of Dermatology, University of California, Davis, 3301 C Street, Suite 1400, Sacramento, CA 95816, USA. Tel: +916 734 6876. Fax: +916 442 5702. E-mail: [email protected]
Outcome measures Clinical improvement of CLP lesions after 4–8 weeks of treatment was considered the primary outcome measure of the study. Secondary outcomes included complete resolution of CLP after 4–8 weeks of therapy and adverse events. Other endpoints were considered, if the above-mentioned outcomes were not reported. Methodological quality assessment The following criteria were used to assess the methodological quality of the RCTs: randomization, explanation of sequence generation for randomization, explanation of allocation concealment, blindness methods, sample size calculation, evaluating for comparability of baseline data, intention to treat analysis, and patient follow-up after the final treatment. The quality of the trials was categorized into ‘‘high’’ or ‘‘moderate’’. If an RCT qualified for equal or more than half of the criteria, it was considered as a high-quality study.
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N. Fazel
Meta-analysis Review Manager version 5.1.6 was used to perform a metaanalysis, if needed. The comparative results of the dichotomous data were presented as odds ratios (OR) with 95% confidence intervals (CI). The I22 statistic was used to determine statistical heterogeneity. We sought the reasons for heterogeneity, if the I22 value was greater than 50%. The results of the meta-analysis were reported, if the I22 statistic was less than 80%.
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Results Two relevant systematic reviews and nine relevant RCTs were found for CLP (Table 1). Cribier et al. (10) performed a systematic review on cutaneous and mucosal LP. The authors did not limit the evidence to RCTs and included non-randomized controlled trials as well as case series studies. They reported three RCTs involving 137 patients. Additionally, a systematic review by Samycia et al. (11) found no RCTs for pimecrolimus or tacrolimus. Table 2 summarizes the level of evidence and the strength of recommendation of the included treatment modalities. Acitretin In the only randomized trial on CLP, acitretin 30 mg daily for 8 weeks was more efficacious when compared to placebo. About 21 out of 32 patients (65.6%) in the acitretin group and 8 out of 33 (24.2%) in the placebo group showed clinical improvement. Adverse events such as dryness of the mouth, lips, nose and skin and hair loss occurred more frequently in the acitretin group than the placebo group (87.5% versus 51.5%, respectively) (1). Vitamin D analogues (KH1060 and calcipotriol) KH1060 is a vitamin D3 analogue that has been used in clinical trials. It has the same potency as 1,25-dehydroxyvitamin D3 in calcium metabolism. In vitro and in vivo studies showed that it can affect immunologic responses and cell growth (12–14). Two randomized placebo-controlled trials investigated the efficacy of KH1060 1 mg/g ointment twice daily in comparison with placebo in CLP patients, and neither of them indicated a significant benefit for KH1060 (2,3). No serious side effects were reported with KH1060 treatment (2,3). Another randomized trial compared calcipotriol 50 mg/g ointment with betamethasone 0.1% ointment and found no significant difference in their efficacy (4). Side effects of pruritus and erythema were more frequent with calcipotriol in comparison with betamethasone (20% versus 0%, respectively) (4). Sulfasalazine An RCT compared oral sulfasalazine (initial dose of 1 g/day, increasing 0.5 g every 3 days up to 2.5 g/day) with placebo. The study noted greater clinical improvement of generalized lichen planus (LP) with sulfasalazine treatment (80.7%) as compared to placebo (7.6%). In this RCT, eight patients in the sulfasalazine group experienced adverse effects such as headache, nausea, epigastric pain and mild truncal rash. Additionally, three patients abandoned the study due to side effects such as nausea, epigastric pain, diarrhea, leukopenia, and low grade fever (5). Hydroxychloroquine In an RCT, Bhuiyan et al. compared hydroxychloroquine (400 mg daily) with griseofulvin (500 mg daily) for 6 months. They reported a significantly better clinical response in patients treated with hydroxychloroquine (70%) as compared to patients treated
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with griseofulvin (42.5%). No serious adverse events were reported for hydroxychloroquine (6). Griseofulvin Sehgal et al. compared griseofulvin 500 mg/day with placebo. They found significantly higher clinical improvement with griseofulvin (91.6%) as compared to placebo (20.8%). Complete clinical response followed the same pattern (7). In a similar study, complete resolution of CLP was higher with griseofulvin (63.1%) than placebo (31.5%) as well (8). We performed a meta-analysis to compare the complete resolution of the lesions after the treatment with griseofulvin and placebo. The results were not reported because the I2 value was 82%, which is an indicator of the statistical heterogeneity between these two studies (7,8). Both Bhuiyan et al. (6) and Sehgal et al. (8) reported no side effects for griseofulvin. Narrow band ultraviolet B Narrow band ultraviolet B (NBUVB) treatment (70% MED at the maximum dose of 9 J/cm2) 3 times a week has been compared to oral prednisolone (0.3 mg/kg) for the treatment of patients with generalized LP in a 6-week trial. NBUVB and oral prednisolone improved the CLP lesions. However, NBUVB had a better complete clinical response rate than systemic prednisolone (52.1% versus 13%, respectively). Patient satisfaction was higher with NBUVB as well (9). No serious adverse events were reported for NBUVB phototherapy (9).
Discussion Laurberg et al. (1) showed that acitretin is effective and can be considered in the treatment of CLP; but patients must be monitored closely for potentially serious side effects. Acitretin is highly teratogenic, and can cause serious skeletal and metabolic defects in the fetus. Therefore, women must strictly avoid pregnancy for at least 3 years after the discontinuation of the medication. The teratogenic side effects of acitretin require adequate contraception and regular pregnancy testing during the course of therapy. Moreover, it is recommended that patients undergo testing of liver enzymes and lipid levels every 3 months to monitor for liver side effects and hyperlipidemia (15). The side effects are less threatening in men. The safety/efficacy ratio of acitretin should be thoroughly discussed with the patient. The only available RCT on sulfasalazine demonstrates remarkable efficacy with an unfavorable safety profile. Also, in an uncontrolled study, severe side effects of gastric pain, poor glycemic control, fever and cutaneous rash occurred during the course of sulfasalazine therapy resulting in discontinuation of the medication in 20% of patients (16). Sulfasalazine should only be reserved for generalized LP or severe flares in which case patients need to be monitored closely for side effects. Reports in the literature are inconsistent concerning the efficacy of griseofulvin for the treatment of CLP. In an uncontrolled study, Massa and Rogers noted that griseofulvin improved oral lichen planus lesions better than cutaneous lesions (17). Bhuiyan et al. (6) found griseofulvin to be less effective than hydroxychloroquine in the treatment of CLP. Side effects of griseofulvin included headache, facial pain, nausea, vomiting and diarrhea in up to 50% of patients treated with griseofulvin in a trial (18). Although Sehgal et al. (7,8) showed that griseofulvin is an effective drug for CLP, the non-randomized studies debate against the efficacy (6,17) and safety (18) of this drug. Phototherapy can be considered as a treatment option for generalized LP. In a retrospective non-randomized controlled
23 vs 23
19 vs 19 (17 vs 17)
24 vs 24 (22 vs 22)
40 vs 40
Hydroxychloroquine 400 mg vs griseofulvin 500 mg; daily Oral griseofulvin 500 mg vs placebo; daily Oral griseofulvin 500 mg vs placebo; daily NBUVB therapy 3 times weekly vs oral prednisolone 0.3 mg/kg/ day
Oral sulfasalazine (initial dose of 1 g/day, increasing 0.5 g every 3 days up to 2.5 g/day) vs placebo
No significant difference (details have not been provided) Clinical improvement and/or complete resolution: 37% vs 42%, p40.05 Thickness improvement: 7/15 (46.6%) vs 8/16 (50.0%), p40.05
21/32 (65.6%) vs 8/33 (24.2%), p50.05
Clinical improvement
–
29.4
3.1 7.6
4–6 weeks 12/19 (63.1%) vs 6/19 (31.5%), p ¼ 0.05 6 weeks
23/23 (100%) vs 20/23 (86.9%), p40.05
1.4
22/24 (91.6%) vs 5/24 (20.8%), p50.05
8 weeks
6.6
28/40 (70.0%) vs 17/40 (42.5%), p50.05
1.3
12/23 (52.1%) vs 3/23 (13.0%); p50.05
7/40 (17.5%) vs 2/40 (5%); p40.05 18/24 (75.0%) vs 0/24 (0.0%); p50.05
–
–
20
5.0
–
6/32 (18.7%) vs 1/33 (3.0%); p ¼ 0.05
Complete resolution
–
2.4
NNT for clinical improvement
24 weeks
Pigmentation improvement: 3/15 (20%) vs 0/15 (0%), p40.05 3–6 weeks 21/26 (80.7%) vs 2/26 (7.6%), p50.05
12 weeks Calcipotriol 50 mg/g ointment vs betamethasone 0.1% ointment; twice daily
The numbers in the parenthesis denote the number of patients who completed the study. NNT, number needed to treat.
a
Bhuiyan, 2010 (6) Randomized, openlabel, active-controlled, multi-center Sehgal, 1980 (7) Randomized, placebocontrolled, doubleblinded, single center Sehgal, 1972 (8) Randomized, placebocontrolled, doubleblinded, single center Iraji, 2011 (9) Randomized, activecontrolled, openlabel, multi-center
Omidian, 2010 (5) Randomized, placebo- 26 vs 26 (23 vs 21) controlled, doubleblinded, single center
Theng, 2004 (4)
Bouloc, 2000 (3)
8 weeks
8 weeks
KH1060 1 mg/g ointment vs placebo; twice daily KH1060 ointment vs placebo; twice daily
Glade, 1998 (2)
Randomized, placebo- 5 vs 5 controlled, doubleblinded, single center Randomized, placebo- 49 vs 43 (38 vs 36) controlled, doubleblinded, single center 15 vs 16 Randomized, activecontrolled, openlabel, single center
Treatment arms 8 weeks
No. of patientsa Acitretin 10 mg vs placebo; 3 times daily
Study design
Therapy duration
Laurberg, 1991 (1) Randomized, placebo- 32 vs 33 (28 vs 31) controlled, doubleblinded, multi-center
Author/year
Table 1. RCTs in cutaneous lichen planus.
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2.5
1.3
No side effects
No side effects
Unclear
8.0
Erythema: 1/15 (6.6%) vs 0/16 (0%), p40.05; pruritus: 2/15 (13.3%) vs 0/16 (0%); p40.05
Dryness of the mouth, lips, nose and skin and hair loss: 28/32 (87.5%) vs 17/33 (51.5%), p50.05 Burning sensation: 1/5 (20%) vs 3/5 (60%), p40.05 Unclear
Adverse events
Headache, nausea, epigastric pain and truncal rash: 8/26 (30.7%) vs 0/26 (0%), p50.05; withdraw due to side effects (nausea, epigastric pain, diarrhea, leukopenia, and low grade fever): 3/26 (11.5%) vs 0/26, p40.05 No side effects
–
–
–
–
6.3
NNT for complete resolution
DOI: 10.3109/09546634.2014.933167
Treatments for CLP 3
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N. Fazel
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Table 2. Level of evidence and grade of recommendation for included RCTs.
Treatment
Study
Acitretin KH1060
Laurberg, 1991 (1) Glade, 1998 (2) Bouloc, 2000 (3) Calcipotriol Theng, 2004 (4) Sulfasalazine Omidian, 2010 (5) Hydroxychloroquine Bhuiyan, 2010 (6) Griseofulvin Sehgal, 1980 (7) Sehgal, 1972 (8) NBUVB Iraji, 2011 (9)
Grade of Level of evidencea recommendationa High Moderate High Moderate High High Moderate Moderate Moderate
Strong Weak Weak Weakb Weak Strong Strong
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a
The American College of Physician’s Guideline Grading System (http:// annals.org/article.aspx?articleid ¼ 745942). b Strong for generalized LP and severe flare-ups. NBUVB, narrow band ultraviolet B.
study, patients with generalized LP were treated with either PUVA or NBUVB. Although PUVA had a significantly better initial response than NBUVB (100% versus 77%, p: 0.0426), recurrence rates upon long-term follow-up were not significantly different in the two groups (47% versus 30%, respectively, p: 0.8593) (19). No serious adverse events were reported for NBUVB (19). However, some patients treated with PUVA (8-MOP) experienced side effects of nausea and/or vomiting (19). NBUVB is more efficacious than oral prednisolone regarding complete resolution of lesions (9), and comparable to PUVA in its long-term efficacy (19). In the long term, NBUVB has lower carcinogenic effects than PUVA. The GI upset is less significant than the long-term carcinogenic effects of PUVA when compared to NBUVB. Thus, NBUVB may be considered a safer option in the setting of generalized LP. Topical corticosteroids are conventionally used as first line therapy, but high-level scientific evidence is lacking (20). However, it is considered the standard of care (21). Moreover, oral corticosteroids are frequently used in severe acute flares, although there are no relevant RCTs. Other treatment modalities such as dapsone, and calcineurin inhibitors have been utilized for the management of CLP without strong evidence supporting their efficacy and safety. Additionally, there are no reported RCTs to ascertain the efficacy and safety of biologics in the treatment of LP patients. Thus, the effectiveness of these treatment modalities in the treatment of CLP remains to be determined. In conclusion, the current scientific literature provides very little high-quality evidence from large-scale comparative randomized trials focused on the safety and efficacy of available therapeutic modalities for CLP. Considering the incidence and severity of this condition, further investigation into this arena of research is warranted.
Declaration of interest The author declares no conflict of interest.
References 1. Laurberg G, Geiger JM, Hjorth N, et al. Treatment of lichen planus with acitretin. A double-blind, placebo-controlled study in 65 patients. J Am Acad Dermatol. 1991;24:434–7. 2. Glade CP, Van Der Vleuten CJ, van Erp PE, et al. The epidermis of chronic idiopathic lichen planus during topical treatment with the vitamin D3 analogue KH 1060. Clin Exp Dermatol. 1998;23:14–18. 3. Bouloc A, Revuz J, Bagot M, et al. KH 1060 for the treatment of lichen planus: a multicenter, randomized, double-blind, vehiclecontrolled study. Arch Dermatol. 2000;136:1272. 4. Theng CT, Tan SH, Goh CL, et al. A randomized controlled trial to compare calcipotriol with betamethasone valerate for the treatment of cutaneous lichen planus. J Dermatol Treat. 2004;15:141–5. 5. Omidian M, Ayoobi A, Mapar MA, et al. Efficacy of sulfasalazine in the treatment of generalized lichen planus: randomized doubleblinded clinical trial on 52 patients. J Eur Acad Dermatol Venereol. 2010;24:1051–4. 6. Bhuiyan I, Wahab MA, Ali A, et al. Comparative efficacy of hydroxychloroquine and griseofulvin in the treatment of lichen planus. J Pak Assoc Dermatol. 2010;20:79–33. 7. Sehgal VN, Bikhchandani R, Koranne RV, et al. Histopathological evaluation of griseofulvin therapy in lichen planus. A double-blind controlled study. Dermatologica. 1980;161:22–7. 8. Sehgal VN, Abraham GJ, Malik GB. Griseofulvin therapy in lichen planus. A double-blind controlled trial. Br J Dermatol. 1972;87: 383–5. 9. Iraji F, Faghihi G, Asilian A, et al. Comparison of the narrow band UVB versus systemic corticosteroids in the treatment of lichen planus: a randomized clinical trial. J Res Med Sci. 2011;16: 1578–82. 10. Cribier B, Frances C, Chosidow O. Treatment of lichen planus. An evidence-based medicine analysis of efficacy. Arch Dermatol. 1998;134:1521–30. 11. Samycia M, Lin AN. Efficacy of topical calcineurin inhibitors in lichen planus. J Cutan Med Surg. 2012;16:221–9. 12. Lillevang ST, Rosenkvist J, Andersen CB, et al. Single and combined effects of the vitamin D analogue KH1060 and cyclosporin A on mercuric-chloride-induced autoimmune disease in the BN rat. Clin Exp Immunol. 1992;88:301–6. 13. Binderup L, Latini S, Binderup E, et al. 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune responses. Biochem Pharmacol. 1991;42:1569–75. 14. Veyron P, Pamphile R, Binderup L, Touraine JL. Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice. Transpl Immunol. 1993;1:72–6. 15. Ormerod AD, Campalani E, Goodfield MJ. British Association of Dermatologists guidelines on the efficacy and use of acitretin in dermatology. Br J Dermatol. 2010;162:952–63. 16. Bauza A, Espan˜a A, Gil P, et al. Successful treatment of lichen planus with sulfasalazine in 20 patients. Int J Dermatol. 2005;44: 158–62. 17. Massa MC, Rogers III RS. Griseofulvin therapy of lichen planus. Acta Derm Venereol. 1981;61:547–50. 18. Matthews RW, Scully C. Griseofulvin in the treatment of oral lichen planus: adverse drug reactions, but little beneficial effect. Ann Dent. 1992;51:10–11. 19. Wackernagel A, Legat FJ, Hofer A, et al. Psoralen plus UVA vs. UVB-311 nm for the treatment of lichen planus. Photodermatol Photoimmunol Photomed 2007;23:15–19. 20. Le Cleach L, Chosidow O. Clinical practice. Lichen planus. N Engl J Med 2012;366:723–32. 21. Pandhi D, Singal A, Bhattacharya SN. Lichen planus in childhood: a series of 316 patients. Pediatr Dermatol. 2014;31:59–67.
REVIEW ARTICLE
Cutaneous lichen planus: A systematic review of treatments Nasim Fazel
J Dermatolog Treat Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/14/14 For personal use only.
Department of Dermatology, University of California, Davis, Sacramento, CA, USA
Abstract
Keywords
Various treatment modalities are available for cutaneous lichen planus. Pubmed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database were searched for all the systematic reviews and randomized controlled trials related to cutaneous lichen planus. Two systematic reviews and nine relevant randomized controlled trials were identified. Acitretin, griseofulvin, hydroxychloroquine and narrow band ultraviolet B are demonstrated to be effective in the treatment of cutaneous lichen planus. Sulfasalazine is effective, but has an unfavorable safety profile. KH1060, a vitamin D analogue, is not beneficial in the management of cutaneous lichen planus. Evidence from large scale randomized trials demonstrating the safety and efficacy for many other treatment modalities used to treat cutaneous lichen planus is simply not available.
Cutaneous, lichen planus, randomized controlled trial, systematic review History Received 14 May 2014 Revised 26 May 2014 Accepted 27 May 2014 Published online 9 July 2014
Abbreviations: CLP: cutaneous lichen planus; LP: lichen planus; NBUVB: narrow band ultraviolet B; PUVA: psoralen plus ultraviolet A; RCT: randomized controlled trial
Introduction
Search strategy
Cutaneous lichen planus (CLP) is a chronic immunologic disease that involves the skin and its appendages including hair and nails. While a wide range of therapeutic modalities have been utilized in the management of cutaneous lichen planus, no single treatment has emerged as the standard of care. Therapies such as topical and systemic corticosteroids, retinoids, calcineurin inhibitors, immunosuppressive agents, phototherapy, and biologics are used to decrease the time to lesion resolution, alleviate patient discomfort, and enhance quality of life. However, high-quality scientific evidence for the effectiveness and safety of many treatment options is lacking. In this article, we systematically review the current literature and discuss all of the randomized controlled trials (RCTs) for CLP.
Terms ‘‘lichen’’ and ‘‘planus’’ were used to search the following databases: Pubmed (1950–1 November 2012), EMBASE (1980–1 September 2012), Cochrane Database of Systematic Reviews (Cochrane Reviews, Issue 8, August 2012), Cochrane Central Register of Controlled Trials (Clinical Trials, Issue 8, August 2012), Database of Abstracts of Reviews of Effects (Other Reviews, Issue 3, July 2012), and Health Technology Assessment Database (Technology Assessments, Issue 3, July 2012). The list of references for the included systematic reviews and RCTs was reviewed.
Materials and methods Eligibility criteria All systematic reviews and RCTs of any design that investigated the efficacy of any therapeutic modality for the treatment of lichen planus with skin, nail and/or hair involvement were considered. RCTs that compared at least one active treatment arm with a control arm, including a placebo, an alternative therapy, or no treatment were included. In all included RCTs, the diagnosis of CLP was confirmed clinically and histopathologically.
Correspondence: Nasim Fazel, MD, DDS, Associate Professor, Department of Dermatology, University of California, Davis, 3301 C Street, Suite 1400, Sacramento, CA 95816, USA. Tel: +916 734 6876. Fax: +916 442 5702. E-mail: [email protected]
Outcome measures Clinical improvement of CLP lesions after 4–8 weeks of treatment was considered the primary outcome measure of the study. Secondary outcomes included complete resolution of CLP after 4–8 weeks of therapy and adverse events. Other endpoints were considered, if the above-mentioned outcomes were not reported. Methodological quality assessment The following criteria were used to assess the methodological quality of the RCTs: randomization, explanation of sequence generation for randomization, explanation of allocation concealment, blindness methods, sample size calculation, evaluating for comparability of baseline data, intention to treat analysis, and patient follow-up after the final treatment. The quality of the trials was categorized into ‘‘high’’ or ‘‘moderate’’. If an RCT qualified for equal or more than half of the criteria, it was considered as a high-quality study.
2
N. Fazel
Meta-analysis Review Manager version 5.1.6 was used to perform a metaanalysis, if needed. The comparative results of the dichotomous data were presented as odds ratios (OR) with 95% confidence intervals (CI). The I22 statistic was used to determine statistical heterogeneity. We sought the reasons for heterogeneity, if the I22 value was greater than 50%. The results of the meta-analysis were reported, if the I22 statistic was less than 80%.
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Results Two relevant systematic reviews and nine relevant RCTs were found for CLP (Table 1). Cribier et al. (10) performed a systematic review on cutaneous and mucosal LP. The authors did not limit the evidence to RCTs and included non-randomized controlled trials as well as case series studies. They reported three RCTs involving 137 patients. Additionally, a systematic review by Samycia et al. (11) found no RCTs for pimecrolimus or tacrolimus. Table 2 summarizes the level of evidence and the strength of recommendation of the included treatment modalities. Acitretin In the only randomized trial on CLP, acitretin 30 mg daily for 8 weeks was more efficacious when compared to placebo. About 21 out of 32 patients (65.6%) in the acitretin group and 8 out of 33 (24.2%) in the placebo group showed clinical improvement. Adverse events such as dryness of the mouth, lips, nose and skin and hair loss occurred more frequently in the acitretin group than the placebo group (87.5% versus 51.5%, respectively) (1). Vitamin D analogues (KH1060 and calcipotriol) KH1060 is a vitamin D3 analogue that has been used in clinical trials. It has the same potency as 1,25-dehydroxyvitamin D3 in calcium metabolism. In vitro and in vivo studies showed that it can affect immunologic responses and cell growth (12–14). Two randomized placebo-controlled trials investigated the efficacy of KH1060 1 mg/g ointment twice daily in comparison with placebo in CLP patients, and neither of them indicated a significant benefit for KH1060 (2,3). No serious side effects were reported with KH1060 treatment (2,3). Another randomized trial compared calcipotriol 50 mg/g ointment with betamethasone 0.1% ointment and found no significant difference in their efficacy (4). Side effects of pruritus and erythema were more frequent with calcipotriol in comparison with betamethasone (20% versus 0%, respectively) (4). Sulfasalazine An RCT compared oral sulfasalazine (initial dose of 1 g/day, increasing 0.5 g every 3 days up to 2.5 g/day) with placebo. The study noted greater clinical improvement of generalized lichen planus (LP) with sulfasalazine treatment (80.7%) as compared to placebo (7.6%). In this RCT, eight patients in the sulfasalazine group experienced adverse effects such as headache, nausea, epigastric pain and mild truncal rash. Additionally, three patients abandoned the study due to side effects such as nausea, epigastric pain, diarrhea, leukopenia, and low grade fever (5). Hydroxychloroquine In an RCT, Bhuiyan et al. compared hydroxychloroquine (400 mg daily) with griseofulvin (500 mg daily) for 6 months. They reported a significantly better clinical response in patients treated with hydroxychloroquine (70%) as compared to patients treated
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with griseofulvin (42.5%). No serious adverse events were reported for hydroxychloroquine (6). Griseofulvin Sehgal et al. compared griseofulvin 500 mg/day with placebo. They found significantly higher clinical improvement with griseofulvin (91.6%) as compared to placebo (20.8%). Complete clinical response followed the same pattern (7). In a similar study, complete resolution of CLP was higher with griseofulvin (63.1%) than placebo (31.5%) as well (8). We performed a meta-analysis to compare the complete resolution of the lesions after the treatment with griseofulvin and placebo. The results were not reported because the I2 value was 82%, which is an indicator of the statistical heterogeneity between these two studies (7,8). Both Bhuiyan et al. (6) and Sehgal et al. (8) reported no side effects for griseofulvin. Narrow band ultraviolet B Narrow band ultraviolet B (NBUVB) treatment (70% MED at the maximum dose of 9 J/cm2) 3 times a week has been compared to oral prednisolone (0.3 mg/kg) for the treatment of patients with generalized LP in a 6-week trial. NBUVB and oral prednisolone improved the CLP lesions. However, NBUVB had a better complete clinical response rate than systemic prednisolone (52.1% versus 13%, respectively). Patient satisfaction was higher with NBUVB as well (9). No serious adverse events were reported for NBUVB phototherapy (9).
Discussion Laurberg et al. (1) showed that acitretin is effective and can be considered in the treatment of CLP; but patients must be monitored closely for potentially serious side effects. Acitretin is highly teratogenic, and can cause serious skeletal and metabolic defects in the fetus. Therefore, women must strictly avoid pregnancy for at least 3 years after the discontinuation of the medication. The teratogenic side effects of acitretin require adequate contraception and regular pregnancy testing during the course of therapy. Moreover, it is recommended that patients undergo testing of liver enzymes and lipid levels every 3 months to monitor for liver side effects and hyperlipidemia (15). The side effects are less threatening in men. The safety/efficacy ratio of acitretin should be thoroughly discussed with the patient. The only available RCT on sulfasalazine demonstrates remarkable efficacy with an unfavorable safety profile. Also, in an uncontrolled study, severe side effects of gastric pain, poor glycemic control, fever and cutaneous rash occurred during the course of sulfasalazine therapy resulting in discontinuation of the medication in 20% of patients (16). Sulfasalazine should only be reserved for generalized LP or severe flares in which case patients need to be monitored closely for side effects. Reports in the literature are inconsistent concerning the efficacy of griseofulvin for the treatment of CLP. In an uncontrolled study, Massa and Rogers noted that griseofulvin improved oral lichen planus lesions better than cutaneous lesions (17). Bhuiyan et al. (6) found griseofulvin to be less effective than hydroxychloroquine in the treatment of CLP. Side effects of griseofulvin included headache, facial pain, nausea, vomiting and diarrhea in up to 50% of patients treated with griseofulvin in a trial (18). Although Sehgal et al. (7,8) showed that griseofulvin is an effective drug for CLP, the non-randomized studies debate against the efficacy (6,17) and safety (18) of this drug. Phototherapy can be considered as a treatment option for generalized LP. In a retrospective non-randomized controlled
23 vs 23
19 vs 19 (17 vs 17)
24 vs 24 (22 vs 22)
40 vs 40
Hydroxychloroquine 400 mg vs griseofulvin 500 mg; daily Oral griseofulvin 500 mg vs placebo; daily Oral griseofulvin 500 mg vs placebo; daily NBUVB therapy 3 times weekly vs oral prednisolone 0.3 mg/kg/ day
Oral sulfasalazine (initial dose of 1 g/day, increasing 0.5 g every 3 days up to 2.5 g/day) vs placebo
No significant difference (details have not been provided) Clinical improvement and/or complete resolution: 37% vs 42%, p40.05 Thickness improvement: 7/15 (46.6%) vs 8/16 (50.0%), p40.05
21/32 (65.6%) vs 8/33 (24.2%), p50.05
Clinical improvement
–
29.4
3.1 7.6
4–6 weeks 12/19 (63.1%) vs 6/19 (31.5%), p ¼ 0.05 6 weeks
23/23 (100%) vs 20/23 (86.9%), p40.05
1.4
22/24 (91.6%) vs 5/24 (20.8%), p50.05
8 weeks
6.6
28/40 (70.0%) vs 17/40 (42.5%), p50.05
1.3
12/23 (52.1%) vs 3/23 (13.0%); p50.05
7/40 (17.5%) vs 2/40 (5%); p40.05 18/24 (75.0%) vs 0/24 (0.0%); p50.05
–
–
20
5.0
–
6/32 (18.7%) vs 1/33 (3.0%); p ¼ 0.05
Complete resolution
–
2.4
NNT for clinical improvement
24 weeks
Pigmentation improvement: 3/15 (20%) vs 0/15 (0%), p40.05 3–6 weeks 21/26 (80.7%) vs 2/26 (7.6%), p50.05
12 weeks Calcipotriol 50 mg/g ointment vs betamethasone 0.1% ointment; twice daily
The numbers in the parenthesis denote the number of patients who completed the study. NNT, number needed to treat.
a
Bhuiyan, 2010 (6) Randomized, openlabel, active-controlled, multi-center Sehgal, 1980 (7) Randomized, placebocontrolled, doubleblinded, single center Sehgal, 1972 (8) Randomized, placebocontrolled, doubleblinded, single center Iraji, 2011 (9) Randomized, activecontrolled, openlabel, multi-center
Omidian, 2010 (5) Randomized, placebo- 26 vs 26 (23 vs 21) controlled, doubleblinded, single center
Theng, 2004 (4)
Bouloc, 2000 (3)
8 weeks
8 weeks
KH1060 1 mg/g ointment vs placebo; twice daily KH1060 ointment vs placebo; twice daily
Glade, 1998 (2)
Randomized, placebo- 5 vs 5 controlled, doubleblinded, single center Randomized, placebo- 49 vs 43 (38 vs 36) controlled, doubleblinded, single center 15 vs 16 Randomized, activecontrolled, openlabel, single center
Treatment arms 8 weeks
No. of patientsa Acitretin 10 mg vs placebo; 3 times daily
Study design
Therapy duration
Laurberg, 1991 (1) Randomized, placebo- 32 vs 33 (28 vs 31) controlled, doubleblinded, multi-center
Author/year
Table 1. RCTs in cutaneous lichen planus.
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2.5
1.3
No side effects
No side effects
Unclear
8.0
Erythema: 1/15 (6.6%) vs 0/16 (0%), p40.05; pruritus: 2/15 (13.3%) vs 0/16 (0%); p40.05
Dryness of the mouth, lips, nose and skin and hair loss: 28/32 (87.5%) vs 17/33 (51.5%), p50.05 Burning sensation: 1/5 (20%) vs 3/5 (60%), p40.05 Unclear
Adverse events
Headache, nausea, epigastric pain and truncal rash: 8/26 (30.7%) vs 0/26 (0%), p50.05; withdraw due to side effects (nausea, epigastric pain, diarrhea, leukopenia, and low grade fever): 3/26 (11.5%) vs 0/26, p40.05 No side effects
–
–
–
–
6.3
NNT for complete resolution
DOI: 10.3109/09546634.2014.933167
Treatments for CLP 3
4
N. Fazel
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Table 2. Level of evidence and grade of recommendation for included RCTs.
Treatment
Study
Acitretin KH1060
Laurberg, 1991 (1) Glade, 1998 (2) Bouloc, 2000 (3) Calcipotriol Theng, 2004 (4) Sulfasalazine Omidian, 2010 (5) Hydroxychloroquine Bhuiyan, 2010 (6) Griseofulvin Sehgal, 1980 (7) Sehgal, 1972 (8) NBUVB Iraji, 2011 (9)
Grade of Level of evidencea recommendationa High Moderate High Moderate High High Moderate Moderate Moderate
Strong Weak Weak Weakb Weak Strong Strong
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a
The American College of Physician’s Guideline Grading System (http:// annals.org/article.aspx?articleid ¼ 745942). b Strong for generalized LP and severe flare-ups. NBUVB, narrow band ultraviolet B.
study, patients with generalized LP were treated with either PUVA or NBUVB. Although PUVA had a significantly better initial response than NBUVB (100% versus 77%, p: 0.0426), recurrence rates upon long-term follow-up were not significantly different in the two groups (47% versus 30%, respectively, p: 0.8593) (19). No serious adverse events were reported for NBUVB (19). However, some patients treated with PUVA (8-MOP) experienced side effects of nausea and/or vomiting (19). NBUVB is more efficacious than oral prednisolone regarding complete resolution of lesions (9), and comparable to PUVA in its long-term efficacy (19). In the long term, NBUVB has lower carcinogenic effects than PUVA. The GI upset is less significant than the long-term carcinogenic effects of PUVA when compared to NBUVB. Thus, NBUVB may be considered a safer option in the setting of generalized LP. Topical corticosteroids are conventionally used as first line therapy, but high-level scientific evidence is lacking (20). However, it is considered the standard of care (21). Moreover, oral corticosteroids are frequently used in severe acute flares, although there are no relevant RCTs. Other treatment modalities such as dapsone, and calcineurin inhibitors have been utilized for the management of CLP without strong evidence supporting their efficacy and safety. Additionally, there are no reported RCTs to ascertain the efficacy and safety of biologics in the treatment of LP patients. Thus, the effectiveness of these treatment modalities in the treatment of CLP remains to be determined. In conclusion, the current scientific literature provides very little high-quality evidence from large-scale comparative randomized trials focused on the safety and efficacy of available therapeutic modalities for CLP. Considering the incidence and severity of this condition, further investigation into this arena of research is warranted.
Declaration of interest The author declares no conflict of interest.
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