Are You Confident of the Diagnosis?
Lichen planopilaris (LPP) is a rare chronic scarring folliculitis of the scalp of unknown cause (Figure 1). It is considered a primary scarring alopecia since the follicle itself is targeted by inflammatory cells and scarring occurs first and primarily around the follicular unit. Because T cells are the overwhelmingly present inflammatory cell, it is categorized as a lymphocytic primary scarring alopecia based upon criteria of the North American Hair Research Society (NAHRS).
This entity is considered a part of the lichen planus complex, even though typical lesions of lichen planus are not seen in the scalp, and only about 30% of patients may present with typical cutaneous or mucosal lesions of lichen planus elsewhere. Furthermore, although it predominantly affects the vertex and occasionally the parietal scalp alone, two associated presentations—that of frontal fibrosing alopecia (FFA) and Piccardi–Lassueur–Graham–Little syndrome (PLGLS ) are also considered part of the complex.
Seventy to eighty percent of patients are women, almost all postmenopausal (average age 53), and almost all Caucasian, although all races are affected; uniquely, a study in Cleveland, Ohio, had 31% African-Americans. A mostly patchy but very symptomatic hair loss develops on the scalp and progresses in a random irregular pattern with eventual merging of hairless patches. Occasionally a more diffuse uniform alopecic pattern of the central vertex with peripheral spreading prevails. Nonscalp lesons of typical lichen planus may be concurrent with active scalp disease or be non-concurrent..
Characteristic findings on physical examination
Perifollicular erythema and scaling, especially at the edges of patches, with loss of follicular ostia, are characteristic and measurable criteria for following the course of the disease and its treatment. Symptomatology, unlike in other primary scarring alopecias, is usually pronounced with pruritus and pain; a severe burning sensation and tenderness are common. The active follicular lesions are papules, not pustules, which may be red or violaceous and have a small collarette of scale. A “positive anagen pull test” is universally accepted as characteristic of this disease. Pulling on 10 to 20 hairs with moderate slow finger traction will show release of many hairs with a great preponderance of anagen, not telogen, hairs.
Clinical confusion with cutaneous lupus is easy although it is claimed that perifollicular hyperpigmentation is more common in the latter. Though follicular dilatation can occur in LPP, significant follicular plugging, especially in non-scalp areas such as the ear conchal bowl, are more charactreristic of lupus. A burned out scarred and hypopigmented dyschromic clinical picture analogous to the pseudopelade of Brocq may be the nondistinguishable end-result of either LPP or lupus. The incidence of this very rare syndrome of LPP, even in four major hair research centers, was 3 to 44 new cases per year!
Frontal fibrosing alopecia (FFA) is an even more rare disease (about 8% to 15% of all LPP cases) of mostly, but not solely, postmenopausal women presenting with an expanding band of alopecia along the frontal hairline. FFA demonstrates follicular scaling and erythema along the edge of the hairline with an absence of follicular ostia in this band, even with dermoscopy. Alopecia of eyebrows, and in 20% of those afflicted, even upper and lower limbs, occurs comcomitantly. This is customarily without visible inflammation or scale, whereas more typical LPP of the vertex is inflammatory.
Alopecia areata is differentiated by showing no loss of ostia and in fact may have yellow dots, black dots or exclamation hairs on dermoscopy in those remaining follicles, none of which is evident in FFA. Conversely FFA shows a loss of ostia and the presence of perifollicular scale and erythema not evident in alopecia areata.
The very rare Graham-Little (only 1/45 LPP cases reviewed by Spencer) or PLGLS is constituted by a triad of scarring alopecia of the scalp in a patchy pattern, non-scarring alopecia of the axillae and pubic regions, and spinous follicular papules of the trunk and limbs.
Expected results of diagnostic studies
Histopathology of LPP and FFA has been reported in similar fashion by multiple authors as a lymphocytic infiltration of the upper hair follicle centered around the bulge area and sebaceous gland with no significant deeper follicular involvement. Only Price seems to consider any presence of neutrophils or plasma cells at any time as disqualifying features for this diagnosis. There are no significant epidermal changes in most cases.
There is a lichenoid variably dense inflammatory infiltrate of lymphocytes at the infundibulo-isthmic region with variable perifollicular fibrosis and absence of thickened basement membrane or fungal elements, as confirmed by a periodic acid–Schiff stain (Figure 2). The inflammation eventually results in reduction or loss of sebaceous glands and of arrector pili muscles, concentric lamellar perifollicular fibrosis, permanent destruction of the follicle, and replacement with perifollicular hyalinization of the stroma in both the upper and lower dermis and within the follicular tract. Mucinous perifollicular fibroplasia is present, but mucin is absent in the interfollicular dermis, unlike lupus. Loss of elastic staining on Verhoeff-van Gieson stain reveals a superficial perifollicular wedge-shape.
The recently invented “Hovert” method of sectioning one punch biopsy specimen vertically in the upper follicle and horizontally in the lower follicle will allow differentiation of LPP from lupus requiring only one biopsy specimen.
Direct immunofluorescence illuminates colloid bodies in the peri-infundibular / isthmic area by staining with IgM (occasionally with IgG, IgA and C3). A band of fibrinogen may be evident along the basement membrane zone of the affected follicle.
No consistently abnormal laboratory or hormonal findings have been identified in LPP or FFA.
Who is at Risk for Developing this Disease?
FFA is an even more rare disease (about 8% to 15% of all LPP cases) of mostly, but not solely, postmenopausal women.
What is the Cause of the Disease?
The panoply of important inflammatory mediators in LPP is not known. For the few discovered, comprehension of their effect is either tentative (b-FGF and TGF-β ), or in the instance of TNF-alpha, which is increased in LPP, idiosyncratic.
b-FGF and TGF-β induce activation of fibroblasts and are abundantly produced in both neutrophilic folliculitis decalvans and lymphocytic LPP. They may be partially responsible for the late fibrosis occurring in each of the conditions. Although TNF-alpha is increased in LPP, case reports of LPP induced by TNF-alpha blocking agents, etanercept and infliximab, have sown a field of confusion. Ghoreishi noted that the distribution pattern of the interferon
signature and cytotoxicity-associated proteins in cicatricial alopecia differs from alopecia areata. It has been reported that there is a significantly higher ratio of Langerhans cells to T lymphocytes in lichen planopilaris than, for instance, in traction alopecia.
The most promising recent scenario has been achieved by a mouse model and complementary human studies on LPP patients concerning PPAR-gamma genetic downregulation. It is known that the location of the inflammatory infiltrate in LPP centers near the bulge area and markers of bulge cell proliferation are downregulated in LPP. Transgenic mice in which bulge cells undergo targeted deletion show complete hair follicle disappearance in the affected murine skin, even though the inflammatory changes seen clinically in humans are not seen in the mouse model.
Karnik showed significant downregulation of PPAR-gamma gene expression in paired lesional and uninvolved samples from patients with LPP. PPAR-
gamma genes are required for lipid metabolism and peroxisome biogenesis; this dysfunction in turn deregulates lipid metabolism in the pilosebaceous unit, possibly leading to the accumulation of proinflammatory lipids. Karnik’s scalp biopsies showed progressive loss of peroxisomes, proinflammatory lipid accumulation,and infiltration of inflammatory cells, followed by destruction of the pilosebaceous unit.
Even more enthralling was the fact that agonists of PPAR-gamma in keratinocytes such as ciglitazone (Cig), rosiglitazone (Rosi), pioglitazone (Pio), and troglitazone are already available in the pharmacopeia for the treatment of dyslipidemias, type 2 diabetes, cardiovascular disease, and the metabolic syndrome. Price has effectively used pioglitazone therapeutically at 15mg daily in combination with mycophenolate mofetil 500 to 1000mg orally twice daily.
Systemic Implications and Complications
There are no established systemic complications.
TREATMENT OPTIONS CITED IN LITERATURE
Intralesional: Corticosteroids (triamcinolone acetonide 3.5 to 10mg/cc)
Optimal Therapeutic Approach for this Disease
Sperling’s pithy commentary cites many instances of mixed results, with competing anecdotal studies showing effectiveness or ineffectiveness of the same agent. Even when effective, with a high relapse rate—all these results occur in a primary scarring alopecia that, unlike some of the others (eg, CCCA or pseudopelade of Brocq) at least has some ease in determining the decrease of symptoms and visible signs, since there is something to see and measure other than scar. Many case series are too small to be other than anecdotal since LPP is such a rare condition—less than 50 cases were evaluable over 5 years in a large clinical center in Vancouver, drawing from a whole province, and other centers register only 3 to 44 cases per year.
For good results, topical corticosteroids such as clobetasol solution within 12 weeks of use have shown complete clearing of inflammation and halting of disease progression. Tacrolimus topically at 0.1% took 9 months for very good resolution. Intralesional triamcinolone may be required in doses as high as 10mg/cc but may well leave atrophic depressions in its wake.
For oral agents, Sperling cites one study showing ineffectiveness of oral etretinate whereas Shapiro (see Kang et al) in his large experience finds the
alternative retinoid, isotretinoin, very effective. Mycophenolate mofetil may be very effective in as little as 2 to 8 months.
The most striking attempt to make sense of anecdotal studies of such a rare disease was recently formulated by Price in her establishing an LPP Activity Index (LPPAI), which is based on a standardized but weighted system for recording clinical information at each patient visit.
Reductions in symptomatology after treatment showed real and statistically significant “improvement” in LPP in 83% of patients with LPP after 12 months of oral hydroxychloroquine 200mg BID with most of the change occurring within the first 6 months. Similarly in a large series of 36 patients with FFA, her group showed similar benefit—such that aggressive treatment with hydroxychloroquine is now considered first-line therapy in her group, but supplemented by topical tacrolimus, minoxidil, etc.
Mycophenolate mofetil at 500mg twice daily (and up) exhibited similarly positive results in LPP by LPPAI. However, though subjective symptoms and measurable erythema may improve and even support use of such a scale, Donati recently challenged Price’s assertion by photographic hair counts that reveal that hydroxychloroquine in proper doses did not stop the scarring process as hair density continued to vanish significantly while the patients may have felt better.
Spencer used a stepwise approach to therapy and got some good remissions, but her sample was too small to recommend any one course of therapy. Until it becomes clear that the Price LPPAI scale is useful and supported by truly objective photographic measurements, jumping to significant systemic agents immediately may not provide more than symptomatic relief and a false sense of remission while the LPP is still evolving in a more subtle manner.
Spencer’s regimen begins with oral doxycycline hyclate, 100mg twice daily for 3 to 6 months, with 27% improving, and the others moving on to hydroxychloroquine sulfate 6.5mg/kg/d for 6 to 12 months with 41% improving. Then for the remaining, mycophenolate mofetil, 1000 to 3000mg orally twice daily for 3 to 6 months with 30% responding. This would be followed by oral acitretin 25mg/d for 3 to 6 months or methotrexate orally at 10mg weekly. Others have recommended acetretin followed by hydroxychloroquine based on improvement of symptoms and lack of progression.
Topical agents such as corticosteroids and 5% minoxidil and oral biotin may be partially useful as adjuncts.
Unusual Clinical Scenarios to Consider in Patient Management
Since TNF-alpha is elevated in lichen planus, it would seem appropriate that anti-TNF biologic blockers would be therapeutically helpful. Unfortunately two inexplicable case reports illustrate that the use of such medications in the treatment of psoriasis actually induced the appearance of LPP. Garcovich presented a 56-year-old Italian woman with psoriatic arthritis who responded to etanercept; however, by week 32 she developed severe and painful LPP of her scalp. This, in turn, responded to discontinuing the etanercept and starting cyclosporine; her LPP recurred on a repeated etanercept course.
Abbasi reported an 8-year-old child with psoriasis placed on etanercept at 0.8mg/kg/week, who then developed intense perifollicular inflammation, follicular plugging, and scarring of the frontal scalp; though epidermal histologic changes are rare in LPP, there was infundibular hypergranulosis, orthokeratosis, and focal parakeratosis. Lichenoid cutaneous reactions have been reported to occur anywhere from 3 weeks to 16 months of anti-TNF medications, although usually in the first few months of administration. Infliximab has produced lichenoid skin reactions.
What is the Evidence?
Abbasi, N, Orlow, S. “Lichen planopilaris noted during etanercept therapy in a child with severe psoriasis”. Ped Dermatol. vol. 26. 2009. pp. 118(A case report of an 8-year-old child who developed histologically confirmed LPP with the use of etanercept for psoriasis.)
Chew, A, Bashir, S, Wain, M, Fenton, DA, Stefanato, CM. “Expanding the spectrum of frontal fibrosing alopecia: A unifying concept”. J Am Acad Dermatol. vol. 63. 2010. pp. 653-60. (Extensive review of FFA showing the destruction is more generalized than thought even without evidence of clinical inflammation.)
Chiang, C, Sah, D, Cho, B, Ochoa, BE, Price, VH. “Hydroxychloroquine and lichen planopilaris: Efficacy and introduction of Lichen Planopilaris Activity Index scoring system”. J Am Acad Dermatol. vol. 62. 2010. pp. 387-92. (Landmark evaluation system even though subjective and with a personally weighted scale shows symptomatic and visible improvement of at least 25% in 83% of patients by 1 year.)
Cho, BK, Sah, D, Chwalek, J, Roseborough, I, Ochoa, B, Chiang, C. “Efficacy and safety of mycophenolate mofetil for lichen planopilaris”. J Am Acad Dermatol. vol. 62. 2010. pp. 393-7. (Even hydroxychloroquine-resistant patients showed improvement by LPPAI index within just 6 months in 10 of 12 instances with dosing of 500mg twice a day for 1 month, then 1000mg orally twice a day for many months.)
Garcovich, S, Manco, S, Zampetti, A, Amerio, P, Garcovich, A. “Onset of lichen planopilaris during treatment with etanercept”. Br J Dermatol. vol. 158. 2008. pp. 1161(A case report of a 56-year-old Italian woman with psoriatic arthritis who responded to etanercept; however, by week 32 she developed severe and painful LPP of her scalp.)
Harries, M, Paus, R. “Scarring alopecia and the PPAR-γ Connection”. J Invest Dermatol. vol. 129. 2009. pp. 1066-70. (A fascinating review of preliminary data based on a mouse model showing sebaceous gland dysfunction and downregulation of PPAR-gamma gene and changes in LPP patients showing abnormalities in similar pathways—pathogenesis of LPP?)
Karnik, P, Tekeste, Z, McCormick, TS, Gilliam, AC, Price, VH, Cooper, KD. “Hair follicle stem cell-specific PPARc deletion causes scarring alopecia”. J Invest Dermatol. vol. 129. 2009. pp. 1243-57. (Hair follicle stem cell-specific PPARc deletion or downregulation causes scarring alopecia of mice and women.)
Kang, H, Alzolibani, AA, Otberg, N, Shapiro, J. “Lichen planopilaris”. Derm Ther. vol. 21. 2008. pp. 249-56. (A seminal review)
Sperling, LC, Nguyen, J. “Commentary: Treatment of lichen planopilaris: Some progress, but a long way to go”. J Am Acad Dermatol. vol. 62. 2010. pp. 398-401. (Recent key critical review of limitations of evaluating therapies in small patient populations with LPP.)
Samrao, A, Chew, A, Price, V. “Frontal fibrosing alopecia: a clinical review of 36 patients”. Br J Dermatol. vol. 163. 2010. pp. 1296-1300. (Large series of 36 patients showing early aggressive oral therapy especially with hydroxychloroquine produces measurable significant improvement within 6 months.)
Spencer, L, Hawryluk, E, English, J. “Lichen planopilaris: Retrospective study and stepwise therapeutic approach”. Arch Dermatol. vol. 145. 2009. pp. 333-334. (Authors suggest sensible but stepwise approach for LPP based on their 45 cases and support concept that data samples are too small to suggest only one definitive mode of therapy.)
Tandon, Y, Somani, N, Cevasco, N, Bergfeld, W. “A histologic review of 27 patients with lichen planopilaris”. J Am Acad Dermatol. vol. 59. 2008. pp. 91-8. (Thorough review including newly discovered pathologic features.)
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