IL-1β, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis...

IL-1�, IL-6, and TNF gene polymorphisms do not

affect the treatment outcome of rheumatoid

arthritis patients with leflunomide

Andrzej Pawlik1, Magdalena Herczyñska2, Mateusz Kurzawski1, Krzysztof

Safranow3, Violetta Dziedziejko3, Zygmunt Juzyszyn1, Marek DroŸdzik1

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Abstract:

Leflunomide is an isoxazole derivative that is structurally and functionally unrelated to other known immunomodulatory drugs. Pre-

vious studies have revealed that therapy with leflunomide causes decreased production of mediators such as IL-1�, IL-6, and TNF-�,

which are involved in inflammatory process. The aim of the present study was to examine whether the polymorphisms in genes

IL1B, IL6, and TNF may affect treatment outcomes in RA patients treated with leflunomide.

The study was carried out on 129 patients (106 women, 23 men, mean age 52.9 ± 11.03) diagnosed with RA and treated with leflu-

nomide 20 mg daily. Clinical improvement was evaluated according to the American College of Rheumatology (ACR) 20% and

50% response criteria.

There were no statistically significant associations between the studied genotypes and improvement of disease activity parameters.

The results of the present study suggest that IL1�, IL6, and TNF gene polymorphisms are not significant factors influencing the ther-

apy outcome of RA patients with leflunomide.

Key words:

rheumatoid arthritis, leflunomide, cytokines, polymorphism

Introduction

Rheumatoid arthritis (RA) is a common autoimmune

disease in which a combination of risk alleles from

different susceptibility genes predisposes the patient

to development of clinical symptoms following expo-

sure to as yet unknown environmental factors. Treat-

ment of this disease is mainly based on drugs which

modulate its course, and previous studies have shown

that genetic factors influence the response to drugs

used in RA therapy [21]. Pharmacogenetics focuses

on the genetic variations responsible for drug metabo-

lism, drug transport, and drug targets to determine

how these variations result in inherited alterations in

medication outcomes [11, 14]. Identification of ge-

netic determinants of drug efficacy and toxicity will

be valuable because they can be ascertained in the in-

dividual patient before initiation of therapy [1, 12].

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Leflunomide is an isoxazole derivative that is

structurally and functionally unrelated to other known

immunomodulatory drugs. [2] In the intestinal mu-

cosa and in plasma, almost 100% of the compound is

nonenzymatically converted into the active open ring

malononitrile metabolite A77 1726. The main mo-

lecular target of A77 1726 is dihydroorotate dehydro-

genase (DHODH), a key enzyme of the novo py-

rimidine synthesis [5]. Consequently, the main effect

of leflunomide in immunomediated diseases has been

attributed to the inhibition of proliferation of B and T

cells. When activation occurs, these cells may expand

their pyrimidine biosynthesis [7, 10]. It is still not

clear which of these modes of action are relevant to

the immunosuppressive effect of leflunomide ob-

served in various autoimmune mediated diseases. Pre-

vious studies have revealed that therapy with leflu-

nomide causes the decreased production of mediators

such as IL-1�, IL-6, and TNF-�, which are involved

in the inflammatory process [6, 16]. The synthesis of

these mediators is genetically determined, and previ-

ous studies have indicated that polymorphisms in cy-

tokine genes may influence treatment outcome with

antirheumatic drugs. The aim of the present study was

to examine whether the polymorphisms in genes en-

coding IL-1�, IL-6, and TNF-� may affect the treat-

ment outcome in RA patients treated with leflu-

nomide.

Material and Methods

Patients

The study was carried out on 129 patients (106

women, 23 men, mean age 52.9 ± 11.3) diagnosed

with rheumatoid arthritis, treated with leflunomide

20 mg daily. Rheumatoid arthritis was diagnosed ac-

cording to the criteria of American College of Rheu-

matology (ACR). All patients underwent a monthly

evaluation for one year, applying the 1995 ACR pre-

liminary definition of improvement in rheumatoid ar-

thritis. Clinical improvement was evaluated according

to the American College of Rheumatology (ACR)

20% and 50% response criteria. The ACR core set of

variables included: the number of swollen joints, the

number of tender joints, patient assessment of pain on

a 100-mm visual analog scale (VAS), erythrocyte

sedimentation rate, C-reactive protein, and disease ac-

tivity score (DAS28). A 28-joint count (including the

metacarpophalangeal joints, the proximal interphalan-

geal joints, wrists, and elbows) was also used [8, 9,

22, 27]. The study was approved by the local ethics

committee and written informed consent was obtained

from all subjects.

Genotyping

The polymorphisms of IL1� (rs1143634:C>T silent

polymorphism in exon 5), IL6 (rs1800795:C>G in

promoter region), and TNF (rs1800629:G>A in gene

promoter) were determined by means of PCR-RFLP

methods, as previously described [13].

Statistical analysis

Allele and genotype frequencies were compared using

the two-sided Fisher exact test. Odds ratios (OR) and

their 95% confidence intervals (95% CI) were calcu-

lated for the chance of response to treatment using

a multivariate logistic regression model with three

analyzed polymorphisms as independent variables.

A p-level of less than 0.05 was considered statistically

significant. Calculations were performed using the

Statistica 6.1 software package.

Results

The baseline disease activity parameters of RA pa-

tients enrolled in the study are presented in Table 1.

Tables 2–7 present the percentage of patients that

reached clinical improvement after 6 and 12 months

of therapy according to particular parameters as de-

fined by the American College of Rheumatology

(ACR) 20% and 50% response criteria.

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Parameter Value

Blood sedimentation rate 53.73 ± 26.53

Swollen joints 8.3 ± 3.37

Tender joints 10.05 ± 3.7

VAS 7.87 ± 1.38

DAS28 5.33 ± 0.62

CRP [mg/dl] 41.93 ± 38.26

As shown in Tables 2–7, there were no statistically

significant differences in percentage of patients that

reached the 20% and 50% improvement in ESR, CRP,

DAS28, and VAS values, as well as the number of

swollen and tender joints after 6 and 12 months of

treatment in correlation with IL-1� and TNF-� geno-

types. Similarly, there were no statistically significant

differences in percentage of patients that reached the

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Parameter IL1� + 3953 genotypes Statisticalsignificance p*TC + CC vs. TTTT

(N = 85)TC + CC

(N = 41 + 3)

After 6 months of therapy

ESR (26.25%) (26.19%) 1.000

Swollen joints (66.67%) (66.67%) 1.000

Tender joints (50.62%) (52.38%) 1.000

VAS (33.33%) (45.00%) 0.234

DAS28 (3.90%) (2.38%) 1.000

CRP (56.58%) (55.26%) 1.000


ESR (25.35%) (42.86%) 0.077

Swollen joints (92.75%) (97.14%) 0.661

Tender joints (84.06%) (88.57%) 0.768

VAS (78.26%) (80.00%) 1.000

DAS28 (19.12%) (14.29%) 0.596

CRP (63.24%) (70.59%) 0.513

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Parameter IL1 � + 3953 genotype Statisticalsignificance p*TC + CC vs. TTTT

(N = 85)TC + CC

(N = 41 + 3)


ESR (55.00%) (61.90%) 0.563

Swollen joints (95.06%) (95.24%) 1.00

Tender joints (93.83%) (90.48%) 0.489

VAS (88.89%) (87.50%) 1.00

DAS28 (50.65%) (47.62%) 0.848

CRP (73.68%) (81.58%) 0.483


ESR (59.15%) (65.71%) 0.534

Swollen joints (97.10%) (97.14%) 1.00

Tender joints (95.65%) (94.29%) 1.00

VAS (89.86%) (97.14%) 0.261

DAS28 (77.94%) (91.43%) 0.105

CRP (80.88%) (85.29%) 0.783

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Parameter IL-6 -174 G > C genotypes Statistical significance p*GG vs.

(GC + CC)GG (N = 38) GC (N = 63) CC (N = 28)


ESR (54.29%) (56.67%) (62.96%) 0.689

Swollen joints (94.44%) (93.33%) (100%) 1.000

Tender joints (94.44%) (90%) (96.3%) 1.000

VAS (77.14%) (89.83%) (100%) 0.024

DAS28 (51.43%) (47.46%) (52%) 0.842

CRP (75%) (70.91%) (88.89%) 0.811


ESR (53.33%) (69.09%) (52.38%) 0.376

Swollen joints (96.67%) (96.23%) (100%) 1.000

Tender joints (93.33%) (94.34%) (100%) 0.624

VAS (96.67%) (90.57%) (90.48%) 0.433

DAS28 (86.67%) (82.69%) (76.19%) 0.577

CRP (90%) (82.35%) (71.43%) 0.259

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Parameter IL-6 -174 G > C genotypes Statistical significance p*GG vs. (GC + CC)

GG (N = 38) GC (N = 63) CC (N = 28)


ESR (22.86%) (28.33%) (25.93%) 0.655

Swollen joints (50%) (70%) (81.48%) 0.019

Tender joints (41.67%) (51.67%) (62.96%) 0.234

VAS (34.29%) (30.51%) (55.56%) 0.835

DAS28 (2.86%) (3.39%) (4%) 1.000

CRP (56.25%) (52.73%) (62.96%) 1.000


ESR (23.33%) (36.36%) (28.57%) 0.354

Swollen joints (93.33%) (92.45%) (100%) 1.000

Tender joints (90%) (84.91%) (80.95%) 0.545

VAS (76.67%) (81.13%) (76.19%) 0.792

DAS28 (10%) (19.23%) (23.81%) 0.260

CRP (70%) (62.75%) (66.67%) 0.650

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Parameter TNF� -209 genotypes Statisticalsignificance p*GA + AA vs. GGGG

(N = 87)GA + AA

(N = 39 + 3)


ESR (56.79%) (58.54%) 1.000

Swollen joints (97.56%) (90.24%) 0.094

Tender joints (93.90%) (90.24%) 0.479

VAS (90.12%) (85.00%) 0.546

DAS28 (51.90%) (45.00%) 0.561

CRP (74.03%) (81.08%) 0.485


ESR (62.86%) (58.33%) 0.678

swollen joints (98.55%) (94.29%) 0.261

Tender joints (95.65%) (94.29%) 1.000

VAS (92.75%) (91.43%) 1.000

DAS28 (88.41%) (70.59%) 0.050

CRP (85.51%) (75.76%) 0.270

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Parameter TNF�-209 genotypes Statisticalsignificance p*GA + AA vs. GGGG

(N = 87)GA + AA

(N = 39 + 3)


ESR (28.40%) (21.95%) 0.517

Swollen joints (69.51%) (60.98%) 0.417

Tender joints (52.44%) (48.78%) 0.707

VAS (38.27%) (35.00%) 0.842

DAS28 (5.06%) (0.00%) 0.299

CRP (57.14%) (54.05%) 0.840


ESR (30.00%) (33.33%) 0.825

Swollen joints (95.65%) (91.43%) 0.401

Tender joints (88.41%) (80.00%) 0.254

VAS (78.26%) (80.00%) 1.00

DAS28 (14.49%) (23.53%) 0.278

CRP (66.67%) (63.64%) 0.825

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20% and 50% improvement in ESR, CRP, and DAS28

values as well as the number of swollen and tender

joints after 6 and 12 months of treatment in associa-

tion with IL-6 genotypes. In contrast, the percentage

of subjects with 20% improvement in VAS values af-

ter 6 months of the therapy was significantly in-

creased in patients with IL-6 rs1800795 GC + CC

genotype. However, this association was not observed

after 12 months of the therapy.

When the multivariate logistic regression model

was used to study the influence of three polymor-

phisms on each parameter of clinical improvement,

significant associations (p < 0.05) were observed only

for three parameters. The IL-6 GC + CC genotypes

were associated with a higher rate of 50% improve-

ment in swollen joints (OR = 2.73, 95% CI = 1.20–6.21,

p = 0.015) and 20% improvement in VAS values

(OR = 3.88, 95%CI = 1.21–12.37, p = 0.021) after

6 months of therapy. The TNF-� GA + GG genotypes

were associated with lower (OR = 0.24, 95% CI =

0.08–0.73, p = 0.011) and IL-1� TC + CC with higher

(OR = 4.19, 95% CI = 1.03–17.01, p = 0.043) rates of

20% improvement in DAS28 after 12 months of therapy.

During therapy, an increase of erythrocytes and he-

moglobin was observed. There was also an increase

of alanine aminotransferase activity, but the values re-

mained within the range of normal values. The

number of thrombocytes was decreased, and the cre-

atinine concentrations remained unchanged. There

were no statistically significant correlations between

studied genotypes and changes in alanine aminotrans-

ferase activity, creatinine and hemoglobin concentra-

tions, and number of erythrocytes and thrombocytes

(data not shown).

Discussion

According to our knowledge, this is the first study ex-

amining the association between IL1-�, IL-6, and

TNF gene polymorphisms and leflunomide treatment

outcome in RA patients. The efficacy of the therapy

was satisfactory. About 60% of patients reached 20%

improvement in ESR values after 12 months of treat-

ment. More than 90% of patients reached the 20% im-

provement level in number of swollen and tender

joints and VAS values after a 12-month course of

treatment. A 20% improvement of DAS values was

noted in about 80% of patients. Generally, there were

no significant associations between clinical improve-

ment and studied genotypes. Only the improvement in

VAS values and swollen joints after 6 months of ther-

apy correlated significantly with IL-6 genotypes.

Moreover, the improvement in DAS28 correlated

with IL-1� and TNF� polymorphisms.

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IL-1� + 3953genotypes

TNF� –209genotypes

IL-6 -174 genotypes Total for all IL-6genotypes

GG GC CC

TT GG 16 33 12 61

TT GA 7 11 5 23

TT AA 0 0 1 1

Total for IL-1� TT genotype 23 44 18 85

TC GG 8 10 6 24

TC GA 6 8 2 16

TC AA 1 0 0 1

Total for IL-1� TC genotype 15 18 8 41

CC GG 0 0 2 2

CC GA 0 0 0 0

CC AA 0 1 0 1

Total for IL-1� CC genotype 0 1 2 3

Total for all IL-1� and TNF� genotypes 38 63 28 129

The clinical efficacy and safety of leflunomide has

been assessed in several clinical trials. In placebo-

controlled studies, clinical improvement as defined by

the American College of Rheumatology (ACR) 20%

response criteria [24] was statistically significant for

leflunomide (20 mg/day) as compared with placebo.

Leflunomide showed ACR 20% response rates com-

parable with those of sulfasalazine (2 g/day) and

methotrexate (7.5–15 mg/week), and significant im-

provement in health-related quality of life and func-

tional ability compared with sulfasalazine and

methotrexate in the placebo-controlled clinical trials

[23]. The most common adverse events associated

with leflunomide treatment were gastrointestinal, con-

sisting primarily of diarrhea, increased aminotransfe-

rase activity, abdominal pain, and nausea/vomiting

[18, 20, 23–25]. In our study, leflunomide was gener-

ally well tolerated, the adverse events in the majority

were mild and often transient. There was no signifi-

cant association between adverse events and studied

genotypes. Previous studies indicated the effect of le-

flunomide on production of proinflammatory cytoki-

nes. Litinsky et al. studied the effect of leflunomide

on serum levels of MMP-1, MMP-3, IL-10, and IL-6

in patients with refractory RA and observed a signifi-

cant decrease of these parameters after therapy [16].

The authors of another study examined the effect of

leflunomide on IL-1�, TNF-�, MMP3, and nitric ox-

ide by activated human synovial tissue [6]. These

authors revealed that leflunomide inhibits the produc-

tion of IL-1�, TNF-�, MMP3, and nitric oxide by ac-

tivated human synovial tissue. The results of Li et al.

suggest also that the antiinflammatory mechanisms of le-

flunomide might be related to the inhibitory level of IL-1,

IL-6, and TNF-� from macrophages [15]. Manna et al.

showed that leflunomide also blocks NF-�B reporter

gene expression induced by TNFR1, TNFR-associated

factor 2, and NF-�B-inducing kinase (NIK), but not

strongly activated by the p65 subunit of NF-�B, suggest-

ing that leflunomide acts downstream of NIK [17]. The

authors of another study examined the immunoregulatory

action of leflunomide in the cytokine network involved in

RA pathogenesis [26]. They observed an increase in IL-

10 secretion, and a decrease in IL-11 as well as decreased

IL-6 and prostaglandin E2 synthesis.

Moreover, the results of Burger et al. and Migita et

al. confirmed that the antiinflammatory properties of

leflunomide are associated with decreased production

of proinflammatory mediators [3, 19]. In our study,

the outcome of therapy with leflunomide was associ-

ated with the improvement of disease activity parame-

ters; nevertheless, there was no significant association

with the studied polymorphisms of cytokine genes.

The results of the present study suggest that IL1�,

IL6, and TNF gene polymorphisms are not the signifi-

cant factors influencing the therapy outcome of RA

patients with leflunomide.

References:

1. Bartnicka L, Kurzawski M, DroŸdzik A, P³oñska-

Goœciniak E, Górnik W, DroŸdzik M: Effect of ABCB1

(MDR1) 3435C >T and 2677G >A,T polymorphisms and

P-glycoprotein inhibitors on salivary digoxin secretion in

congestive heart failure patients. Pharmacol Rep, 2007,

59, 323–329.

2. Brazelton TR, Morris RE: Molecular mechanisms of action

of new xenobiotic immunosuppressive drugs: tacrolimus

(FK506), sirolimus (rapamycin), mycophenolate mofetil

and leflunomide. Curr Opin Immunol, 1996, 8, 710–720.

3. Burger D, Begué-Pastor N, Benavent S, Gruaz L, Kauf-

mann MT, Chicheportiche R, Dayer JM: The active me-

tabolite of leflunomide, A77 1726, inhibits the produc-

tion of prostaglandin E(2), matrix metalloproteinase 1

and interleukin 6 in human fibroblast-like synoviocytes.

Rheumatology, 2003, 42, 89–96.

4. Chrzanowska M, Kurzawski M, DroŸdzik M, Mazik M,

Oko A, Czekalski S: Thiopurine S-methyltransferase

phenotype-genotype correlation in hemodialyzed patients.

Pharmacol Rep, 2006, 58, 973–978.

5. Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland

RA: The immunosuppressive metabolite of leflunomide

is a potent inhibitor of human dihydroorotate dehydroge-

nase. Biochemistry, 1996, 35, 1270–1273.

6. Elkayam O, Yaron I, Shirazi I, Judovitch R, Caspi D, Ya-

ron M: Active leflunomide metabolite inhibits inter-

leukin 1�, tumour necrosis factor �, nitric oxide, and

metalloproteinase-3 production in activated human syno-

vial tissue cultures. Ann Rheum Dis, 2003, 62, 440–443.

7. Fairbanks LD, Jacomelli G, Micheli V, Slade T, Sim-

monds HA: Severe pyridine nucleotide depletion in fi-

broblasts from Lesch-Nyhan patients. Biochem J, 2002,

366, 265–272.

8. Felson DT, Anderson JJ, Boers M: American College of

Rheumatology. Preliminary definition of improvement in

rheumatoid arthritis. Arthritis Rheum, 1995, 38, 727–735.

9. Felson DT, Anderson JJ, Boers M: The American Col-

lege of Rheumatology preliminary core set of disease ac-

tivity measures for rheumatoid arthritis clinical trials.

The Committee on Outcome Measures in Rheumatoid

Arthritis Clinical Trials. Arthritis Rheum, 1993, 36, 729–740.

10. Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflu-

nomide: an immunomodulatory drug for the treatment of

rheumatoid arthritis and other autoimmune diseases. Im-

munopharmacology, 2000, 47, 273–289.

286 ��

11. Kotrych K, Sulikowski T, Domañski L, Bia³ecka M,

DroŸdzik M: Polymorphism in the P-glycoprotein drug

transporter MDR1 gene in renal transplant patients

treated with cyclosporin A in a Polish population. Phar-

macol Rep, 2007, 59, 199–205.

12. Kurzawski M, Bartnicka L, Florczak M, Górnik W,

DroŸdzik M: Impact of ABCB1 (MDR1) gene polymor-

phism and P-glycoprotein inhibitors on digoxin serum

concentration in congestive heart failure patients. Phar-

macol Rep, 2007, 59, 107–11.

13. Kurzawski M, Pawlik A, Czerny B, Domanski L, Rozan-

ski J, Drozdzik M: Frequencies of the common promoter

polymorphisms in cytokine genes in a Polish population.

Int J Immunogenet, 2005, 32, 285–291.

14. Kurzawski M, Pawlik A, Górnik W, DroŸdzik M: Fre-

quency of common MDR1 gene variants in a Polish

population. Pharmacol Rep, 2006, 58, 35–40.

15. Li WD, Ran GX, Teng HL, Lin ZB: Dynamic effects of

leflunomide on IL-1, IL-6, and TNF-alpha activity pro-

duced from peritoneal macrophages in adjuvant arthritis

rats. Acta Pharmacol Sin, 2002, 23, 752–756.

16. Litinsky I, Paran D, Levartovsky D, Wigler I, Kaufman

I, Yaron I, Yaron M et al.: The effects of leflunomide on

clinical parameters and serum levels of IL-6, IL-10,

MMP-1 and MMP-3 in patients with resistant rheuma-

toid arthritis. Cytokine, 2006, 33, 106–110.

17. Manna SK, Aggarwal BB: Immunosuppressive leflu-

nomide metabolite (A77 1726) blocks TNF-dependent

nuclear factor-�B activation and gene expression. J Im-

munol, 1999, 162, 2095–2102.

18. Martin K, Bentaberry F, Dumoulin C, Dehais J, Haram-

buru F, Bégaud B, Schaeverbeke T: Effectiveness and

safety profile of leflunomide in rheumatoid arthritis: ac-

tual practice compared with clinical trials. Clin Exp

Rheumatol, 2005, 23, 80–84.

19. Migita K, Miyashita T, Ishibashi H, Maeda Y, Nakamura

M, Yatsuhashi H, Ida H et al.: Suppressive effect of le-

flunomide metabolite (A77 1726) on metalloproteinase

production in IL-1� stimulated rheumatoid synovial fi-

broblasts. Clin Exp Immunol, 2004, 137, 612–616.

20. Mladenovic V, Domljan Z, Rozman B, Jajic I, Mi-

hajlovic D, Dordevic J, Popovic M et al.: Safety and ef-

fectiveness of leflunomide in the treatment of patients

with active rheumatoid arthritis. Results of a random-

ized, placebo-controlled, phase II study. Arthritis Rheum,

1995, 38, 1595–1603.

21. Pawlik A, Kurzawski M, Górnik W, D¹browska-¯amo-

jcin E, DroŸdzik M: 677C > T and 1298A > C MTHFR

polymorphisms affect arechin treatment outcome in

rheumatoid arthritis. Pharmacol Rep, 2007, 59, 721–726.

22. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hum-

mon NP: Assessment of patient satisfaction in activities of

daily living using a modified Stanford Health Assessment

Questionnaire. Arthritis Rheum, 1983, 26, 1346–1353.

23. Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK,

Larsen A, Loew-Friedrich I et al.: Efficacy and safety of

leflunomide compared with placebo and sulphasalazine

in active rheumatoid arthritis: a double-blind, random-

ised, multicentre trial. European Leflunomide Study

Group. Lancet 1999, 353, 259–266.

24. Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R,

Cannon G, Fox R et al: Treatment of active rheumatoid

arthritis with leflunomide compared with placebo and

methotrexate. Leflunomide Rheumatoid Arthritis Investi-

gators Group. Arch Intern Med, 1999, 159, 2542–2550.

25. Van Roon EN, Jansen TL, Mourad L, Houtman PM,

Bruyn GA, Griep EN, Wilffert B et al.: Leflunomide in

active rheumatoid arthritis: a prospective study in daily

practice. Br J Clin Pharmacol, 2004, 57, 790–797.

26. Vergne-Salle P, Léger DY, Bertin P, Trèves R, Beneytout

JL, Liagre B: Effects of the active metabolite of le-

flunomide, A77 1726, on cytokine release and the

MAPK signalling pathway in human rheumatoid arthritis

synoviocytes. Cytokine, 2005, 31, 335–348.

27. Wolfe F, O’Dell JR, Kavanaugh A, Wilske K, Pincus T:

Evaluating severity and status in rheumatoid arthritis.

J Rheumatol, 2001, 28, 1453–1462.

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IL-1β, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis...

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