Methods of treatment using topical roflumilast compositions

Abstract

Methods of treating a patient suffering from one or more of epidermal disorders of persistent inflammation—cell kinetics and differentiation disorders, epidermal disorders of persistent inflammation—altered reactivity disorders, disorders of the lips, oral, or vaginal mucosa, epidermal disorders of cohesion—vesicular and bullous disorders, cutaneous lymphomas, skin manifestations of rheumatologic diseases, hypomelanoses and hypermelanoses, or skin manifestations related to oncology treatments. The methods include topical administration of a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

Description

METHODS OF TREATMENT USING TOPICAL ROFLUMILAST COMPOSITIONSCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of continuation of U.S. Patent Application No. 63 / 662,742 filed on June 21, 2024, the disclosures of each of which are incorporated herein in their entireties by reference.FIELD

[0002] The subject matter disclosed herein generally relates to methods of treating a patient by topically administering to the patient a pharmaceutical composition comprising roflumilast. The methods of treatment relate to the treatment of a patient suffering from one or more of disorders of epidermal appendages, epidermal disorders of persistent inflammation — cell kinetics and differentiation disorders, epidermal disorders of persistent inflammation — altered reactivity disorders, disorders of the lips, oral, or vaginal mucosa, epidermal disorders of cohesion — vesicular and bullous disorders, cutaneous lymphomas, skin manifestations of rheumatologic diseases, hypomelanoses and hypermelanoses, or skin manifestations related to oncology treatments.BACKGROUND

[0003] Roflumilast is an inhibitor of phosphodiesterase (PDE) type 4. Oral pharmaceutical compositions of roflumilast are currently marketed under the tradenames Daliresp® (in the United States) and Daxas® (in Europe). Oral pharmaceutical compositions of roflumilast are indicated as a treatment to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Topical pharmaceutical compositions of roflumilast are currently marketed under the tradenameZoryve®. Topical roflumilast compositions are indicated for the treatment of plaque psoriasis, including intertriginous areas.SUMMARY

[0004] The present invention generally relates to methods of treating a patient by administering to the patient a topical pharmaceutical composition of roflumilast. The methods of treatment relate to the topical administration of roflumilast to treat a patient suffering from the disorders or diseases disclosed herein.

[0005] In certain embodiments, a method of treating a patient suffering from a disorder of epidermal appendages (such as an alopecia) is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the disorder of epidermal appendages is selected from the group consisting of cicatricial alopecia (including frontal fibrosing alopecia, central centrifugal cicatricial alopecia, lichen planopilaris, folliculitis decalvans, acne keloidalis nuchae, alopecia mucinosa, erosive pustular dermatosis, and scarring alopecia secondary to traction), alopecia areata, hidradenitis suppurativa, acne vulgaris, nail psoriasis, and rosacea. In certain embodiments, the disorder of epidermal appendages is not alopecia areata or rosacea.

[0006] In certain embodiments, a method of treating a patient suffering from an epidermal disorder of persistent inflammation is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the epidermal disorder of persistent inflammation is a cell kinetic and differentiation disorder. In certain embodiments, the epidermal disorder of persistent inflammation is selected from the group consisting of pityriasis rubra pilaris, pityriasis rosea, pityriasis lichenoides, prurigo nodularis, notalgia paresthetica, lichen planus (including lichenplanus pigmentosus, “LPP”), lichen nitidus, lichen simplex chronicus, hyperkeratosis lenticularis perstans (Flegel’s disease), inherited keratodermas of palms and soles, granuloma annulare, Sweet’s syndrome, pyoderma gangrenosum, and urticaria, including chronic idiopathic urticaria, physical urticaria, and other forms of acquired urticaria. In certain embodiments, the epidermal disorder of persistent inflammation is not psoriasis, lichen planus, or lichen simplex.

[0007] In certain embodiments, a method of treating a patient suffering from an epidermal disorder of persistent inflammation is provided wherein the disorder is an altered reactivity disorder. In certain embodiments, the epidermal disorder of persistent inflammation is selected from the group consisting of perioral dermatitis, allergic contact dermatitis, irritant contact dermatitis, polymorphous light eruption (PMLE), actinic prurigo, cradle cap, diaper dermatitis, stasis dermatitis, brachioradial pruritus, dupilumab-associated erythema / dermatitis, juvenile plantar dermatosis, uremic or cholestatic pruritus, pruritus scroti or ani, necrobiosis lipoidica diabeticorum, ichthyosis, pityriasis amiantacea, intertrigo, nummular eczematous dermatitis, dyshidrotic eczema, hand eczema, and vesicular palmoplantar eczema. In certain embodiments, the epidermal disorder of persistent inflammation is not atopic dermatitis, seborrheic dermatitis.

[0008] In certain embodiments, a method of treating a patient suffering from a disorder of lips, oral, or vaginal mucosa is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the disorder of lips, oral, or vaginal mucosa is selected from the group consisting of actinic cheilitis, atopic cheilitis, mucositis, dry-mouth associated with cystic fibrosis, aphthous ulcers, vulvar aphthae, oral lichen planus, geographic tongue, lichen sclerosus, feminine itch, Behcet’s disease, and linear IgA. In certain embodiments, the disorder of lips, oral, or vaginal mucosa is not aphthous ulcers, lichen planus, or lichen sclerosus.

[0009] In certain embodiments, a method of treating a patient suffering from an epidermal disorder of cohesion is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the disorder of epidermal disorder of cohesion is a vesicular and bullous disorder selected from the group consisting of erythema multiforme, folliculitis decalvans, pityrosporum folliculitis, Gianotti-Crosti syndrome, pemphigus, bullous pemphigoid, linear IgA dermatosis, herpes gestationis, dermatitis herpetiformis, Hailey-Hailey disease, pustular palmoplantar psoriasis, herpes simplex virus I and II, eczema herpeticum, epidermolysis bullosa (both EB simplex and EB acquisita), Behcet’s disease, and Darier disease. In certain embodiments, the epidermal disorder of cohesion is not Hailey-Hailey disease or Darier disease.

[0010] In certain embodiments, a method of treating a patient suffering from hypomelanoses or hypermelanoses is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the hypomelanoses or hypermelanoses is vitiligo, dyschromia, pityriasis alba, post-inflammatory hypo-pigmentation, or post-inflammatory hyper-pigmentation. In certain embodiments, the hypomelanoses or hypermelanoses is not vitiligo.

[0011] In certain embodiments, a method of treating a patient suffering from a cutaneous T-cell or B-cell lymphoma is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the cutaneous lymphoma is selected from the group consisting of lymphomatous papulosis, cutaneous T-cell lymphoma (CTCL), and non-mycosis fungoides cutaneous T-cell or B-cell lymphoma.

[0012] In certain embodiments, a method of treating a patient suffering from a skin manifestation of a rheumatologic disease is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the skin manifestation of a rheumatologic disease is selected from the group consisting of cutaneous lupus erythematosus, discoid lupus, dermatomyositis, sarcoidosis, chronic idiopathic pruritus, cutaneous vasculitis, and scleroderma / morphea. In certain embodiments, the skin manifestation of a rheumatologic disease is not discoid lupus.

[0013] In certain embodiments, a method of treating a patient suffering from a skin manifestation related to an oncology disorder is provided. The method comprises topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast. In certain embodiments, the skin manifestation of an oncology disorder is selected from the group consisting of adverse skin reactions due to epidermal growth factor receptor (EGFR) inhibitors, adverse skin reactions due to cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, adverse skin reactions due to programmed cell death- 1 (PD-1) inhibitors, and adverse skin reactions due to BRAF inhibitors.DETAILED DESCRIPTION

[0014] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0015] Note that as used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “active ingredient” includes a single ingredient and two or more different ingredients.

[0016] The term “about” when used in connection with a numerical value is meant to encompass numerical values within a range having a lower limit that is 5% smaller than the indicated numerical value and having an upper limit that is 5% larger than the indicated numerical value.

[0017] The term “effective” refers to an amount of a compound, agent, substance, formulation or composition that is of sufficient quantity to result in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The amount may be as a single dose or according to a multiple dose regimen, alone or in combination with other compounds, agents or substances.

[0018] The term “pharmaceutically acceptable” means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable component is one that has been approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia, published by the United States Pharmacopeial Convention, Inc., Rockville Md., or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0019] A “pharmaceutical composition” according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and / or carriers are admixed with each other, or may take the form of a combined preparation, where the active ingredients arepresent in partially or totally distinct form. An example for such a combination or combined preparation is a kit-of-parts.

[0020] The term “roflumilasf ’ as used in this application refers to roflumilast and its salts unless specified otherwise or unless it is clear in context that reference is to roflumilast itself.

[0021] As used herein, the terms “subject” or “patient” most preferably refers to a human being. The terms “subject” or “patient” may include any mammal that may benefit from the compounds described herein.

[0022] A “therapeutic amount” or “therapeutically effective amount” is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size of the subject to receive the therapeutic agent, and the purpose of the administration.

[0023] The term “topical” with respect to administration of a drug or composition refers to the application of such drug or composition to the epithelial surface outside the body, including the skin or cornea. For this application, localized delivery to the mucosa inside of a body opening mucosal surface, such as the mouth, vagina, or rectum, is considered a topical application.

[0024] As used herein, “treat,” “treating,” or “treatment” of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).

[0025] The abbreviation “w / v” represents the relative concentration of the components in the composition as “weight to volume.”

[0026] The abbreviation “vi / vi” represents the relative concentration of the components in the composition as “weight to weight” (i.e., percentage refers to percentage of total weight), rather than based on volume or other quantities.

[0027] The present invention relates to methods of treating a patient by administering a pharmaceutical composition of roflumilast to the patient. In certain embodiments, the method comprises topically administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of the phosphodiesterase-4 inhibitor, roflumilast or a pharmaceutically acceptable salt thereof.

[0028] Roflumilast is a compound of the formula (I):(I)wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is 3,5-dichloropyrid-4-yl.

[0029] Roflumilast has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy- 4-difluoromethoxybenzamide. Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298, which is incorporated herein by reference. The pharmaceutical composition described herein can include roflumilast as a free base or a pharmaceutically acceptable salt. Exemplary salts of roflumilast are salt described in paragraphs

[0012] and

[0013] of U.S. Patent Application Publication No. US 2006 / 0084684, the disclosure of which is incorporated herein by reference.

[0030] In certain embodiments, a method of treatment is provided for treating a patient suffering from one or more of disorders of epidermal appendages (such as alopecias), epidermal disorders of persistent inflammation — cell kinetics and differentiation disorders, epidermal disorders of persistent inflammation — altered reactivity disorders, disorders of the lips, oral, or vaginal mucosa, epidermal disorders of cohesion — vesicular and bullous disorders, cutaneous lymphomas, skin manifestations of rheumatologic diseases, hypomelanoses and hypermelanoses, or skin manifestations related to oncology treatments. In certain embodiments, a method of treatment is provided wherein the patient is selected based on a diagnosis of one or more of the disorders or diseases discussed herein. The patient suffering from one or more the disorders or diseases can be topically administered a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0031] In certain embodiments, a method of treatment is provided for treating a patient suffering from an inflammatory disease regulated by Thl and / or Th2 cytokines. In certain embodiments, a method of treatment is provided wherein the patient is selected based on a diagnosis of an inflammatory disease regulated by Thl and / or Th2 cytokines. The patient suffering from an inflammatory disease regulated by Thl and / or Th2 cytokines can be topically administered a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0032] Disorders of Epidermal Appendages, Including Alopecia

[0033] In certain embodiments, a method of treating a patient suffering from a disorder of epidermal appendages is provided. Disorders of epidermal appendages are disorders affecting epidermal and dermal-derived parts of skin such as hair, sweat glands, sebaceous glands, and nails. For example, disorders of epidermal appendages include both scarring and non-scarring alopecias.

[0034] In certain embodiments, the disorder of epidermal appendages is an alopecia. For example, the alopecia may be cicatricial (i.e., scarring) alopecia (e.g., frontal fibrosing alopecia or central centrifugal cicatricial alopecia) or alopecia areata. In certain embodiments, the disorder of epidermal appendages is selected from hidradenitis suppurativa, acne vulgaris, and rosacea. In certain embodiments, the disorder of epidermal appendages is not alopecia areata or rosacea.

[0035] In certain embodiments, a method of treatment is provided for treating a patient with cicatricial alopecia (including frontal fibrosing alopecia, central centrifugal cicatricial alopecia, lichen planopilaris, folliculitis decalvans, acne keloidalis nuchae, alopecia mucinosa, erosive pustular dermatosis, and scarring alopecia secondary to traction). Cicatricial alopecia is hair loss caused by the replacement of hair follicles with fibrotic tissue. Frontal fibrosing alopecia is characterized by progressive frontotemporal recession caused by inflammatory destruction of hair follicles. It is more common in postmenopausal women. Central centrifugal cicatricial alopecia, by contrast, is characterized by progressive recession of hair from the crown of the scalp outward. Finally, lichen planopilaris presents as irregular patches of fibrosing alopecia.

[0036] In certain embodiments, a method of treatment is provided for treating a patient with alopecia areata. Alopecia areata is an autoimmune hair disorder in which patients begin losing hair in patches. These patches may cause itching and redness. Patients also may experience nail changes such as pitting or sandpaper nails.

[0037] In certain embodiments, a method of treatment is provided for treating a patient with hidradenitis suppurativa. Hidradenitis suppurativa is an inflammatory disorder of hair follicles found in intertriginous and anogenital regions. Hidradenitis suppurativa can cause recurrent, painful subcutaneous nodules and hypertrophic scarring that may result in chronic pain and disfigurement.

[0038] In certain embodiments, a method of treatment is provided for treating a patient with acne vulgaris. Acne vulgaris is a common disorder affecting the pilosebaceous unit. Acne vulgaris can be characterized by four key elements: follicular epidermal hyperproliferation, sebum production, presence and activity of Propionibacterhim acnes, and an inflammatory and immune response. Acne vulgaris can manifest in the form of comedones, papules, and nodules on the face, chest, and back.

[0039] In certain embodiments, a method of treatment is provided for treating a patient with nail psoriasis. Nail psoriasis occurs on the fingernails and toenails of people suffering psoriasis or psoriatic arthritis. It manifests as discoloration and pitting of the nails.

[0040] In certain embodiments, a method of treatment is provided for treating a patient with rosacea. Rosacea is a facial skin disease characterized by flushing, transient or persistent erythema, telangiectasia, papules, pustules, phymata, edema, pain, and stinging or burning.

[0041] Epidermal Disorders of Persistent Inflammation — Cell Kinetics and Differentiation Disorders

[0042] In certain embodiments, methods of treatment are provided for treating a patient suffering from an epidermal disorder of persistent inflammation, cell kinetics and differentiation disorder. Immunologic and inflammatory skin disorders result when the body overreacts to external stimuli or internal skin constituents. These reactions can be mediated by leukocytes and non-leukocytes. Cell differentiation orders result from abnormal keratinocyte differentiation..

[0043] In certain embodiments, the epidermal disorder of persistent inflammation, cell kinetics and differentiation disorder is selected from the group consisting of pityriasis rubra pilaris, pityriasis rosea, pityriasis lichenoides, notalgia paresthetica, lichen planus (e.g., LPP), lichen nitidus, lichen simplex chronicus, hyperkeratosis lenticularis perstans (Flegel’s disease), inheritedkeratodermas of palms and soles, granuloma annulare, Sweet’s syndrome, pyoderma gangrenosum, and urticaria, including chronic idiopathic urticaria, physical urticaria, and other forms of acquired urticaria. In certain embodiments, the epidermal disorder of persistent inflammation is not psoriasis, lichen planus, or lichen simplex.

[0044] In certain embodiments, a method of treatment is provided for treating a patient with pityriasis rubra pilaris. Pityriasis rubra pilaris is an inflammatory skin disease that can be categorized into five distinct types. Type I (classic adult) can be characterized by patchy erythematous macules with follicular hyperkeratotic papules on the upper half of the body. Type II can be characterized by ichthyosiform scaling, follicular hyperkeratosis, and sparse scalp hair. Type III (classic juvenile) is the clinical counterpart of Type I but is in juveniles. Type IV can be characterized by demarcated erythematous plaques on elbows and knees. Type V is characterized by hyperkeratotic follicular lesions.

[0045] In certain embodiments, a method of treatment is provided for treating a patient with pityriasis rosea. Pityriasis rosea is a self-limited skin disorder. Pityriasis rosea can be caused by an infection and is characterized by a plaque on the trunk.

[0046] In certain embodiments, a method of treatment is provided for treating a patient with pityriasis lichenoides. Pityriasis lichenoides is a skin condition categorized as pityriasis lichenoides chronica (PLC) or pityriasis lichenoides et varioliformis acuta (PLEVA) depending on how long symptoms last. Both forms can be characterized by a mix of acute and chronic lesions, which often itch or burn. The lesions may recur and spontaneously regress over a period of weeks to months. It is believed that T-cell cytokines play a role in activating an inflammatory response.

[0047] In certain embodiments, a method of treatment is provided for treating a patient with prurigo nodularis. Prurigo nodularis presents as hard, itchy bumps. These bumps result frompersistent, intense scratching and rubbing of the skin. They are usually located in easy-to-scratch areas such as the abdomen, limbs, and those parts of the back that are easily reached.

[0048] In certain embodiments, a method of treatment is provided for treating a patient with notalgia paresthetica. Notalgia paresthetica is a skin disorder characterized by itching in the middle of a patient’ s back. In chronic cases, notalgia paresthetica can be associated with pain, paresthesias, or altered sensation to touch.

[0049] In certain embodiments, a method of treatment is provided for treating a patient with lichen planus. Lichen planus can be characterized by well-demarcated, flat-topped, red-violet papules. Lichen planus pigmentosus (LPP) is a rare form of lichen planus that occurs on sun- exposed portions of the skin. This reaction can be caused by an idiopathic T-cell mediated process.

[0050] In certain embodiments, a method of treatment is provided for treating lichen nitidus. Lichen nitidus can be characterized by small pink, red, or brown papules that spontaneously resolve.

[0051] In certain embodiments, a method of treatment is provided for treating a patient with lichen simplex chronicus. Lichen simplex chronicus is a result of repetitive scratching and rubbing on the skin. Lichen simplex chronicus can present in associated with other dermatologic or systemic diseases.

[0052] In certain embodiments, a method of treatment is provided for treating a patient with hyperkeratosis lenticularis perstans, also known as Flegel’s disease. Hyperkeratosis lenticularis perstans is a rare skin disorder that affects the lower extremities. Hyperkeratosis lenticularis perstans most commonly affects middle-aged patients and presents as red-brown keratotic papules

[0053] In certain embodiments, a method of treatment is provided for treating inherited keratodermas of the palms and soles. Keratodermas of the palms and soles refer to patches ofhyperkeratosis on the hands and feet. There are different types of keratodermas depending on a patient’s genetic mutation, all of which tend to cause issues in the structure of keratinocytes.

[0054] In certain embodiments, a method of treatment is provided for treating granuloma annulare. Granuloma annulare is a common disorder characterized by a ring of beaded papules on the extremities. Granuloma annulare can be further categorized as generalized, subcutaneous, perforating, and patch subtypes.

[0055] In certain embodiments, a method is provided for treating Sweet’s syndrome. Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, presents with pyrexia and painful cutaneous lesions filled with neutrophils. Sweet’s syndrome may be associated with extracutaneous manifestations such as cardiovascular, CNS, GI, hepatic, musculoskeletal, ocular, oral, otic, pulmonary, renal, and splenic issues.

[0056] In certain embodiments, a method of treatment is provided for treating pyoderma gangrenosum. Pyoderma gangrenosum can present as a painful nodule, plaque, or pustule that grows bigger and breaks down to form an enlarging ulcer. The ulcer is characterized by raised, purple-red borders surrounded by redness.

[0057] In certain embodiments, a method of treatment is provided for treating urticaria, including chronic idiopathic urticaria, physical urticaria, and other forms of acquired urticaria. Urticaria is a skin disorder that can involve temporary skin edema and erythema accompanied by pruritus that typically resolves within a day. Urticaria can occur spontaneously or in response to a specific stimulant. Urticaria can be characterized by mast cell activity and the release of histamine.

[0058] Epidermal Disorders of Persistent Inflammation — Altered Reactivity Disorders

[0059] In certain embodiments, methods of treatment are provided for treating a patient suffering from an epidermal disorder of persistent inflammation, altered reactivity disorder.Altered reactivity disorders refer to an inappropriate local or systemic response against selfantigens, foreign antigens, or microbes.

[0060] In certain embodiments, the epidermal disorder of persistent inflammation, altered reactivity disorder is selected from the group consisting of perioral dermatitis, allergic contact dermatitis, irritant contact dermatitis, polymorphous light eruption (PMLE), actinic prurigo, cradle cap, diaper dermatitis, stasis dermatitis, brachioradial pruritus, dupilumab-associated erythema / dermatitis, juvenile plantar dermatosis, uremic or cholestatic pruritus, pruritus scroti or ani, necrobiosis lipoidica diabeticorum, ichthyosis, pityriasis amiantacea, intertrigo, nummular eczematous dermatitis, dyshidrotic eczema, hand eczema, and vesicular palmoplantar eczema. In certain embodiments, the epidermal disorder of persistent inflammation is not atopic dermatitis or seborrheic dermatitis.

[0061] In certain embodiments, a method of treatment is provided for treating a patient with perioral dermatitis. Perioral dermatitis (also known as periorificial dermatitis) is an inflammatory disorder occurring on the face and can be associated with patients diagnosed with rosacea. Perioral dermatitis can be characterized by an eruption of papules and pustules by the nose and chin.

[0062] In certain embodiments, a method of treatment is provided for treating a patient with allergic contact dermatitis. Allergic contact dermatitis is a delayed hypersensitivity reaction caused by contact with an environmental allergen. Allergic contact dermatitis can be characterized by itching, redness, swelling, and vesicles in the area of exposure.

[0063] In certain embodiments, a method of treatment is provided for treating a patient with irritant contact dermatitis (including eyelid dermatitis). Irritant contact dermatitis results from exposure to an allergen, resulting in an innate immune signal. Constant exposure can predispose the patient to allergic dermatitis. Symptoms are commonly confined to the site of exposure.

[0064] In certain embodiments, a method of treatment is provided for treating a patient with polymorphous light eruption (PMLE). PMLE can be thought of as a sort of allergy to sunlight. It presents as a rash of tiny, inflamed bumps or slightly raised patches of skin following exposure to sunlight.

[0065] In certain embodiments, a method of treatment is provided for treating a patient with actinic prurigo. Actinic prurigo is also an itchy rash brought on by exposure to sun, but it is clinically different from PMLE in that is characterized by an excoriated papular and nodular eruption that lasts longer than PMLE. It can affect any area of skin exposed to the sun and is also called Hutchinson’s summer because it is most common during that time of year.

[0066] In certain embodiments, a method of treatment is provided for treating a patient with cradle cap. “Cradle cap” is a form of seborrheic dermatitis commonly observed in infants. It is characterized by scaly, oily patches, mostly on the baby’s head.

[0067] In certain embodiments, a method of treatment is provided for treating a patient with diaper dermatitis, also commonly known as “diaper rash.” Diaper dermatitis can result from infection (often bacterial or yeast infections), but more commonly results simply from the irritation of skin contact with urine and feces. It presents as a rash in areas enclosed by a diaper on infants.

[0068] In certain embodiments, a method of treatment is provided for treating a patient with stasis dermatitis. Stasis dermatitis results from the pooling of blood in the lower legs that follows from poor circulation. It presents as swollen and discolored skin, but usually develops ulcers, skin thickening, bumpiness, and / or a dark brown coloration over time.

[0069] In certain embodiments, a method of treatment is provided for treating a patient with brachioradial pruritus. Brachioradial Pruritus is a skin condition characterized by abnormal skinsensations on the outer forearms, upper arms, and / or the top of the shoulder. The sensations reported include itching, burning, stinging, and prickling.

[0070] In certain embodiments, a method of treatment is provided for treating a patient with dupilumab-associated erythema / dermatitis. Dupilumab-associated erythema / dermatitis is a side effect of treatment with dupilumab characterized by scaly ill-defined erythematous plaques and pustules. It usually presents on the patient’s face, head, or neck.

[0071] In certain embodiments, a method of treatment is provided for treating a patient with juvenile plantar dermatosis. Juvenile plantar dermatosis, also known as sweaty-sock syndrome, is characterized by symmetric, shiny, erythema, along with cracking and peeling of the weightbearing areas of the soles. It is common in school-age children, especially boys.

[0072] In certain embodiments, a method of treatment is provided for treating a patient with uremic or cholestatic pruritus. Uremic pruritus refers to itching related to advanced stage kidney disease, while cholestatic pruritus occurs in patients with cholestatic liver disease. Both are characterized by a near-daily experience of itch in the absence of a primary dermatologic diagnosis that might otherwise account for the itch.

[0073] In certain embodiments, a method of treatment is provided for treating a patient with pruritus scroti or ani. Pruritus scroti is a burning itch in the scrotum, while pruritus ani is a burning itch in the skin of the peri-anus. Both are usually caused by moisture and friction in their immediate environment, although both can also be caused by infection or an underlying metabolic imbalance.

[0074] In certain embodiments, a method of treatment is provided for treating a patient with necrobiosis lipoidica diabeticorum. Necrobiosis lipoidica diabeticorum (NLD) is a rare complication of diabetes, usually insulin-dependent diabetes. It manifests as a rash, most commonly on the shins.

[0075] In certain embodiments, a method of treatment is provided for treating a patient with ichthyosis. Ichthyosis manifests as dry, itchy skin that appears rough, scaly, and red. Ichthyosis of the skin is the most common sort, but some forms of ichthyosis can affect internal organs as well.

[0076] In certain embodiment, a method of treatment is provided for a patient with pityriasis amiantacea. Pityriasis amiantacea derives its name from the French word for asbestos (amiante) because its characteristic scaly formations around the hair follicles look like asbestos. Thick silver or yellow scales form around the hair shafts and bind down the hair. This condition can be complicated by secondary staphylococcal infection.

[0077] In certain embodiments, a method of treatment is provided for treating a patient with intertrigo. Intertrigo is an inflammatory skin condition caused by irritation from heat, friction, moisture, and lack of ventilation. Intertrigo can be characterized by erythematous patches in intertriginous region such as the axilla and abdominal folds.

[0078] In certain embodiments, a method of treatment is provided for treating a patient with nummular eczematous dermatitis. Nummular eczematous dermatitis is a chronic inflammatory skin disorder. Nummular eczematous dermatitis can be characterized by papules and papulovesicles grouped together to form nummular plaques. Potential triggers can include atopy, xerosis, exogenous insult by allergens, and infection.

[0079] In certain embodiments, a method of treatment is provided for treating a patient with dyshidrotic eczema. Dyshidrotic eczema can be characterized by a sudden onset eruption of vesicles on the soles, palms, or both. The vesicles can be itchy and may recur.

[0080] In certain embodiments, a method of treatment is provided for treating a patient with hand eczema. Hand eczema can be of mixed morphology. Hand eczema is an inflammatorydisorder of the skin primarily affecting the epidermis and dermis. Hand eczema can be characterized by red, itchy papules or vesicles that may ooze and crust.

[0081] In certain embodiments, a method of treatment is provided for treating a patient with vesicular palmoplantar eczema. Vesicular palmoplantar eczema can be characterized by a pruritic vesiculobullous eruption typically involving the hands and / or feet.

[0082] Disorders of the Lips, Oral, or Vaginal Mucosa

[0083] In certain embodiments, methods of treatment are provided for treating a patient suffering from a disorder of the lips, oral, or vaginal mucosa. Disorders of the oral or vaginal mucosa refer to ulcerated lesions found in the lips, oral cavity, or the vaginal mucosa.

[0084] In certain embodiments, the disorder of the lips, oral, or vaginal mucosa is selected from the group consisting of actinic cheilitis, atopic cheilitis, mucositis, dry-mouth associated with cystic fibrosis, aphthous ulcers, vulvar aphthae, oral lichen planus, geographic tongue, lichen sclerosus, feminine itch, Behcet’s disease, and linear IgA. In certain embodiments, the disorder of lips, oral, or vaginal mucosa is not aphthous ulcers, lichen planus, or lichen sclerosus.

[0085] In certain embodiments, a method of treatment is provided for treating a patient with actinic cheilitis. Actinic cheilitis is a form of actinic keratosis that presents on the lips. Actinic cheilitis can be characterized as red, chapped lips with fissures and a vermilion border. Patients are likely to have accompanying photodamaged skin.

[0086] In certain embodiments, a method of treatment is provided for treating a patient with atopic cheilitis. Atopic cheilitis is a drying and scaling of the lips, often found in patients with a history of atopic dermatitis.

[0087] In certain embodiments, a method of treatment is provided for treating a patient with mucositis. Mucositis is inflammation of the mucous membranes that line the mouth and gastrointestinal tract. Mucositis is a common side effect of chemotherapy.

[0088] In certain embodiments, a method of treatment is provided for treating a patient with dry mouth. Dry mouth is a common symptom of cystic fibrosis, as is a general dehydration of the oral mucosa.

[0089] In certain embodiments, a method of treatment is provided for treating a patient with aphthous ulcers. Aphthous ulcers (also known as lupus aphthae) are lesions found in the mouth or by the genitals. They are a common symptom of lupus, although they can occur apart from lupus. Aphthous ulcers are classified into minor, major, and herpetiform. The ulcers have varying features and range from abrupt onset with a short duration to more chronic ulcers that have slow onset and progression.

[0090] In certain embodiments, a method of treatment is provided for treating a patient with vulvar aphthae. Vulvar apthae are ulcers found on the vulva, often caused by infection.

[0091] In certain embodiments, a method of treatment is provided for treating a patient with oral lichen planus. Oral lichen planus may be categorized as reticular, plaque-like, atrophic, papular, erosive or ulcerative, or bullous.

[0092] In certain embodiments, a method of treatment is provided for treating a patient with geographic tongue. Geographic tongue, also known as benign migratory glossitis or glossitis areata migrans, is an inflammatory disorder that can cause the local loss of filiform papillae. Geographic tongue can be characterized by asymptomatic erythematous patches with serpiginous borders, resembling a map. The lesions are migratory in nature.

[0093] In certain embodiments, a method of treatment is provided for treating a patient with lichen sclerosus. Lichen sclerosus is a chronic inflammatory dermatosis that is more common in women than men. Lichen sclerosus is caused by the development of antibodies to extracellular matrix protein-1, which results in dermatosis in the anogenital and extragenital regions.

[0094] In certain embodiments, a method of treatment is provided for treating a patient with feminine itch. Feminine itch may be caused by a variety of disorders, such as vulvo-vaginal candidiasis, lichen sclerosus, and vulvar eczema.

[0095] In certain embodiments, a method of treatment is provided for treating a patient with Behcet’s disease. Behcet’s disease is a chronic, recurrent vasculitis. Behcet’s manifests on the skin by developing oval or round ulcers that are well-demarcated with a gray or yellow necrotic base.

[0096] In certain embodiments, a method of treatment is provided for treating a patient with linear IgA. Linear IgA is a disease wherein a linear band of IgA forms at the dermal-epidermal basement membrane. This results in blisters and presents similarly to dermatitis herpetiformis or bullous pemphigoid.

[0097] Epidermal Disorders of Cohesion — Vesicular and Bullous Disorders

[0098] In certain embodiments, a method of treatment is provided for treating a patient suffering from an epidermal disorder of cohesion, vesicular and bullous disorder. Epidermal disorders of cohesion, vesicular and bullous disorders can include diseases in which blister (bulla or vesicles) formation can occur as a skin reaction. Vesicles are fluid-filled papules smaller than one centimeter. Bulla are fluid-filled vesicles that are larger than one centimeter.

[0099] In certain embodiments, the epidermal disorder of cohesion, vesicular and bullous disorder is selected from the group consisting of erythema multiforme, folliculitis decalvans, pityrosporum folliculitis, Gianotti-Crosti syndrome, pemphigus, bullous pemphigoid, linear IgAdermatosis, herpes gestationis, dermatitis herpetiformis, Hailey-Hailey disease, pustular palmoplantar psoriasis, herpes simplex virus I and II, eczema herpeticum, epidermolysis bullosa (EB simplex and EB acquisita), Behcet’s disease, and Darier disease. In certain embodiments, the epidermal disorder of cohesion is not Hailey-Hailey disease or Darier disease.

[0100] In certain embodiments, a method of treatment is provided for treating a patient with erythema multiforme. Erythema multiforme is a disorder resulting in a recurrent cutaneous or mucocutaneous eruption of target lesions on the face or extremities. Erythema multiform may be caused by infections and is often benign, but may result in ocular complications.

[0101] In certain embodiments, a method of treatment is provided for treating a patient with pemphigus. There are two types of pemphigus. Pemphigus vulgaris can be characterized by erosions and flaccid blisters on mucous membranes and skin. Pemphigus foliaceus can be characterized by crusty and scaly lesions. Pemphigus disorders result from autoantigens to desmogleins and transmembrane desmosomal adhesion molecules. In certain embodiments, a method of treatment is provided for treating a patient with paraneoplastic pemphigus. Paraneoplastic pemphigus is a rare complication commonly associated with non-Hodgkin lymphoma, chronic lymphocytic leukemia, or Castleman disease. Paraneoplastic pemphigus can be characterized by painful, erosive stomatitis and polymorphous cutaneous lesions.

[0102] In certain embodiments, a method of treatment is provided for treating a patient with bullous pemphigoid. Bullous pemphigoid is characterized by itchy rashes / plaques and large, tense blisters. The symptoms can develop in response to C3 and IgG anti-basement membrane autoantibodies.

[0103] In certain embodiments, a method of treatment is provided for treating a patient with cicatricial pemphigoid. Cicatricial pemphigoid is a blistering disease most commonly affecting theoral cavity and eye. Cicatricial pemphigoid has a long duration that may result in scarring. Cicatricial pemphigoid can be caused by deposition of an anti-basement membrane zone antibody.

[0104] In certain embodiments, a method of treatment is provided for treating a patient with folliculitis decalvans. Although folliculitis decalvans can also be classified as a disorder of an epidermal appendage (see above), it is a neutrophilic fibrosis believed to stem from an abnormal host immune response involving Staphylococcus aureus. Folliculitis decalvans is characterized by follicular pustules, lack of ostia, follicular tufting, and / or perifollicular erythema. Current treatments focus on resolving inflammation and eradicating the S. aureus.

[0105] In certain embodiments, a method of treatment is provided for treating a patient with pityrosporum folliculitis. Pityrosporum folliculitis results from yeast infecting the hair follicles. The condition causes itchy pustules on the face, scalp, and upper torso.

[0106] In certain embodiments, a method of treatment is provided for treating a patient with Gianotti-Crosti syndrome (GCS). Also known as popular acrodermatitis, GCS is a rare childhood skin disorder that presents as a symmetrical rash that follows after a viral infection or an immunization against a viral infection.

[0107] In certain embodiments, a method of treatment is provided for treating a patient with linear IgA dermatosis. Linear IgA dermatosis is a disease wherein a linear band of IgA forms at the dermal-epidermal basement membrane. This results in blisters and presents similarly to dermatitis herpetiformis or bullous pemphigoid.

[0108] In certain embodiments, a method of treatment is provided for treating a patient with herpes gestationis. Herpes gestationis is a self-limited disease in pregnant and post-partum women. Herpes gestationis can be characterized by itchy rashes and vesiculobullous lesions. Herpes gestationis is caused by the deposition of reactants in the basement membrane zone.

[0109] In certain embodiments, a method of treatment is provided for treating a patient with dermatitis herpetiformis. Dermatitis herpetiformis can be characterized by extremely itchy papulovesicles that erupt symmetrically on extensor surfaces. Dermatitis herpetiformis can be caused by granular IgA deposits.

[0110] In certain embodiments, a method of treatment is provided for treating a patient with Hailey-Hailey disease. Hailey-Hailey disease is an inherited dermatosis characterized by vesicles and blisters with variable expressivity. The lesions are found in intertriginous regions and may occur chronically with spontaneous remissions.

[0111] In certain embodiments, a method of treatment is provided for treating a patient with pustular palmoplantar psoriasis. Pustular palmoplantar psoriasis (also known as palmoplantar pustulosis) is characterized by pustules on the palms and soles. The disorder is chronic and inflammatory in origin.

[0112] In certain embodiments, a method of treatment is provided for treating a patient with herpes simplex virus I (HSV I) or herpes simplex virus II (HSV II). HSV l is a virus that is mostly spread by oral contact, causing infections in and around the mouth but may also cause genital infections. HSV I can present as erythema and vesicles on the lips. HSV II is a virus that is spread by sexual contact, causing infections in the genital area but may also cause orofacial infections. HSV II can be characterized by vesicles, pustules, and erythematous ulcers on the genitals that can take up to 3 weeks to resolve.

[0113] In certain embodiments, a method of treatment is provided for treating a patient with eczema herpeticum. Eczema herpeticum is a cutaneous skin infection with herpes simplex virus that develops from atopic dermatitis. Eczema herpeticum can be characterized by a sudden onset of vesicles and hemorrhagic crusty erosions.

[0114] In certain embodiments, a method of treatment is provided for treating a patient with epidermolysis bullosa (EB). EB simplex (EBS) is a rare genetic disorder. EB simplex EB acquista (EBA) is a rare autoimmune disease that is caused by immunoglobulin G autoantibodies to Type VII collagen. Both forms of EB can be characterized by subepidermal blisters, skin fragility, residual scarring, and milia formation. EBA can be located on the hands, feet, elbows, knees, sacrum, nails, and mouth, while the blisters of EBS form within basal keratinocytes. EB may be associated with an underlying systemic disease.

[0115] In certain embodiments, a method of treatment is provided for treating a patient with Behcet’s disease. Behcet’s disease is a chronic, recurrent vasculitis. Behcet’s manifests on the skin by developing oval or round ulcers that are well-demarcated with a gray or yellow necrotic base. Behcet’s disease can cause mouth or genital ulcers.

[0116] In certain embodiments, a method of treatment is provided for treating a patient with Darier’s disease. Darier’s disease is a genetic disorder characterized by hyperkeratotic warty papules and plaques on the scalp, forehead, retroauricular folds, upper arms, front and back of central trunk, and flexures. It is also associated with nail abnormalities.

[0117] In certain embodiments, a method of treatment is provided for treating a patient with Grover’s disease. Grover’s disease (also known as transient acantholytic dermatosis) is a dermatosis resulting from the degradation of intercellular connections among keratinocytes, and characterized by itchy, papulovesicular, polymorphic dermatitis. It is most commonly found on the chest, back, arms, and thighs.

[0118] Hypomelanoses and Hypermelanoses

[0119] In certain embodiments, a method of treating a patient suffering from hypermelanoses or hypermelanoses is provided. Hypomelanoses and hypermelanoses refer to pigmentationdisorders that may be congenital or acquired. The disorders may be caused by increased or decreased melanin, abnormal distribution of melanin, or deposition of pigments.

[0120] In certain embodiments, the disorder of epidermal appendages is selected from the group consisting of vitiligo, dyschromia, pityriasis alba, post-inflammatory hypo-pigmentation, or post- inflammatory hyper-pigmentation. In certain embodiments, the hypomelanoses or hypermelanoses is not vitiligo.

[0121] In certain embodiments, a method of treatment is provided for treating a patient with vitiligo. Vitiligo is an autoimmune disease in which T-cells initiate destruction of melanocytes. This results in confetti, trichrome, and inflammatory lesions. These lesions can present as milky- white macules.

[0122] In certain embodiments, a method of treatment is provided for treating a patient with dyschromia. Dyschromia is characterized by pigmented macules and patches on sun-exposed areas or areas of inflammation.

[0123] In certain embodiments, a method of treatment is provided for treating a patient with pityriasis alba. Pityriasis alba is a benign skin disorder commonly diagnosed in children and teens. Pityriasis alba can be characterized by macules and patches with mild scaling and pruritis appearing on the face, arms, and upper trunk.

[0124] In certain embodiments, a method of treatment is provided for treating a patient with melasma. Melasma (also known as chloasma faciei) is condition characterized by hyperpigmented patches or macules of discoloration that are darker than the surrounding skin. It is most commonly observed on the cheeks, nose, upper lip, forehead, and / or chin.

[0125] In certain embodiments, a method of treatment is provided for treating a patient with post-inflammatory hypo-pigmentation (e.g., as observed after laser-based skin procedures). Post-inflammatory hypo-pigmentation can result from cutaneous inflammation or injury. Post- inflammatory hypo-pigmentation can be characterized by partial or total loss of skin pigmentation.

[0126] In certain embodiments, a method of treatment is provided for treating a patient with post-inflammatory hyper-pigmentation (e.g., as observed after laser-based skin procedures). Post- inflammatory hyper-pigmentation can result from the overproduction of melanin or melanin deposition in the epidermis after inflammation. This can be characterized as a blue-gray discoloration of the skin.

[0127] Cutaneous Lymphomas

[0128] In certain embodiments, methods of treatment are provided for treating a patient suffering from a cutaneous lymphomas, including cutaneous T-cell and B-cell lymphomas. Cutaneous T-cell lymphomas are a group of T-cell neoplasms affecting the skin. Cutaneous T-cell lymphoma can cause skin redness, slightly raised or scaly patches on the skin, and sometimes skin tumors. Cutaneous B-cell lymphoma is a type of malignant skin cancer that results from abnormal B-lymphocyte cell activity. There are three main subtypes: primary cutaneous follicle center lymphoma (PCFCL), extranodal marginal zone lymphoma / primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma (PCLBCL). PCFCL can be characterized by solitary, red, and firm plaques and tumors on the head and trunk. PCMZL can be characterized by purple papules, plaques, or nodules. PCLBCL can be characterized by solitary or clustered bluish red plaques and tumors on the legs.

[0129] In certain embodiments, the cutaneous lymphoma is selected from the group consisting of mycosis fungoides variants and non-mycosis fungoides cutaneous T-cell or B-cell lymphoma.

[0130] In certain embodiments, a method of treatment is provided for treating a patient with a variant of mycosis fungoides. Mycosis fungoides is characterized by patches and plaques affecting predominantly non-photoexposed areas.

[0131] In certain embodiments, a method of treatment is provided for treating a patient with non-mycosis fungoides cutaneous T-cell or B-cell lymphoma. Non-mycosis fungoides CTCL refer to cutaneous T-cell lymphomas with other causes such as primary cutaneous CD30+ T-cell lymphoproliferative disorders, subcutaneous panniculitis-like T-cell lymphoma, extranodal NK / T- cell lymphoma, and hydroa vacciniforme-like T-cell lymphoma.

[0132] Skin Manifestations of Rheumatologic Diseases

[0133] In certain embodiments, methods of treatment are provided for treating a patient suffering from a skin manifestation of a rheumatologic disease. Rheumatologic diseases involve the joints in addition to other manifestations, commonly cutaneous diseases.

[0134] In certain embodiments the skin manifestation of a rheumatologic disease is selected from the group consisting of cutaneous lupus erythematosus, dermatomyositis, sarcoidosis, chronic idiopathic pruritus, cutaneous vasculitis, and scleroderma / morphea. In certain embodiments, the skin manifestation of a rheumatologic disease is not discoid lupus.

[0135] In certain embodiments, a method of treatment is provided for treating a patient with cutaneous lupus erythematosus. Cutaneous lupus erythematosus is caused by an immune reaction to self-nucleic acids and proteins. Cutaneous lupus erythematosus is associated with the upregulation of type 1 interferon signaling. Cutaneous lupus erythematosus is sub categorized as acute, subacute, or chronic. Acute CLE can be characterized with a malar rash. Subacute CLE can be characterized by erythematous macules or papules that evolve into hyperkeratoticpapulosquamous or annular / polycyclic plaques. Chronic CLE can be characterized by red / purple macules, papules, or small plaques and rapidly develop a hyperkeratotic surface.

[0136] In certain embodiments, a method of treatment is provided for treating a patient with discoid lupus. Discoid lupus is a subcategory of chronic cutaneous lupus erythematosus. Classic discoid lupus erythematosus can be characterized by scaly plaques on the scalp, face, and ears that result in scarring and color change.

[0137] In certain embodiments, a method of treatment is provided for treating a patient with dermatomyositis. Dermatomyositis is a systemic autoimmune disease associated with interstitial lung disease. Dermatomyositis can be characterized by violaceous erythema on the eyelids, upper chest, back, elbows, knees, and lateral hips.

[0138] In certain embodiments, a method of treatment is provided for treating a patient with sarcoidosis. Sarcoidosis is a disease that can affect the entire body but commonly affects the lung and skin. An acute presentation can be characterized by erythema nodosum lesions and may selfresolve. A chronic presentation can be characterized by lupus pernio lesions and may scar.

[0139] In certain embodiments, a method of treatment is provided for treating a patient with chronic idiopathic pruritus. Idiopathic pruritus refers to itchiness of unknown origin that is usually chronic. It is usually considered chronic if lasting longer than six weeks.

[0140] In certain embodiments, a method of treatment is provided for treating a patient with cutaneous vasculitis. Cutaneous vasculitis is a skin disorder that occurs in association with other disorders such as Sjogren’s Syndrome, rheumatoid arthritis, or drug-induced reactions. Cutaneous vasculitis can be characterized primarily by palpable purpura, usually found on the lower extremities.

[0141] In certain embodiments, a method of treatment is provided for treating a patient with scleroderma / morphea. Scleroderma targets the skin in phases, varying from inflammatory, sclerotic, and atrophic phases. Scleroderma may be self-limited or may relapse chronically. Scleroderma results in thickened sclerotic skin, and potentially systemic disease such as arthritis and neurologic disorders.

[0142] Skin Manifestations Related to Oncology Treatments

[0143] In certain embodiments, a method of treating a patient suffering from a skin manifestation related to an oncology disorder is provided. Oncodermatology refers to disorders that may manifest as a secondary effect of anti neoplastic drugs. Examples can include scarring, striae distenae, persistent alopecia, changes in pigment, nail changes, chronic radiation dermatitis, and radiation fibrosis.

[0144] In certain embodiments, the skin manifestation of an oncology disorder is selected from the group consisting of adverse skin reactions due to EGFR inhibitors, adverse skin reactions due to CTLA-4 inhibitors, adverse skin reactions due to PD-1 inhibitors, and adverse skin reactions due to BRAF inhibitors.

[0145] In certain embodiments, a method of treatment is provided for treating a patient with an adverse skin reaction due to an EGFR inhibitor. EGFR inhibitors are oncology drugs that target tumor cell differentiation. Examples include cetuximab, panitumumab, erlotinib, and gefitinib. Usage of an EGFR inhibitor may cause a rash between 2 days and 6 weeks after the initial administration. It can be characterized by tender red papules, which evolve into pustules and crusts after a few days.

[0146] In certain embodiments, a method of treatment is provided for treating a patient with an adverse skin reaction due to a CTLA-4 inhibitor. CTLA-4 inhibitors are oncology drugs commonlyused to treat metastatic melanoma. Examples of CTLA-4 inhibitors include ipilimumab and tremelimumab. Usage of a CTLA-4 inhibitor may cause various skin disorders such as acantholytic dermatitis, maculopapular rashes with pruritus.

[0147] In certain embodiments, a method of treatment is provided for treating a patient with an adverse skin reaction due to a PD-1 inhibitor. PD-1 inhibitors are oncology drugs commonly used to treat metastatic melanoma. Examples of PD-1 inhibitors include ipilimumab and tremelimumab. Usage of a PD-1 inhibitor may cause various skin disorders such as lichenoid eruption, pruritic maculopapular rash, bullous pemphigoid eruption, and vitiligo.

[0148] In certain embodiments, a method of treatment is provided for treating a patient with an adverse skin reaction due to a BRAF inhibitor. BRAF inhibitors are commonly used to treat melanomas, a disease associated with patients who have a BRAF mutation. Examples include vemurafenib and dabrafenib. Usage of a BRAF inhibitor may cause various skin disorders such as actinic keratosis, milia, keratosis pilaris, cheilitis, and hair growth modification.

[0149] Dosing Regimens

[0150] In certain embodiments, the pharmaceutical composition is administered as a regimen, such as at regular intervals. For example, a pharmaceutical composition can be administered once daily, twice daily, thrice daily, four times daily, once per week, twice per week, three times per week, or four times per week, weekly, or as needed (pro re nata or PRN). The pharmaceutical composition can be administered for a prescribed period of time. For example, a pharmaceutical composition can be administered for a period of about two days or more, or until an improvement in the condition or disease is observed. Exemplary periods of time for the treatment regimen include one week, two weeks, three weeks, one month, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, elevenmonths, one year, or two years. The pharmaceutical composition can be topically administered as an ongoing treatment with no end.

[0151] Amount of Roflumilast Administered

[0152] Each dose of roflumilast administered to the patient over the course of the treatment regimen may contain the same, or substantially the same, amount of roflumilast. Alternatively, the amount of roflumilast contained within the individual doses may vary over the course of the treatment regimen. For example, the concentration of roflumilast contained within the individual pharmaceutical composition administered can increase over time (e.g., each subsequent dose can contain more roflumilast than the last), decrease over time (e.g., each subsequent dose can contain less roflumilast than the last), initially increase then decrease, initially decrease then increase, or remain the same throughout the course of the treatment regimen.

[0153] The amount of roflumilast administered to the patient in each dose can be a therapeutically effective amount. In certain embodiments, the pharmaceutical composition can comprise roflumilast in a range from about 0.01% to about 3.0%, or from about 0.01% to about 2.0%, or from about 0.01% to about 1.0%, or from about 0.01% to about 0.3%, or from about 0.05% to about 0.3%, or from about 0.15% to about 0.3%. For example, the pharmaceutical can comprise any of the following concentration of roflumilast: 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, etc.

[0154] Pharmaceutical Compositions

[0155] The present invention includes methods of treatment wherein the roflumilast administered to the patient is contained within a pharmaceutical composition. The pharmaceutical composition can comprise roflumilast and at least one inactive ingredient, such as apharmaceutically acceptable carrier. In preferred embodiments, the pharmaceutical composition is a topical pharmaceutical composition comprising roflumilast.

[0156] Topical pharmaceutical compositions of roflumilast are described in U.S. Patent No. 9,895,359, U.S. 11,534,493, U.S. Application No. 17 / 821,051, and U.S. Application No. 17 / 877,798, which are incorporated by reference herein. In certain embodiments, the pharmaceutical composition is one of the compositions disclosed in one of U.S. Patent No. 9,895,359, U.S. 11,534,493, U.S. Application No. 17 / 821,051, or U.S. Application No. 17 / 877,798.

[0157] The topical formulations disclosed herein can be anorectal preparations, dermatological preparations, mouth and throat products, nasal preparations, ophthalmic preparations, optic preparations, sterile irrigating solutions and vaginal preparations. Suitable pharmaceutical dosage forms include but are not limited to emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, lotions, pastes, gels, or foams. In preferred embodiments, the pharmaceutical compositions can be formulated as an emulsion in the form of a cream or foam.

[0158] For example, the pharmaceutical composition can be formulated as one of the following forms:

[0159] An oil-in-water emulsion: The pharmaceutical composition may be an emulsion comprising a discrete phase of a hydrophobic component and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, cosolvents, salts, surfactants, emulsifiers, and other components. These emulsions may include water-soluble or water-swellable polymers that help to stabilize the emulsion.

[0160] A water-in-oil emulsion: The pharmaceutical composition may be an emulsion that includes a continuous phase of a hydrophobic component and an aqueous phase that includes waterand optionally one or more polar hydrophilic carrier(s) as well as salts or other components. These emulsions may include oil-soluble or oil-swellable polymers as well as one or more emulsifier(s) to help to stabilize the emulsion.

[0161] A microemulsion: The pharmaceutical composition may be a clear, thermodynamically stable isotropic liquid system that contain oil, water and surfactants, frequently in combination with a cosurfactant. Microemulsions may be water continuous, oil continuous or bicontinuous mixtures. The pharmaceutical composition may optionally also contain water up to 60% by weight. Higher levels may be suitable in some compositions.

[0162] A nanoemulsion: The pharmaceutical composition may be an isotropic dispersed system that contains water, oil, and an emulsifier. The system may be an oily system dispersed in an aqueous system, or an aqueous system dispersed in an oily system forming droplets or oily phases of nanometric sizes. Nanoemulsions often have higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients can also be formulated in nanoemulsion. Nanoemulsions may be formed by any suitable method known in the art, including high-pressure homogenization, microfluidization, and phase-inversion temperature.

[0163] Thickened aqueous gels: The pharmaceutical composition may include an aqueous phase which has been thickened by suitable natural, modified natural, or synthetic thickeners such as described below. Alternatively, the thickened aqueous gels can be thickened using suitable polyethoxylate alky chain surfactants or other nonionic, cationic, or anionic systems.

[0164] Thickened hydroalcoholic gels: The pharmaceutical composition may include a blend of water and alcohol as the polar phase which has been thickened by suitable natural, modified natural, or synthetic polymers such as described below. Alternatively, the thickened hydroalcoholic gels can be thickened using suitable polyethoxylate alky chain surfactants or othernonionic, cationic, or anionic systems. The alcohol can be ethanol, isopropyl alcohol or other pharmaceutically acceptable alcohol. In embodiments of the present invention, the amount of alcohol (e.g., ethanol) can be less than 20% and still provide a self-preserving formulation.

[0165] Hydrophilic gels: The pharmaceutical composition may be a system in which the continuous phase includes at least one water soluble or water dispersible hydrophilic component other than water. The formulation may optionally also contain water up to 60% by weight. Higher levels may be suitable in some compositions. Suitable hydrophilic components include one or more glycols such as polyols such as glycerin, propylene glycol, butylene glycols, polyethylene glycols (PEG), random or block copolymers of ethylene oxide, propylene oxide, and / or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, blend of ceteareth-6 and stearyl alcohol as well as combinations thereof, and the like.

[0166] In addition to the active ingredient, the formulation may contain additional excipients commonly present in such dosage forms. Such excipients will vary depending on the type of the dosage form and the desired characteristics. The pharmaceutical compositions for use with the methods disclosed herein may include one or more solvent, moisturizer, surfactant and emulsifier, polymer and thickener or additional excipients. In certain embodiments, the pharmaceutical composition comprises roflumilast and one or more of diethylene glycol monoethyl ether, an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate, and hexylene glycol.

[0167] Solvents

[0168] In certain embodiments, the pharmaceutical composition may include one or more solvents or co-solvents to obtain the desired level of active ingredient solubility in the topicalproduct. The solvent may also modify skin permeation or the activity of other excipients contained in the formulation. Solvents include but are not limited to acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methyl pyrrolidinone, polyethylene glycol, glycerol, propylene glycol, SD alcohol and dimethyl isosorbide. In certain embodiments, the solvent is selected from the group consisting of 1,3- butylene glycol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol (also known as pentylene glycol), dipropylene glycol, 2-(2-butoxy-ethoxy)ethanol (also known as butoxy diglycol), 1,6- hexanediol, propylene glycol methyl ethyl acetate (also known as PGMEA or 1 -methoxylpropanol acetate), 5-methyloxolan-2-one (also known as ammcz-valerolactone), pantolactone, 1,3-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1-heptanol, 1-hexanol, 2-(2-ethoxyethoxyl)ethyl acetate, 2-(2-methoxyethoxy)ethanol, 2 -butoxy ethanol, 2-butoxyethyl acetate, 2-ethoxy ethanol, 2- ethoxyethyl acetate, 2-methoxyethanol, diethylene glycol dimethyl ether (also known as bis(2- methoxy ethyl) ether), diethylene glycol, propylene glycol methyl ether, and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of 1,3-butylene glycol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol, dipropylene glycol, 2-(2-butoxy- ethoxy)ethanol, 1,6-hexanediol, propylene glycol methyl ethyl acetate, 5-methyloxolan-2-one, and pantolactone. When treating a patient with an inflammatory condition, the solvent is preferably not ethanol, isopropyl alcohol or denatured alcohol.

[0169] Moisturizers

[0170] In certain embodiments, the pharmaceutical composition may include a moisturizer to increase the level of hydration. The moisturizer can be a hydrophilic material including humectants or it can be a hydrophobic material including emollients. Suitable moisturizers include but are notlimited to: l,2,6-hexanetriol, 2-ethyl-l,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, white petrolatum, isopropyl palmitate, and stearyl alcohol.

[0171] Surfactants and Emulsifiers

[0172] In certain embodiments, the pharmaceutical composition may include one or more surfactants to emulsify the composition and to help wet the surface of the actives or excipients. As used herein the term “surfactant” means an amphiphile (a molecule possessing both polar and nonpolar regions which are covalently bound) capable of reducing the surface tension of water and / or the interfacial tension between water and an immisicible liquid. Surfactants include but are not limited to alkyl aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate, apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride, Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearyl alcohol / ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-2, ceteth- 20, ceteth-23, choleth-24, cocamide ether sulfate, cocamine oxide, coco betaine, coco diethanolamide, coco monoethanolamide, coco-caprylate / caprate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamido monoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23, laureth-4, lauric di ethanol ami de, lecithin, mehoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12glyceryl laurate, PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-1 0 distearate, PEG- 2 stearate, PEG-20 methyl glucose sesqustearate, PEG-22 methyl ether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45 / dodecyl glycol copolymer, PEG-5 oleate, PEG- 50 Stearate, PEG-54 hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate, Pegoxol 7 stearate, pentaerythritol cocoate, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237 poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32, polyoxyl glyceryl stearate, polyoxyl stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate, PROMULGEN™ 12, propylene glycol diacetate, propylene glycol di caprylate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, tallow glycerides, and emulsifying wax. Preferably, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate, ceteth-10 phosphate, cetearyl alcohol, or any two-way combination thereof, such as dicetyl phosphate and ceteth-10 phosphate.

[0173] Polymers and Thickeners

[0174] In certain embodiments, the pharmaceutical composition may include a soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners such as acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, and methylcellulose,

[0175] Additional Excipients

[0176] In certain embodiments, the pharmaceutical composition may include additional excipients such as fillers, carriers and excipients conventionally found in cosmetic and pharmaceutical topical products. In a preferred embodiment, the fillers, carriers and excipients are suitable for topical administration. Additional excipients including but not limited to antifoaming agents, preservatives (e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol, methylparaben, propylparaben), antioxidants, sequestering agents, stabilizers, buffers, pH adjusting solutions, skin penetration enhancers, film formers, dyes, pigments, diluents, bulking agents, fragrances and other excipients to improve the stability or aesthetics, may be added to the composition.

[0177] Compositions according to the present invention may be formulated with additional active agents depending on other conditions being treated. The additional active agents include but are not limited to NSAIDs (e.g. Aspirin, Ibuprofen, Ketoprofen, Naproxen), Apremilast, JAK inhibitors (e g. Tofacitinib, Ruxolitinib, Oclacit), leukotriene inhibitors (e.g. Zileuton, Zafirlukast, Montelukast), mast cell stabilizers (e.g. Nedocromil, Cromolyn sodium, Ketotifen, Pemirolast), Anthralin (dithranol), Azathioprine, Tacrolimus, Pimecrolimus, Coal tar, Methotrexate, Methoxsalen, Salicylic acid, Ammonium lactate, Urea, Hydroxyurea, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters, Corticosteroids (e.g. Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone, Mometasone, Triamcinolone, Fluocinolone, Fluocinonide, Flurandrenolide, Diflorasone,Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, Prednisone), Corticotropin, Vitamin D analogues (e.g. calcipotriene, calcitriol), Acitretin, Tazarotene, Cyclosporine, Resorcinol, Tapinarof, Colchicine,bronchodilators (e.g. beta-agonists, anticholinergics, theophylline), and antibiotics (e g. erythromycin, ciprofloxacin, metronidazole). Alternatively, the additional active agent can be administered as a separate composition.

[0178] Compositions according to the present invention may be formulated with additional antifungal agents according to the specific fungal infection being treated. The additional antifungal agents include but are not limited to: drugs containing miconazole (Daktarin, Micatin & Monistat), ciclopirox olamine (Batrafen, Loprox, Penlac, and Stieprox), clotrimazole (Canesten, Hydrozole), butenafine (Lotrimin Ultra, Mentax), terbinafine (Lamisil, Terbisil, Zabel), amorolfine (Curanail, Loceryl, Locetar, and Odenil), naftifine (Naftin), tolnaftate (Tinactin), ketoconazole (Nizoral), griseofulvin, imidazoles (bifonazole, clomidazole, econazole, fenti conazole, isoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole), triazole (fluconazole, itraconazole, posaconazole (Noxafil), voriconazole (Vfend)), benzimidazole (thiabendazole), ethylparaben, flucytosine, salicylic acid, selenium sulfide, and undecylenic acid. Alternatively, the additional anti-fungal agent can be administered as a separate composition.

[0179] Compositions according to the present invention may be formulated with common topical anti-inflammatory agents including, but not limited to, Diflucortolone valerate, Fluocinonide, Flurandrenolide, Halobetasol propionate, Amcinonide, Desoximetasone, Diflorasone, Halcinonide, Betamethasone valerate, Diflorasone diacetate, Fluticasone propionate, Mometasone furoate, Triamcinolone acetonide, Clocortolone pivalate, Fluocinolone acetonide, Fluticasone propionate, Hydrocortisone valerate, Mometasone furoate, Desonide, Hydrocortisone butyrate, Hydrocortisone probutate, Hydrocortisone valerate, Prednicarbate, Betamethasone dipropionate augmented Clobetasol propionate, Alclometasone dipropionate, Hydrocortisone(base, >2%), Hydrocortisone (base, <2%), calcineurin inhibitors and Hydrocortisone acetate. Alternatively, the anti-inflammatory agent can be administered as a separate composition.

[0180] Methods of Manufacture

[0181] The topical pharmaceutical compositions may be prepared by processes typically used in the field of manufacture of pharmaceutical formulations for topical application. In order to make a single-phase formulation, such as a liquid, the constituents of the formulation may be combined and mixed until a homogenous solution or suspension of the active ingredient is obtained. In order to make a multiphase formulation such as an emulsion, for example, the components of the aqueous phase and of the oil phase may be separately combined and mixed until homogenous solutions are obtained and then the aqueous solution and the oil solution may be combined and mixed, such as by shear mixing, to form the formulation. The one or more drug actives may be dissolved (molecularly dispersed), complexed, or associated with an excipient or other active, or may be particulate (amorphous or crystalline). The oil phase may be added to the water phase, or the water phase may be added to the oil phase. The phases may be combined and mixed, such as at elevated temperatures of 50-90°C or at room temperature, that is between 20-30°C, or at a temperature between room temperature and the elevated temperatures.

[0182] Further Aspects

[0183] Aspect 1. A method of treating a patient suffering from an epidermal disorder of persistent inflammation, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast, and wherein the epidermal disorder of persistent inflammation is not one of psoriasis, atopic dermatitis, or seborrheic dermatitis.

[0184] Aspect 2. The method of aspect 1, wherein the epidermal disorder of persistent inflammation is a cell kinetic and differentiation disorder and is not psoriasis.

[0185] Aspect 3. The method of aspect 2, wherein the epidermal disorder of persistent inflammation is selected from the group consisting of pityriasis rubra pilaris, pityriasis rosea, pityriasis lichenoides, prurigo nodularis, notalgia paresthetica, lichen planus, lichen nitidus, lichen simplex chronicus, hyperkeratosis lenticularis perstans, inherited keratodermas of palms and soles, granuloma annulare, Sweet’s syndrome, pyoderma gangrenosum, and urticaria.

[0186] Aspect 4. The method of any one of aspects 1 to 3, wherein the patient is diagnosed with pityriasis rubra pilaris.

[0187] Aspect 5. The method of any one of aspects 1 to 4, wherein the patient is diagnosed with pityriasis rosea.

[0188] Aspect 6. The method of any one of aspects 1 to 5, wherein the patient is diagnosed with pityriasis lichenoides.

[0189] Aspect 7. The method of any one of aspects to 6, wherein the patient is diagnosed with prurigo nodularis.

[0190] Aspect 8. The method of any one of aspects 1 to 7, wherein the patient is diagnosed with notalgia paresthetica.

[0191] Aspect 9. The method of any one of aspects 1 to 8, wherein the patient is diagnosed with lichen planus.

[0192] Aspect 10. The method of any one of aspects 1 to 9, wherein the patient is diagnosed with lichen nitidus.

[0193] Aspect 11. The method of any one of aspects 1 to 10, wherein the patient is diagnosed with lichen simplex chronicus.

[0194] Aspect 12. The method of any one of aspects 1 to 11 , wherein the patient is diagnosed with hyperkeratosis lenticularis perstans.

[0195] Aspect 13. The method of any one of aspects 1 to 12, wherein the patient is diagnosed with inherited keratodermas of palms and soles.

[0196] Aspect 14. The method of any one of aspects 1 to 13, wherein the patient is diagnosed with granuloma annulare.

[0197] Aspect 15. The method of any one of aspects 1 to 14, wherein the patient is diagnosed with Sweet’s syndrome.

[0198] Aspect 16. The method of any one of aspects 1 to 15, wherein the patient is diagnosed with pyoderma gangrenosum.

[0199] Aspect 17. The method of any one of aspects 1 to 16, wherein the patient is diagnosed with urticaria.

[0200] Aspect 18. The method of any one of aspects 1 to 17, wherein the epidermal disorder of persistent inflammation is an altered reactivity disorder and is not one of atopic dermatitis or seborrheic dermatitis.

[0201] Aspect 19. The method of any one of aspects 1 to 18, wherein the epidermal disorder of persistent inflammation is selected from the group consisting of perioral dermatitis, allergic contact dermatitis, irritant contact dermatitis, polymorphous light eruption (PMLE), actinic prurigo, cradle cap, diaper dermatitis, stasis dermatitis, brachioradial pruritus, dupilumab- associated erythema / dermatitis, juvenile plantar dermatosis, uremic pruritus, cholestatic pruritus, pruritus scroti, pruritis ani, necrobiosis lipoidica diabeticorum, ichthyosis, pityriasis amiantacea, intertrigo, nummular eczematous dermatitis, dyshidrotic eczema, hand eczema, and vesicular palmoplantar eczema.

[0202] Aspect 20. The method of any one of aspects 1 to 19, wherein the patient is diagnosed with perioral dermatitis.

[0203] Aspect 21. The method of any one of aspects 1 to 20, wherein the patient is diagnosed with allergic contact dermatitis.

[0204] Aspect 22. The method of any one of aspects 1 to 21, wherein the patient is diagnosed with irritant contact dermatitis.

[0205] Aspect 23. The method of any one of aspects 1 to 22, wherein the patient is diagnosed with PMLE.

[0206] Aspect 24. The method of any one of aspects 1 to 23, wherein the patient is diagnosed with actinic prurigo.

[0207] Aspect 25. The method of any one of aspects 1 to 24, wherein the patient is diagnosed with cradle cap.

[0208] Aspect 26. The method of any one of aspects 1 to 25, wherein the patient is diagnosed with diaper dermatitis.

[0209] Aspect 27. The method of any one of aspects 1 to 26, wherein the patient is diagnosed with stasis dermatitis.

[0210] Aspect 28. The method of any one of aspects 1 to 27, wherein the patient is diagnosed with brachioradial pruritus.

[0211] Aspect 29. The method of any one of aspects 1 to 28, wherein the patient is diagnosed with dupilumab-associated erythema / dermatitis.

[0212] Aspect 30. The method of any one of aspects 1 to 29, wherein the patient is diagnosed with juvenile plantar dermatosis.

[0213] Aspect 31 . The method of any one of aspects 1 to 30, wherein the patient is diagnosed with uremic pruritus.

[0214] Aspect 32. The method of any one of aspects 1 to 31, wherein the patient is diagnosed with cholestatic pruritus.

[0215] Aspect 33. The method of any one of aspects 1 to 32, wherein the patient is diagnosed with pruritus scroti.

[0216] Aspect 34. The method of any one of aspects 1 to 33, wherein the patient is diagnosed with pruritis ani.

[0217] Aspect 35. The method of any one of aspects 1 to 34, wherein the patient is diagnosed with necrobiosis lipoidica diabeticorum.

[0218] Aspect 36. The method of any one of aspects 1 to 35, wherein the patient is diagnosed with ichthyosis.

[0219] Aspect 37. The method of any one of aspects 1 to 36, wherein the patient is diagnosed with pityriasis amiantacea.

[0220] Aspect 38. The method of any one of aspects 1 to 37, wherein the patient is diagnosed with intertrigo.

[0221] Aspect 39. The method of any one of aspects 1 to 38, wherein the patient is diagnosed with nummular eczematous dermatitis.

[0222] Aspect 40. The method of any one of aspects 1 to 39, wherein the patient is diagnosed with dyshidrotic eczema.

[0223] Aspect 41. The method of any one of aspects 1 to 40, wherein the patient is diagnosed with hand eczema.

[0224] Aspect 42. The method of any one of aspects 1 to 41 , wherein the patient is diagnosed with vesicular palmoplantar eczema.

[0225] Aspect 43. A method of treating a patient suffering from a disorder of lips, oral, or vaginal mucosa, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0226] Aspect 44. The method of aspect 43, wherein the disorder of lips, oral, or vaginal mucosa is selected from the group consisting of actinic cheilitis, atopic cheilitis, mucositis, drymouth associated with cystic fibrosis, aphthous ulcers, vulvar aphthae, oral lichen planus, geographic tongue, lichen sclerosus, feminine itch, Behcet’s disease, and linear IgA.

[0227] Aspect 45. The method of aspect 43 or 44, wherein the patient is diagnosed with actinic cheilitis.

[0228] Aspect 46. The method of any one of aspects 43 to 45, wherein the patient is diagnosed with atopic cheilitis.

[0229] Aspect 47. The method of any one of aspects 43 to 46, wherein the patient is diagnosed with mucositis.

[0230] Aspect 48. The method of any one of aspects 43 to 47, wherein the patient is diagnosed with dry-mouth associated with cystic fibrosis,

[0231] Aspect 49. The method of any one of aspects 43 to 48, wherein the patient is diagnosed with aphthous ulcers.

[0232] Aspect 50. The method of any one of aspects 43 to 49, wherein the patient is diagnosed with vulvar aphthae.

[0233] Aspect 51. The method of any one of aspects 43 to 50, wherein the patient is diagnosed with oral lichen planus.

[0234] Aspect 52. The method of any one of aspects 43 to 51 , wherein the patient is diagnosed with geographic tongue.

[0235] Aspect 53. The method of any one of aspects 43 to 52, wherein the patient is diagnosed with lichen sclerosus.

[0236] Aspect 54. The method of any one of aspects 43 to 53, wherein the patient is diagnosed with feminine itch.

[0237] Aspect 55. The method of any one of aspects 43 to 54, wherein the patient is diagnosed with Behcet’s disease.

[0238] Aspect 56. The method of any one of aspects 43 to 55, wherein the patient is diagnosed with linear IgA.

[0239] Aspect 57. A method of treating a patient suffering from an epidermal disorder of cohesion, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0240] Aspect 58. The method of aspect 57, wherein the disorder of epidermal disorder of cohesion is a vesicular and bullous disorder selected from the group consisting of erythema multiforme, folliculitis decalvans, pityrosporum folliculitis, Gianotti-Crosti syndrome, pemphigus, bullous pemphigoid, linear IgA dermatosis, herpes gestationis, dermatitis herpetiformis, Hailey-Hailey disease, pustular palmoplantar psoriasis, herpes simplex virus I or II, eczema herpeticum, epidermolysis bullosa, Behcet’s disease, and Darier disease.

[0241] Aspect 59. The method of aspect 57 or 58, wherein the patient is diagnosed with erythema multiforme.

[0242] Aspect 60. The method of any one of aspects 57 to 59, wherein the patient is diagnosed with folliculitis decalvans.

[0243] Aspect 61 . The method of any one of aspects 57 to 60, wherein the patient is diagnosed with pityrosporum folliculitis.

[0244] Aspect 62. The method of any one of aspects 57 to 61, wherein the patient is diagnosed with Gianotti-Crosti syndrome.

[0245] Aspect 63. The method of any one of aspects 57 to 62, wherein the patient is diagnosed with pemphigus.

[0246] Aspect 64. The method of any one of aspects 57 to 63, wherein the patient is diagnosed with bullous pemphigoid.

[0247] Aspect 65. The method of any one of aspects 57 to 64, wherein the patient is diagnosed with linear IgA dermatosis

[0248] Aspect 66. The method of any one of aspects 57 to 65, wherein the patient is diagnosed with herpes gestationis.

[0249] Aspect 67. The method of any one of aspects 57 to 66, wherein the patient is diagnosed with dermatitis herpetiformis.

[0250] Aspect 68. The method of any one of aspects 57 to 67, wherein the patient is diagnosed with Hailey-Hailey disease.

[0251] Aspect 69. The method of any one of aspects 57 to 68, wherein the patient is diagnosed with pustular palmoplantar psoriasis.

[0252] Aspect 70. The method of any one of aspects 57 to 69, wherein the patient is diagnosed with herpes simplex virus I or II.

[0253] Aspect 71. The method of any one of aspects 57 to 70, wherein the patient is diagnosed with eczema herpeticum.

[0254] Aspect 72. The method of any one of aspects 57 to 71 , wherein the patient is diagnosed with epidermolysis bullosa (EB).

[0255] Aspect 73. The method of aspect 72, wherein the EB is EB simplex.

[0256] Aspect 74. The method of aspect 72, wherein the EB is EB acquisita.

[0257] Aspect 75. The method of any one of aspects 57 to 74, wherein the patient is diagnosed with Behcet’s disease.

[0258] Aspect 76. The method of any one of aspects 57 to 75, wherein the patient is diagnosed with Darier disease.

[0259] Aspect 77. A method of treating a patient suffering from a disorder of an epidermal appendage, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0260] Aspect 78. The method of aspect 77, wherein the disorder of the epidermal appendage is selected from the group consisting of acne vulgaris, cicatricial alopecia, nail psoriasis, alopecia areata, rosacea, and hi dradenitis suppurativa.

[0261] Aspect 79. The method of aspect 77 or 78, wherein the patient is diagnosed with acne vulgaris.

[0262] Aspect 80. The method of any one of aspects 77 to 79, wherein the patient is diagnosed with cicatricial alopecia.

[0263] Aspect 81. The method of any one of aspects 77 to 80, wherein the cicatricial alopecia is frontal fibrosing alopecia.

[0264] Aspect 82. The method of any one of aspects 77 to 81, wherein the cicatricial alopecia is central centrifugal cicatricial alopecia.

[0265] Aspect 83. The method of any one of aspects 77 to 82, wherein the cicatricial alopecia is lichen planopilaris.

[0266] Aspect 84. The method of any one of aspects 77 to 83, wherein the patient is diagnosed with nail psoriasis.

[0267] Aspect 85. The method of any one of aspects 77 to 84, wherein the patient is diagnosed with alopecia areata.

[0268] Aspect 86. The method of any one of aspects 77 to 85, wherein the patient is diagnosed with rosacea.

[0269] Aspect 87. The method of any one of aspects 77 to 86, wherein the patient is diagnosed with hidradenitis suppurativa.

[0270] Aspect 88. A method of treating a patient suffering from hypermelanoses or hypomelanoses, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0271] Aspect 89. The method of aspect 88, wherein the hypermelanoses or hypomelanoses is selected from the group consisting of dyschromia, pityriasis alba, post-inflammatory hypopigmentation, and post-inflammatory hyper-pigmentation.

[0272] Aspect 90. The method of aspect 88 or 89, wherein the patient is diagnosed with dyschromia.

[0273] Aspect 91. The method of any one of aspects 88 to 90, wherein the patient is diagnosed with pityriasis alba.

[0274] Aspect 92. The method of any one of aspects 88 to 91, wherein the patient is diagnosed with post-inflammatory hypo-pigmentation.

[0275] Aspect 93. The method of any one of aspects 88 to 92, wherein the patient is diagnosed with post-inflammatory hyper-pigmentation.

[0276] Aspect 94. A method of treating a patient suffering from a cutaneous lymphoma, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0277] Aspect 95. The method of aspect 94, wherein the patient is diagnosed with a cutaneous T-cell lymphoma.

[0278] Aspect 96. The method of aspect 94 or 95, wherein the patient is diagnosed with a cutaneous B-cell lymphoma.

[0279] Aspect 97. The method of any one of aspects 94 to 96, wherein the patient is diagnosed with mycosis fungoides.

[0280] Aspect 98. The method of any one of aspects 94 to 97, wherein the patient is diagnosed with non-mycosis fungoides cutaneous T-cell lymphoma (CTCL).

[0281] Aspect 99. A method of treating a patient suffering from a skin manifestation of a rheumatologic disease, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0282] Aspect 100. The method of aspect 99, wherein the skin manifestation of a rheumatologic disease is selected from the group consisting of cutaneous lupus erythematosus, discoid lupus, dermatomyositis, sarcoidosis, chronic idiopathic pruritus, cutaneous vasculitis, and scl eroderm a / m orphea.

[0283] Aspect 101. The method of aspect 99 or 100, wherein the patient is diagnosed with cutaneous lupus erythematosus.

[0284] Aspect 102. The method of any one of aspects 99 to 101 , wherein the patient is diagnosed with discoid lupus.

[0285] Aspect 103. The method of any one of aspects 99 to 102, wherein the patient is diagnosed with dermatomyositis.

[0286] Aspect 104. The method of any one of aspects 99 to 103, wherein the patient is diagnosed with sarcoidosis.

[0287] Aspect 105. The method of any one of aspects 99 to 104, wherein the patient is diagnosed with chronic idiopathic pruritus.

[0288] Aspect 106. The method of any one of aspects 99 to 105, wherein the patient is diagnosed with cutaneous vasculitis.

[0289] Aspect 107. The method of any one of aspects 99 to 106, wherein the patient is diagnosed with scleroderma / morphea.

[0290] Aspect 108. A method of treating a patient suffering from a skin manifestation related to an oncology treatment, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

[0291] Aspect 109. The method of aspect 108, wherein the skin manifestation related to an oncology treatment is selected from the group consisting of an adverse skin reaction due to an epidermal growth factor receptor (EGFR) inhibitor, an adverse skin reaction due to a cytotoxic T- lymphocyte antigen-4 (CTLA-4) inhibitor, an adverse skin reaction due to a programmed cell death-1 (PD-1) inhibitor, and an adverse skin reaction due to a BRAF inhibitor.

[0292] Aspect 110. The method of aspect 108 or 109, wherein the patient suffers from an adverse skin reaction due to an EGFR inhibitor.

[0293] Aspect 11 1. The method of any one of aspects 108 to 110, wherein the patient suffers from an adverse skin reaction due to a CTLA-4 inhibitor

[0294] Aspect 112. The method of any one of aspects 108 to 111, wherein the patient suffers from an adverse skin reaction due to a PD-1 inhibitor.

[0295] Aspect 113. The method of any one of aspects 108 to 112, wherein the patient suffers from an adverse skin reaction due to a BRAF inhibitor.

[0296] Aspect 114. A method of treating a patient suffering from an inflammatory disease regulated by Thl and / or Th2 cytokines, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.EXAMPLES

[0297] The following examples illustrate certain embodiments of the invention without limitation. While various embodiments have been described above, they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.Example 1

[0298] Two compositions will be prepared: (1) a roflumilast cream having Formulation 1 as disclosed in Table 1; and (2) a vehicle (Comparative Formulation A) having the same composition disclosed in Table 1 except without an active ingredient (z.e., roflumilast) or preservative.Table 1 (Formulation 1)Example 2

[0299] Two compositions will be prepared: (1) a roflumilast cream having Formulation 2 as disclosed in Table 2; and (2) a vehicle (Comparative Formulation B) having the same composition disclosed in Table 2 except without an active ingredient (i.e., roflumilast) or preservative.Table 2 (Formulation 2)Example 3

[0300] Two compositions will be prepared: (1) a roflumilast cream having Formulation 3 as disclosed in Table 3; and (2) a vehicle (Comparative Formulation C) having the same composition disclosed in Table 3 except without an active ingredient (i.e., roflumilast) or preservative.Table 3 (Formulation 3)Example 4

[0301] Two compositions will be prepared: (1) a roflumilast foam having Formulation 1 as disclosed in Table 4; and (2) a vehicle (Comparative Formulation D) having the same composition disclosed in Table 4 except without an active ingredient (z.e., roflumilast) or preservative.Table 4 (Formulation 4)Example 5

[0302] A male subject was examined with a cicatricial bald patch that began at the vertex of his scalp with redness and swelling. The subject was diagnosed with lichen planopilaris. This cicatricial balding was not controlled by either application of topical corticosteroids or injectionsof triamcinolone acetonide into the lesions. The patient was prescribed roflumilast cream 0.3% (w / w) and doxycycline for daily use. At a follow-up clinic visit the redness and swelling had decreased.Example 6

[0303] A study will be conducted in subjects with frontal fibrosing alopecia. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 7

[0304] A study will be conducted in subjects with central centrifugal cicatricial alopecia. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 8

[0305] A study will be conducted in subjects with lichen planopilaris. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second groupwill be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 9

[0306] A study will be conducted in subjects with hidradenitis suppurativa. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 10

[0307] A study will be conducted in subjects with allergic contact dermatitis. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 11

[0308] A study will be conducted in subjects with oral lichen planus. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3,or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 12

[0309] A study will be conducted in subjects with lichen sclerosus. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 13

[0310] A study will be conducted in subjects with Hailey-Hailey disease. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 14

[0311] A study will be conducted in subjects with mycosis fungoides. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 15

[0312] A study will be conducted in subjects with cutaneous lupus erythematosus. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.Example 16

[0313] A study will be conducted in subjects with scleroderma / morphea. The subjects will be randomized into at least two groups. One group will be administered one of Formulation 1, 2, 3, or 4 (i.e., a topical roflumilast composition) once daily for a set period of time. The second group will be administered one of Comparative Formulation A, B, C, or D (i.e., a vehicle) for a set period of time. The study population, including each treatment group, will be assessed at baseline prior to treatment. During the course of the study, at set intervals, the subjects will be assessed for treatment success.

[0314] The foregoing description has been presented for purposes of illustration and description. This description is not intended to limit the invention to the precise form disclosed. Persons of ordinary skill in the art will appreciate that modifications and substitutions of the basic inventive description may be made.

[0315] It will be understood that all embodiments described herein may be applied to all aspects of the invention and vice versa.

[0316] Other features and advantages of the present invention will be apparent from the description provided herein. It should be understood, however, that the description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications will become apparent to those skilled in the art. The following studies and protocols illustrate embodiments of the methods described herein.

[0317] Any of the above protocols or similar variants thereof can be described in various documentation associated with a pharmaceutical product. This documentation can include, without limitation, protocols, statistical analysis plans, investigator brochures, clinical guidelines, medication guides, risk evaluation and mediation programs, prescribing information and other documentation that may be associated with a pharmaceutical product. It is specifically contemplated that such documentation may be physically packaged with a pharmaceutical product according to the present disclosure as a kit, as may be beneficial or as set forth by regulatory authorities.

[0318] While the subject matter of this disclosure has been described and shown in considerable detail with reference to certain illustrative embodiments, including various combinations and sub-combinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof as encompassed within the scope of thepresent disclosure. Moreover, the descriptions of such embodiments, combinations, and subcombinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of this disclosure is intended to include all modifications and variations encompassed within the spirit and scope of the following appended claims.

Claims

1. CLAIMSWhat is claimed is:

1. A method of treating a patient suffering from a disorder of an epidermal appendage, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

2. The method of claim 1, wherein the disorder of the epidermal appendage is selected from the group consisting of cicatricial alopecia, hidradenitis suppurativa, acne vulgaris, nail psoriasis, alopecia areata, and rosacea.

3. The method of claim 2, wherein the patient is diagnosed with cicatricial alopecia.

4. The method of claim 3, wherein the cicatricial alopecia is frontal fibrosing alopecia.

5. The method of claim 3, wherein the cicatricial alopecia is central centrifugal cicatricial alopecia.

6. The method of claim 3, wherein the cicatricial alopecia is lichen planopilaris.

7. The method of claim 2, wherein the patient is diagnosed with hidradenitis suppurativa.

8. The method of claim 2, wherein the patient is diagnosed with acne vulgaris.

9. The method of claim 2, wherein the patient is diagnosed with nail psoriasis.

10. The method of claim 2, wherein the patient is diagnosed with alopecia areata.

11. The method of claim 2, wherein the patient is diagnosed with rosacea.

12. A method of treating a patient suffering from hypermelanoses or hypomelanoses, the method comprising topically administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of roflumilast.

13. The method of claim 12, wherein the hypermelanoses or hypomelanoses is selected from the group consisting of dyschromia, pityriasis alba, post-inflammatory hypo-pigmentation, and post-inflammatory hyper-pigmentation.

14. The method of claim 13, wherein the patient is diagnosed with dyschromia.

15. The method of claim 13, wherein the patient is diagnosed with pityriasis alba.

16. The method of claim 13, wherein the patient is diagnosed with post-inflammatory hypopigmentation.

17. The method of claim 13, wherein the patient is diagnosed with post-inflammatory hyperpigmentation.

18. Use of roflumilast for the manufacture of a medicament for the treatment of a disorder of an epidermal appendage.

19. The use of claim 18, wherein the disorder of the epidermal appendage is selected from the group consisting of cicatricial alopecia, hidradenitis suppurativa, acne vulgaris, nail psoriasis, alopecia areata, and rosacea.

20. The use of claim 19, wherein the disorder is cicatricial alopecia.

21. The use of claim 20, wherein the cicatricial alopecia is frontal fibrosing alopecia.

22. The use of claim 20, wherein the cicatricial alopecia is central centrifugal cicatricial alopecia.

23. The use of claim 20, wherein the cicatricial alopecia is lichen planopilaris.

24. The use of claim 19, wherein the disorder is hidradenitis suppurativa.

25. The use of claim 19, wherein the disorder is with acne vulgaris.

26. The use of claim 19, wherein the disorder is nail psoriasis.

27. The use of claim 19, wherein the disorder is alopecia areata.

28. The use of claim 19, wherein the disorder is rosacea.

29. Use of roflumilast for the manufacture of a medicament for the treatment of hypermelanoses or hypomelanoses.

30. The use of claim 29, wherein the hypermelanoses or hypomelanoses is selected from the group consisting of dyschromia, pityriasis alba, post-inflammatory hypo-pigmentation, and post- inflammatory hyper-pigmentation.

31. The use of claim 30, wherein the disorder is dyschromia.

32. The use of claim 30, wherein the disorder is pityriasis alba.

33. The use of claim 30, wherein the disorder is post-inflammatory hypo-pigmentation.

34. The use of claim 30, wherein the disorder is post-inflammatory hyper-pigmentation.