Accepted Manuscript

Possible alternative therapies for oral lichen planus cases refractory to steroid
therapies

Huamei Yang, MD, Yuanqin Wu, MD, Hui Ma, MD, Lu Jiang, DDS, PhD, Xin Zeng,
DDS, PhD, Hongxia Dan, DDS, PhD, Yu Zhou, DDS, PhD, Qianming Chen, DDS,
PhD
PII: S2212-4403(16)00052-3
DOI: 10.1016/j.oooo.2016.02.002
Reference: OOOO 1426

To appear in: Oral Surgery, Oral Medicine, Oral Pathology and Oral
Radiology

Received Date: 8 August 2015

Revised Date: 15 January 2016
Accepted Date: 2 February 2016

Please cite this article as: Yang H, Wu Y, Ma H, Jiang L, Zeng X, Dan H, Zhou Y, Chen Q, Possible
alternative therapies for oral lichen planus cases refractory to steroid therapies, Oral Surgery, Oral
Medicine, Oral Pathology and Oral Radiology (2016), doi: 10.1016/j.oooo.2016.02.002.

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 ACCEPTED MANUSCRIPT

1. Full title: Possible alternative therapies for oral lichen planus cases refractory to

steroid therapies

2. Running head: Therapies for steroid-resistant OLP

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3. The names of all authors with institutional affiliations:

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a
Huamei, Yang, MD, Yuanqin, Wu, MD, a Hui, Ma, MD, a
Lu, Jiang, DDS, PhD, a

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a a a
Xin, Zeng, DDS, PhD, Hongxia, Dan, DDS, PhD, Yu, Zhou, DDS, PhD,

Qianming, Chen, DDS, PhD a

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State Key Laboratory of Oral Diseases, West China Hospital of Stomatology,
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Sichuan University, No.14 Renminnan Road, Chengdu, 610041, China.
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The e-mail address of each author:

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huameiyangmelody@163.com;
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1094162189@qq.com;

mahui0163@163.com;
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jianglu@scu.edu.cn;
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zengxin22@163.com;
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hxdan@foxmail.com;

zhouyu19830306@sina.com;

qmchen@scu.edu.cn

4. Corresponding Author:

Yu Zhou, zhouyu19830306@sina.com or
 ACCEPTED MANUSCRIPT

Hongxia Dan, hxdan@foxmail.com

State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, No.14

People's South Road, Chengdu, 610041, China; Tel: +86-28-85503480; Fax:

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+86-28-85405251.

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5. Conflicts of interest: none.

6. This manuscript has been approved by all authors and has not been published or

considered to be submitted elsewhere.

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7. This work was supported by grants from the Nonprofit Industry Research

Specific Fund of National Health and Family Planning Commission of China

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(No.201502018), the National Natural Science Foundation of China (No.

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81470747 ), the National Natural Science Foundation of China (No.81321002),

the International Science and Technology Cooperation Program of China (No.

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2012DFA31370), the National Natural Science Foundation of China (No.

81200791, 81472533, 81102060 and 81270040), the Doctoral Program of the

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Ministry of Education of China (No. 20110181110055).

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8. A word count for the abstract: 147

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9. A complete manuscript word count: 4401

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10. Number of references: 169

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11. Number of tables: 4

12. Key words: Oral lichen planus; Therapy; Steroid-refractory

13. Abstract:

Oral lichen planus (OLP) is a chronic inflammatory disorder with multifactorial

etiopathogenesis. Immune dysregulation plays a critical role in the development

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and progression of this disease. Patients’ life may be affected by pain caused by

atrophic-erosive lesions. Treatment is usually symptomatic given the obscure

etiology. Topical steroids remain the mainstay of management. However, their

therapeutic benefits are not always evident. There are substantial data on the

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possible therapeutic strategies that are effective in OLP cases refractory to

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steroids. This review provides an overview of the current approaches for the

management of steroid-refractory OLP. The miscellaneous treatment regimens

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include tacrolimus, pimecrolimus, thalidomide, low-level laser therapy,

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photodynamic therapy, and surgical excision. Some results obtained from these
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studies were promising. However, further studies, especially randomized

controlled trials with strict inclusion and exclusion criteria and larger sample
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sizes, are required for the evaluation of long-term safety and efficacy of these
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therapies.
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Possible alternative therapies for oral lichen planus cases refractory to steroid

therapies

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Oral lichen planus (OLP) is a common chronic inflammatory disorder of

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immunological basis. OLP affects 0.5% to 2.6% of the world population, more often

1, 2
females at the ages between 30 to 60 years. OLP has various clinical forms, such

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as papule, reticular, bullous, erosive and atrophic lesions, which often coexists in

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various combinations.3, 4
The atrophic-erosive form may cause symptoms ranging
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from mild burning sensation to severe pain, which greatly affect patients’ quality of

life. Additionally, OLP is identified as a potentially malignant disorder by the World

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Health Organization (WHO) working group, with approximate malignant

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transformation rate of 1.09%, and may be even higher among those with
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atrophic-erosive lesions.5-8

The etiopathogenesis of OLP is associated with multiple factors, such as

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antigen-specific cell-mediated immunity, nonspecific inflammation, and genetic

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factors.9 Treatment is usually symptomatic given the obscure etiology. Topical

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corticosteroids are recommended as the mainstay of treatment for OLP. In addition,

short courses of systemic corticosteroids are often given to patients with acute

exacerbation, and widespread or recalcitrant lesions.10, 11

However, the therapeutic

benefits of steroids are not always evident, which leads to the need for treatment

alternatives, especially for patients who do not respond to routine therapy.12 There are
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substantial data on the possible therapeutic strategies that are effective in such cases.13,

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This review provides an overview of the current approaches for the management of

steroid-refractory OLP.

We searched PubMed and Medline for articles published before 2016 using terms

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‘oral lichen planus AND treatment’. Among all the publications in English, papers in

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which OLP was clinically and histologically diagnosed and unresponsive to topical or

systemic corticosteroid treatment were considered. For patients being treated for both

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skin and oral lichen planus, only the data of OLP was extracted. Some of these

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therapies had also been tested in studies which did not explicitly include patients with
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steroid-refractory OLP. The findings of these studies were summarized in

Supplemental Table 4, but would not be discussed in detail.15-60, 148, 149

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1 Drug therapy
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Both topical and systemic treatment modalities which had been reported effective

for steroid-refractory OLP were listed in Table 1.

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1.1 Topical agents

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1.1.1 Macrolide immunosuppressants

Macrolide immunosuppresants, a group of compounds sharing a macrolide-like

structure, are potentially useful for the prevention of transplant rejection and treatment

of immune-mediated diseases.61 Their topical formulations have been increasingly

studied for treatment of multiple chronic inflammatory dermatoses.62, 63

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Calcineurin (CaN), a eukaryotic Ca2+- and calmodulin-dependent serine/threonine

protein phosphatase, is a major player in Ca2+-CaN-nuclear factor of activated T cells

(NFAT) signal transduction pathways and required for developmental events such as

immune responses.64 CaN inhibitors (CNIs) can form complexes respectively with

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their cytoplasmic immunophilin proteins to prevent the translocation of NFATs into

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the nucleus via inhibition of CaN activation. NFATs regulate the mRNA transcription

of a number of inflammatory cytokines leading to the blocking of transcription of

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multiple cytokines and costimulatory molecules critical for full activation of T cells,

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including interleukin(IL)-2, transforming growth factor(TGF)-β, Interferon (IFN)-γ,
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tumor necrosis factor-α (TNF-α), IL-4, IL-5,and IL-13.65, 66 Responses to treatment of

corticosteroid-refractory OLP with topical CNIs were shown in Table 2.

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Tacrolimus
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Systemic tacrolimus (TAC, FK 506) has shown efficacy for prophylaxis of

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transplantation rejection and for the treatment of other immunologic disorders.

TAC binds first to the immunophilins, termed FK506-binding proteins (FKBP12).

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This complex inhibits dephosphorylation of NFAT by CaN, thus reduces T-cell

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cytokine production and arrests T cell activation.67 Besides, TAC inhibits mast cell
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activation and affects function of Langerhans cells.62 Moreover, TAC can decrease

Treg proliferation and inhibit NF-κB pathway, both of which are supposed to be

involved in the pathogenesis of OLP.68, 69

The efficacy and safety of topical TAC in the management of

corticosteroid-refractory OLP was shown in Table 2. Hodgson et al.70 evaluated the

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long-term (mean duration of 19.8 months) safety and clinical benefit of 0.1% topical

TAC ointment twice daily for the management of 50 patients with erosive or

ulcerative OLP recalcitrant to topical corticosteroids. 94% of patients had either

complete or partial remission of mucosal erosions. Three other trials suggested that

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0.1% topical TAC applied twice a day in the form of cream71 or ointment72, 73 was

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effective for the treatment of topical steroid-resistant OLP. Furthermore, a total of 9

patients with refractory symptomatic OLP were described in case reports, 8 of whom

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showed partial or complete remission using 0.1% TAC74-78. Additionally, flare-ups

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were observed after the suspension of treatment.73, 74, 76, 79-81
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The most common adverse effects of topical TAC are transient burning and tingling

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sensation at the site of application. Mucosal staining was also observed in 2 cases.
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Systemic absorption of topically applied TAC was possible but may be
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unpredictable or detectable without noted clinical significance.70, 73, 74, 77, 81

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Pimecrolimus
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Pimecrolimus (PIM) is an ascomycin macrolactam derivative. Cream containing 1%

PIM is indicated for mild-to-moderate atopic dermatitis, which is common in both

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children and adults.84

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Like TAC, the action mechanism of PIM is the blockage of T cell activation. PIM

binds to macrophillin-12, also known as FKBP12, then inhibits CaN and hence

reduces T-cell cytokine production and inhibits T-cell activation. Besides, topical PIM

reduces CD95 (Fas) expression on keratinocytes in OLP.85

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Thirty steroid-unresponsive OLP patients were treated with 0.5% PIM or 0.05%

TAC ointment twice daily for 2 months in a randomized, double-blind controlled

trial.14 patients treated with TAC improved, whereas 11 patients treated with PIM

had a positive response. It demonstrated that PIM had a more stable therapeutic

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effectiveness within 6 months after the withdrawal.72 Two recalcitrant symptomatic

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OLP patients were also reported to benefit from 0.5% or 1% topical PIM treatment for

3 or 4 months in case reports.86, 87

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The frequently published adverse event was transient burning sensation. No blood

test anomalies were reported.72,

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No clinical, laboratory side-effects or systemic
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immunosuppression were observed even with the detectable blood levels of PIM.28
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Treatment with systemic CNIs may cause nephrotoxicity, hypertension, diabetes

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mellitus, tremor, nausea, seizures, gingival hyperplasia, and dyslipidemia. Whereas

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the safety of topical use in OLP is still doubtful. 89, 90 In 2005, the US Food and Drug

Administration (FDA) requested a black-box warning for topical TAC/PIM regarding

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a theoretical oncogenic risk, indicating that use of the drugs should be limited to those
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conditions that have received FDA approval pending the outcome of further studies.91
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A case of squamous cell carcinoma was described in a patient with OLP treated with

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intermittent topical TAC. The suspected causal relationship was also suggested

before.93 However, OLP itself may undergo carcinogenesis mediated by chronic

inflammation.94 Regarding these conditions, some clinicians suggested that

continuous long-term use of topical CNIs should be avoided.15

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Cyclosporine A

Cyclosporine A (CsA), initially isolated from the fungus Tolypocladium inflatum, is

widely used in organ transplant recipients and for the treatment of a variety of

autoimmune diseases.

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CsA inhibits of CaN activity by binding to cyclophilins, which leads to suppression

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of the nuclear translocation of NFAT. Consequently, the activation and differentiation

of inflammatory cells is blocked. CsA can inhibit Treg proliferation and reduce Treg

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activity.95 In addition to the mechanism mentioned above, CsA can down-regulate

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NF-κB signaling pathway to induce apoptosis of T cells and inhibit immortalized
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proliferation of human skin keratinocytes. 96 Furthermore, CsA may directly act in situ

by suppressing the production of IFN–γ from activated T cells, and IFN-γ-induced

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overexpression of intercellular adhesion molecule-1(ICAM-1) and HLA-DR by

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keratinocytes.97
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Detailed information about the CsA employed in the included trials were shown in

Table 2. There were two open-label prospective studies describing topical CsA for the
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treatment of intractable OLP with ambivalent results. Formulation including 50 mg/ml

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98, 99
or 0.025% CsA applied topically four times daily had a little benefit. There was
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also a case report of corticosteroid-resistant erosive OLP (EOLP) successfully treated

with topical CsA solution (100 mg/mL).97

The adverse effects include bad taste, transient burning sensation, gastrointestinal

upsets, swelling and itching lips, dizziness, and petechial hemorrhages.100

Rapamycin
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Rapamycin (RAPA), also called sirolimus, is a potent immunosuppressive agent

101
with anti-proliferative and tumor-inhibitory properties. It was approved by the

FDA for acute renal allograft rejection in 1999.

Mammalian target of RAPA (mTOR) is a regulatory protein kinase involved in

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lymphocyte differentiation and function, developmental processes, and tumor cell

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growth. RAPA can inhibit mTOR by binding to FKBP-12, which will inhibit the

response to IL-2 and thereby halt T-cell progression from the G1 to the S phase of cell

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cycle and block the activation of T cells and B cells.101, 102

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In an open prospective study of 7 female patients with histologically proven EOLP
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refractory to topical corticosteroids, a RAPA solution (1mg/ml) was used topically

twice a day. Of the 6 patients who had either complete or partial remission at 3
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months, 1 had detectable blood RAPA level. All patients suffered from tingling or
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burning sensations and one patient withdrew due to this adverse effect.103
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The adverse effects of systemic RAPA included pulmonary toxicity, hematological

disorders, dysmetabolism, lymphedema, stomatitis and fertility/gonadic toxicity, most

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of which are dose related.104 Black box warnings were issued twice for its use in liver
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transplantation after the reported hepatic artery thrombosis and a higher mortality
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rate.105

1.1.2 TNF-α inhibitors

TNF-α is a cytokine with both proinflammatory and immunoregulatory functions,

which may mediate the pathogenesis of OLP.106 Biologic drugs targeting TNF include

receptor blockers and monoclonal antibodies.

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Etanercept (ENT), currently the most prescribed TNF inhibitor in the US, is

approved to treat rheumatoid arthritis, psoriasis, and some other immune-mediated

inflammatory conditions.107OLP patients have up-regulated levels of serum TNF-α

and high expression of TNF-α mRNA in T lymphocytes of the local lesion area.38

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ENT, a TNF-receptor-IgG fusion protein directed against cell surface receptor

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interaction, can downregulate TNF-mediated cellular responses effectively by binding

soluble TNF-α.106

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It has been reported that an EOLP patient given ENT 25 mg twice weekly showed

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90% symptomatic improvement 4 weeks after the therapy. 108 However, the treatment
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was discontinued due to the expense 10 weeks later.

The adverse effect is mild-to-moderate tenderness at the site of injection. ENT is

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associated with an increased risk of infection, congestive heart failure, and

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development of malignancy.109
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1.1.3 Tetracycline

Tetracyclines, discovered in the 1940s, are broad-spectrum antibiotics with activity

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against a wide range of microorganisms including both Gram-positive and

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Gram-negative bacteria as well as protozoan parasites.110

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The major biologic effects of tetracycline are mediated through suppression of

T-lymphocytes and neutrophils, inhibition of matrix metalloproteinases (MMPs), and

reducing the production of cytokines involved in inflammation and epithelial damage.

111

A 74-year-old woman with EOLP resistant to 0.05% clobetasol propionate was

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treated with topical tetracycline solution (0.25%, rinse 2-3 times per day).

Considerable pain relief was noticed 1 week later. Erosive lesions disappeared and

re-epithelization was observed after 6 weeks with no known major adverse effects.112

Systemic reactions may include gastrointestinal irritation. Tetracyclines are

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contraindicated in known hypersensitivity, pregnancy and children no more than 8

years old.113

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1.2 Systemic agents

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Thalidomide AN
Thalidomide, introduced as sedative and anti-emetic, was withdrawn from the

market after the reported teratogenicity. Nowadays it is widely used in treating

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multiple myeloma, leprosy, immunological disorders, and other malignancies.114

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Thalidomide can reduce TNF-α production by enhancing degradation of TNF-α

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mRNA and suppressing NF-κB activity. Besides, it can increase activity of suppressor

T cells, inhibit activity of Th cells, and inhibit angiogenesis.115

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The efficacy and safety of systemic thalidomide treatment was evaluated in one
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patient with severe EOLP resistant to oral prednisone. Thalidomide was started at an
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initial dose of 50 mg/day and then progressively increased to 200 mg/day over 3

months. He suffered from dizziness, edema and rash, necessitating a dosage decrease

(100 mg/day). The patient achieved nearly complete resolution after 11 months of

treatment. Relapse occurred in 2 weeks after thalidomide withdrawal. 116

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Systematic thalidomide treatment may lead to some adverse events, such as

teratogenicity, peripheral neropathy, somnolence, rash, and erythema nodosum-like

lesions.117

Mycophenolate mofetil

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Mycophenolate mofetil (MMF), a pro-drug of the active agent mycophenolic acid,

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is widely used for the prevention of acute rejection after organ transplantation and

various autoimmune diseases.118

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MMF, the inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibits

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purine nucleotide synthesis and depletes lymphocytes and monocytes of guanosine
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triphosphate. Thereby, MMF can suppress both dendritic cell maturation and the

formation of antibodies as well as inhibit the proliferation of lymphocytes.119 In

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addition to the immunosuppressive properties, MMF also has antitumor effects.

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A patient with EOLP resistant to topical steroids responded successfully to MMF

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2000 mg/day in combination with CsA 150 mg/day in less than a month. CsA dose
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was then tapered and finally withdrawn. The erosions was eradicated with MMF at a

dosage of 2000 mg/day as monotherapy for 2 months. The patient remained

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asymptomatic with 100 mg/day of MMF 1 year later. 120

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Potential adverse effects include gastrointestinal disturbances, headache, tiredness,

myelosuppression and embryopathy.121

Retinoids

Retinoids are derivatives of all-trans-retinol, bearing a structural resemblance to

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vitamin A. In terms of structural features and the time of introduction, they can be

divided into four different generations. 122

Retinoids can induce apoptosis, regulate differentiation, and suppress

carcinogenesis. These actions are mediated by binding to specific nuclear receptors

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(the retinoic acid receptors (RARs) RARα, -β, and -γ or retinoid X receptors (RXRs)

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RXRα, -β, and -γ), which targets DNA response sites upstream of retinoid responsive

genes and regulates transcription. Retinoids also have a modulating function on

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inflammatory and immunocompetent cells, including T cells and macrophages. 111, 123

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A thymoma patient with cutaneous LP and EOLP lesions was reported . After
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thymectomy, cutaneous LP lesions subsided spontaneously, while the oral ones

persisted. These oral lesions responded well to oral etretinate rather than topical
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steroids and CsA.

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The systemic adverse effects include hyperlipidemia, skin and mucosal dryness,
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hepatotoxicity, skeletal toxicity, and teratogenicity.125

Curcumin
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Curcumin, a polyphenolic antioxidant, is the major biological active constituent of

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the spice turmeric plant. It has long been used in Asian herbal medicine to manage
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various ailments such as wounds and inflammation. Curcumin also shows a vital role

in cancer management.126

Curcumin has a wide range of biological activities, including antioxidant,

anti-inflammatory, anti-carcinogenic, antiseptic, and analgesic activities.127 Curcumin

can increase salivary and serum levels of vitamins C and E, and prevent lipid
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peroxidation and DNA damage in OLP patients.128

A 22-year-old OLP patient who had been treated earlier with topical steroid showed

repeated symptomatic recurrence. The treatment was shifted to curcumin which

generated positive results. The dose was initially started at 1g for 2 weeks, and then

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tapered to 500 mg for 2 weeks. The symptoms and clinical signs disappeared with no

adverse effect after the treatment.129

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Adverse effects may include diarrhea, nausea, headache, and rash.126

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Glycyrrhizin

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Glycyrrhizin (GZ) is a triterpenoid saponin derived from licorice, the dried roots
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and stolons of Glycyrrhiza glabra. GZ is an established phytochemical remedy for

chronic liver dysfunction, as well as a flavoring and sweetening additive in Europe

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and Asia.130
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It have been demonstrated that glycyrrhetinic acid, the metabolite of GZ, has many
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pharmacological properties such as steroid-like anti-inflammatory, antiviral,

anti-oxidative, anticancer, and hepato-protective activities. Besides, GZ can lead to

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attenuation of tissue injury.131 The anti-inflammatory effect may rely on the inhibition
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of release of TNF-α, myeloperoxidase activity, and translocation of NF-κB into the

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nuclei.130

The effects of GZ for patients with steroid-refractory OLP and chronic HCV

infection was investigated.132 Six of the nine patients administered with 0.2% GZ

solution (intravenously, 40ml daily, for 4 consecutive weeks) improved clinically,

while one of the eight control patients given dental cleaning showed improvement of
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redness. Three patients suffered recurrence after withdrawl of treatment. Adverse

effect was not documented.

The possible adverse effects are pseudo-aldosteronism with sodium retention,

hypokalaemia and hypertension, decrease in muscle strength, and muscle pain.133

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2 Nonpharmacologic interventions

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2.1 Phototherapy

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Phototherapy (light therapy, heliotherapy) has been accepted as a supplementary

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modality in inflammatory skin conditions. The clinical techniques related to the
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phototherapy applied in steroid-resistant OLP and the underlying mechanisms were
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shown in Table 3 and Table 1 respectively.

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2.1.1 Laser therapy

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Lasers have been normally used in various different areas of medicine and
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biotechnology.

Low-level laser therapy

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Low-level laser therapy (LLLT) is an approach increasingly used in medicine,

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which has potential bio-stimulating effects by improving wound healing, enhancing

epithelization after periodontal surgery, and preventing or managing induced-oral

mucositis.134

The mechanisms underlying the immunomodulation, stimulation of tissue healing

capacity, and analgesic properties of LLLT remain unknown. The proposed

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redox-regulation mechanism may be a fundamental explanation for the

bio-stimulation of LLLT.135 Modulation of mast cell functions, decreased production

of pro-inflammatory prostaglandin E2, and increased production of basic growth

factors have also been noted in LLLT.51

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135
In a prospective study, 13 steroid-refractory OLP patients received

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bio-stimulation with a 904-nm pulsed infrared laser (four sessions weekly). All

patients had complete remission of symptoms. During the follow-up period (6.46

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months on average), a new lesion occurred in one patient 1 month after the treatment.

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Later, the same team134 further validated their previous findings in another cohort of
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30 patients with atrophic erosive OLP, with a 980-nm gallium-aluminum-arsenide

diode laser. Each session was performed weekly delivering a fluence of 4 J/cm2 per
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lesion. 65 of the 82 treated leisions (79.27 %) had symptom improvements after the
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first four sessions. No complications or therapy adverse effects were observed.

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CO2 laser

The CO2 laser resection has been widely applied in treatment of benign oral lesions
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and potentially malignant disorders. Additionally, CO2 laser excision has become the
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preferred option for oral and oropharyngeal carcinomas in early stages.136, 137
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The features of CO2 laser surgery include the sealing of blood and lymphatic

vessels, cauterization of nerve endings, and immediate sterilization of laser wounds.

The tissue effect of CO2 laser is mainly produced by heat generation which can

carbonize and vaporize the irradiated tissues.138

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Pakfetrat et al 139found a pronounced reduction in pain and size of the OLP lesions

resistant to standard therapy after CO2 laser surgery. Significant improvement (3 or 4

degrees) in sign scores was achieved in 46% of the lesions and moderate

improvement (1 or 2 degrees) was observed in 23%. The rest 23% remained

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unchanged 3 months after surgical ablation. Magalhaes-Junior et al138 used CO2 laser

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on one patient previously unsuccessfully treated with steroids for 3 months, showing

no recurrence and disappearance of the burning sensation in 1 year.

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The reported intra-or postoperative complications include pain, swelling, bleeding,

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edema, and minor scarring.56, 140
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Yttrium aluminum garnet laser

Erbium-doped yttrium aluminum garnet (Er:YAG) laser (ERL) irradiation has been
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proposed as an alternative technique for cavity preparation and in oral surgery since it
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presents a high effectiveness on ablation of hard and soft tissues.

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ERL is a solid active medium, which emits radiation in the infrared portion of the

spectrum with the higher absorbability in water and hydroxyapatite. ERL produces
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thermal coagulation effects, ablation, and evaporation.141

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A clinical report studied the efficiency of ERL (2.94 µm wavelength) on 2 females

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with OLP unresponsive to topical corticosteroids. Both patients had a rapid complete

healing with slight discomfort and scanty bleeding during and after the treatment. A

small recurrence was observed in one case after 15 months. 141

The potential clinical complications include prolonged erythema, purpura, erosions,

pigmentary alteration, and scarring in skin resurfacing treatment. 142

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308-nm excimer laser

The excimer lasers have become a widely accepted modality in vast medical fields

like dermatology, cardiology, and ophthalmology. Monochromatic excimer light

(MEL, 308 nm) emits a monochromatic coherent light targeting at affected skin, using

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a xenon-chloride (XeCl) lasing medium, and induces immunomodulating

photobiological effects similar to narrow-band ultraviolet B (NB-UVB). 143

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Based on what is known about UVB, the action of 308-nm UVB excimer laser

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therapy may involve apoptosis, T-cell depletion, decreased antigen presentation, and

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the ability to regulate inflammatory mediators. What’s more, MEL has already been
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found to be a more potent inducer of lymphocyte apoptosis in selectively target

lesions.144
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Two refractory OLP patients subjected to 308-nm UVB excimer laser treatment
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had complete remission and one showed lesion recurrence after 4 weeks.145 Both
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patients suffered from erythema and erosions. Another before-after trial suggested the

use of 308-nm excimer laser radiation as a promising treatment for patients with
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symptomatic and steroid-refractory OLP. Of the eight participants who completed the
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study, five demonstrated excellent (>75%) clinical improvement for 2 to 17 months

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without recurrence or adverse effects, two responded fairly, and one responded

poorly.146

The sessions are generally well tolerated and adverse effects are minimal, including

erythema, hyperpigmentation, blisters, erosions, and pruritus.59, 143

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2.1.2 Photodynamic therapy

Photodynamic therapy (PDT), a form of photochemotherapy, involves application

of photosensitizer, by intravenous injection or topical application, and activation of

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the sensitizer by light of a specific wavelength. PDT has been recommended to

palliate or eradicate various types of cancers and dysplasia.147, 148

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The exact mechanism of action of PDT is unclear. It has been suggested that PDT

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may influence the adaptive immune response and impart an immunomodulatory effect.

Furthermore, PDT induces direct oxidative damage to cellular organelles, demolition

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of microvasculature, and induction of apoptosis in hyperplastic inflammatory cells by
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producing intracellular singlet oxygen and free radicals.147, 149
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Laser light was applied on lesions of 13 intractable OLP patients 10 minutes after

gargling a 5% methylene blue solution. Symptomatic alleviation and lesion size

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reduction were reported 1 week after treatment and at follow-up sessions up to 3

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months with no adverse reactions or visible scarring.150

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No adverse effects has been reported.148, 149

Skin photosensitivity may occur

following systemic administration of the photosensitizer.

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2.1.3 Ultraviolet Therapy

Ultraviolet (UV) therapy for OLP consists of psoralen plus UVA (PUVA) and

targeted UVB.

2.1.3.1 PUVA Therapy

Photochemotherapy utilizing administration of photosensitizing psoralen drug and

 ACCEPTED MANUSCRIPT

subsequent exposure to ultraviolet radiation is referred to as PUVA. It has been

established for the treatment of psoriasis.

Upon photoactivation, 8-methoxy-psoralen (8-MOP) can inhibit DNA replication

and cause apoptosis ultimately, which may be responsible for the anti-hyperplastic

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effect. PUVA has also been shown to have a suppressive effect on T cells and

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cytokine expression, resulting in inhibition of immune responses. Psoralens directly

interact with cellular components and indirectly modify them via reactive oxygen

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species.151

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Eighteen OLP patients, refractory to topical corticosteroids treatment, were treated
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with PUVA.152 8-MOP was ingested orally before long-wave UV light irradiation,

which was given at intervals of 2-3 days. Thirteen treated sites showed dramatic
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improvement compared with six control sites. Two patients dropped out due to nausea.
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Fourteen patients had nausea, dizziness, eye symptoms, numbness, and headache of
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various degrees.

Short-term adverse effects mainly include nausea, pruritus, redness, and

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generalized photosensitization when psoralen is taken orally. UV light has potential

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carcinogenic effects in skin in the long run, although the effect on oral mucosa is yet
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to be determined.153, 154

Photopheresis

Photopheresis, also called extracorporeal photochemotherapy ( ECP), involves

extracorporeal exposure of leukocytes to photoactivated 8-MOP, followed by

 ACCEPTED MANUSCRIPT

reinfusion into the patient. ECP is an effective therapeutic method in a variety of

haematological malignancies, graft-versus-host disease, and autoimmune

conditions.155

The rationale of ECP includes apoptosis-induction and modifications of

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immuno-regulatory processes and the downregulation of immune response and

tolerance induced by regulatory T cells. 156, 157

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Guyot et al.158 described a three-year follow up study of patients with drug

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recalcitrant OLP treated by ECP twice weekly for 3 weeks. Of the twelve patients

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who showed reduction of the erosive surface with no adverse events, nine had
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complete remission, and three attained partial remission. Seven patients relapsed as

ECP frequency decreased. Partial or complete remission was reestablished by

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restoring frequency of ECP.

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Hypotension, anemia, pruritus and fevers may occur during or after ECP
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treatment.157

2.1.3.2 UVB phototherapy

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UVB light therapy has been commonly prescribed for patients with psoriasis and
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vitiligo. Targeted UVB phototherapy applies radiation to lesional skin while spares
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potential harmful effects to adjacent normal skin.159

UVB radiation exerts a variety of effects on keratinocytes, lymphocytes and

dendritic cells in the skin, triggering a variety of biological effects. The mechanisms

of action include suppression of the adaptive immune responses, induction of innate

immunity, and induction of apoptosis in T-cells and keratinocyte.160

 ACCEPTED MANUSCRIPT

In a single-center study, 14 patients with EOLP resistant to topical treatments

including steroids were treated with targeted UVB therapy (3 times a week, gradual

increase in dose every other session). Complete response was achieved in 9 patients

and partial response was achieved in 5 patients after 8 weeks. Four patients had

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relapse after cessation of the maintenance regimen. No significant adverse effects

were observed except transient burning in 1 patient.161

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Adverse effects may include acute erythema, hyperpigmentation, burning, itching,

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erosions and blisters. Some results indicated that UVB radiation increased

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carcinogenic risks of exposed oral tissues compared to skin.162
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2.2 Traditional surgery
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Associated neoplasm resection

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Thymomas are neoplasms known to be frequently associated with paraneoplastic

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autoimmune disorders. OLP may rarely be associated with tumors such as thymoma,
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Good syndrome, and Castleman's disease.163 Though the precise relationship remains

to be defined, it suggests that complete thymoma resection may achieve definitive

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regression of OLP in such cases. However, thymectomy may not induce stable clinical
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remission of EOLP.124, 164

One possible mechanism connecting EOLP and thymoma may be the direct tissue

injury by CD8 (+) T cells, activated by abnormal regulation of lymphocytes within the

thymus.124Besides, the generation of specific autoreactive T lymphocyte clones,

which cross-reacts with specific mucosal keratinocyte antigens and secrete TNF-α and
 ACCEPTED MANUSCRIPT

MMP-9, may cause lichen planus.164

Bobbio et al.165 described a case of EOLP resistant to corticosteroids in a

79-year-old male patient with thymoma. Generalized oral erosive lesions completely

subsided 1 month after thymoma resection.

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Other surgeries

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Surgical excision has been recommended for isolated plaques or non-healing

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erosions because it resects localized lesions and provides tissue specimens for

histopathologic examination.166 A 52-year-old male with persistent OLP had little

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improvement after treatment with topical and systemic steroids. No relapse was

observed in 2 years after the surgical removal.167

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Cryosurgery is another documented mode of drug-resistant OLP treatment.

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Complete resolution of extensive lingual EOLP resistant to therapeutic attempts

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including topical steroids has been reported in a case using cryosurgery. The patient

did well after surgery and the lesion was healed with mild scarring by day 16. He was
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asymptomatic 20 months later. 168

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Treatment of recalcitrant erythematous gingival lichen planus with autogenous

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palatal grafts has also been described previously.169

Conclusion

In this study, we summarized various treatment modalities for OLP lesions

refractory to corticosteroids. However, no RCTs has verified these findings except for
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TAC, PIM, CsA, thalidomide, isotretinoin, curcumin, and LLLT. Further studies,

especially RCTs with strict inclusion and exclusion criteria and larger sample sizes,

are required for the evaluation of long-term safety and efficacy of these therapies.

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[159] Mudigonda T, Dabade TS, Feldman SR. A review of targeted ultraviolet B phototherapy for
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of Dentistry and Oral Hygiene 2013;5(1):1-3.
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D
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 ACCEPTED
Table 1. Miscellaneous treatment regimens MANUSCRIPT
and the mechanisms of actions

Intervention RCT Targets and Proposed Mechanisms

Tacrolimus Yes CNIs, FKBP12, inhibition of NFAT dephosphorylation and blockage of cytokine

gene transcription

PT
RI
Pimecrolimus Yes CNIs, FKBP12, inhibition of cytokine gene transcription and blockage of

T-lymphocyte activation

SC
Cyclosporine A Yes CNIs, Cyclophilins, inhibition of NFAT nuclear translocation and blockage of T

U
cell activation
AN
Rapamycin No mTOR inhibitors, FKBP12， inhibiting the response to IL-2 and blocking the

activation of lymphocytes
M
D

Etanercept No TNF-α inhibitors, blocking TNF-mediated cellular responses

TE

Thalidomide Yes Anti-inflammatory effects, T-cell immunomodulation, and anti-angiogenesis

EP

action

Mycophenolate mofetil No IMPDH inhibitor, immunosuppressive and antitumor actions

C
AC

Tetracycline No Antibiotics, immunomodulatory and anti-inflammatory effects

Retinoids Yes RARs and RXRs, regulation of differentiation and the immune response,

suppression of carcinogenesis, and induction of apoptosis

Curcumin Yes Antioxidant, anti-inflammatory, anti-carcinogenic and pro-apoptotic properties

Glycyrrhizin No ACCEPTED MANUSCRIPT
Anti-inflammatory, anti-oxidative, anticancer and hepatoprotective activities

Low-level laser therapy Yes Immunomodulation, biostimulation, and anti-inflammation

CO2 laser therapy No Carbonization and evaporation

Er-YAG laser therapy No Coagulation and evaporation

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Excimer laser therapy No Apoptosis-induction and immunomodulation

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Photodynamic therapy No Apoptosis and immunomodulation

SC
PUVA (Psoralen + UVA) No Apoptosis promotion and downregulation of immune response

Photopheresis No Apoptosis-induction and immunomodulation

U
AN
Targeted UVB No Apoptosis and immunomodulation
M

RCT, randomized controlled trial; FKBP12, FK506-binding proteins; CNIs, calcineurin inhibitors; NFAT,
D

nuclear factor of activated T cells; IMPDH, inosine monophosphate dehydrogenase; RARs, retinoic acid
TE

receptors; RXRs, retinoid X receptors; UVA, ultraviolet A; UVB, ultraviolet B.

C EP
AC
 ACCEPTED MANUSCRIPT

Table 2. Studies reporting the use of topical calcineurin inhibitors in the management

of corticosteroid-refractory OLP

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U SC
AN
M
D
TE
C EP
AC
Author Study No. Clinical Refract Dosage regimen Results Adverse effects

design type of ory to

(F/M)
ACCEPTED MANUSCRIPT(No. /Percent. ) (No. /Percent. )
OLP treatme

nts

Arduino et RCT 30 Atrophic TCS TAC 0.1% TAC vs. PIM: TAC,burning(2),

al, -erosive ointment vs. transient sialorrhoea

(23/7) CR(5/15 vs. 5/15)

PT
PIM 1% cream, (1), blood TAC
2014
PR (9/15 vs. 6/15)
both 1:1 mixed undetectable or low

RI
with NR(1/15 vs. 4/15), (<5 ng/mL);

SC
hydroxyethyl
stable at 6m(4/15 PIM, xerostomia(2),
cellulose gel,

U
vs. 10/15) gastroesophageal
AN
bid, 2 m
reflux(2), herpes

labialis(1)
M

Resende et Prospecti 15 Sympto SCS TAC 0.1% CR(12/15), Dry mouth(2),

D

al, ve matic cream, bid, 2 m PR(2/15),

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(11/4) burning (1),

2013 NR(1/15)
palatal changes (1),
EP

dry mouth and

C

burning(1), dry
AC

mouth and palatal

changes(1)

Riano et Case 1 TAC 0.1% Improvement Not reported

Erosive TCS
al, report cream, qd, 2 m within 15d,
(1/0)
 ACCEPTED MANUSCRIPT

2006 asymptomatic

during 3m

Shichinoh Case 2 Erosive TCS TAC 0.1%, bid, Improvement None;

e et al, report 6m within 4w or 5w,

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(2/0) blood TAC within a
no recurrence
2006 safe level(2.5 ng/mL)

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during 6 m
(1)

U SC
Donovan Case 1 Erosive TCS TAC 0.1% CR, no recurrence Not reported
AN
et al, 2005 report ointment, bid, 2 during 1y
(1/0)
M

w
D

Eckardt et Open 18 Erosive/ TCS or TAC 0.1% Symptom relief Burning;

TE

al, 2005 clinical ulcerativ SCS ointment, bid, (94%),

(13/5) blood TAC within
phase II e
2m NR (6%), the therapeutic range
EP

trial
(0-2.9ng/mL)(12/18)
relapse within
C

3w-10w (10/18)
AC
 ACCEPTED MANUSCRIPT

Hodgson Retrospe 50 Erosive/ TCS TAC 0.1% CR(14%),PR Burning (16%),

et al, 2003 ctive (39/11 ulcerativ paraffin, bid, (80%), NR(6%)

taste disturbance(8%
) e 2m-39 m
);blood TAC

detectable 0.5-2.7µg

PT
/L (5/50)

RI
Lener et Case 1 Erosive TCS TAC 0.1% CR, no relapse Not reported

SC
al, report ointment, within 1 y
(1/0)
qd-bid, 4m

U
2001 AN
Vente et Case 4 Erosive TCS at TAC 0.1% CR (3/4), PR (1/4), Burning(2); blood
M

al, report least ointment, bid, at relapse after TAC detectable

(3/1)
least 4 w cessation within 8w (9-15mg/L)(1)
1999
D

(1/4)
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Dissemon Case 1(1/0) Erosive TCS PIM 1% cream Nearly CR Burning

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d et al, report 1:1 mixed with

2004 hydrophilic gel

C
AC

base, bid, 4 m

Esquivel-P Case 1(1/0) Sympto TCS PIM 1% cream, CR at 2w, no None

edraza et report matic bid, 3 m recurrences within

al, 2004 8m
 ACCEPTED MANUSCRIPT

Demitsu et Case 1(1/0) Erosive TCS CsA 100 CR No; blood CsA level

al, 2000 report mg/mL, bid,4w below 20 ng/mL

Epstein Prospecti 14(6/8 Sympto TCS or CsA 0.5 mg/dl, PR (8/14), Bad taste, discomfort

and ve ) matic TCS+S

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qid,1 m NR (6/14)
Truelove,1 CS

RI
996

SC
Voute et Prospecti 9 Sympto TCS or CsA 0.025%, PR (4/9), NR or None

al,1994 ve matic SCS qid, 3w worsening (4/9)

U
AN
M

No., number of patients; F/ M, female/male; Percent., percentage of patients; TCS,

topical corticosteroids; SCS, systemic corticosteroids; PIM, pimecrolimus; TAC,

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tacrolimus; d, day/days; w, week/weeks; m, month/months; y, year/years; qd, once

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daily; bid, twice daily; tid, three times daily; qid, four times daily; CR, complete
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resolution; NR, no response; PR, partial remission; versus, vs.; CsA, cyclosporine A.
C
AC
 ACCEPTED MANUSCRIPT

Table 3. Studies of phototherapy in the management of steroid-refractory OLP

PT
RI
U SC
AN
M
D
TE
C EP
AC
Author Study No. Clinical Refract Treatment protocol Results Adverse

design type of ory to effects

(F/M)
ACCEPTED MANUSCRIPT (No. / Percent. )
OLP treatme
(No. /
nts
Percent. )

Cafaro et Prospectiv 30 Atrophic/ TCS LLLT(980nm, CR with 11.8 SS (64/82), None

al, 2014 e (19/11 erosive GaAIAs diode laser,

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PR with 13.5 SS (14/82),
) cw), qw, until the
NR with 12.7SS ( 4/82),

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resolution

relapse within 26.6m

SC
(15/30)

Cafaro et Prospectiv 13 Atrophic/ TCS

U
LLLT(904 nm, CR with 7.8 SS (14/25), None
AN
al, e (8/5) erosive GaAs pulsed laser,
PR with 9.5 SS (8/25),
M

cw), biw, until the

2010
NR with 10.7SS (3/25),
resolution
D

relapse within 6.46m

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(1/13)
EP

Pakfetrat Prospectiv 10 Atrophic/ TCS CO2 laser (10600 Remission at 1m and 3m, Not
C

et al, e (7/3) erosive nm, cw, slightly reported

0≤EI<25% (31%),
AC

defocused)
2014
25% ≤ EI<75% (23%),

75% ≤ EI<100% (46% )

at 3 m
 ACCEPTED MANUSCRIPT

Magalhaes Case 1 Symptom CS CO2 laser (10600 CE and symptom relief Mild

-Junior et report atic nm, 10W, slightly within 3 w, no recurrence discomfort

(1/0)
al, 2011 defocused) within 1 y

PT
Trehan et Before-aft 9(3/6) Symptom TCS at MEL (308 nm, initial Withdrawal (1/9), None

al, er atic least dose 100 mJ/cm2 and

RI
excellent response (5/8),
400 mJ/cm2
2004

SC
fair response (2/8),
maximum), qw, 30

SS or until clearing poor response (1/8)

U
AN
Kollner et Case 2 Erosive TCS MEL (308 nm, nitial CR, relapse 1 m later(1/2) Erythema

al report dose 75 mJ/cm2 and and

M

(1/1)
150 mJ/cm2 finally),
2003 erosions
D

tiw, 12SS
(2/2)
TE

Fornaini et Case 2(2/0) Symptom TCS Er:YAG laser (2940 CR in 10d, relapse 15 m Much less
EP

al, report atic nm, 12.6-18.9 J/cm2) later(1/2) discomfort

, scanty
C

2012
AC

bleeding

Aghahosse Before-aft 13 Symptom TCS+S PDT (MB, laser Sign improvement at 1w Few

ini et al, er (12/1) atic CS at irradiation, 632nm, (16/26), no reduction patients

least 120 J/cm2) (10/26); lesion size burning

2006
reduction (44.3%) stable
 ACCEPTED MANUSCRIPT

at 12w

Lundquist Controlled 18 Erosive/ TCS PUVA (oral 8-MOP, Withdrawal (2/18), Nausea

al, ulcerative UVA, 320-400nm,

(13/5) the treated sites vs. (14/16),
17.5 m W/cm2), 2-3d

PT
1995 control sites: marked dizziness,
intervals, 12SS
improvement (9/16vs. eye

RI
2/16), slight improvement symptoms,

SC
(4/16vs.4/16), NR numbness,

(3/16vs.10/16) headache

U
AN
Guyot et Prospectiv 12 Erosive TCS at ECP(8-MOP, UVA CR (9/12), PR (3/12), Difficult

al, 2007 e least 3 J/cm2), biw, 3w, venous

M

(10/2) relapse (11/12)

and then tapered access
D

(1/12)
TE

Kassem et Prospectiv 14 Erosive TCS at UVB (290-320nm, CR (9/14), PR (5/14) Burning

EP

al, e least nitial 20% of after 8 w; relapse within 6 (1/14)

(9/5)
minimal erythemal w (4/14)
2012
C

dose), tiw
AC

LLLT, low-level laser therapy; qw, once a week; biw, twice a week; tiw, three times a

week; SS, (average)treatment sessions; cw, continuous wave; EI, efficacy index; CS,

corticosteroids; 8-MOP, 8-methoxypsoralen; PDT, photodynamic therapy; MB,

methylene blue; CE, complete epithelialization; MEL, monochromatic excimer light.

 ACCEPTED MANUSCRIPT
Author Study No. Clinical Treatment protocol Results Adverse effects

design type of
(F/ (No. / Percent. ) (No. / Percent. )
OLP
M)

PT
TAC, 6 RCT, 3 Retrospective, and 2 Prospective

RI
Ribero et Retrosp 21 Symptoma TAC 0.1% Lost at follow-up (2/21); CR Occasional unpleasant

SC
al 2015 ective tic ointment or 0.03% (4/21), MR (2/21), PR taste or burning
(15/

U
mouthwash, bid, (8/21), NR (7/21) at 2m; CR
6)
AN
2m or 6m (7/21), MR (1/21), PR (4/21)

at 6m
M

Jain et al, Retrosp 29(2 Symptoma TAC 0.1% Symptomatic improvement Burning/irritation (18%),
D

2015 ective 0/9) tic ointment, tid, 6m (81%), lesion clearance/ tingling (3%)
TE

reduction (84%), relapse

EP

after cessation (43%)

Sonthalia RCT 40(2 Symptoma TAC 0.1% TAC vs. CP: CR+PR (95% TAC, burning (15%);
C
AC

et al, 4/16 tic ointment vs. CP vs. 70%) at 8w CP, burning (15%),

2012 ) 0.05% ointment, candidal infection (20%)

bid, 8 w

Supplemental Table 4. Review of modalities for OLP management

 ACCEPTED MANUSCRIPT

Revanap RCT 60(2 Symptoma TAC 0.1% in TAC vs. TA: clinical scores None

pa et al, 3/37 tic orabase vs. TA reduction(74.4% vs. 45.1%)

2012 ) 0.1% in orabase, at 4w

tid, 2w

PT
Corroche RCT 32(2 Symptoma TAC 0.1% TAC vs. TA: CR of pain TAC, burning (56.3%);

RI
ret al 0/12 tic ointment vs. CP (68.8% vs. 6.3%) at 4 w blood TAC undetectable

SC
2008 ) 0.05% ointment,

qid, 4w

Radfar et RCT 29(1 Symptoma TAC

U 0.1% TAC vs. CP: VAS reduction Not reported
AN
al, 2008 6/13 tic ointment or CP (52.3% vs. 38.0%), lesion
M

) 0.05% ointment, sizes reduction (82.6%

D

qd-qid, 6w vs.81.6%) at 6w; relapse

TE

1m-6m later (3/15 vs. 2/14)

Laeijend RCT 40(3 Symptoma TAC 0.1% TAC vs. TA: CR (6/20 vs. Burning or stinging (8/20
EP

ecker et 0/10 tic ointment vs. TA 2/20) PR (12/20 vs. vs. 3/20)
C

al, 2006 ) 0.1% ointment, qid, 7/20) NR (2/20 vs. 11/20);

AC

6w relapse within 3w-9w

(72%vs. 78%)

Byrd et Retrosp 37(3 Symptoma TAC 0.03% or CR+PR (84%), relapse Burning (5), irritation

al, 2004 ective 2/5) tic 0.1% ointment, bid, following cessation (56%) (4), tingling (3)
 ACCEPTED MANUSCRIPT

5d-2.7y

Tavassol Prospec 11(8 Erosive TAC 0.1% Subjective and objective Rare and minor

et al, tive /3) ointment, bid, 8 w improvement (10/11)

2008

PT
RI
Lozada- Prospec 10 Symptoma TAC 0.1% in Signs reduction from 1.58 Headaches (1/7), burning

Nur et al, tive tic (OLP orabase, tid, 2 w to 0.78, symptoms reduction (1/7)

SC
2006 7/10, from 1.95 to 1.11 at 4w

U
lichenoid AN
3/10)
M

Vohra et RCT 40(1 Symptoma TAC 0.1% TAC vs. PIM: decline in TAC, burning (6/20),

al, 2016 9/21 tic ointment vs. PIM NCS from 10.9 ±4.5 to 5.4 dysgeusia (2/20); PIM
D

) 1% cream, bid, 8 w ±3.5 vs. from 9.9 ±4.6 to burning (1/20)

TE

5.3±4.2 at 12 w
EP

PIM, 7 RCT
C

Pakfetrat RCT 28(2 Atrophic/e PIM 1% cream vs. PIM vs. TA: CR (10/14 vs. None
AC

et al, 2/6) rosive TA 0.1% in 12/14) PR (2/14 vs.

2015 orabase, tid, 2m 0/14) NR (2/14vs. 2/14)

 ACCEPTED MANUSCRIPT

Arunku RCT 30(2 Symptoma PIM 1% cream vs. PIM showed better None

mar et al, 0/10 tic TA 0.1% oral paste, therapeutic response; relapse

2015 ) qid, 2m 2m later, PIM vs. TA (6.7%

vs. 33.3%)

PT
McCaug RCT 21(1 Erosive PIM 1% cream PIM was superior to vehicle TAC, blood PIM

RI
hey et al, 6/5) vs. vehicle, bid, 6 w in reducing pain score and detectable (≤0.814

SC
2011 erosion size ng/mL); vehicle, a blister

(1/11), a cold sore(1/11)

Volz et RCT 20(1 Erosive PIM 1%

U
cream PIM was superior to vehicle Vehicle, mucosal
AN
al, 2008 5/5) vs. vehicle, bid, 30d in reducing lesions and paraesthesia (1); PIM,
M

VAS, relapse 1m later (1) paraesthesia (1), burning

D

(4), blood PIM detectable

TE

(≤3.81 ng/mL) 5

Gorouhi RCT 40 Erosive PIM 1% cream vs. Withdrawal 5.Similar PIM , burning (2)
EP

et al, TA 0.1% paste, improvement in VAS,

C

2007 qid, 2m; follow-up OHIP, and clinical score

AC

2m

Passeron RCT 12(5 Erosive PIM 1% cream PIM was superior to placebo PIM, burning(2/6), blood

et al, /7) vs. placebo, bid, 4 in reducing lesions and PIM detectable

2007 w VAS, relapse 1m later (6/6) (≤6.19ng/mL) (6/6)

 ACCEPTED MANUSCRIPT

Swift et RCT 20(1 Erosive PIM 1% cream PIM was superior to placebo PIM, burning(1/10)

al, 2005 4/6) vs. placebo, bid, 4 in reducing lesions and VAS

PT
CsA, 3 RCT, 1 Prospective, and 1 Controlled

Yoke et RCT 139( Symptoma CsA 100 mg/mL Withdrawal 11. CsA was TA, burning (3/71); CsA,

RI
al, 2006 94/4 tic solution vs. TA no more effective than TA in burning (14/68) local

SC
5) 0.1% in orabase, reducing VAS, lesion size, swelling and itching of

U
tid, 8w AN and clinical score the lip (1/68),

gastrointestinal upsets

(4/68); blood CsA

M

undetectable or ≤ 340
D

ng/mL
TE

Conrotto RCT 40(2 Atrophic/e CsA 1.5% vs. CP Withdrawal 1. CP is more CP, dyspepsia (3), skin
EP

et al, 6/14 rosive 0.025% in effective in inducing clinical rashes(2), parotid

2006 ) hydroxyethyl response. CsA has swelling (1), blood

C

cellulose gel, bid, comparable effects on cortisol stable; CsA,

AC

2m, 2m follow-up symptoms and is more stable dyspepsia (1), blood CsA

undetectable
 ACCEPTED MANUSCRIPT

Jungell et Prospec 7(6/ Atrophic/e CsA 100 mg/mL PR(2),NR(5), relapse 1m Burning (7), blood CsA

al, 1996 tive 1 rosive mouthwash, tid, 4w later (2/2) undetectable

PT
Harpena Control 14(1 Atrophic/e CsA 100 mg/mL CsA was superior to placebo None, blood CsA

u et al, led 1/3) rosive mouthwash vs. in reducing lesions and pain undetectable

RI
1995 placebo,5 minutes scores

SC
daily,4w, 3-month

follow-up

U
AN
Eisen et RCT 16 Symptoma CsA 100 mg/mL CsA was superior to placebo Burning (16), blood CsA

al, 1990 tic mouthwash vs. in reducing lesions and pain detectable (30-151
M

vehicle, 5 ml, tid, scores. Relapse within ng/mL ) (9/16)

D

8w 1m-6m(8/12)
TE

Thalidomide, 1 RCT
EP

Wu et al, RCT 69 Erosive Thalidomide 1% Withdrawal 6. Topical Thalidomide vs. DMT,

2010 paste vs. DMT thalidomide was as effective burning and tingling
C
AC

0.043% paste in reducing erosive areas and (2/37 vs. 2/32)

tid,1w-4w VAS scores. No differences

in the recurrence rate at 1m

and 3m follow-up
 ACCEPTED MANUSCRIPT

Retinoids, 1 RCT, 4 Controlled, and 4 Prospective

Kunz et Prospec 10(4 Symptoma Alitretinoin 30 mg, Withdrawal 2. Significant Headache (40%),

al, 2015 tive /6) tic qd, 24w, 5w–24w clinical response (4/10), no mucocutaneous dryness,

PT
follow-up significant change in pain musculoskeletal pain,

score or OHIP dyslipidaemia, elevated

RI
TSH(1), hair loss and

SC
loss of appetite(1)

U
Gorsky Prospec 6(4/ Symptoma Etretinate, 25 mg, Asymptomatic(3/6), Mucocutaneous
AN
et al, tive 2) tic tid, 2m improvement of clinical dryness(4/6), skin

1992 signs and symptoms (6/6); sloughing(2/6), rash and

M

relapse 2m later (6/6) itching(3/6), hair loss

D

(1/6), slight elevation of

TE

ALT(1/6), slight

elevation of
EP

triglyceride(1/6)
C

Camisa Prospec 6(3/ Erosive Isotretinoin (10 to Withdrawal 1. Minimal Pruritus(100%),xerophth

AC

et al, tive 3) 60 mg daily), 8 w subjective and objective almia(1), headache,

1986 improvement(5), relapse cheilitis, dry skin, rash,

within 2m(4) joint pain

 ACCEPTED MANUSCRIPT

Ferguson Prospec 10(7 Erosive Placebo, first 2 w; Withdrawal 2. Slight Rash and pruritus(7),

et al, tive /3) etretinate, 25 mg, decrease in ulceration size cheilitis(6),

1984 tid, 8w (maximum desquamation of hands

daily dose 75mg) and feet(6),

PT
paronychia(4), severe

RI
Beau’s lines on nails(2),

temporary hair loss (1)

SC
Piattelli Control 20(1 Atrophic/e Isotretinoin 0.1% CR 10 PR10 None

et al, led 0/10 rosive gel vs.

U
placebo,
AN
2007 ) tid, 4m; then the
(4),
M

initially placebo
reticular(1
group, isotretinoin
D

0), plaque
gel, another 4m
TE

(6)

Scardina RCT 70(4 Atrophic/e Topical isotretinoin Clinical and histological Transitory soreness
EP

et al, 0/30 rosive (60 0.05% and 0.18% improvement: reticular

C

2006 ) lesions),ret concentration, bid, OLP(0%); atrophic-erosive

AC

icular (10 3m OLP, concentration 0.18%

lesions) (26), concentration 0.05%

(9)
 ACCEPTED MANUSCRIPT

Giustina Control 22(1 Erosive, Isotretinoin 0.1% Withdrawal 2. CR (90%), Burning, superficial

et al, led 1/11 gel vs. vehicle, bid, isotretinoin 0.1% was more desquamation, erythema
reticular/pl
1986 ) 2m; then the efficacious than placebo
aque
initially vehicle

PT
group, isotretinoin

RI
gel, another 8w

SC
Sloberg Control 25(1 Atrophic/e Etretinate 0.6 Withdrawal 2. First Dryness of the lips

et led 9/6) rosive (49 mg/kg/day, 2m, treatment, CR+PR (85%); and skin(25/25), transient

al,1983 lesions), followed

U by second treatment, the hair loss(3/25), moderate
AN
reticular/ Etretinate 0.3 improvement maintained or increase in transaminase
M

plaque (5 mg/kg/day(16), or increased (70%) (1/16), oral soreness

lesions) Tretinoin 0.1% in

D

an adhesive base
TE

(9), 4m
EP

Sloberg Control 38(2 Erosive Tretinoin 0.1% in Tretinoin vs. vehicle, Slight redness and
C

et al, led 6/12 (31 orabase vs. vehicle, improvement in scaling of the lip(2),
AC

1979 ) lesions ), bid or qid, 2m atrophic-erosive lesions soreness

reticular/pl (71% vs. 29%),

aque (32 reticular-plaque lesions

lesions) (74% vs. 15%); relapse

within 3m (39%)
 ACCEPTED MANUSCRIPT

Curcumin, 2 RCT, 1 Retrospective

Chainani Retrosp 53 Atrophic/e Curcuminoids Reduction of symptoms 2137.5 mg/daily,

-Wu et ective rosive 2137.5 mg/daily (22/37), unsure(13/37), NR diarrhea (2); 5058

al, 2012 (18/25),30m, (2/37) mg/daily, abdominal

PT
68.2m follow-up, discomfort

RI
or 5058 (3/19),diarrhea (2/19),

mg/daily(19/19), slight urgency in

SC
9.6m, 15.8m defecation on the capsule

U
follow-up (1/19)
AN
Chainani RCT 20(1 Atrophic/e Curcuminoids vs. Curcuminoids, the changes Diarrhea(3), constipation
M

-Wu et 3/7) rosive placebo, 2000mg, from baseline statistically (2), abdominal pain(1),

al, 2012 tid, 12d, 2w significant in NRS, heartburn(1), nausea(1),

D

follow-up erythema, ulceration, and slight elevation of

TE

MOMI; greater reduction in ALT(2)

EP

clinical signs and symptoms

than placebo
C
AC
 ACCEPTED MANUSCRIPT

Chainani RCT 33(2 Atrophic/e Curcuminoids vs. No significant difference Curcuminoids vs.

-Wu et 3/10 rosive placebo, 1000mg, between the curcuminoids placebo, headache(5

al, 2007 ) bid, 7w (Prednisone and placebo vs.1), rash(1 vs.1),

60 mg/d, for the flatulence(2 vs.0), pitted

PT
first 1w) fingernails(1 vs.0), dry

RI
mouth(1 vs.2), metallic

taste (0 vs.1)

SC
LLLT, 3 RCT, 2 Controlled

Kazancio Control 120( Atrophic/e LLLT(808

U
nm, Ozone therapy and TCS None
AN
glu et al, led 64/5 rosive 2.5min, q3d, 10 SS therapy, sign improvement,
M

2015 6) maximum); ozone symptom improvement, and

D

therapy(60% higher EI; LLLT, symptom

TE

intensity, 10s, q3d, improvement. Relapse, TCS

10 SS maximum); group within 4∼17 w

EP

DMT or placebo (50%); ozonated group

C

mouthwash, 5min, within 3.5∼16 w (40%)

AC

qid, 1m

El-Shena Control 24 Atrophic/e LLLT(970nm, biw, TA group show reduced None

wy et al, led rosive 10 SS maximum) VAS score than LLLT

2015 vs. TA (0.1% in group

orabase, qid, 4w)

 ACCEPTED MANUSCRIPT

Dillenbu RCT 42(3 Atrophic/e InGaAlP diode Both groups: significant CP, burning (3),

rg et al, 5/7) rosive laser (660 nm, tiw, reductions in clinical scores, gastrointestinal distress

2014 12 SS) vs. CP VAS, and functional scores. (2), normal cortisol level;

(0.05%, tid, 1m) Laser group, higher laser none

PT
percentage of CR. Relapse

RI
laser vs. CP (4.8% vs.

47.6%) within 1m

SC
Agha-Ho RCT 28(2 Erosive LLLT(890 nm or Both groups, improvements Not reported

sseini et 1/7)
U
633 nm, q2d, 5SS) in size of lesions, in pain and
AN
al, 2012 vs. CO2 laser clinical response scores;
M

surgery partial to complete clinical

(10.6µm,3W ) improvement 3m later,

D

LLLT vs. CO2 laser (100%

TE

vs. 85%)
EP

Jajarm et RCT 30 Atrophic/e LILT(630nm,2.5 LILT was as effective as None

C

al, 2011 rosive min, q3d, 10 SS DMT in reducing

AC

maximum) vs. appearance score, VAS, and

DMT mouthwash lesion severity

(0.1 mg/ml, 5min,

qid, 1m)

CO2 laser, 1 Controlled, 1 Retrospective, and Prospective

 ACCEPTED MANUSCRIPT

Mücke et Control 171( Erosive CO2 laser (10.6 µm, CO2 laser vs. analgesic, Not reported

al, 2015 led 87/8 cw, defocused) vs. relapse (26/68 vs. 90/103);

4) symptomatic malignant transformation to

treatment OSCC, (2/16 vs. 14/16)

PT
van der Retrosp 21(9 Symptoma CO2 laser CE in 3w, relapse within None

RI
Hem et ective /12) tic 1y-18y (38%)
(15-20W, slightly

SC
al, 2008
defocused)

U
Deppe et Prospec 145 Erosive CO2 laser, Group1 Successfully treated in group None
AN
al, 2012 tive OLP (cw, defocused), 1, 2, and 3 (41.7%, 33.4%,

lesions Group2 and 50%); relapse within

M

(50), OLK (cw/scanner), 4m-123m, (58.3%, (66.6%,

D

lesions and 50%) ; Defocused

Group3
TE

(98) technique was better

(sp/scanner)
EP

308nm excimer laser, 1 Prospective

C

Passeron Prospec 4(3/ Erosive 308nm excimer PR1, stable 1m later; Moderate erythema
AC

et al, tive 1) laser, 50-200

NR or worsening 3
2004 mJ/cm2, biw, 12 SS

PDT, 3 Prospective
 ACCEPTED MANUSCRIPT

Kvaal et Prospec 14 Symptoma The treated side, Reduction in clinical scores None

al, 2013 tive tic PDT (MAL, diode 1m, 3m, 6m, and 4y after a

laser, 600-60nm); single treatment: no

6-48m follow-up difference, improvement,

PT
improvement, and

RI
improvement respectively

SC
Sobaniec Prospec 23(1 Not PDT Lesion size reduced None

et al, tive 7/6) reported (chlorin-e6-Photolo significantly (55% on

2013 n®, 660nm),

U2w average)
AN
intervals, 10 SS
M

maximum
D

Sadaksha Prospec 20(1 Symptoma PDT(MB, Xenon 4w after the treatment: CR None
TE

ram et al, tive 3/7) tic arc lamp, 630 ± 5 (2), marked improvement

2012 nm), 4SS (6), moderate improvement

EP

(9), NR (3)
C

MR, major remission; NCS, net clinical score; CP, clobetasol propionate; TA,
AC

triamcinolone acetonide; VAS, visual analog scale; OHIP, Oral Health Impact Profile;

ESS, Escudier severity score; TSH, thyroid-stimulating hormone; ALT, alanine

aminotransferase; MOMI, Modified Oral Mucositis Index; NRS, Numerical Rating

Scale; DMT, dexamethasone; q3d, once every third day; min, minute/minutes; s,

second/seconds; q2d, every other day; LILT, low intensity laser therapy; OSCC, oral
 ACCEPTED MANUSCRIPT

squamous cell carcinoma; OLK, oral leukoplakia; sp, sp-mode; MAL, methyl

5-aminolevulinate.

PT
RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT
Clinical Relevance: informing Oral Medicine specialists of the current alternative
strategies for the management of symptomatic OLP cases refractory to steroid
therapies.

PT
RI
U SC
AN
M
D
TE
C EP
AC