No association of IL-4 gene polymorphisms in Chinese patients with RA in Taiwan.

Letters to the Editor

871

Two injections of

interferon-could trigger the development

of rheumatoid arthritis

Va rious autoimmune diseases incl u d i n g rheumatoid arthritis (RA) have been admit-t e d ly manifesadmit-ted afadmit-ter inadmit-terfe ron (IFN)-α therapy against malignancies or viral he-patitis (1-3). The manifestation of RA from the therapy takes usually several months (4-7). Here we present a case of RA which has been precipitated after only 2 injections of I F N -α and discussed the significance of IFN-αas a trigger of immune abnormalities in the pathogenesis of RA.

Eighteen months earlier, a 50-year-old wo-man began to feel polya rt h ra l gia in the metacarpal, proximal interphalangeal (PIP) and wrist joints and the serum rheumatoid factor (RF) was positive, although her symp-toms were self-limiting. Three months be-fore admission, because of the renal cell carcinoma, she was administered after ne-phrectomy with 3 x 106_{units of IFN-}α

(Su-miferon, Sumitomo Pharmaceutics, Japan), followed by spike fever and pol yarthralgia, and the former subsided with aspirin. Be-cause polya rt h ra l gia gra d u a l ly wo rs e n e d and morning stiffness of the fingers was noted after the second injection performed a week later, IFN-αwas discontinued, and she was referred to our clinic. There were no abnormalities except for swelling of bi-lateral PIP and wrist joints. The erythrocyte sedimentation rate (ESR) was 38 mm/h and CRP was 1.0 mg/dl. The titer of the serum RF determined by RF-III ELISA kit (Eiken Chemical Co., Japan) was 30 IU/ml (N < 10 IU/ml) and increased to 56 IU/ml 2 weeks later. The serum anti-nuclear antibody and antibodies to various viruses including EB v i ru s , h ep atitis C virus or human T- c e l l leukemia virus-1 was negative. An X-ray of the hand disclosed no osteoporosis or bone erosions. Under the diagnosis of RA accor-ding to the criteria by American Rheuma-tism Association (8), bucillamine, an anti-r h e u m atic age n t , was administeanti-re d. Te n weeks later, polyarthralgia, swelling of the joints and morning stiffness became mild, as the titer of RF decreased to 7 to 19 IU/ ml. There has been no recurrence of renal cell carcinoma for more than 9 months. In this case , polyarthritis flared up, persist-ed for over 8 weeks with elevatpersist-ed RF titers after only 2 injections of IFN-αand became mild 10 weeks after discontinuation of IFN-α, while the effect of bucillamine was un-c e rtain. On the other hand, her un-cl i n i un-c a l course was not compatible with paraneo-plastic syndrome or viral infections. A l-though coincidence of the manifestation of RA and IFN-αtherapy could not be exclud-ed, from difference of the clinical course

between 15 months before and 9 months after the IFN-αtherapy, it is likely that the administration of IFN-α might have trig-gered off the manifestation of RA.

IFN-αis known to activate macrophages to secrete tumor necrosis factor (TNF)-α or interleukin (IL)-1, and to show chemotactic activity for neutrophils. Furthermore, it has been reported that IFN-αup-regulates ex-pression of major histocompatibility com-p l ex antigens on antige n - com-p resenting cells (9). Among pro i n fl a m m at o ry cy t o k i n e s , TNF-αand IL-1 have been thought impor-tant because they induce production of other proinflammatory cytokines or prosta-glandins, proliferation of fibroblasts or acti-vation of osteoclasts, all of which are in-volved in the pathogenesis of RA. There-fo re, ch ronic stimu l ation with IFN-α i s likely to be associated with exacerbation of RA. In general, 3 to 10 x 106_{units/day of}

IFN-αis administered daily or once a week for several months. Time to onset of differ-ent autoimmune diseases after initiation of the IFN-αtherapy has varied from 3 to 5 months in RA (2,10). From this case, very minor doses of IFN-αcould be enough to trigger a vicious cycle of immune abnor-malities associated with the pathogenesis of RA. Particularly, when the patients have a history of rheumatoid arthritis or arthralgia, IFN-αshould be used carefully under con-sideration of the manifestation of RA.

M. F

M. O

Y. N

K. K

M. S

A. K

Division of Hematology, Nephrology and Rheumatology, Kinki University School of Medicine, Osaka, Japan.

Address correspondence and reprint requests to: Masanori Funauchi, Division of Hematol-ogy, Nephrology and RheumatolHematol-ogy, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Osaka, Japan.

E-mail: [email protected]

References

1.P I T TAU E, BOGLIOLO A , TINTI A et al.:

Development of arthritis and hypothyroidism during alpha-interferon therapy for chronic hepatitis C. Clin Exp Rheumatol 1997; 15: 415-9.

2.OKANOUE T, SAKAMOTO S, ITOH Yet al.:

Side effect of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996; 25: 283-91.

3.I OA N N O U Y, ISENBERG DA: C u rrent ev i-dence for the induction of autoimmune rheu-m atic rheu-manife s t ations by cytokine therapy.

Arthritis Rheum 2000; 43: 1431-42.

4.NADIR F, FAGIUOLI S, WRIGHT HI et al.:

Rheumatoid arthritis: A complication of in-t e r fe ron in-therapy. J Okla Sin-tain-te Med A s s o c 1994; 87: 228-30.

5.PASSOS DE SOUZA E, E VA N G E L I S TA SE-GUNDO PT, JOSE FF, LEMAIRE D,

SANTIA-GO M: R h e u m atoid art h ritis induced by a l p h a - i n t e r fe ron therapy. Clin Rheumat o l 2001; 20: 297-9.

6.JOHNSON DM, H AYAT SQ, BU RTON G V: R h e u m atoid art h ritis complicating adjuva n t interferon-alpha therapy for malignant mela-noma. J Rheumatol 1999; 26: 1009-10. 7.NESHER G, RUCHLEMER R:

Alpha-interfer-on-induced art h ri t i s : Clinical pre s e n t at i o n t re at m e n t , and prevention. Semin A rt h ri t i s

Rheum 1998; 27: 360-5.

8.ARNETT FC, EDWOTHY SM, BLOCH DA et al.: The American Rheumatism Association

1987 revised cri t e ria for cl a s s i fi c ation of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-34.

9.DE M A E YA R E , DE MA E YA R - G U I G NA R D J: Type I interferon. Int Rev Immunol 1998; 17: 53-73.

10.KOTTER L, MULLER CA, EINSELE H, MOH-REN M, KANZ L: I n t e r fe ro n -α - a s s o c i at e d polyarthritis. Possible induction arthritis by interferon-α: Two case report and review of the literature. J Rheumatol 1999; 58: 185-95.

No association of

interleukin-4 gene polymorphisms in

Chinese patients with

rheuma-toid arthritis in Taiwan

Sirs,

The genetic background of RA is still most-ly unknown. Onmost-ly a few cytokine ge n e polymorphisms (TNFα, IL-6, and IL-1α) have been studied. To date, genetic studies of multifactorial diseases have been diffi-cult due to uncertainty surrounding the presence of a polygenic trait. In the present study, we chose 2 gene polymorphisms (IL-4 promoter and IL-(IL-4 intron 3) to screen can-didate genes located outside the MHC. The gene for IL-4 has been mapped to the q arm (q23-31) of chromosome 5 (1), in a cluster of cytokine genes (IL-3, IL-5, IL-9, IL-13, IL-15, GM-CSF, and interferon regulatory factor). The poly m o rphism is a C to T change at position –590 counting from the first ATG codon (2). The polymorphism is u p s t ream of all the prev i o u s ly descri b e d control elements of IL-4. Another polymor-phism has been located in the third intron, and is composed of a variable number of tandem rep e ats (VNTR) of a 70-bp se-quence (3).

The purpose of this study was to examine whether Interleukin-4 gene polymorphism are markers of susceptibility of rheumatoid arthritis (RA) in Taiwan. The study includ-ed 104 patients with RA (4) and 103 unre-lated, healthy individuals who were living in the middle of Taiwan were used as con-t rols. From genomic DNA , 2 poly m o r-phisms in genes for IL-4 (IL-4 intron 3 and IL-4 promoter) were typed. Allelic frequen-cies and carriage rates were compared

be-Letters to the Editor

tween RA patients and control populations. As shown in tabl e, no significant as-sociations were observed in the distribution of genotypes, cytokine allele frequencies, and carriage rates between patients with RA and healthy controls. Furthermore, no sta-tistical association in the distribution of IL-4 gene polymorphism frequency between RF positive and RF negative patients was observed.

In our present study, the distribution of IL-4 genotype at intron 3 (RP1/RP1 64.1%,RP1/ RP2 32% and RP2/RP 23.9%) and promot-er (C/C 5.8%, C/T 31.1%, and T/T 63.1%) in healthy Taiwanese subjects was different with data reported by Cantagrel et al. (5) in Fre n ch Caucasian controls (intron 3 RP1/RP1 0%, RP1/RP2 17.9% and RP2/ RP2 82.1% and promoter C/C 69.5%, C/T 30.5%, and T/T 0%, respectively). Recent-ly, Cantagrel et al. demonstrated that the RP1 allele of the IL-4 gene was found a significantly higher frequency in French Cau -casian RA patients compared with controls (5). In addition, the independent OR for IL-4 RP1 and IL-IL-4 –590* T alleles in RA sus-ceptibility were both much lower than the OR for carri age of both of these alleles together. While RA patients positive for the RP2 allele was found associated with less joint destruction in another report by Buchs et al. (6). In our present study, we did not observe any association in the distribution of IL-4 (intron 3 and promoter) genotypes, cytokine allele fre q u e n c i e s , and carri age rates between patients with RA and healthy c o n t rols. Although the fre q u e n cy of the genotype of IL-4 promoter C/T in the RF positive patients was higher than that of the RF negative patients,the association did not reach significant difference.

In summary, the polymorphisms in the IL4 gene (intron 3 and promoter) studied here did not reveal any association with an in-creased risk of developing RA in Taiwan Chinese when compared with the control group. These results may be due to ethnic

factors and will need further confirmation.

C.-M. H

J.-Y. W

M.-C. W

_{F.-J. T}

Division of Immunology and Rheumatology, Department of Internal Medicine, and

1_{Department of Medicine Genetics, China}

Medical College Hospital, Taichung, Taiwan. Address correspondence and reprint requests to: Fuu-Jen Tsai, Department of Medical Genetics, China Medical College Hospital, No 2, Yuh Der Road, Taichung, Taiwan. E-mail: [email protected]

References

1.Le BEAU MM,LEMONS RS, ESPINOSA R,LAR-SON RA, ARAI N , ROWLEY JD: Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and re-ceptors and are deleted in myeloid leukemias with a del (5q). Blood 1989; 73: 647-50. 2.RO S E N WASSER LJ, KLEMM DJ, D R E S BAC K

J K et al. : P romoter poly m o rphisms in the

chromosome 5 gene cluster in asthma and ato-py. Clin Exp Allergy 1995; 25: 74-8. 3.MOUT R, WILLEMZE R, LANDEGENT JE:

Re-peat polymorphisms in the interleukin-4 gene.

Nucleic Acid Res 1991; 19: 3763.

4.ARNETT FC, EDWORTHY SM, BLOCH DA et a l. : The A m e rican Rheumatism A s s o c i at i o n

1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 3: 315-24.

5.CA N TAGREL A , NAVAUX F, L O U B E T- L E S-COULIE Pet al.: Interleukin-1β, interleukin-1 receptor antagonist, interleukin-4, and inter-leukin-10 gene polymorphisms. Relationship to occurrence and seve rity of rheumat o i d arthritis. Arthritis Rheum 1999; 42: 1093-100. 6.BU C H S N, S I LV E S T R I T, DI GIOV I N E F S e t al.: IL-4 VNTR gene polymorphism in

chron-ic polyarthritis. The rare allele is associated with protection against destruction. Rheuma

-tology 2000; 39: 1126-31.

Melatonin in rheumatoid

arthritis: A disease-promoting

and modulating hormone ?

An altered functioning of the hypothalamic-pituitary-adrenal/gonadal axis seems to be an important factor in the perpetuation and circadian symptoms of rheumatoid arthritis (RA) (1). As a matter of fact, the clinical symptoms of RA show a circadian variation with joint stiffness and pain being more prominent in the early morning. Consistent-ly, human inflammatory cytokine pro-duction exhibits a diurnal rhythmicity with peak levels during the night and early morn-ing at a time when plasma cortisol is lowest (2). The existence of a causal relationship between plasma cortisol and production of inflammatory cytokines is suggested by the finding that administration of cort i s o n e acetate at physiological doses results in a corresponding reduction in pro-inflamma-tory cytokine production (2). An inappro-priate low secretion of cortisol is a further typical feature of the inflammatory disease in patients with RA (1). Similarly, t h e secretion of adrenal androgens is signifi-cantly reduced (1).

However, cortisol may not be the only hor-mone affecting cytokine rhythms; a strong candidate is the pineal indoleamine mela-t o n i n , mela-the circadian hormone “par ex c e l-l e n c e ” , whose synthesis and secretion is regulated by the photoperiod with peak lev-els during the night,darkness hours (3). The circadian nocturnal release of melatonin has a profound influence on the internal envi-ronment of the organism with diverse phys-iological effects. Its main function seems to be that of synchronising the organism in the photoperiod and may play a role in repro-d u c t i o n , m e t ab o l i s m , s e a s o n a l i t y, t h e r-moregulation and immunity (4). In periph-e ral blood mononu clperiph-ear cperiph-ells, m periph-e l at o n i n has been reported to stimulate the produc-tion of interleukin-2 interferon-gamma and interleukin-6 but not that of interleukin-4 (5). Phy s i o l ogi c a l ly, the nocturnal MLT peak has been associated with high IFN-γ/ i n t e rleukin-10 rat i o , i . e. the melat o n i n rhythm positively correlated with the rhyth-micity of T-helper cell type 1/ T helper cell type 2 ratio (6). In ischaemic stroke patients an impaired nocturnal MLT excretion has been associated with impaired cell-mediat-ed immunity and changes of lymphocyte subsets (7). Relevant to RA, melatonin can promote collagen-induced arthritis in mice (8) and stimulate primary cultures of syn-ovial macrophages from RA patients to pro-duce interleukin-12 as well as nitric oxide (9).

872

Table I. Comparison of allelic frequency between rheumatoid arthritis (RA) patients and

control subjects.

Alleles frequency Carriage rate

RA Controls P RA Controls P IL4 Intron 3 RP1 173 (83.2) 165 (80.1) NS 101 (97) 99 (96.1) NS RP2 34 (16.3) 41 (19.9) NS 31 (29.8) 37 (35.9) NS RP0 1 (0.5) 0 NS 1 (0.9) 0 IL-4 promoter C 30 (14.4) 44 (21.4) NS 27 (26) 38 (35.8) NS T 178 (85.6) 162 (78.6) NS 101 (97.1) 97 (94.2) NS *NS: not significant.