Figure 1. Stepwise approach of treating patients with rheumatoid arthritis.

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3 Establish diagnosis early Document baseline disease activity and damage Estimate prognosis Initiate therapy Begin patient education Start DMARD therapy within 3 months Consider NSAID Consider local or low-dose systemic corticosteroids Start physical therapy or occupational therapy Periodically assess disease activity Adequate response with decreased disease activity Inadequate response (ongoing active disease after 3 months of maximal therapy) Change or add DMARDs No previous MTX treatment Suboptimal response to MTX MTX other monotherapy combination therapy combination therapy biologic DMARDs monotherapy monotherapy combination therapy Figure 1. Stepwise approach of treating patients with rheumatoid arthritis.

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6 Table 1. Disease modifying anti-rheumatic drugs of interest for pharmacogenetic studies. DMARD Polymorphic genes reported or likely to influence DMARD response and/or safety Sulphasalazine Metabolizing enzyme N-acetyltransferase 2 (NAT2) Drug transporter reduced folate carrier (RFC) Hydroxychloroquine Drug transporter of the ATP-binding cassette type A (ABCA4) Azathioprine Metabolizing enzyme thiopurine methyltransferase (TPMT) Drug targets such as enzymes in the purine synthesis Ciclosporin Metabolizing cytochrome P450 enzymes Drug transporter multi drug resistance protein (MRP) Leflunomide Metabolizing cytochrome P450 enzymes Drug targets dihydroorotate dehydrogenase (DHODH) and enzymes in the pyrimidine syntheses Methotrexate Drug transporters reduced folate carrier, P-glycoprotein and multi resistant proteins (RFC, ABCB1, MRP) Drug targets such as enzymes in the pyrimidine and purine syntheses Biological milieu genes such as genes in the major histocompatibility complex region Anakinra Drug target interleukine-1 gene Biological milieu genes such as genes in the major histocompatibility complex region Etanercept Infliximab Adalimumab Abatacept Rituximab Drug target TNF gene and promoter region, TNF receptor gene Drug target immunoglobulin G fragment C receptor type IIa, type IIIa and b Biological milieu genes such as genes in the major histocompatibility complex region Drug target CTLA4 Biological milieu genes such as genes in the major histocompatibility complex region Drug target immunoglobulin G fragment C receptor type IIa and type IIIa Biological milieu genes such as genes in the major histocompatibility complex region

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9 Table 2. Pharmacogenetic association studies of methotrexate with treatment outcome in rheumatoid arthritis. Gene Role in pathways, relation with MTX SNP Postulated effect SNP Clinical effects MTHFR ATIC DHFR MTHFD1 SHMT1 TSER TYMS AMPD1 MTR MTRR Catalyzes methylene THF to methyl-thf; indirect target MTX Conversion of AICAR to 10-formyl-AICAR; target of polyglutamated MTX Reduction of DHF to THF; target of MTX 677C>T Thermolibale MTHFR with decreased activity and increased homocysteine levels 1298 A>C May further decrease MTHFR activity and increase homocysteine levels 347C>G 473G>A 35389G>A catalyzes interconversion of 1-carbon 1958G>A derivatives of THF; indirect target MTX catalyzes conversion 1420C>T of serine and THF to glycine and methylene-thf: indirect target MTX Enhancer region of 5 UTR TYMS; indirect target 28bp of MTX repeat Conversion of dump to dtmp; target of MTX 3 UTR 6bp deletion Conversion of AMP 34C>T to ADP and ATP; indirect target MTX Methylation of 2756A>G homocysteine to methionine; indirect target MTX Methylation of 66A>G cofactors required for MTR action; indirect target MTX Increases homocysteine level [42]; No increased homocysteine level [44]; Effect on GI toxicity [42]; T-allele associated with increased liver enzyme levels [39]; T-allele associated with toxicity [46]; No association with toxicity [32,35,37,38,40,42,45]; No association with efficacy [39,40,40,45]; Association with efficacy [32,35] A-allele associated with toxicity [38,45]; C-allele associated with toxicity and GI toxicity [32,35]; No association with toxicity [40]; No association with efficacy [35,40,45]; Association with efficacy [32,46] May decrease ATIC Association with efficacy activity, affect AICAR [33,37,51]; No association with accumulation and adenosine release toxicity and GI toxicity [33,35,37]; efficacy [35]; GG associated with No effect on toxicity [49] Possibly affecting mrna transcription, affinity of MTX May decrease enzyme activity May decrease enzyme activity May increase enzyme activity May decrease TYMS mrna stability and expression Decreased enzyme activity, may enhance conversion to adenosine May decrease enzyme activity; increase homocysteine levels May decrease MTRR activity; increase homocysteine levels No effect on efficacy or toxicity [32] AA associated with inefficacy [51] No association with efficacy [51]; CC associated with efficacy [35]; No association with toxicity [35,37]; CC associated with alopecia and CNS side effects [37] No association with efficacy [35,40,51]; No association with toxicity [35,40]; Association with toxicity and alopecia [37] May affect MTX efficacy [40]; No effect on efficacy as defined by MTX dose [49]; No effect on toxicity [49] T-allele associated with efficacy [33,51]; No association with toxicity [33] No association with efficacy [33,35]; AA associated with toxicity [35]; No association with toxicity [33] No effect on efficacy [33,35]; No association with toxicity [33]; Association with toxicity [35]

10 Table 2. Pharmacogenetic association studies of methotrexate with treatment outcome in rheumatoid arthritis. (continued) Gene ITPA FPGS GGH ABCB1 RFC Role in pathways, relation with MTX Conversion ITP to IMP; indirect target MTX Adding polyglutamates to MTX; prolonging cellular retention MTX Conversion of long chain polyglutamated MTX into short chain by removing polyglutamates Efflux transporter on cells; efflux of MTX Folate entry in the cell SNP Postulated effect SNP Clinical effects 94C>A 1994A>G 114G>A 452C>T 16C>T 401C>T 3435C>T 80G>A Decreased enzyme activity; may enhance conversion to AMP and adenosine May affect MTX polyglutamation Decreased binding affinity for polyglutamated MTX May affect polyglutamated MTX levels May decrease enzyme expression or mrna stability; may increase intracellular MTX levels May affect transcriptional activity and increased MTX entry in the cell CC associated with efficacy [33,51]; Association with toxicity [33] No association with efficacy [41]; No association with toxicity [41] May affect efficacy [41]; No association with efficacy [51]; No association with toxicity [41] No association with efficacy [35]; May affect efficacy [36]; CC associated with toxicity [35] TT associated with increased MTX dose [49]; T-allele associated with inefficacy [50] No effect efficacy as defined by MTX dose [49]; No association with efficacy [32,35]; No association with toxicity [32,35,49] ABCB1 = P-glycoprotein; ADP = adenosine diphosphate; AICAR = aminoimidazole-4-carboxamide ribonucleotide; AMP = adenosine monophosphate; AMPD1 = adenosine monophosphate deaminase; ATIC = 5- aminoimidazole-4-carboxamide ribo-nucleotide transformylase; ATP = adenosine triphosphate; CNS= central nervous system; DHF = dihydrofolate; DHFR = dihydrofolate reductase; dtmp = deoxy thymidine monophosphate; dump = deoxy-uridine monophosphate; FPGS = folylpoly-glutamate synthetase; GI= gastrointestinal; GGH = -glutamyl hydrolase; IMP = inosine monophosphate; ITP = inosine triphosphate; ITPA = inosine triphosphatase; MTHFD1 = methylenetetrahydrofolate dehydrogenase; MTHFR = methylene tetrahydrofolate reductase; MTR = methyltetrahydrofolate-homocysteine methyltransferase; MTRR = 5- methyltetrahydrofolate-homocysteine methyltransferase reductase; MTX= methotrexate; RFC1 = reduced folate carrier; SHMT1 = serine hydroxymethyltransferase; THF = tetrahydrofolate; TSER = thymidylate synthetase enhancer region; TYMS = thymidylate synthetase.

11 Table 3. Pharmacogenetic association studies of anti-tnf agents and their efficacy of treatment in rheumatoid arthritis. Gene Function SNP Postulated effect SNP Clinical effects TNF TNFRSF1 TNFRSF2 TNF / microsatellites Lymphotoxin (LTA) HLA DRB1, DRQ1 alleles (SE) Interleukine-10 (IL-10) Interleukine-1 (IL-1) IL-1 receptor antagonist TNF production and regulation TNF soluble receptor type 1 TNF soluble receptor type 2 Linked to TNF 308 polymorphism Mediation of inflammatory actions Antigen presenting molecules Influence cell activation, apoptosis. Indirect target anti-tnf Fc receptor polymorphisms Anti-inflammatory cytokine Pro-inflammatory cytokine Inhibits action of interleukine G>A promotor region 857C>T, promoter region 863C>A, promoter region 238G>A, promoter region 1031T>C promoter region +488 intronic region G>T a,b,c,d,e +177A>G +319C>A See references May increase transcriptional activity; May increase TNF levels See above See above GG associated with efficacy INF [59 61]; No effect on efficacy INF [62,78]; No effect on efficacy ETA [51,64,66]; GA associated with increased TNF levels after INF [78] T-allele associated with efficacy ETA [64] No effect on efficacy ETA[64]; No effect on efficacy ETA [51,64]; No effect on efficacy INF [62] See above No effect on efficacy ETA [64] Unknown Unknown May affect TNF binding May increase interleukine 6 production and affect TNF binding May influence TNF levels; increased RA susceptibility risk Exhibits pro-inflammatory effects May affect anti-tnf efficacy; associated with increased susceptibility and severity of RA 131H/R (Fc RIIa) May affect IgG Fc 176F/V (Fc RIIIa) binding affinity NA1/NA2 (Fc RIIIb) 158V/F (Fc IIIa) 1087G>A Several microsatellites, see reference IL C>T IL-1-RN +2018T>C GG associated with increased anti-inflammatory response May affect inflammatory response May affect inflammatory response No effect on efficacy ETA [51] No effect on efficacy INF [62] No effect on efficacy ETA [51] No effect on efficacy ETA [51]; GG associated with inefficacy ETA and INF [63] No effect on efficacy ETA [51]; TNF 11 and 4 haplotype associated with efficacy INF [79] No effect on efficacy ETA [64] No effect on efficacy ETA [51] No effect on efficacy INF [62,79]; HLA-DBRB1 associated with efficacy ETA [51]; No effect on efficacy ETA [64,66] No effect on efficacy ETA [51] No effect on efficacy ETA and INF [67]; FF associated with efficacy all 3 anti-tnf agents [68] No effect on efficacy ETA [66] IL-10 R3 and haplotype IL-10 R3-R9 associated with efficacy ETA [65] No effect on efficacy INF [62] C-allele associated with inefficacy INF [62] ETA = etancercept; HLA = human leukocyte antigen; INF = infliximab; TNF = tumor necrosis factor-.

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