METHODS AND COMPOSITIONS FOR TREATING RHEUMATOID ARTHRITIS

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/661329, filed April 23, 2018, the contents of which are incorporated herein by reference in its entirety.

BACKGROUND

Rheumatoid arthritis is an autoimmune disease in which the body’s immune system mistakenly attacks the joints. This creates inflammation that causes the tissue that lines the inside of joints (the synovium) to thicken. In healthy patients, the synovium makes a fluid that lubricates joints and helps them move smoothly. However, thickening of the synovium results in swelling and pain in and around the joints. While inflammation of the tissue around the joints and inflammatory arthritis are characteristic features of rheumatoid arthritis, the disease can also cause inflammation and injury in other organs in the body. Because it can affect multiple other organs of the body, rheumatoid arthritis is referred to as a systemic illness and is sometimes called rheumatoid disease. There is currently no cure for rheumatoid arthritis. Thus, novel and innovative therapies are currently needed to treat rheumatoid arthritis.

SUMMARY

In some aspects, the methods and compositions disclosed herein relate to treating and/or preventing diseases and disorders characterized by inflammation of joints. In some embodiments, the disease or disorder is a disease or disorder associated with inflammation of joints as a result of an autoimmune disease and/or degeneration of cartilage in joints. The disease or disorder may be a type of inflammatory arthritis, such as rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, and psoriatic arthritis. Also provided herein are methods and compositions related to slowing the progression of inflammatory arthritis and/or for treating and/or preventing a symptom or symptoms of inflammatory arthritis in a subject by administering to the subject ( e.g ., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide

Dtinic acid, nicotinamide, and/or a compound of Formula III (e.g, pterostilbene). In some embodiments, the subject has rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, or psoriatic arthritis.

In some embodiments, a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene) may be administered to the subject conjointly with a second therapeutic for the treatment of inflammatory arthritis (e.g., an type of inflammatory arthritis disclosed herein). In some embodiments, the rheumatoid arthritis is seropositive rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is seronegative rheumatoid arthritis. In some embodiments, the subject has tested positive for rheumatoid factor.

In certain embodiments of the compositions and methods provided herein, the composition comprises a compound of Formula I or Formula II (e.g, nicotinamide riboside) (e.g, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g, nicotinamide riboside)). In some embodiments, the composition comprises a compound of Formula III (e.g, pterostilbene) (e.g, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g, pterostilbene)). In certain embodiments, the composition comprises both a compound of Formula I or Formula II (e.g, nicotinamide riboside) (e.g, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g, nicotinamide riboside)) and a compound of Formula III (e.g, pterostilbene) (e.g, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g, pterostilbene)). In certain embodiments, the method comprises administering a plurality of doses of the composition. In some embodiments, at least 7 doses of the composition are

administered. In some embodiments, at least 30 doses of the composition are administered. In some embodiments, at least 60 or more doses of the composition are administered. In some embodiments, each dose comprises at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II ( e.g ., nicotinamide riboside). In some embodiments, each dose comprises at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least

55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least

85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene). In certain embodiments, each dose comprises at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g, nicotinamide riboside) at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least

50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least

80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of formula III (e.g, pterostilbene).

In certain embodiments, a dose of the composition is administered at regular intervals over a period of time. In some embodiments, a dose of the composition is administered at least once a week. In some embodiments, a dose of the composition is administered at least twice a week. In certain embodiments, a dose of the composition is administered at least three times a week. In some embodiments, a dose of the composition is administered at least once a day. In some embodiments, a dose of the composition is administered at least twice a day. In some embodiments, doses of the composition are administered for at least 1 week, for at least 2 weeks, for at least 3 weeks, for at least 4 weeks, for at least 1 month, for at least 2 months, for at least 3 months, for at least 4 months, for at least 5 months, for at least 6 months or for at least 1 year. In certain embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is formulated as a pill, a tablet, or a capsule. In some embodiments, the composition is administered orally. In certain embodiments, the composition is self-administered.

DETAILED DESCRIPTION

General

In some aspects, the methods and compositions disclosed herein relate to treating and/or preventing diseases and disorders characterized by inflammation of joints, such as inflammatory arthritis. Also provided herein are methods and compositions related to slowing the progression of inflammatory arthritis and/or for treating and/or preventing a symptom or symptoms of inflammatory arthritis in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene).

Definitions

For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

The articles“a” and“an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example,“an element” means one element or more than one element.

As used herein, the term“ administering " means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. Administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g, patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

As used herein,“ inflammatory arthritis’’ includes any form or type of arthritis associated with inflammation. Non-limiting examples of inflammatory arthritis include rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, or psoriatic arthritis.

Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent ( e.g ., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

The phrase“ pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material.

As used herein, the term“ subject” means a human or non-human animal selected for treatment or therapy.

The phrases " therapeutically-effective amount " and“ effective amount’ as used herein means the amount of an agent which is effective for producing the desired therapeutic effect in at least a sub-population of cells in a subject at a reasonable

benefit/risk ratio applicable to any medical treatment.

“ Treating’ a disease in a subject or“treating’ a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening.

As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, when administered to a statistical sample prior to the onset of the disorder or condition, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

An“ alkyF group or“ alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. In some embodiments, the alkyl group has from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.

The term “Cx-y” when used in conjunction with a chemical moiety, such as, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term“Cx- _y alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms“C2- _y alkenyl” and“C2- _y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term“ aralkyF , as used herein, refers to an alkyl group substituted with an aryl group. Representative examples of arylalkyl include, but are not limited to, benzyl, 2- phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term“ aryF as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 6- or 20- membered ring, more preferably a 6-membered ring. The term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

A “ cycloalkyF group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Preferably, a cycloalkyl group has from 3 to 20 carbon atoms. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term“fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds. The terms“/M/O” and“ halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The term“ heteroaralkyF , as used herein, refers to an alkyl group substituted with a hetaryl group.

The term“ heteroaryF includes substituted or unsubstituted aromatic single ring structures, preferably 5- to 20-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and“hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term“ heteroatonf as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

The terms“heterocyclyF ,“ heterocycle”, and“ heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 20-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and“heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocycloalkyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term“ heterocyclolalkyF , as used herein, refers to an alkyl group substituted with a heterocycle group.

It will be understood that“ substitution” or“ substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term“ substituted” is contemplated to include all permissible substituents of organic compounds. Such substituents, if not otherwise specified, can include, for example, a halogen (e.g., fluoro), a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF ₃ , - CN, and the like.

Compositions

Provided herein are pharmaceutical compositions comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g, pterostilbene).

Nicotinamide riboside is a pyridine-nucleoside form of niacin (i.e., vitamin B ₃ ) that serves as a precursor to nicotinamide adenine dinucleotide (NAD ⁺ ). As used herein, “nicotinamide riboside” also includes nicotinamide riboside salts, such as nicotinamide riboside chloride. The chemical structure of nicotinamide riboside is provided below:

In some embodiments, provided herein are pharmaceutical compositions comprising epresented by Formula (I) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

R , R ₂ , and Ri are selected from hydrogen, halogen, -CN, -NO2, -OR ₁₄ , -N(R ₁₄ )m, - R13, substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R ₄ and R ₅ are selected from hydrogen, halogen, -CN, -NO2, -OR ₁₄ , -N(R ₁₄ )m, substituted or unsubstituted (C ₁ -C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R ₆ , R ₈ , R ₁₁ , and R12 are selected from hydrogen, (C ₁ -C ₆ )alkyl, -((C ₁ - C ₆ )alkylene)N(R ₁₄ )m, -C(O)((C ₁ -C ₆ )alkylene)N(R ₁₄ )m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -OR ₁₄ , and -N(R ₁₄ ) _m ;

R ₇ and R9 are selected from -( (C ₁ - C ₆ )alkylene)N(R ₁₄ )m, -OR ₁₄ , and -N(R ₁₄ ) _m ;

R ₁₀ is selected from - ((C ₁ - C ₆ )alkylene)N(R ₁₄ )m, -OR ₁₄ , -0P(O)(OR ₁₄ )2, and - N(R ₁₄ ) _m ;

R ₁ 3 is selected from -OR ₁₄ , -N(R ₁₄ )m, -C(O)(R ₁₄ ), -C(O)(OR ₁₄ ), -C(O)N(R ₁₄ )m, - S(O) ₂ (OR ₁₄ ), -S(O)0R ₁₄ , and - S(O) ₂ N(R ₁₄ )m;

R ₁₄ is selected from hydrogen,(C ₁ -C ₆ ) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; and

X is O, S, or N(R ₁₄ );

m is 2 or 3;

provided that at least one of R ₁ , R ₂ , and R3 is R ₁₃ .

In some embodiments, R is R ₁₃ . In some embodiments, R2 is R ₁₃ . In some embodiments, R ₃ is R13.

In some embodiments, R13 is selected from -OR ₁₄ , -N(R ₁₄ )m, -C(O)(R ₁₄ ), - C(O)(OR ₁₄ ), and -C(O)N(R ₁₄ )m. In some embodiments, R ₁₃ is selected from -C(O)(R ₁₄ ), - C(O)(OR ₁₄ ), and -C(O)N(Rf ₄ )m. In some embodiments, R ₁₃ is -C(O)N(R ₁₄ )m.

In some embodiments, R ₇ , R9, and R ₁₀ are each independently -OR ₁₄ or -N(Rl· 4)m. In some embodiments, R ₇ , R9, and R ₁₀ are -OR ₁₄ .

In some embodiments, R ₁₀ is -0P(O)(OR ₁₄ )2. In some embodiments, the compound of formula (I) is represented by Formula (II) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

R2 and R3 are selected from hydrogen, halogen, -CN, -NO2, -OR ₁₄ , -N(R ₁₄ )m, -R13, substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R4 and Rs are selected from hydrogen, halogen, -CN, -NO2, -OR ₁₄ , -N(R ₁₄ )m, substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R ₆ , R ₈ , R _{1 1} , and R12 are selected from hydrogen, -OR ₁₄ , -N(R ₁ s)m, substituted or unsubstituted (C ₁ - C ₆ )alkyl, -( (C ₁ - C ₆ )alkylene)N(R ₁₄ )m, -C(O)( (C ₁ - C ₆ )alkylene)N(R ₁₄ )m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R ₁₀ is -OR ₁₄ or -0P(O)(OR ₁₄ )2;

R13 is selected from -OR ₁₄ , -N(R ₁₄ )m, -C(O)(R ₁₄ ), -C(O)(OR ₁₄ ), -C(O)N(R ₁₄ )m, - S(O) ₂ (OR ₁₄ ), -S(O)0R ₁₄ , and - S(O) ₂ N(R ₁₄ )m;

R14 is selected from hydrogen, (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; and

m is 2 or 3.

In some embodiments of the compounds of formula (I) or (II), R ₁ , R2, and R3 are each independently, if present, selected from hydrogen, halogen, -CN, -NO2, -OR ₁₄ , - N(R ₁₄ )m, -R13, and substituted or unsubstituted (C ₁ - C ₆ )alkyl. In some embodiments, R ₁ , R2, and R ₃ are each independently, if present, selected from hydrogen, -OR ₁₄ , -N(R ₁₄ )m, and unsubstituted (C ₁ - C ₆ )alkyl. In some embodiments, R ₁ , R2, and R3 are each independently, if present, selected from substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl,

heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R ₁ , R2, and Rs are each independently, if present, hydrogen. In some embodiments of the compounds of formula (I) or (II), R ₄ and Rs are each independently selected from hydrogen, halogen, -CN, -NO2, -OR ₁₄ , -N(R ₁₄ )m, and substituted or unsubstituted (C ₁ - C ₆ )alkyl. In some embodiments, R ₄ and R ₅ are each independently selected from hydrogen, -OR ₁₄ , -N(R ₁₄ )m, and unsubstituted (C ₁ - C ₆ )alkyl. In some embodiments, R ₄ and Rs are each independently selected from substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R ₄ and Rs are each hydrogen.

In some embodiments of the compounds of formula (I) or (II), Re, Rs, R11, and R12 are selected from hydrogen, -OR ₁₄ , -N(R ₁₄ )m, unsubstituted (C ₁ - C ₆ )alkyl, -((C ₁ - C ₆ )alkylene)N(R ₁₄ )m, -C(O)((C ₁ - C ₆ )alkylene)N(R ₁₄ )m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, Re, Rs, R·,·, and R ₁₄ are each independently selected from hydrogen, -OR ₁₄ , -N(R ₁₄ )m, unsubstituted (C ₁ - C ₆ )alkyl, - ((C ₁ - C ₆ )alkylene)N(R ₁₄ )m, and -C(O)( (C ₁ - C ₆ )alkylene)N(R ₁₄ )m. In some embodiments, Re, Rs, R11, and R12 are each independently selected from hydrogen, -OR ₁₄ , and -N(R ₁₄ )m. In some embodiments, Re, Rs, Ru, and R12 are each independently selected from unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, Re, Rs, Rn, and R12 are each hydrogen.

In some embodiments of the compounds of formula (I) or (II), R ₇ , Ry and R ₁₀ are each independently -OR14 or -N(R ₁₄ )m. In some embodiments, R 7, Ry and R ₁₀ are each -OR ₁₄ . In some embodiments, R ₇ , Ry and R ₁₀ are each -OH.

In some embodiments of the compounds of formula (I) or (II), R ₁₀ is - OP(O)(OR ₁₄ )2.

In some embodiments of the compounds of formula (I) or (II), R ₁₄ is hydrogen or (C ₁ - C ₆ )alkyl.

In some embodiments of the compounds of formula (I) or (II), X is O or N(R ₁₄ ). In some embodiments, X is O.

In some embodiments of the compounds of formula (I) or (II), the compound is

In some embodiments of the compounds of formula (I) or (II), the compound is

In some embodiments, provided herein are pharmaceutical compositions comprising nicotinic acid (also referred to as niacin). The chemical structure of nicotinic acid is provided below:

In some embodiments, provided herein are pharmaceutical compositions comprising nicotinamide (also referred to as niacinamide). The chemical structure of nicotinamide is provided below:

Pterostilbene is a stilbenoid and an analog of polyphenol reservatrol that has better bioavailability due to the presence of two methoxy groups that allow it to have increased lipophilic and oral absorption as well as a longer half-life due to reduced oxidation. The chemical structure of pterostilbene is provided below:

In some embodiments, provided herein are pharmaceutical compositions comprising a compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

R ₁ s is selected from halogen, -CN, -NO2, -OR10, -N(R ₁₆ ) _R , -S(O)2(OR ₁₆ ), -S(O)0R ₁₆ , substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R ₁₆ is selected from hydrogen, (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

n is an integer from 0 to 5; and

p is 2 or 3;

provided that at least one n is 1; and at least one R ₁ s is -OR ₁₆ ;

provided that the compound of formula (III) is not

In some embodiments of the compounds of formula (III), R15 is selected from, halogen, -CN, -NO2, -OR ₁₆ , -N(R ₁₆ ) _P , and substituted or unsubstituted (C ₁ - C ₆ )alkyl. In some embodiments, R ₁ s is selected from -OR ₁₆ , -N(R ₁₆ )p, and unsubstituted (C ₁ - C ₆ )alkyl. In some embodiments, R ₁ s is selected from substituted or unsubstituted (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R ₁ s is -OR ₁₆ In some embodiments, R ₁ s is -OR ₁₆ ; and R ₁₆ is hydrogen or (C ₁ - C ₆ )alkyl. In some embodiments, R ₁ s is -OR ₁₆ ; and R10 is (C ₁ - C ₆ )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R ₁ s is -OR ₁₆ ; and R ₁₆ is (C ₁ - C ₆ )alkyl. In some embodiments, R ₁ s is -OR ₁₆ ; and R ₁₆ is (C ₁ - C ₆ )alkyl, cycloalkyl, or heterocycloalkyl.

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2.

In some embodiments, p is 2. In some embodiments, p is 3.

In one aspect, the provided herein are pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described herein ( e.g ., nicotinamide riboside and/or pterostilbene), formulated together with harmaceutically acceptable carriers (additives) and/or diluents. In another aspect, the agents described herein can be administered as such, or administered in mixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with other agents. Conjunctive therapy thus includes sequential, simultaneous and separate, or co-administration of one or more compounds of the invention, wherein the therapeutic effects of the first administered has not entirely disappeared when the subsequent compound is administered.

As described in detail below, the pharmaceutical compositions described herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g ., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; or (3) sublingually.

In some embodiments, the composition comprises additional agents. For example, the composition may comprise a nutritional agent, such as an antioxidant. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The formulations of the compounds described herein may be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the agent which produces a therapeutic effect.

In certain embodiments, a formulation described herein comprises an excipient, including, but not limited to, cyclodextrins, liposomes, micelle forming agents, e.g. , bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and an agent of the invention. In some embodiments, an aforementioned formulation renders orally bioavailable an agent of the invention. Methods of preparing these formulations or compositions may include the step of bringing into association a compound of the invention with the carrier and, optionally, one or more accessory ingredients.

Liquid dosage forms for oral administration of the formulations provided herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations provided herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. A compound of the invention may also be administered as a bolus, electuary, or paste.

In solid dosage forms of the invention for oral administration ( e.g ., capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,

carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate;

(5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. Compositions described herein may also be formulated for rapid release, e.g ., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.

Pharmaceutical compositions provided herein suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Therapeutic Methods

Provided herein are methods and compositions related to preventing, treating, or slowing the progression of inflammatory arthritis ( e.g ., rheumatoid arthritis) in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Also provided herein are methods and compositions related to slowing the progression of inflammatory arthritis and/or for treating and/or preventing a symptom or symptoms of inflammatory arthritis in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). The subject may be male or female. In some embodiments, the subject is a mammal, preferably, a human.

Arthritis is a disease that causes damage to the healthy cartilage of joints, leading to degenerative changes, loss of function and joint instability. Inflammatory arthritis is caused, in part, by an increase of cytokines which leads to degradation of articular cartilage and a decrease of growth factors which induce chondrogenesis. Examples of inflammatory arthritis include, but are not limited to, rheumatoid arthritis, ankylosing spondylitis, gouty arthritis or psoriatic arthritis.

In some embodiments, the subject has rheumatoid arthritis. In some embodiments, the subject may have refractory rheumatoid arthritis. Rheumatoid arthritis is a systemic autoimmune disease characterized by the simultaneous inflammation of the synovium of multiple joints. This condition causes chronic damage of joints including destruction, deformation and disability. Also provided herein are methods and compositions related to slowing the progression of inflammatory arthritis ( e.g ., rheumatoid arthritis) in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Clinically, inflammatory arthritis, such as rheumatoid arthritis, can be assessed and monitored using any of a number of structural (anatomical) and functional tests to measure the inflammation of joints. The progression of rheumatoid arthritis may be measured according to the classification criteria introduced by the ACR (American College of Rheumatology) and described in Arnett, F.C., et al., Arthritis Rheum. (1998) 31 ;315-324, hereby incorporated by reference in its entirety. The seven ACR 1987 criteria are as follows: 1) morning stiffness, 2) arthritis of 3 or more joint areas, 3) arthritis of hand joints, 4) symmetric arthritis, 5) rheumatoid nodules, 6) serum rheumatoid factor, and 7) radiographic changes. Rheumatoid arthritis is defined by the presence of four or more criteria for at least six weeks. Thereafter, the ACR 1987 revised criteria for the classification of rheumatoid arthritis was established in 2010. According to the ACR 2010 classification, cases fulfilling the 1987 criteria with the presence of joint synovitis are defined as rheumatoid arthritis. Using the 2010 criteria, the number and site of involved joints are scored on a 0 to 5 scale (see Table 1 for full classification details). Large joints consist of the hip, knee, shoulder and elbow. Small joints include the wrist and hand. The scores are based on serological tests according to elevated levels of rheumatoid factor or presence of anti-CCP antibody (cyclic citrullinated peptide antibody) (range, 0-3), according to CRP and/or ESR (range, 0- 1) and duration of symptoms (<6 weeks, 0; >6 weeks, 1). Based on the sum of point scores in the four domains, a total score of 6 or greater out of 10 signifies rheumatoid arthritis. Patients with a score of less than 6 out of 10 require frequent monitoring. In some embodiments, the subject has an ACR score of 6 or greater. In some embodiments, the subject has an ACR score of less than 6.

The various methods disclosed herein include methods for slowing joint

inflammation or improving joint pain in a subject with inflammatory arthritis ( e.g ., rheumatoid arthritis), and/or methods for improving joint mobility in a subject, such as a subject with inflammatory arthritis (e.g., rheumatoid arthritis). Thus, in certain

embodiments, the methods of treatment disclosed herein include methods for treating joint inflammation, whereby the patient’s joint inflammation (as measured by a test disclosed herein) after a therapy (e.g, after about one month, about three months, after about six months, after about nine months, after about one year, after about two years, or after about three years of therapy) comprising administration of a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene) is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% improved relative to a control patient not receiving a therapy disclosed herein. Alternatively, the patient’s joint inflammation (as measured by a test disclosed herein) after a therapy (e.g, after about one month, about three months, after about six months, after about nine months, after about one year, after about two years, or after about three years) comprising administration of a composition disclosed herein is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% improved than the earlier assessment.

Provided herein are methods and compositions related to treating, preventing, and/or improving a symptom of inflammatory arthritis by administering (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Symptoms of may include, but are not limited to, redness around the joints, joint swelling, joint pain, joint stiffness, and loss of joint function. A symptom may be any symptom disclosed herein.

In some embodiments, the subject has rheumatoid arthritis or is at risk for developing rheumatoid arthritis. The diagnosis of rheumatoid arthritis falls under two overarching types: seropositive and seronegative. An individual who is clinically diagnosed as seropositive has blood that contains antibodies that can attack their bodies and lead to joint inflammation. The specific antibodies in the blood of seropositive patients are rheumatoid factor, anti-CCPs (cyclic citrullinated peptide antibodies), or both. Rheumatoid factor is an antibody that is detectable in the blood of approximately 80% of adults with rheumatoid arthritis. Cyclic citrullinated peptide antibodies are autoantibodies produced by the immune system that are directed against cyclic citrullinated peptides. Citrulline is naturally produced in the body as part of the metabolism of the amino acid arginine. However, in joints with inflammatory arthritis, such as rheumatoid arthritis, this conversion may occur at a higher rate. Citrulline changes the protein structure and can trigger an immune response, producing autoantibodies against proteins found in joints. In some embodiments, the rheumatoid arthritis is seropositive rheumatoid arthritis (i.e., the subject has tested positive for rheumatoid factor and/or anti-CPP antibodies) or

seronegative rheumatoid arthritis (i.e., the subject tested negative for rheumatoid factor). In some embodiments, the subject has tested positive for rheumatoid factor. Clinically, the "normal" range (or negative test result) for rheumatoid factor is less than 14 IU/ml. Any result with values 14 IU/ml or above is considered abnormally high, elevated, or positive. Therefore, in some embodiments, the subject has undergone a blood test to detect rheumatoid factor, and the subject has a rheumatoid factor blood level of 14 IU/ml or above. In some embodiments, the subject has undergone a blood test to detect rheumatoid factor, and the subject has a rheumatoid factor blood level of below 14 IU/m. Rheumatoid factor may be tested by any means known in the art. Rheumatoid arthritis may be tested using classic agglutination techniques, wherein the assay tests the ability of IgMs to induce agglutination. Rheumatoid arthritis may also be tested using automated techniques such as nephelometry and enzyme-linked immunosorbent assays. Multiplexed immunoassaying is a high-throughput technique for the quantitative detection of multiple analytes from a single biological sample. Additional details on the detection of rheumatoid factor may be found in U.S. patents 4153417, 4184847, 5124250 and 5698393, each of which are hereby incorporated by reference in their entireties. Anti-CPP antibodies may be detected by any assay known in the art, including, but not limited to, Diastat anti-CCP ELISA assay, Axsym anti-CCP assay, Architect anti-CCP assay, and the Elecsys anti-CCP assay). More details concerning the detection of anti-CPP antibodies can be found in Kim et al, Rheumatology (2010) 49:3, 450-457, which is hereby incorporated by reference in its entirety.

In some embodiments, the subject has ankylosing spondylitis. Ankylosing spondylitis is associated with chronic inflammation of the spine and bone-to-tendon attachment area of the sacroiliac joint that causes back pain and progressive spinal stiffness. At the final stage of ankylosing spondylitis, bony fusion and severe hyperkyphosis may occur. Ankylosing spondylitis is a type of spondyloarthritis that may cause musculoskeletal symptoms (e.g., spondylitis, oligoarthritis, enthesitis, dactylitis), and non-musculoskeletal symptoms (e.g., anterior uveitis, psoriasis, inflammatory bowel disease). Ankylosing spondylitis is subdivided into axial and peripheral types based on whether symptoms chiefly affect the spine or the peripheral joints, and it can be diagnosed when sacroiliitis is clearly present in axial type. All disorders classified as spondyloarthritis can progress to ankylosing spondylitis. Provided herein are methods and compositions related to preventing, treating, or slowing the progression of ankylosing spondylitis in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene).

In some embodiments, the subject has ankylosing spondylitis or is at risk for ankylosing spondylitis. Also provided herein are methods and compositions related to treating and/or preventing a symptom or symptoms of ankylosing spondylitis (e.g., a symptom disclosed herein) in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Clinically, ankylosing spondylitis is characterized by inflammatory back pain (IBP), which is distinguished from mechanical back pain manifested in herniated intervertebral disc, muscle sprain and degenerative spinal disease. IBP is characterized by: i) onset before the age of 40 years after a symptom period of more than 3 months, ii) insidious onset, iii) improvement with exercise, iv) no improvement during rest periods, and v) nocturnal symptoms. Furthermore, additional symptoms include morning stiffness for more than 30 minutes and bilateral hip pain. Hip joint lesions are associated in more than 25% to 35% of patients with ankylosing spondylitis. In particular, more severe hip lesions are manifested radiographically in cases of early onset and severe radiographic deformity in the spine and sacroiliac joint.

In some embodiments, the subject has gouty arthritis or is at risk for gouty arthritis. Provided herein are methods and compositions related to preventing, treating, or slowing the progression of gouty arthritis in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Also provided herein are methods and compositions related to treating and/or preventing a symptom or symptoms of gouty arthritis (e.g., a symptom disclosed herein) in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Gout is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot, and swollen joint. Pain typically comes on rapidly in less than twelve hours. It may also result in tophi, kidney stones, or urate nephropathy. Gout can present in multiple ways, although the most usual is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint). The metatarsal-phalangeal joint at the base of the big toe is affected most often, accounting for half of cases. Other joints, such as the heels, knees, wrists, and fingers, may also be affected.

In some embodiments, the subject has psoriatic arthritis or is at risk for psoriatic arthritis. Provided herein are methods and compositions related to preventing, treating, or slowing the progression of psoriatic arthritis in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Also provided herein are methods and compositions related to treating and/or preventing a symptom or symptoms of psoriatic arthritis (e.g, a symptom disclosed herein) in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene). Psoriatic arthritis is a form of arthritis that affects some people who have psoriasis, a condition that features red patches of skin topped with silvery scales. Most people develop psoriasis first and are later diagnosed with psoriatic arthritis, but the joint problems can sometimes begin before skin lesions appear. Joint pain, stiffness and swelling are the main symptoms of psoriatic arthritis. They can affect any part of your body, including your fingertips and spine, and can range from relatively mild to severe. In both psoriasis and psoriatic arthritis, disease flares may alternate with periods of remission.

Provided herein are methods and compositions related to treating inflammatory arthritis in a subject by administering to the subject (e.g, orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene) conjointly with a second therapeutic for inflammatory arthritis. The second therapeutic may be nonsteroidal anti-inflammatory agents (NSAIDS), analgesics (e.g., acetaminophen), steroids (e.g, prednisone and methylprednisolone), disease modifying agents (DMARDs)(e.^., hydroxychloroquine, sulfasalazine, methotrexate, or leflunomide), biologic agents, JAK inhibitors (e.g, tofacitinib). In some embodiments, the subject is administered one or more of the therapeutics disclosed herein. In some embodiments, a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), nicotonic acid, nicotinamide, and/or a compound of Formula III (e.g., pterostilbene) is administered conjointly with a second therapeutic. In some embodiments, the second therapeutic is an analgesic. One non-limiting example of an analgesic is acetaminophen. Acetaminophen may be in an oral formulation or topical formulation, such as topical lidocaine patches or roll-on applications. In some

embodiments, the second therapeutic is a narcotic pain medication, such as tramadol.

In some embodiments, the second therapeutic is a corticosteroid. The corticosteroid may be in an intra-articular, IV, intra-muscular, or oral formulation. The use of

corticosteroids in inflammatory arthritis may be highly individualized in view of the potential for toxicity. For example, a subject may be administered a corticosteroid prior to a compound disclosed herein to manage immediate pain associated with inflammatory arthritis, and discontinued once a composition disclosed herein is administered. In some embodiments, the corticosteroid and a compositions disclosed herein is administered at the same time.

In some embodiments, the second therapeutic is a DMARD (disease-modifying anti -rheumatic drug, also called“slow acting agents”). Slow-acting agents may be administered in combination with any composition disclosed herein. In some

embodiments, a DMARD is defined as any compound which slows or stops joint damage. Examples of DMARDs include, but are not limited to, azathioprine imuran, atabrine, cyclophosphamide cytoxan, cyclosporine, gold-injected, hydroxychloroquine, leflunomide arava, methotrexate, minocycline, or sulfasalazine azulfidine. In some embodiments, a composition disclosed herein is administered conjointly with hydroxychloroquine. In some embodiments, the second therapeutic is sulfasalazine. In some embodiments, the subject is undergoing a combination regimen with sulfasalazine, methotrexate, and

hydroxychloroquine (“triple therapy”), in addition to a composition described herein. In some embodiments, the second therapeutic is azathioprine, penicillamine, methotrexate, leflunomide, or minocycline.

Actual dosage levels and administration regimen of the compositions disclosed herein may be varied so as to obtain an amount of a compound of Formula I or Formula II ( e.g ., nicotinamide riboside) and/or a compound of Formula III (e.g, pterostilbene) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In some embodiments, the subject continuously self-administers the compounds disclosed herein. In other

embodiments, the subject may take a compound disclosed herein as needed.

In some embodiments, administration of the composition comprises administration of the composition in one or more dose(s). In some embodiments, administration of the composition comprises administration of the composition in one or more, five or more, ten or more, twenty or more, thirty or more, forty or more, fifty or more, one hundred or more, or one thousand or more dose(s). In some embodiments, the dose comprises at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, or at least 850 mg of a compound of Formula I or Formula II (e.g, nicotinamide riboside). In some embodiments, the dose comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, least 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, or at least 250 mg of a compound of formula III (e.g, pterostilbene) .

The compositions disclosed herein may be administered over any period of time effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The period of time may be at least 1 day, at least 10 days, at least 20 days, at least 30, days, at least 60 days, at least three months, at least six months, at least a year, at least three years, at least five years, or at least ten years. The dose may be administered when needed, sporadically, or at regular intervals. For example, the dose may be administered monthly, weekly, biweekly, triweekly, once a day, or twice a day.

Incorporation by Reference

All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.