COMPOSITIONS AND METHODS FOR THE TREATMENT OF PALMOPLANTAR PUSTULOSIS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63/078,761 filed on September 15, 2020, andU.S. Provisional Application No. 63/089,975 filed October 9, 2020, each of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Palmoplantar pustulosis (PPP) is a chronic autoimmune disorder characterized by the appearance of fluid-filled sores known as pustules on the hands and feet. Other symptoms include dry skin, cracked skin, pain, erythema, and desquamation.

SUMMARY OF THE INVENTION

[0003] Provided herein, in one aspect, is a method for treating palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0004] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0005] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0006] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0007] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) in a subject with progressing disease, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0008] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administeringto the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0009] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0010] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0011] Provided herein, in another aspect, is a method for treating progressing palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0012] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subjecta CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0013] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0014] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0015] In some embodiments, the severity of PPP flare-ups is decreased as compared to a subject receiving no therapy. In some embodiments, the severity of the flare-ups is decreased by at least about 50%.

[0016] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0017] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP. [0018] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0019] In some embodiments, the severity of PPP flare-ups is decreased as compared to a subject receiving no therapy. In some embodiments, the severity of the flare-ups is decreased by at least about 50%.

[0020] In some embodiments, the CXCR-2 inhibitor is N-(6-(((2R, 3 S)-3,4-dihydroxy butan-2- yl)oxy)-2-((4-fluoro benzyl)thio)pyrimidin-4-yl)-3 -methylazetidine- 1 -sulfonamide: , or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, progressing disease comprises pustules on the hands, pustules on the feet, dry skin, cracked skin, pain, erythema, desquamation, or any combinations thereof.

[0022] In some embodiments, the CXCR-2 inhibitor is administered in a therapeutically effective amount. In some embodiments, the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 300 mg/day.

[0023] In some embodiments, the CXCR-2 inhibitor is formulated for oral administration. In some embodiments, the CXCR-2 inhibitor is formulated as a solution.

[0024] In some embodiments, the method’s efficacy is assessed using the palmoplantar pustulosis area and severity index (PPPASI). In some embodiments, the method’s efficacy is assessed using the palmoplantar pustulosis severity index (PPSI). In some embodiments, the method’s efficacy is assessed by determining a total number of pustules. In some embodiments, the method’s efficacy is assessed by determining a change in a total number of pustules.

[0025] In some embodiments, progressing disease comprises an increase in the total number of pustules over a period of time prior to administration of the CXCR-2 inhibitor.

[0026] In some embodiments, the increase in the total number of pustules comprises an increase of greater than 5 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 10 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 15 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 20 pustules.

[0027] In some embodiments, the period of time comprises more than 1 day. In some embodiments, the period of time comprises more than 1 week. In some embodiments, the period of time comprises more than 2 weeks. In some embodiments, the period of time comprises more than 3 weeks. In some embodiments, the period of time comprises more than 1 month.

[0028] In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 1 month.

[0029] In some embodiments, progressing disease comprises an increase in the palmoplantar pustulosis area and severity index (PPPASI) over a period of time prior to administration of the CXCR-2 inhibitor.

[0030] In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 5. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 10. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 15. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 20.

[0031] In some embodiments, the period of time comprises more than 1 day. In some embodiments, the period of time comprises more than 1 week. In some embodiments, the period of time comprises more than 2 weeks. In some embodiments, the period of time comprises more than 3 weeks. In some embodiments, the period of time comprises more than 1 month.

[0032] In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month.

INCORPORATION BY REFERENCE

[0033] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0035] FIG. 1 depicts the phase 2a clinical trial timeline.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. [0037] As used herein, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0038] The term “subject” refers to individuals suffering from a disorder and encompasses mammals and non -mammals. In some embodiments, “subject” refers to a human.

[0039] The term “about” refers to ±10% of a stated number or value.

[0040] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p -toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0041] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0042] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0043] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

CXCR-2 Inhibitors

[0044] Chemokines play an important role in immune and inflammatory responses in various diseases and disorders. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterized by a conserved cysteine motif.

[0045] The chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the C-X-C, C-C and C-X ₃ -C families. The C-X-C chemokines include several potent chemo-attractants and activators of neutrophils such as interleukin -8 (IL-8) and neutrophilactivating peptide 2 (NAP -2).

[0046] Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CXCR-1, CXCR-2, CXCR-3, CXCR-4 and CXCR-5 (for the C-X-C family). Only IL-8, and certain other C-X-C chemokines that bind IL-8 receptors, are known to chemo-attract human neutrophils. Only CXCR2 ligands such as IL-8 and CXCL-1 (GROa) are known to chemo-attract human neutrophils. C-X-C chemokines that chemo-attract neutrophils share specific sequence motifs. These receptors represent good targets for drug development since agents that modulate these receptors would be useful in the treatment of immune and inflammatory related disorders and diseases, such as palmoplantar pustulosis.

[0047] CXCR-2 is an IL-8 receptor. Chemokines that bind CXCR-2 are required for neutrophilic inflammation, for example in acute gout (Terkeltaub et al, Arthritis & Rheumatism, (1998), Vol 41, (No 5) pp 900-909). Urate crystals can initiate, amplify and sustain an intense inflammatory attack because they stimulate the synthesis and release of humoral and cellular inflammatory mediators. Neutrophilic synovitis is the hallmark of an acute gouty attack. Neutrophils are rare in normal synovial fluid. Monosodium urate monohydrate (MSUM) crystals from supersaturated extracellular fluids are deposited in synovial tissue, which activates resident mononuclear phagocytes and synovial lining cells to release neutrophil chemotaxins - CXCR-2 ligands, including IL-8. The newly generated neutrophil chemotaxins direct neutrophil transmigration. MSUM crystals interact with the phagocyte through two broad mechanisms. First, the crystals activate cells as opsonized and phagocytosed particles, eliciting the phagocyte response and release of inflammatory mediators. Second, urate crystals interact directly with lipid membranes and proteins, leading to the activation of several signal transduction pathways. These steps are critical for crystal-induced IL-8 expression. IL-8 is abundant in the synovial fluid in both acute gout and pseudogout. The rapid release of IL-8 (and other neutrophil chemotactic C-X-C chemokines) by crystal-activated resident mononuclear phagocytes and synovial lining cells triggers acute gout. Once in the synovial tissue, the neutrophils follow concentration gradients of chemo-attractants such as C5a, leukotriene B4, platelet-activating factor, IL-1, and IL-8. Of these factors, IL-8 plays a central role in neutrophil invasion, accounting for approximately 90% of the neutrophil chemotactic activity of monocytes in response to urate crystals.

[0048] In some embodiments, neutralization of IL-8 or its receptor CXCR-2 substantially reduces the IL-8 -induced neutrophilic inflammatory process and provide a potential therapeutic target for PPP.

[0049] In some embodiments, the following compounds provided in the following table, or pharmaceutically acceptable salts thereof, may be useful to treat diseases in which the chemokine receptor belongs to the CXC chemokine receptor subfamily. In some embodiments, the target chemokine receptor is the CXCR-2 receptor. In some embodiments, the compounds 1, 2, 3, and 4 are CXCR-2 inhibitors.

[0050] In some embodiments, the CXCR-2 inhibitor is Compound 3, or a pharmaceutically acceptable saltthereof. Compounds (N-(2-((2,3-difluorobenzyl)thio)-6-(((2R,3S)-3,4- dihydroxybutan-2-yl)oxy)pyrimidin-4-yl)azetidine-l -sulfonamide) and compound 4 (N-(6- (((2R,3S)-3,4-dihydroxybutan-2-yl)oxy)-2-((4-fluorobenzyl)th io)pyrimidin-4-yl)-3- methylazetidine- 1-sulfonamide) are pyrimidinyl sulphonamides and are useful as modulators of chemokine receptors.

[0051] WO 2004/011443 describes pyrimidinyl sulphonamide derivatives for use as modulators of chemokine receptors.

[0052] The in vitro potency andPK parameters of compound 3 are described in WO 2006/024823 and WO 2010/007427. Compounds displays good bioavailability in rat (49%), a long half-life in dog, good solubility properties and high potency. Compound 3 was in Phase II trials for COPD. The preparation of compound 3, along with six crystalline forms, is described in WO 2012/007748.

[0053] In some embodiments, the CXCR-2 inhibitor is N-(6-(((2R, 3 S)-3,4-dihydroxy butan-2- yl)oxy)-2-((4-fluoro benzyl)thio)pyrimidin-4-yl)-3 -methylazetidine- 1-sulfonamide: , ora pharmaceutically acceptable saltthereof.

[0054] In some embodiments, the CXCR-2 inhibitor is Compound 4, or a pharmaceutically acceptable saltthereof. The preparation of compound 4, along with several distinct crystalline forms, is described in WO 2013/008002.

[0055] Examples of other CXCR-2 inhibitors include, but are not limited to, elubrixin, danirixin, navarixin, reparixin, ladarixin, andmeraxin. [0056] Examples of other CXCR-2 inhibitors include, but are not limited to, LY-3041658,DF-

1970, DF-2162,DF-2755A, CCX-872, andMGTA-MlOO.

[0057] Additional examples of other CXCR-2 inhibitors include, but are not limited to, the compounds in the following table:

[0058] Additional examples of other CXCR-2 inhibitors include, but are not limited to, the compounds in the following table:

CXCR-2 Inhibitor Dosing

[0059] The amount of CXCR-2 inhibitor administered will firstly be dependent on the mammal being treated. In some embodiments, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, sex, diet, weight, general health and response of the individual patient, the severity of the patient’s symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, time of administration, route of administration, drug absorption, the disposition of the composition, rate of excretion, drug combination, and the discretion of the prescribing physician. Also, the route of administration varies depending on the condition and its severity. The pharmaceutical composition is, in some embodiments, in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Determination of the proper dosage for a particular situation is within the skill of the art. In some embodiments, the total daily dosage is divided and administered in portions during the day if desired. The amount and frequency of administration will be regulated according to the judgment of the attending clinician physician considering such factors as described above. Thus, the amount of pharmaceutical composition to be administered is variable depending upon the circumstances. In some embodiments, the CXCR-2 inhibitor is administered in a therapeutically effective amount. In some embodiments, the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 300 mg/day.

Pharmaceutical Compositions

[0060] The compound, compound forms and compositions described herein are administered either alone, or in combination with, pharmaceutically acceptable adjuvants, carriers, excipients, or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. [0061] Described herein in some embodiments are pharmaceutical compositions comprising a CXCR-2 inhibitor, such as any one of the compounds described herein, or the pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier. In some embodiments, the CXCR-2 inhibitor is N-(2 -((2,3 -difluorobenzyl)thio)-6- (((2R,3R)-3,4-dihydroxybutan-2-yl)amino)pyrimidin-4-yl)azeti dine-l-sulfonamide (compound 1), or a pharmaceutically acceptable saltthereof. In some embodiments, the CXCR-2 inhibitor is (R)-5-((2, 3-difluorobenzyl)thio)-7-((l -hydroxy propan-2-yl)amino)thiazolo[4,5-d]pyrimidin- 2(3H)-one (compound 2), or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR-2 inhibitor is N-(2-((2, 3 -difluorobenzyl)thio)-6-(((2R, 3 S)-3,4-dihy droxybutan-2- yl)oxy)pyrimidin-4-yl)azetidine-l-sulfonamide (compound 3) or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR-2 inhibitor is N-(6-(((2R, 3 S)-3,4-dihydroxybutan- 2-yl)oxy)-2-((4-fluorobenzyl)thio)pyrimidin-4-yl)-3-methylaz etidine-l -sulfonamide (compound 4), or a pharmaceutically acceptable salt thereof. Also described herein in some embodiments are pharmaceutical compositions comprising a CXCR-2 inhibitor in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of a CXCR-2 inhibitor.

[0062] Also described herein are processes for the preparation of a pharmaceutical composition of the invention which comprise mixing a CXCR-2 inhibitor (e.g. , compound 3 or 4), or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable adjuvant, diluent, or carrier. In some embodiments, compound s or compound 4, or pharmaceutically acceptable salts thereof, is administered orally. In some embodiments, the CXCR-2 inhibitor is formulated for oral administration. In some embodiments, the CXCR-2 inhibitor is formulated as a solution.

Methods of Use

[0063] Palmoplantar pustulosis (PPP), also known as pustulosis palmaris etplantaris, is a chronic autoimmune disorder characterized by the appearance of neutrophil-filled sores known as pustules on the hands and feet. Other symptoms include dry skin, cracked skin, pain, erythema, and desquamation. PPP is commonly comorbid with chronic plaque psoriasis, streptococcal tonsillitis, and other autoimmune disorders, particularly celiac disease, thyroid disease, arthritis, and type 1 diabetes. Less commonly, PPP is comorbid with synovitis-acne-pustulosis- hyperostosis-osteomyelitis (SAPHO) syndrome.

[0064] While the exact cause of PPP remains unknown, several theories have been advanced. Some speculate that PPP is caused by dysfunction of the eccrine sweat glands because of their abundance on the palms of the hands and soles of the feet. Due to the presence of several cases of the disease within single families, it is believed that a genetic component is involved, and some cases have been associated with mutations in the IL36RN gene. In rare cases, PPP can be induced by treatment with tumor necrosis factor alpha (TNFa) inhibitors, such as infliximab, adalimumab, and etanercept. Because 65% to 90% of PPP patients are current or previous smokers, it is believed that the activation of nicotine receptors within sweat glands may be key to disease genesis. PPP is more prevalent in women than in men, and onset typically occurs between ages 40 and 60. [0065] Because CXCR-2 inhibitors blockthe trafficking of neutrophils from the bone marrow to the specific site of inflammation, PPP patients benefit from treatment with CXCR-2 inhibitors. [0066] Although PPP is a chronic illness, it is characterized by sporadic attacks or flare -ups. Factors contributing to PPP flare-ups include streptococcal bacteria infections, other infections, stress, treatment with certain medications, and smoking. In some embodiments, a subject having been diagnosed with PPP will experience PPP flare-ups. In some embodiments, a subject experiencing a PPP flare-up will experience an active PPP flare-up, meaning that the severity of symptoms is increasing. In some embodiments, a subject experiencing a PPP flare-up is a subject with progressing disease, meaning that the severity of symptoms is increasing. In some embodiments, a subject experiencing a PPP flare-up will experience a declining PPP flare-up, meaning that the severity of symptoms is diminishing. In some embodiments, a subject experiencing a PPP flare-up is a subject with declining disease, meaning that the severity of symptoms is diminishing. In some embodiments, treatment with a CXCR-2 inhibitor will result in greater relief of symptoms for a subject experiencing an active PPP flare-up than for a subject experiencing a declining PPP flare-up. In some embodiments, treatment with a CXCR-2 inhibitor will result in greater relief of symptoms for a subject with progressing disease than for a subject with declining disease. In some embodiments, an active PPP flare-up comprises pustules on the hands, pustules on the feet, dry skin, cracked skin, pain, erythema, desquamation, or any combinations thereof. In some embodiments, progressing disease comprises pustules on the hands, pustules on the feet, dry skin, cracked skin, pain, erythema, desquamation, or any combinations thereof.

[0067] Provided herein, in one aspect, is a method for treating palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare- up.

[0068] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

[0069] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

[0070] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administeringto the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

[0071] Provided herein, in one aspect, is a method for treating palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0072] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0073] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0074] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0075] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) in a subject with progressing disease, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0076] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0077] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0078] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP. [0079] Provided herein, in another aspect, is a method for treating progressing palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0080] Provided herein, in another aspect, is a method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0081] Provided herein, in another aspect, is a method for treating palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0082] Provided herein, in another aspect, is a method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0083] In some embodiments, the severity of PPP flare-ups is decreased as compared to a subject receiving no therapy. In some embodiments, the severity of the flare-ups is decreased by at least about 10%. In some embodiments, the severity of the flare-ups is decreased by at least about 20%. In some embodiments, the severity of the flare-ups is decreased by at least about 30%. In some embodiments, the severity of the flare-ups is decreased by at least about 40%. In some embodiments, the severity of the flare-ups is decreased by at least about 50%. In some embodiments, the severity of the flare-ups is decreased by at least about 60%. In some embodiments, the severity of the flare-ups is decreased by at least about 70%. In some embodiments, the severity of the flare-ups is decreased by at least about 80%. In some embodiments, the severity of the flare-ups is decreased by at least about 90%. In some embodiments, the severity of the flare-ups is decreased by at least about 99%.

[0084] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

[0085] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease.

[0086] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject havingbeen diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0087] Provided herein, in another aspect, is a method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP.

[0088] In some embodiments, the frequency of PPP flare-ups is decreased as compared to a subject receiving no therapy. In some embodiments, the frequency of the flare-ups is decreased by at least about 10%. In some embodiments, the frequency of the flare-ups is decreased by at least about20%. In some embodiments, the frequency of the flare-ups is decreasedby atleast about 30%. In some embodiments, the frequency of the flare-upsis decreasedby at least about 40%. In some embodiments, the frequency of the flare-upsis decreasedby atleast about 50%. In some embodiments, the frequency of the flare-ups is decreased by at least about 60%. In some embodiments, the frequency of the flare-ups is decreasedby at least about 70%. In some embodiments, the frequency of the flare-ups is decreasedby at least about 80%. In some embodiments, the frequency of the flare-ups is decreasedby at least about 90%. In some embodiments, the frequency of the flare-ups is decreasedby at least about 99%.

[0089] The methods described herein can be assessed according to any metric known in the art for the evaluation of palmoplantar pustulosis. In some embodiments, the method is assessed usingthe palmoplantar pustulosis severity index (PPSI). In some embodiments, the method is assessed usingthe palmoplantar pustulosis area and severity index (PPPASI). In some embodiments, the method is assessed by determining a total number of pustules. In some embodiments, the method is assessed by determining a change in a total number of pustules. In some embodiments, the method is assessed by determining a change in a number of pustules on the target area (defined as the palm or sole with the highest number of pustules at baseline) .

[0090] In some embodiments, the methods described herein are better suited for the treatment of PPP in subjects experiencing active PPP flare-ups than for the general population of patients diagnosed with PPP.

[0091] In some embodiments, an active PPP flare-up comprises an increase in the total number of pustules over a period of time prior to administration of the CXCR-2 inhibitor. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 0 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 5 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 10 pustules. In some embodim ents, the increase in the total number of pustules comprises an increase of greater than 15 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 20 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 25 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 30 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 35 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 40 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 45 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 50 pustules. In some embodiments, the period of time comprises more than 0 days. In some embodiments, the period of time comprises more than 1 day. In some embodiments, the period of time comprises more than 2 days. In some embodiments, the period of time comprises more than 3 days. In some embodiments, the period of time comprises more than 4 days. In some embodiments, the period of time comprises more than 5 days. In some embodiments, the period of time comprises more than 6 days. In some embodiments, the period of time comprises more than 1 week. In some embodiments, the period of time comprises more than 2 weeks. In some embodiments, the period of time comprises more than 3 weeks. In some embodiments, the period of time comprises more than 1 month.

[0092] In some embodiments, an active PPP flare-up comprises an increase of 5 pustules over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of 10 pustules over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of 15 pustules over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of 20 pustules over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of more than 5 pustules over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of more than 10 pustules over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of more than 15 pustules over a period of 1 day. In some embodiments, an active PPP flare -up comprises an increase of more than 20 pustules over a period of 1 day.

[0093] In some embodiments, an active PPP flare-up comprises an increase of 5 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of 10 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of 15 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of 20 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 5 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 10 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 15 pustules over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 20 pustules over a period of 1 week.

[0094] In some embodiments, an active PPP flare-up comprises an increase of 5 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of 10 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of 15 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of 20 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 5 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 10 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 15 pustules over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 20 pustules over a period of 2 weeks.

[0095] In some embodiments, an active PPP flare-up comprises an increase of 5 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of 10 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of 15 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of 20 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 5 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 10 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 15 pustules over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 20 pustules over a period of 3 weeks.

[0096] In some embodiments, an active PPP flare-up comprises an increase of 5 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of 10 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of 15 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of 20 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 5 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 10 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 15 pustules over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 20 pustules over a period of 1 month.

[0097] In some embodiments, an active PPP flare-up comprises an increase in the palmoplantar pustulosis area and severity index (PPPASI) over a period of time prior to administration of the CXCR-2 inhibitor. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 0. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 5. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 10. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 15. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 20. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 25. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 30. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 35. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 40. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 45. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 50. In some embodiments, the period of time comprises more than 0 days. In some embodiments, the period of time comprises more than 1 day. In some embodiments, the period of time comprises more than 2 days. In some embodiments, the period of time comprises more than 3 days. In some embodiments, the period of time comprises more than 4 days. In some embodiments, the period of time comprises more than 5 days. In some embodiments, the period of time comprises more than 6 days. In some embodiments, the period of time comprises more than 1 week. In some embodiments, the period of time comprises more than 2 weeks. In some embodiments, the period of time comprises more than 3 weeks. In some embodiments, the period of time comprises more than 1 month. [0098] In some embodiments, an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an activePPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an active PPP flare-up comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, an active PPP flare- up comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day.

[0099] In some embodiments, an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare-up comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, an active PPP flare- up comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week.

[0100] In some embodiments, an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. [0101] In some embodiments, an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, an active PPP flare-up comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks.

[0102] In some embodiments, an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, an active PPP flare-up comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month.

[0103] In some embodiments, the methods described herein are better suited for the treatment of PPP in subjects with progressing disease than for the general population of patients diagnosed with PPP.

[0104] In some embodiments, progressing disease comprises an increase in the total number of pustules over a period of time prior to administration of the CXCR-2 inhibitor. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 0 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 5 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 10 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 15 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 20 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 25 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 30 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 35 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 40 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 45 pustules. In some embodiments, the increase in the total number of pustules comprises an increase of greater than 50 pustules. In some embodiments, the period of time comprises more than 0 days. In some embodiments, the period of time comprises more than 1 day. In some embodiments, the period of time comprises more than 2 days. In some embodiments, the period of time comprises more than 3 days. In some embodiments, the period of time comprises more than 4 days. In some embodiments, the period of time comprises more than 5 days. In some embodiments, the period of time comprises more than 6 days. In some embodiments, the period of time comprises more than 1 week. In some embodiments, the period of time comprises more than 2 weeks. In some embodiments, the period of time comprises more than 3 weeks. In some embodiments, the period of time comprises more than 1 month.

[0105] In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 5 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 10 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 15 pustules over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 20 pustules over a period of 1 day.

[0106] In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 5 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 10 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 15 pustules over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 20 pustules over a period of 1 week.

[0107] In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 5 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 10 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 15 pustules over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 20 pustules over a period of 2 weeks.

[0108] In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 5 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 10 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 15 pustules over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 20 pustules over a period of 3 weeks.

[0109] In some embodiments, progressing disease comprises an increase of 5 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of 10 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of 15 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of 20 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 5 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 10 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 15 pustules over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 20 pustules over a period of 1 month.

[0110] In some embodiments, progressing disease comprises an increase in the palmoplantar pustulosis area and severity index (PPPASI) over a period of time prior to administration of the CXCR-2 inhibitor. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 0. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 5. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 10. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 15. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 20. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 25. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 30. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 35. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 40. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 45. In some embodiments, the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 50. In some embodiments, the period of time comprises more than 0 days. In some embodiments, the period of time comprises more than 1 day. In some embodiments, the period of time comprises more than 2 days. In some embodiments, the period of time comprises more than 3 days. In some embodiments, the period of time comprises more than 4 days. In some embodiments, the period of time comprises more than 5 days. In some embodiments, the period of time comprises more than 6 days. In some embodiments, the period of time comprises more than 1 week. In some embodiments, the period of time comprises more than 2 weeks. In some embodiments, the period of time comprises more than 3 weeks. In some embodiments, the period of time comprises more than 1 month.

[0111] In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. In some embodiments, progressing disease comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day.

[0112] In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. In some embodiments, progressing disease comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week.

[0113] In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks. In some embodiments, progressing disease comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 2 weeks.

[0114] In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks. In some embodiments, progressing disease comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 3 weeks.

[0115] In some embodiments, progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. In some embodiments, progressing disease comprises an increase of more than 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. Kits

[0116] The compounds, compound forms, compositions, and methods described herein provide kits for the treatment of diseases and disorders, such as the ones described herein. These kits comprise a compound, compound form, compounds, compound forms, or compositions described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein. Such kits, in some embodiments, also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information maybe based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Kits described herein are provided, marketed, and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits are also, in some embodiments, marketed directly to the consumer.

[0117] Described herein are compositions or kits comprising a CXCR-2 inhibitor, such as any one of the compounds described herein, or the pharmaceutically acceptable salt thereof. In some embodiments, the CXCR-2 inhibitor is N-(2 -((2,3 -difluorob enzyl)thio)-6-(((2R, 3 S)-3, 4- dihydroxybutan-2-yl)oxy)pyrimidin-4-yl)azetidine-l -sulfonamide (compound 3) or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR-2 inhibitorisN-(6- (((2R,3S)-3,4-dihydroxybutan-2-yl)oxy)-2-((4-fluorobenzyl)th io)pyrimidin-4-yl)-3- methylazetidine-l-sulfonamide (compound 4), or a pharmaceutically acceptable salt thereof. [0118] Described herein are compositions or kits for treating a subject having been diagnosed with palmoplantar pustulosis (PPP) comprising a CXCR-2 inhibitor, such as any one of the compounds described herein, instructions for identification of an active PPP flare-up, and instructions for administration of the CXCR-2 inhibitor to treat or prevent the palmoplantar pustulosis (PPP) flare-ups. In some embodiments, the CXCR-2 inhibitor is N-(2-((2, 3- difluorobenzyl)thio)-6-(((2R,3 S)-3 ,4-dihydroxybutan-2-yl)oxy)pyrimidin-4-yl)azetidine-l- sulfonamide (compound 3) or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR-2 inhibitor is N-(6-(((2R,3 S)-3 ,4-dihydroxybutan-2-yl)oxy)-2-((4- fluorobenzyl)thio)pyrimidin-4-yl)-3-methylazetidine-l-sulfon amide (compound 4), or a pharmaceutically acceptable salt thereof.

[0119] Described herein are compositions or kits for treating a subject having been diagnosed with palmoplantar pustulosis (PPP) comprising a CXCR-2 inhibitor, such as any one of the compounds described herein, instructions for identification of progressing disease, and instructions for administration of the CXCR-2 inhibitor to treat or prevent the palmoplantar pustulosis (PPP) flare-ups. In some embodiments, the CXCR-2 inhibitor is N-(2-((2, 3- difluorobenzyl)thio)-6-(((2R,3 S)-3 ,4-dihydroxybutan-2-yl)oxy)pyrimidin-4-yl)azetidine-l- sulfonamide (compound 3) or a pharmaceutically acceptable salt thereof. In some embodiments, the CXCR-2 inhibitor is N-(6-(((2R,3 S)-3,4-dihydroxybutan-2-yl)oxy)-2-((4- fluorobenzyl)thio)pyrimidin-4-yl)-3-methylazetidine-l-sulfon amide (compound 4), or a pharmaceutically acceptable salt thereof.

[0120] Provided in certain embodiments, are compositions or kits comprising a CXCR-2 inhibitor, a double low density polyethylene plastic bag, and an HDPE container. In further embodiments, the composition or kit further comprises a foil bag (e.g., an anhydrous f oil bag, such as a heat sealed anhydrous foil bag). In some embodiments, the composition or kit further comprises a desiccant; in still other embodiments, a desiccant is not necessary and/or present. In some instances, such packing improves the stability of the CXCR-2 inhibitor.

[0121] In some embodiments, the compounds, compound forms, and pharmaceutical compositions described herein are utilized for diagnostics and as research reagents. For example, in some embodiments, the compounds, compound forms, and pharmaceutical compositions, either alone or in combination with other compounds, are used as tools in differential and/or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues. As one non-limiting example, expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses are performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.

Examples

[0122] The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.

Example 1: Phase 2a Clinical Trial for Treating Patients with Palmoplantar Pustulosis (PPP) with Compound 4

[0123] A timeline of the Phase 2a Clinical Trial is shown in FIG. 1. Approximately 30 subjects with moderate to severe palmoplantar pustulosis (as defined by a palmoplantar pustulosis area and severity index (PPPASI) score of greater than 8 and a palmoplantar psoriasis physician global assessment (PPPGA) score of greater than 3 at Day -1, and a minimum of 20 fresh pustules (fresh pustule count on palms of both left and right hands and soles of both left and right feet) at Day -1) were included in a 4-week, multicenter, randomized, double-blind, placebo- controlled, Phase 2a study to evaluate the safety and efficacy of Compound 4.

[0124] Following a screening period of no more than 30 days to determine subject eligibility, the subjects were randomized into two equally sized groups at Day -1 . Randomization was stratified by consent to biopsy collection. Members of the study group were dosed orally with a solution containing 300 mg Compound 4 once daily for 28 days, while members of the placebogroup were dose orally with a placebo solution once daily for 28 days. Subjects came to the study site on 7 occasions: screening, baseline (Day -1), andDays 7, 14, 21, 28, and 42 (follow-up) or early termination (ET) visit. The Compound 4 was dispensed to subjects weekly.

[0125] Treatment efficacy was evaluated using fresh pustule count, total pustule count, palmoplantar pustulosis area and severity index (PPPASI), palmoplantar psoriasis physician global assessment (PPPGA), palmoplantar pustulosis severity index (PPSI), and pain visual analogue scale (VAS). Quality of life was evaluated using the dermatology life quality index (DLQI). Safety was assessed with physical examinations, vital signs, electrocardiogram (ECG), clinical laboratory tests (hematology, biochemistry, and urinalysis), and collection of adverse events (AEs).

[0126] There were no statistically significant differences between the study and placebo groups in the relative change from baseline in fresh and total pustule counts at Day 28. The mean ± standard deviation relative change from baseline in fresh pustule count at Day 28 (defined as the ratio of Day 28 to baseline) was numerically greater for the placebo (0.53±0.561) compared to the study (0.86±0.692) group (P=0.240). The mean ± standard deviation relative change from baseline in total pustule count atDay 28 was comparable between the study (0.99±0.667) and placebo (0.96±0.672) treatment groups (P=0.804).

[0127] At baseline, the mean ± standard deviation total pustule counts were comparable between the study (93.1±81.51) and placebo (92.6±75.28) groups. At the end of the treatment period (Day 28), the mean ± standard deviation total pustule counts were 89.1±89.98 and 88.6±89.43 in the study and placebo groups, respectively.

[0128] In general, the severity of PPP, as assessed by the PPPASI and PPSI, improved from baseline to Day 28. However, similar differences in the change from baseline were observed in these efficacy parameters, and none of the comparisons reached statistical significance (PPPASI: -7.7 and -7.6 for the study and placebo groups, respectively (P = 0.470); PPSI: -1.9 and -2.0 for the study and placebo groups respectively (P = 0.927)).

[0129] At Day 28, the proportion of subjects who achieved a 50% reduction in PPPASI score (PPPASI-50) was numerically greater in the study group (N = 6 (40.0%)) compared to the placebo group (N = 5 (26.3%)) as shown in Table 1 below. No statistically significant differences between treatment groups were observed for the proportion of subjects with at least a 50% reduction in PPPASI score at any of the study visits. The proportion of subjects who achieved a 50% reduction in PPSI score (PPSI-50) was comparable between treatment groups (study: N = 2 (13.3%); placebo: N = 3 (15.8%)). Neither of the comparisons for PPPASI-50 and PPSI 50 were statistically significant.

Table 1: Summary and Statistical Analysis ofProportion of Subjects With at Least a 50% Reduction in PPPASI at Day 28 (mITT Analysis Set)

[0130] Subgroup Analysis of subjects who had an increase in total pustule countbetween screening and baseline demonstrated that there were notable differences between the study and placebo groups. The fresh pustule count inclusion criteria (>20 fresh pustules at randomization) may not have allowed for the inclusion of subjects with progressing disease. Therefore, utilizing a different subgroup (e.g. subjects with increases in total pustule counts from screening to baseline) allows for better homogenization for a group of subjects enrolled with progressing disease prior to randomization. There were 20 subjects in that subgroup (13 subjects randomized to the placebo group and 7 subjects randomized to the study group). The data shown in Table 2 below are analyses conducted at Day 28 across different efficacy parameters.

Table 2: Total Pustule Count Increasing Subgroup Analysis

[0131] Notably, the proportion of subjects with a 50% reduction in PPPASI at Day 28 in this subgroup was significantly higher for subjects treated with Compound 4 as compared to placebo (p value <0.050). These data suggest treatment with Compound 4 displays greater efficacy for subjects with progressing disease than for the overall population.

[0132] Additional analyses demonstrate that there is a correlation between biomarkers associated with CXCR-2 antagonism and improvements in clinical parameters. Several biomarkers were identified as statistically different and biologically plausible at Days 7 and 21 between study and placebo groups: IL-8 (Compound 4> placebo), CD8A (Compound 4< placebo), CXCL9 (Compound 4< placebo), CXCL11 (Compound 4< placebo), IFNy (Compound 4< placebo). IL-8 has the strongest effect in terms of numerical difference and statistical significance. Spearman rank correlation with clinical endpoints assessed showed that there was a weak and moderate correlation with clinical endpoints (e.g. as IL-8 decreases, clinical endpoints worsen, and increases in IL-8 correlate with improved clinical outcomes), as shown in Table 3 below. These data suggest that there is a correlation between CXCR-2 antagonism and improvements in clinical outcomes.

Table 3: Correlation Analyses with Clinical Endpoints [0133] Further, subjects with progressing disease experienced a significant reduction in pustule count on the target area (defined as the palm or sole with the highest number of pustules at baseline). The target area pustule counts obtained at day 28 are summarized in Table 4 below. These data suggest that subjects with progressing disease experience a greater reduction in target area pustule count than the generalized patient cohort.

Table 4: Target Area Pustule Count Analysis

Exemplary Embodiments

1 . A method for treating palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

2. A method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

3. A method for treating palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

4. A method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up.

5. The method of embodiment 4, wherein the severity of PPP flare-upsis decreased as compared to a subject receiving no therapy. The method of embodiment 5, wherein the severity of the flare-ups is decreased by at least about 50%. A method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an active PPP flare-up. The method of embodiment 15, wherein the frequency of PPP flare-ups is decreased as compared to a subject receiving no therapy. The method of embodiment 16, wherein the frequency of the flare-ups is decreasedby at least about 50%. The method of any one of embodiments 1 to 19, wherein the CXCR-2 inhibitor is N-(6- (((2R,3 S)-3 ,4-dihydroxy butan-2-yl)oxy)-2-((4-fluoro benzyl)thio)pyrimidin-4-yl)-3 - methylazetidine- 1-sulfon amide: , or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 2 to 20, wherein an active PPP flare-up comprises pustules on the hands, pustules on the feet, dry skin, cracked skin, pain, erythema, desquamation, or any combinations thereof. The method of any one of embodiments 1 to 21, wherein the CXCR-2 inhibitor is administered in a therapeutically effective amount. The method of embodiment 22, wherein the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 300 mg/day. The method of any one of embodiments 1 to 23, wherein the CXCR-2 inhibitor is formulated for oral administration. The method of embodiment 24, wherein the CXCR-2 inhibitor is formulated as a solution. The method of any one of embodiments 1 to 25, wherein the method’s efficacy is assessed using the palmoplantar pustulosis severity index (PPSI). The method of any one of embodiments 1 to 25, wherein the method’s efficacy is assessed using the palmoplantar pustulosis area and severity index (PPPASI). The method of any one of embodiments 1 to 25, wherein the method’s efficacy is assessed by determining a total number of pustules. The method of any one of embodiments 1 to 25, wherein the method’s efficacy is assessed by determining a change in a total number of pustules. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase in the total number of pustules over a period of time prior to administration of the CXCR-2 inhibitor. The method of embodiment 30, wherein the increase in the total number of pustules comprises an increase of greater than 5 pustules. The method of embodiment 30 or 31, wherein the increase in the total number of pustules comprises an increase of greater than 10 pustules. The method of any one of embodiments 30 to 32, wherein the increase in the total number of pustules comprises an increase of greater than 15 pustules. The method of any one of embodiments 30 to 33, wherein the increase in the total number of pustules comprises an increase of greater than 20 pustules. The method of any one of embodiments 30 to 34, wherein the period of time comprises more than 1 day. The method of any one of embodiments 30 to 35, wherein the period of time comprises more than 1 week. The method of any one of embodiments 30 to 36, wherein the period of time comprises more than 2 weeks. The method of any one of embodiments 30 to 37, wherein the period of time comprises more than 3 weeks. The method of any one of embodiments 30 to 38, wherein the period of time comprises more than 1 month. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 5 pustules over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 10 pustules over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 15 pustules over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 20 pustules over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 5 pustules over a period of 1 week. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 10 pustules over a period of 1 week. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 15 pustules over a period of 1 week. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 20 pustules over a period of 1 week. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 5 pustules over a period of 1 month. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 10 pustules over a period of 1 month. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 15 pustules over a period of 1 month. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 20 pustules over a period of 1 month. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase in the palmoplantar pustulosis area and severity index (PPPASI) over a period of time prior to administration of the CXCR-2 inhibitor. The method of embodiment 52, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 5. The method of embodiment 52 or 53, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 10. The method of any one of embodiments 52 to 54, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 15. The method of any one of embodiments 52 to 55, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 20. The method of any one of embodiments 52 to 56, wherein the period of time comprises more than 1 day. The method of any one of embodiments 52 to 57, wherein the period of time comprises more than 1 week. The method of any one of embodiments 52 to 58, wherein the period of time comprises more than 2 weeks. The method of any one of embodiments 52 to 59, wherein the period of time comprises more than 3 weeks. The method of any one of embodiments 52 to 60, wherein the period of time comprises more than 1 month. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. 8. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. 9. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. 0. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. 1. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. . The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. 3. The method of any one of embodiments 1 to 29, wherein an active PPP flare-up comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. . A method for treating palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease. 5. A method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, wherein the subjectis a subject with progressing disease. 6. A method for treating palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, wherein the subjectis a subject with progressing disease. A method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, wherein the subject is a subject with progressing disease. A method for treating palmoplantar pustulosis (PPP) in a subject with progressing disease, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, thereby treating the PPP. A method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, thereby treating the PPP. A method for treating palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, thereby treating the PPP. A method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, thereby treating the PPP. A method for treating progressing palmoplantar pustulosis (PPP) in a subject in need thereof, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, thereby treating the PPP. A method for preventing palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, ora pharmaceutically acceptable saltthereof, thereby treating the PPP. A method for treating palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, thereby treating the PPP. 5. A method for decreasing the severity of palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP. 6. The method of any one of the preceding embodiments, wherein the severity of PPP flare-ups is decreased as compared to a subject receiving no therapy. 7. The method of embodiment 76, wherein the severity of the flare-ups is decreased by at least about 50%. 8. A method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the subject is a subject with progressing disease. 9. A method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject having been diagnosed with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP. 0. A method for decreasing the frequency of palmoplantar pustulosis (PPP) flare-ups in a subject with progressing PPP, comprising administering to the subject a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the PPP. 1 . The method of any one of the preceding embodiments, wherein the frequency of PPP flare- ups is decreased as compared to a subject receiving no therapy. . The method of embodiment 81 , wherein the frequency of the flare-ups is decreased by at least about 50%. 3. The method of any one of the preceding embodiments, wherein the CXCR-2 inhibitor is N- (6-(((2R,3 S)-3,4-dihydroxy butan-2-yl)oxy)-2-((4-fluorobenzyl)thio)pyrimidin-4-yl)-3- methylazetidine-l-sulfon amide: , or a pharmaceutically acceptable salt thereof. . The method of any one of the preceding embodiments, wherein progressing disease comprises pustules on the hands, pustules on the feet, dry skin, cracked skin, pain, erythema, desquamation, or any combinations thereof. 5. The method of any one of the preceding embodiments, wherein the CXCR-2 inhibitor is administered in a therapeutically effective amount. 6. The method of embodiment 85, wherein the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable saltthereof, is about 300 mg/day. 7. The method of any one of the preceding embodiments, wherein the CXCR-2 inhibitor is formulated for oral administration. 8. The method of embodiment 87, wherein the CXCR-2 inhibitor is formulated as a solution. 9. The method of any one of the preceding embodiments, wherein the method’s efficacy is assessed using the palmoplantar pustulosis severity index (PPSI). 0. The method of any one of the preceding embodiments, wherein the method’s efficacy is assessed using the palmoplantar pustulosis area and severity index (PPPASI). 1 . The method of any one of the preceding embodiments, wherein the method’s efficacy is assessed by determining a total number of pustules. . The method of any one of the preceding embodiments, wherein the method’s efficacy is assessed by determining a change in a total number of pustules. The method of any one of the preceding embodiments, wherein progressing disease comprises an increase in the total number of pustules over a period of time prior to administration of the CXCR-2 inhibitor. The method of embodiment 93, wherein the increase in the total number of pustules comprises an increase of greater than 5 pustules. The method of embodiment 93 or 94, wherein the increase in the total number of pustules comprises an increase of greater than 10 pustules. The method of any one of embodiments 93 to 95, wherein the increase in the total number of pustules comprises an increase of greater than 15 pustules. The method of any one of embodiments 93 to 96, wherein the increase in the total number of pustules comprises an increase of greater than 20 pustules. The method of any one of embodiments 93 to 97, wherein the period of time comprises more than 1 day. The method of any one of embodiments 93 to 98, wherein the period of time comprises more than 1 week. The method of any one of embodiments 93 to 99, wherein the period of time comprises more than 2 weeks. The method of any one of embodiments 93 to 100, wherein the period of time comprises more than 3 weeks. The method of any one of embodiments 93 to 101, wherein the period of time comprises more than 1 month. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 5 pustules over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 10 pustules over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 15 pustules over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 20 pustules over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 5 pustules over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 10 pustules over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 15 pustules over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 20 pustules over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 5 pustules over a period of 1 month. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 10 pustules over a period of 1 month. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 15 pustules over a period of 1 month. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 20 pustules over a period of 1 month. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase in the palmoplantar pustulosis area and severity index (PPPASI) over a period of time prior to administration of the CXCR-2 inhibitor. The method of embodiment 115, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 5. The method of embodiment 115 or 116, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 10. The method of any one of embodiments 115 to 117, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 15. The method of any one of embodiments 115 to 118, wherein the increase in the palmoplantar pustulosis area and severity index (PPPASI) comprises an increase of greater than 20. The method of any one of embodiments 115 to 119, wherein the period of time comprises more than 1 day. The method of any one of embodiments 115 to 120, wherein the period of time comprises more than 1 week. The method of any one of embodiments 115 to 121, wherein the period of time comprises more than 2 weeks. The method of any one of embodiments 115 to 122, wherein the period of time comprises more than 3 weeks. The method of any one of embodiments 115 to 123, wherein the period of time comprises more than 1 month. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 day. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 week. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 5 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month. 134. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 10 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month.

135. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 15 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month.

136. The method of any one of embodiments 64 to 92, wherein progressing disease comprises an increase of 20 in the palmoplantar pustulosis area and severity index (PPPASI) over a period of 1 month.

[0134] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.