**11. Differential diagnoses**

There is a spectrum of oral lesions that resembles OLP both clinically and histopathologically. [33, 34] These "lichen planus–like" ("lichenoid") lesions include the following conditions: (1) Oral lichenoid contact lesions (OLCL) as a result of allergic contact stomatitis (delayed immune mediated hypersensitivity). They are seen in direct topographic relationship to dental restor‐ ative materials, such as amalgam. In regards to the approach to oral lichenoid contact lesions, the value of patch testing remains controversial. (2) Oral lichenoid drug reactions (OLDR), wherein oral and/or cutaneous lesions arise in temporal association with the taking of certain medications, for example, oral hypoglycaemic agents, angiotensin-converting enzyme inhibitors, and non-steroidal anti-inflammatory agents. Confirmation of the diagnosis of an oral lichenoid drug reaction may be difficult, since empiric withdrawal of the suspected drug and/or its substitution by an alternative agent may be complicated. [38] (3) Oral lichenoid lesions (OLL-GVHD) of graft-versus-host disease are confined to allogeneic haematopoietic stem transplant recipients who have developed acute, or more commonly, chronic graftversus-host disease (cGVHD). There is evidence that there is a greater risk of malignant transformation with OLL-GVHD than seen with OLP. [40]

The oral presentation of discoid lupus erythematosus (DLE) can also present with reticular or plaque-like lesions, but it is an uncommon condition that tends to present very much unilat‐ erally, so meriting biopsy for histopathological and direct immune-fluorescence investiga‐ tions, the latter being most useful in distinguishing OLP from DLE. [34]

#### **11.1. Treatment**

**Laboratory Investigations:** Generally are not required, except in patients with severe OLP warranting high-dose systemic corticosteroids, with the need to exclude underlying latent infectious diseases that can be reactivated by the corticosteroids (HIV, Hepatitis B and C, and tuberculosis). Again generally not required, except if considering treatment with a suitable 'steroid-sparing systemic agent (e.g.: hydroxychloroquine (Plaquenil), azathioprine or methotrexate) then routine full blood count, and assessment of liver and renal function may be warranted, for baseline assessment and monitoring in patients needing long-term manage‐

**Patch Testing and the Removal of Lichenoid-Inducing Dental Restorative Materials:** Idiopathic OLP needs to be distinguished from oral lichenoid contact lesions (OLCL), most commonly seen in direct topographic relationship with amalgam. Cutaneous patch testing, undertaken by a clinician skilled and experienced in "reading" the cutaneous response to a variety of test agents can be useful to confirm the diagnosis of a OLCL, [36, 37] especially in severe, symptomatic cases, in which wide-spread replacement of the amalgam fillings is being considered, given the expense in time and money to the patient concerned. The benefit of such patch testing is to ensure that the alternate dental restorative materials also, in turn, do not incite a lichenoid contact reaction (e.g.: as has been seen with gold and even composite materials). In select cases, and if practical, consideration should be given to the replacement of those isolated restorations, seemingly to be in direct topographic relationship with a lichenoid oral mucosal lesion, particularly if symptomatic, with an alternate material, but the patient needs to be counselled that this may not necessarily prove beneficial. As an interim step, temporary coverage of the suspecting inciting material may be considered to determine if resolution of the OLCL occurs before undertaking definitive removal and replacement of

**Additional Measures:** Referral for examination by a dermatologist or gynaecologist should be considered, depending on the presenting signs and symptoms reported by the patient.

There is a spectrum of oral lesions that resembles OLP both clinically and histopathologically. [33, 34] These "lichen planus–like" ("lichenoid") lesions include the following conditions: (1) Oral lichenoid contact lesions (OLCL) as a result of allergic contact stomatitis (delayed immune mediated hypersensitivity). They are seen in direct topographic relationship to dental restor‐ ative materials, such as amalgam. In regards to the approach to oral lichenoid contact lesions, the value of patch testing remains controversial. (2) Oral lichenoid drug reactions (OLDR), wherein oral and/or cutaneous lesions arise in temporal association with the taking of certain medications, for example, oral hypoglycaemic agents, angiotensin-converting enzyme inhibitors, and non-steroidal anti-inflammatory agents. Confirmation of the diagnosis of an oral lichenoid drug reaction may be difficult, since empiric withdrawal of the suspected drug and/or its substitution by an alternative agent may be complicated. [38] (3) Oral lichenoid lesions (OLL-GVHD) of graft-versus-host disease are confined to allogeneic haematopoietic

ment. [33]

162 Skin Biopsy - Diagnosis and Treatment

the suspected inciting material.

**11. Differential diagnoses**

An essential first step is patient education as to the chronic nature of OLP and that therapy is not curative, but directed at relieving their symptoms. For treatment to be effective, patients need educated regarding the need to be patient and persistent with the recommended therapy. Instilling in patients the need for ongoing monitoring, not only for patients' response to treatment, but for malignant transformation is also important.

#### **11.2. Supportive measures**

The elimination of precipitating or provoking factors is an important initial step in the management of symptomatic OLP. The undertaking of active measures to resolve or minimize mechanical trauma from dental procedures, sharp cusps, rough dental restorations, and illfitting prostheses, or chemical trauma from acidic, spicy, or strongly flavoured foods and beverages should be encouraged. Of themselves, such supportive measures can lead to symptomatic improvement, or, more rarely, resolution of the disease.

The accumulation of bacterial plaque, often as a result of the discomfort associated with oral hygiene procedures in patients with gingival involvement, may also exacerbate the condition. The use of supplemental oral hygiene measures, including the use of alcohol-free chlorhexidine gluconate mouth rinses, may be helpful in such cases. [41]

#### **11.3. Pharmacotherapy**

Given the immune-mediated aetiology of OLP (and similar conditions such as mucous membrane pemphigoid (MMP)), the aim of therapy, is to minimise or "restrain" the body's immune-mediated inflammatory response, but without risking the activation of opportunistic infections. Treatment should be kept as simple as possible and should not inordinately burden the patient with expensive, complex, unwieldy or protracted treatments that result in noncompliance; therefore, topical corticosteroids remain the mainstay of treatment. [1, 33] Unfortunately, there are only limited evidence-based studies regarding the therapeutic interventions in OLP, and so treatment remains largely empirical. [1]

**Topical Treatment:Home Remedies and Over-the-Counter (OTC) Preparations:** patient prepared "salty" (saline) mouthwashes are of very limited clinical utility, somewhat palliative, and do not address the aetiological factors seen in OLP, but may facilitate oral hygiene. Patients also often self-prescribe and use any of the variety of OTC anti-microbial mouthwashes, in the mistaken understanding that OLP may be infective in nature, but often complain of their astringency, especially the alcohol containing mouthwashes (and a useful clue as to the diagnosis).

about control of severe ulcerative OLP or in patients with multiple, highly active, sites of lichen planus. Secondly, longer-term, to supplement topical therapies, at sub-physiological doses (equal or less than 7.5 mg prednisone (or equivalent) daily). [1] Monitoring for the principle side-effects (and other adverse effects) of systemic corticosteroid therapy, such as, hyperten‐ sion, cataract formation, diabetes mellitus, gastric ulceration, osteoporosis, and infection, is

Oral Lichen Planus

165

http://dx.doi.org/10.5772/56482

**Corticosteroid Alternatives: Retinoids (Topical and Systemic):** overall, the published studies suggest that retinoids are potentially effective in the treatment of OLP, but probably inferior to corticosteroids. [42] Systemic retinoids are associated with a number of serious adverse effects that would prohibit their routine use for the management of OLP, and include elevated/ deranged transaminase levels, hyper-lipidemia, cheilitis, dryness and desquamation of the skin, alopecia, and dystrophic nail formation, and as well, being teratogenic and therefore their

**Topical Calcineurin Inhibitors.** Cyclosporine, is one of the oldest such agents, but it is relatively expensive and unpleasant tasting, with studies showing an improvement in the oral

Tacrolimus and pimecrolimus are newer calcineurin inhibitors, [44] with an improved safety profile in comparison with cyclosporine, but there are only limited studies as to their benefits, they are expensive and the United States Food and Drug Administration (FDA) has a "Black Box" warning attached to the use of these agents because of a theoretical increased risk of malignancy (squamous cell carcinoma and lymphoma) in patients using topical tacrolimus/ pimecrolimus for cutaneous psoriasis. Therefore, the use of these agents should be restricted

**Phototherapy:** there is one study of the benefits of phototherapy using psoralen ultraviolet A light (PUVA) and was included in a recent Cochrane review. However, UV light has a known

**Other and/or "Steroid-Sparing" Systemic Medications:** These agents are indicated in patients with refractory LP, confined to the oral cavity, or also involving extra-oral sites, requiring systemic corticosteroids for control. There is only limited evidence supportive of only few potentially useful agents and the use of such agents is best restricted to clinicians highly familiar with these drugs and importantly their adverse effects: (1) *Lysosomotropic amines (the antimalarials chloroquine and hydroxychloroquine):* hydroxychloroquine, at doses of 200 to 400 mg daily, has also been shown to be effective for OLP. [47] (2) *Azathioprine* has been reportedly successful as a "steroid-sparing agent" for cutaneous lichen planus, and there is limited published evidence suggesting it may have a similar role in recalcitrant OLP at doses ranging from 1-2 mg per kilogram (patients' bodyweight), daily. [48] (3) *Mycophenolate mofetil (MMF)* has been employed for treatment of OLP. It is a newer immunosuppressive agent introduced for treatment of immune-mediated skin disorders and also for chronic GVHD. [49, 50] Side effects related to its use are consistent seen with other steroid-sparing alternate immunesuppressive therapies, including a risk of infections and malignancy, in particular, lympho‐ proliferative neoplasms. MMF, at moderate dosage, appears to be more effective than

use in women of childbearing age would be contraindicated.

and patients should be made aware of these concerns. [45]

oncogenic potential and therefore, its use for OLP is questionable. [46

symptoms that is not significantly better than 1% triamcinolone paste. [43]

needed.

Kenalog in Orabase® is one topical corticosteroid (0.1% triamcinolone) preparation that has the distinct advantage of being mixed with a vehicle for applying medication to the oral surfaces – Orabase® (composed of gelatin, pectin and carmellose in a Plastibase (hydrocarbon gel ointment base)). [1] The use of such an adhesive addresses an important therapeutic issue in treating OLP; that is having sufficient "contact time" between the medicament and the mucosal lesion(s) of OLP. It maintains the medication in close contact with the lesion and provides a protective covering that augments the effects of the corticosteroid. [33]

**Prescription Treatments: Topical Corticosteroid Preparations**. Topical corticosteroids come in a range of strengths, rated from mild – e.g.: hydrocortisone, to moderate – e.g.: betametha‐ sone valerate, to highly potent, e.g.; clobetasone and means of delivery: pastes, ointments, gels or as inhaled agents (as used in asthma treatment). All agents, used in a variety of delivery methods have demonstrated some efficacy in treating OLP.[1] However, the basic principles guiding topical corticosteroids therapy, is firstly, to use the lowest strength agent possible to achieve a therapeutic benefit, and secondly, for oral mucosal lesions, (as opposed to skin conditions) to favour the use of adhesive containing preparations to prolong contact time, and so avoid the agent being simply washed away by the ever-present saliva.

**Compounded Preparations**: Empirically, patients report modest to good responses, to the use of moderate, to highly potent topical corticosteroids such as betamethasone valerate mixed with an equal amount (by weight) of Orobase, used 3-4 times daily (after meals) given they are suitably adhesive. One limitation is that they often need to be prepared by specialist compounding pharmacists. A second limitation is that many patients often complain how unpleasant and "tacky" they find this mixture. Use of specially fabricated modified topical fluoride trays, with extended coverage of the gingiva and adjacent alveolar mucosa to hold topical agents in place in the treatment of the desquamative gingivitis form of OLP are reported to be helpful, but again, patient compliance can be poor. [1]

Potent corticosteroids, such as dexamethasone, compounded as a mouthwash suspension (0.1% strength - 40 mg Dexamethasone mixed with 400 ml sterile water) are better tolerated by patients. However, patients must be carefully instructed in their use, emphasising that it is to be used as rinse, for at least 3 minutes (for sufficient therapeutic contact time), at most four times a day (after meals) and to spit out well, to minimise systemic uptake of this highly potent corticosteroid and thereby avoid its adverse effects.

Antifungal Agents: supplemental use of an antifungal agents, such as Daktarin® (miconazole) Oral Gel, or chlorhexidine-containing mouthwashes is warranted given the risk of candidial overgrowth and possible infection secondary to the use of the corticosteroids (whether they be used topically or systemically).

**Systemic Agents:** Corticosteroids: systemic corticosteroids are used in two ways mainly: firstly, as short-term "pulse" dose of prednisolone up to 0.5 mg per kilogram (of the patient's) body weight for a short period of time (i.e.: 4 days or less and then rapidly tapered) to bring about control of severe ulcerative OLP or in patients with multiple, highly active, sites of lichen planus. Secondly, longer-term, to supplement topical therapies, at sub-physiological doses (equal or less than 7.5 mg prednisone (or equivalent) daily). [1] Monitoring for the principle side-effects (and other adverse effects) of systemic corticosteroid therapy, such as, hyperten‐ sion, cataract formation, diabetes mellitus, gastric ulceration, osteoporosis, and infection, is needed.

mistaken understanding that OLP may be infective in nature, but often complain of their astringency, especially the alcohol containing mouthwashes (and a useful clue as to the

Kenalog in Orabase® is one topical corticosteroid (0.1% triamcinolone) preparation that has the distinct advantage of being mixed with a vehicle for applying medication to the oral surfaces – Orabase® (composed of gelatin, pectin and carmellose in a Plastibase (hydrocarbon gel ointment base)). [1] The use of such an adhesive addresses an important therapeutic issue in treating OLP; that is having sufficient "contact time" between the medicament and the mucosal lesion(s) of OLP. It maintains the medication in close contact with the lesion and

**Prescription Treatments: Topical Corticosteroid Preparations**. Topical corticosteroids come in a range of strengths, rated from mild – e.g.: hydrocortisone, to moderate – e.g.: betametha‐ sone valerate, to highly potent, e.g.; clobetasone and means of delivery: pastes, ointments, gels or as inhaled agents (as used in asthma treatment). All agents, used in a variety of delivery methods have demonstrated some efficacy in treating OLP.[1] However, the basic principles guiding topical corticosteroids therapy, is firstly, to use the lowest strength agent possible to achieve a therapeutic benefit, and secondly, for oral mucosal lesions, (as opposed to skin conditions) to favour the use of adhesive containing preparations to prolong contact time, and

**Compounded Preparations**: Empirically, patients report modest to good responses, to the use of moderate, to highly potent topical corticosteroids such as betamethasone valerate mixed with an equal amount (by weight) of Orobase, used 3-4 times daily (after meals) given they are suitably adhesive. One limitation is that they often need to be prepared by specialist compounding pharmacists. A second limitation is that many patients often complain how unpleasant and "tacky" they find this mixture. Use of specially fabricated modified topical fluoride trays, with extended coverage of the gingiva and adjacent alveolar mucosa to hold topical agents in place in the treatment of the desquamative gingivitis form of OLP are reported

Potent corticosteroids, such as dexamethasone, compounded as a mouthwash suspension (0.1% strength - 40 mg Dexamethasone mixed with 400 ml sterile water) are better tolerated by patients. However, patients must be carefully instructed in their use, emphasising that it is to be used as rinse, for at least 3 minutes (for sufficient therapeutic contact time), at most four times a day (after meals) and to spit out well, to minimise systemic uptake of this highly potent

Antifungal Agents: supplemental use of an antifungal agents, such as Daktarin® (miconazole) Oral Gel, or chlorhexidine-containing mouthwashes is warranted given the risk of candidial overgrowth and possible infection secondary to the use of the corticosteroids (whether they

**Systemic Agents:** Corticosteroids: systemic corticosteroids are used in two ways mainly: firstly, as short-term "pulse" dose of prednisolone up to 0.5 mg per kilogram (of the patient's) body weight for a short period of time (i.e.: 4 days or less and then rapidly tapered) to bring

provides a protective covering that augments the effects of the corticosteroid. [33]

so avoid the agent being simply washed away by the ever-present saliva.

to be helpful, but again, patient compliance can be poor. [1]

corticosteroid and thereby avoid its adverse effects.

be used topically or systemically).

diagnosis).

164 Skin Biopsy - Diagnosis and Treatment

**Corticosteroid Alternatives: Retinoids (Topical and Systemic):** overall, the published studies suggest that retinoids are potentially effective in the treatment of OLP, but probably inferior to corticosteroids. [42] Systemic retinoids are associated with a number of serious adverse effects that would prohibit their routine use for the management of OLP, and include elevated/ deranged transaminase levels, hyper-lipidemia, cheilitis, dryness and desquamation of the skin, alopecia, and dystrophic nail formation, and as well, being teratogenic and therefore their use in women of childbearing age would be contraindicated.

**Topical Calcineurin Inhibitors.** Cyclosporine, is one of the oldest such agents, but it is relatively expensive and unpleasant tasting, with studies showing an improvement in the oral symptoms that is not significantly better than 1% triamcinolone paste. [43]

Tacrolimus and pimecrolimus are newer calcineurin inhibitors, [44] with an improved safety profile in comparison with cyclosporine, but there are only limited studies as to their benefits, they are expensive and the United States Food and Drug Administration (FDA) has a "Black Box" warning attached to the use of these agents because of a theoretical increased risk of malignancy (squamous cell carcinoma and lymphoma) in patients using topical tacrolimus/ pimecrolimus for cutaneous psoriasis. Therefore, the use of these agents should be restricted and patients should be made aware of these concerns. [45]

**Phototherapy:** there is one study of the benefits of phototherapy using psoralen ultraviolet A light (PUVA) and was included in a recent Cochrane review. However, UV light has a known oncogenic potential and therefore, its use for OLP is questionable. [46

**Other and/or "Steroid-Sparing" Systemic Medications:** These agents are indicated in patients with refractory LP, confined to the oral cavity, or also involving extra-oral sites, requiring systemic corticosteroids for control. There is only limited evidence supportive of only few potentially useful agents and the use of such agents is best restricted to clinicians highly familiar with these drugs and importantly their adverse effects: (1) *Lysosomotropic amines (the antimalarials chloroquine and hydroxychloroquine):* hydroxychloroquine, at doses of 200 to 400 mg daily, has also been shown to be effective for OLP. [47] (2) *Azathioprine* has been reportedly successful as a "steroid-sparing agent" for cutaneous lichen planus, and there is limited published evidence suggesting it may have a similar role in recalcitrant OLP at doses ranging from 1-2 mg per kilogram (patients' bodyweight), daily. [48] (3) *Mycophenolate mofetil (MMF)* has been employed for treatment of OLP. It is a newer immunosuppressive agent introduced for treatment of immune-mediated skin disorders and also for chronic GVHD. [49, 50] Side effects related to its use are consistent seen with other steroid-sparing alternate immunesuppressive therapies, including a risk of infections and malignancy, in particular, lympho‐ proliferative neoplasms. MMF, at moderate dosage, appears to be more effective than azathioprine in treatment of cutaneous LP. [51] This is probably due to the fact that MMF has also anti-inflammatory properties exerted by inhibition of leukocyte recruitment and adhesion to endothelial cells. MMF has been used for treatment of severe, erosive-ulcerative oral and genital lichen planus recalcitrant to other systemic therapies. [52, 53] It induced complete, longlasting remissions without flare-ups over a follow-up period of 4 years. However, the im‐ provement of lesions was delayed, evident only after 4–6 week of treatment. No short-or longterm side effects were experienced, except minor gastrointestinal disturbances. (4) *Methotrexate*. Lundqvist et al carried out an open trial with methotrexate, which has an antiinflammatory and immunomodulating activity, supplemented with steroid ointments for severe erosive lichen. [54] Four patients were given methotrexate in a dosage of 10–15 mg/ week for about 17 months and they all improved their symptoms. This and another case series demonstrated that methotrexate was a well-tolerated and effective treatment for severe OLP. [54, 55] However, there was a delay in the effect of the methotrexate, so ongoing treatment with systemic corticosteroids may be needed, which are then weaned as the methotrexate becomes increasingly effective. (5) *Other Systemic Agents*: a variety of other immune-suppres‐ sant or immune-modifying agents have been trialled in OLP, including Dapsone (diaminodiphenyl sulfone – an anti-tuberculotic/anti-leprotic medication), [56] and thalidomide, [57, 58] but only in the context of isolated, case reports.

specificity, and the immunoglobulin-structure imparts stability and other useful features in

Oral Lichen Planus

167

http://dx.doi.org/10.5772/56482

The management of various immune-mediated disorders has been changed dramatically by the advent of biologic therapies. Biologics are designed to target every stage, as presently understood, in the pathogenesis of immune-inflammatory diseases, by either modulation of T-cells and T-cell functions, or cytokines. However, the future use of biologics will depend on whether they have the ability to truly treat and modify disease, to prevent disease progression and chronicity, or, merely offer more sophisticated, but more expensive palliation, a particular concern in chronic conditions, such as OLP. The other concern is by interfering in the funda‐ mental processes of the immune system, are patients at risk of previously rare and indeed fatal infectious disease, such as progressive multifocal leukoencephalopathy, and is this warranted for a disease such as OLP, which is associated with distress and discomfort, but not serious morbidity or mortality. To date, there have only been limited case reports and case series using biologics for OLP. As with other, more potent immune-suppressive agents now used for OLP, caution is required and patience needed to await and observe the benefits, safety and longterm adverse effects of biologic therapies used in immune-mediated diseases with greater morbidity and potential mortality, such as rheumatoid arthritis, Behçet's disease and the

The rationale for the use of biologics in OLP is based on our present understanding of that activated CD8+ and CD4+ lymphocytes play a pivotal role in the pathogenesis of OLP and cytokines such as TNF-α, IL-2 and IFN-γ are involved in the activation and persistence of OLP. **Efalizumab (Raptiva):** a humanized monoclonal antibody that binds the CD11a subunit of Lymphocyte function-associated antigen-1 (LFA-1). LFA-1 is a T-cell surface molecule and Intercellular Adhesion Molecule-1 (ICAM-1) is its partner molecule. The interaction between LFA-1 and ICAM-1 regulates many normal T-cell functions. Binding of efalizumab to CD11a on T cells blocks the interaction between LFA-1 and ICAM-1, thus interfering with T-cell activation, migration and cytotoxic functions. This blockade is reversible, and seemingly does not deplete T cells or cause end-organ toxicity, opportunistic infections or malignancy. [60] Cheng and Mann, in 2006, reported a case of a 54-year-old woman with recalcitrant OLP resistant to topical and systemic corticosteroid therapy treated with efalizumab (Raptiva) reported an improvement of oral and cutaneous lesions at 5 weeks after commencement efalizumab therapy (initial dose of 0.7 mg/kg/week, followed by 1.0 mg/kg per week). [61] However, of interest and concern is that efalizumab has been withdrawn from both the American and European markets over safety concerns following the development of three fatal cases of progressive multifocal leucoencephalopathy (PML), a condition linked to immuno‐ suppression that emerged after 3 years of continuous treatment in patients with psoriasis. [62] **Etanercept (Enbrel):** This is an example of a fusion protein, consisting of a fully humanised TNF soluble receptor composed of the extracellular portion of two TNF type II receptors joined to the Fc portion of IgG1. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNF receptor (TNFR), preventing TNF mediated cellular responses by rendering TNF biologically inactive. [63] Etanercept may also modulate biological responses controlled by additional downstream molecules (e.g. cytokines, adhesion

inflammatory bowel diseases, before their use in patients with OLP.

terms of pharmacology.

Evidence for the use of "'steroid-sparing" and/or "alternate" systemic immune-suppressant agents is poor, limited to case series or case reviews and these agents all have significant side effects that would suggest caution in their use for OLP. However, this needs to be balanced against the known and significant adverse side-effects of high dose corticosteroids needed for recalcitrant OLP, or patients with LP active in several sites. The limitation of much of the literature pertaining to the treatment of OLP is the lack of any unified or agreed objective measures for disease activity and outcomes, which needs to be urgently addressed, so that the various treatments used in OLP can be usefully compared.

#### **11.4. Biological therapies**

Biologic therapies, more commonly referred to as "biologics", is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombi‐ nant therapeutic protein, or living cells that are used as therapeutics to treat diseases. [59] Biologics are produced by means of biological processes involving recombinant DNA tech‐ nology, rather than being chemically synthesized. These medications are usually one of three types: (1) Substances that are (nearly) identical to the body's own key signalling proteins, for example are the blood-production stimulating protein erythropoietin; (2) Monoclonal anti‐ bodies. These are similar to the plasma-cell derived antibodies that are produced in response to infection, but they are "custom-designed" (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type, for example rituximab that selectively targets CD20+ B-cells; and (3) Fusion proteins (receptor constructs), usually based on a naturally-occurring receptor linked to the immunoglobulin frame wherein, the receptor provides the construct with detailed specificity, and the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology.

azathioprine in treatment of cutaneous LP. [51] This is probably due to the fact that MMF has also anti-inflammatory properties exerted by inhibition of leukocyte recruitment and adhesion to endothelial cells. MMF has been used for treatment of severe, erosive-ulcerative oral and genital lichen planus recalcitrant to other systemic therapies. [52, 53] It induced complete, longlasting remissions without flare-ups over a follow-up period of 4 years. However, the im‐ provement of lesions was delayed, evident only after 4–6 week of treatment. No short-or longterm side effects were experienced, except minor gastrointestinal disturbances. (4) *Methotrexate*. Lundqvist et al carried out an open trial with methotrexate, which has an antiinflammatory and immunomodulating activity, supplemented with steroid ointments for severe erosive lichen. [54] Four patients were given methotrexate in a dosage of 10–15 mg/ week for about 17 months and they all improved their symptoms. This and another case series demonstrated that methotrexate was a well-tolerated and effective treatment for severe OLP. [54, 55] However, there was a delay in the effect of the methotrexate, so ongoing treatment with systemic corticosteroids may be needed, which are then weaned as the methotrexate becomes increasingly effective. (5) *Other Systemic Agents*: a variety of other immune-suppres‐ sant or immune-modifying agents have been trialled in OLP, including Dapsone (diaminodiphenyl sulfone – an anti-tuberculotic/anti-leprotic medication), [56] and thalidomide, [57,

Evidence for the use of "'steroid-sparing" and/or "alternate" systemic immune-suppressant agents is poor, limited to case series or case reviews and these agents all have significant side effects that would suggest caution in their use for OLP. However, this needs to be balanced against the known and significant adverse side-effects of high dose corticosteroids needed for recalcitrant OLP, or patients with LP active in several sites. The limitation of much of the literature pertaining to the treatment of OLP is the lack of any unified or agreed objective measures for disease activity and outcomes, which needs to be urgently addressed, so that the

Biologic therapies, more commonly referred to as "biologics", is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombi‐ nant therapeutic protein, or living cells that are used as therapeutics to treat diseases. [59] Biologics are produced by means of biological processes involving recombinant DNA tech‐ nology, rather than being chemically synthesized. These medications are usually one of three types: (1) Substances that are (nearly) identical to the body's own key signalling proteins, for example are the blood-production stimulating protein erythropoietin; (2) Monoclonal anti‐ bodies. These are similar to the plasma-cell derived antibodies that are produced in response to infection, but they are "custom-designed" (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body,

or to target any specific cell type, for example rituximab that selectively targets CD20+

and (3) Fusion proteins (receptor constructs), usually based on a naturally-occurring receptor linked to the immunoglobulin frame wherein, the receptor provides the construct with detailed

B-cells;

58] but only in the context of isolated, case reports.

various treatments used in OLP can be usefully compared.

**11.4. Biological therapies**

166 Skin Biopsy - Diagnosis and Treatment

The management of various immune-mediated disorders has been changed dramatically by the advent of biologic therapies. Biologics are designed to target every stage, as presently understood, in the pathogenesis of immune-inflammatory diseases, by either modulation of T-cells and T-cell functions, or cytokines. However, the future use of biologics will depend on whether they have the ability to truly treat and modify disease, to prevent disease progression and chronicity, or, merely offer more sophisticated, but more expensive palliation, a particular concern in chronic conditions, such as OLP. The other concern is by interfering in the funda‐ mental processes of the immune system, are patients at risk of previously rare and indeed fatal infectious disease, such as progressive multifocal leukoencephalopathy, and is this warranted for a disease such as OLP, which is associated with distress and discomfort, but not serious morbidity or mortality. To date, there have only been limited case reports and case series using biologics for OLP. As with other, more potent immune-suppressive agents now used for OLP, caution is required and patience needed to await and observe the benefits, safety and longterm adverse effects of biologic therapies used in immune-mediated diseases with greater morbidity and potential mortality, such as rheumatoid arthritis, Behçet's disease and the inflammatory bowel diseases, before their use in patients with OLP.

The rationale for the use of biologics in OLP is based on our present understanding of that activated CD8+ and CD4+ lymphocytes play a pivotal role in the pathogenesis of OLP and cytokines such as TNF-α, IL-2 and IFN-γ are involved in the activation and persistence of OLP.

**Efalizumab (Raptiva):** a humanized monoclonal antibody that binds the CD11a subunit of Lymphocyte function-associated antigen-1 (LFA-1). LFA-1 is a T-cell surface molecule and Intercellular Adhesion Molecule-1 (ICAM-1) is its partner molecule. The interaction between LFA-1 and ICAM-1 regulates many normal T-cell functions. Binding of efalizumab to CD11a on T cells blocks the interaction between LFA-1 and ICAM-1, thus interfering with T-cell activation, migration and cytotoxic functions. This blockade is reversible, and seemingly does not deplete T cells or cause end-organ toxicity, opportunistic infections or malignancy. [60] Cheng and Mann, in 2006, reported a case of a 54-year-old woman with recalcitrant OLP resistant to topical and systemic corticosteroid therapy treated with efalizumab (Raptiva) reported an improvement of oral and cutaneous lesions at 5 weeks after commencement efalizumab therapy (initial dose of 0.7 mg/kg/week, followed by 1.0 mg/kg per week). [61] However, of interest and concern is that efalizumab has been withdrawn from both the American and European markets over safety concerns following the development of three fatal cases of progressive multifocal leucoencephalopathy (PML), a condition linked to immuno‐ suppression that emerged after 3 years of continuous treatment in patients with psoriasis. [62]

**Etanercept (Enbrel):** This is an example of a fusion protein, consisting of a fully humanised TNF soluble receptor composed of the extracellular portion of two TNF type II receptors joined to the Fc portion of IgG1. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNF receptor (TNFR), preventing TNF mediated cellular responses by rendering TNF biologically inactive. [63] Etanercept may also modulate biological responses controlled by additional downstream molecules (e.g. cytokines, adhesion molecules or proteinases) that are induced or regulated by TNF. It was the first TNF antagonist approved for treatment of psoriasis and psoriatic arthritis and is administered as subcutaneous injection. Yarom published a case report in 2007 of a 56-year-old woman with resistant to treatment to the usual immune-suppressant drugs and whose diabetes and hypertension precluded the use of high dose corticosteroids. [64] Subcutaneous etanercept (25 mg twice weekly) was administered with a 90% symptomatic improvement lesions documented 4 week after beginning therapy. After 10 weeks, the patients stopped the treatment because of the expense, which highlights another concern with the use of the new biologic therapies, their cost.

**Alefacept (Amevive):** a recombinant protein that, binds to CD2 on the T cell membrane thereby blocking the costimulatory molecule LFA-3/CD2, inhibiting the activation of CD4+ and CD8+ T cells by interfering and inducing apoptosis of memory-effector T lymphocytes. It is composed of an LFA-3 protein and human IgG1 fragment crystallizable (Fc) domain. [65] The rationale for alefacept use in the treatment of lichen planus is the established role for CD4+ T-cells and alefacept induces T-cells apoptosis through natural-killer cells release of granzyme with a reduction in the CD4+ T-cell lymphocyte numbers. Fivenson et al in 2006, reported two cases of generalized lichen planus, with OLP, treated with alefacept, with both patients having full resolution of their lesions and remaining free of lesions and symptoms with completion of the course alefacept therapy, suggesting that it may have a disease modifying effect, negating the need for ongoing therapy for patients with seemingly recalcitrant lichen planus, including OLP. [66]

**Figure 10.** Microstomia secondary to long-standing OLP

The potential for OLP to undergo malignant transformation is controversial. If there is a risk, the risk is very difficult to quantify and possibly so low that it is very difficult to determine if OLP is truly associated with a significant risk for malignant transformation. Prudence would dictate to treat OLP as a potentially malignant lesion. [1, 33] If this approach is favoured, then ongoing, and at the least, annual monitoring, of the oral mucosa, by a clinician experienced in the management of OLP, is indicated. Any lesion suspected to harbour dysplasia and/or frank malignancy (oral squamous cell carcinoma) merits biopsy, and histopathological assessment, preferably by a pathologist experienced in oral pathology. Clinical suspicion should be aroused in the case of a lesion (or lesions) not typical for OLP, a lesion that is heterogeneous in texture and colour (a mixture of erythema and keratosis), or, any isolated area of mucosa that appears to be distinctly unresponsive to therapeutic interventions - such as persistent ulceration - despite clinical improvement in the remainder of the mucosa affected by the OLP. Before undertaking a biopsy, consideration should be given to a trial of topical (and if indicated systemic) corticosteroids and anti-fungal treatments to lessen any associated inflammatory or infectious changes that on histopathological assessment may mask the degree of dysplasia or

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Oral lichen planus is a disease that results from CD8+ T cell-mediated apoptosis of basal keratinocytes in response to an unknown endogenous or at times a known exogenous antigen.

**12.1. Malignant transformation**

malignancy within the lesion. [33, 34]

**13. Conclusion**

**Rituximab:** was approved for the treatment of malignancy by the US Food and Drug Admin‐ istration in 1997, has been used in certain B-cell lymphomas and treatment resistant rheuma‐ toid arthritis. It is a chimeric murine–human monoclonal antibody to CD20 that depletes normal as well as malignant B cells. Currently, rituximab has been introduced into therapies of numerous immune-mediated conditions in dermatology. [67] Parmentier et al reported in 2008, successful treatment with rituximab for muco-cutaneous LP with oesophageal involve‐ ment. [24] There has been no follow-up cases reported since. It is controversial that rituximab targeting B cells could improve T-cell mediated OLP, but it suggests that the humoral arm of the immune system may have some role in the immune-pathogenesis of OLP.
