Effect of vitamin D on the recurrence rate of rheumatoid arthritis

Transcription

1 1812 Effect of vitmin D on the recurrence rte of rheumtoid rthritis JUNXIA YANG 1, LIN LIU 1, QINGLIN ZHANG 2, MEIRONG LI 1 nd JINGYA WANG 1 1 Deprtment of Rheumtology, 2 Centrl Lbortory, Xuzhou Centrl Hospitl, Xuzhou, Jingsu , P.R. Chin Received July 22, 2015; Accepted September 8, 2015 DOI: /etm Abstrct. Rheumtoid rthritis (RA) is n utoimmune disese tht is chrcterized by chronic inflmmtion ffecting trget tissues including the joints, bones, nd synovil membrne. However, the etiology nd pthogenesis of RA remins to be determined, nd investigtions into the tretment of RA re impertive. Vitmin D (Vit D) ws previously found to be ssocited with the ctivity of RA nd exerts therpeutic benefits. The im of the present study ws to investigte the effect of Vit D on the recurrence rte of RA. A totl of 377 ptients with RA t remission stge were divided into the norml Vit D group nd the Vit D deficient group ccording to their Vit D levels t bseline. The ptients in the Vit D deficient group were further rndomly llocted to receive tretment with or without Vit D. The ptients were followed up for 24 months, nd the visul nlogue scle, s well s the number of pin nd swelling joints were recorded every 2-3 months. In ddition, C-rective protein nd the blood sedimenttion rte were mesured every 2-3 months to ssess the recurrence of RA bsed on disese ctivity score 28 (DAS28). The recurrence rte of RA ws 16.7, 19.0 nd 29.5% for the norml Vit D group (n=168), Vit D tretment subgroup (n=84), nd non-vit D tretment subgroup (n=88), respectively. The recurrence rte of the norml Vit D group ws lower, compred to the non-vit D tretment subgroup, nd the difference ws sttisticlly significnt. However, the difference ws not sttisticlly significnt between the Vit D tretment subgroup nd non-vit D tretment subgroup. In conclusion, decresed level of Vit D is risk fctor for the recurrence of RA. Introduction Rheumtoid rthritis (RA) is n utoimmune disese chrcterized by chronic inflmmtion ffecting trget tissues including the joints, bones, nd synovil membrne. RA Correspondence to: Dr Lin Liu, Deprtment of Rheumtology, Xuzhou Centrl Hospitl, 199 Jiefng South Rod, Xuzhou, Jingsu , P.R. Chin E-mil: yngjunxi0127@126.com Key words: recurrence, rthritis, rheumtoid, vitmin D, rndomized controlled tril cuses high rte of disbility nd ultimtely leds to deth in ptients (1). However, the etiology nd pthogenesis of RA hve yet to be determined. Thus, investigtions into tretment strtegies for RA re crucil. Currently, most studies re bsed on the premise tht RA develops through n ntigentriggered chllenge-chined immune rection process, with infection nd utoimmune responses plying centrl roles in the development nd progression of RA, while genetic nd environmentl fctors re importnt influencing fctors tht my ctivte Th1 cells nd increse the secretion of cytokines including interleukin-1 (IL-1), IL-6 nd TNF-α through the mjor histocomptibility complex (2,3). These cytokines re useful in mediting the continuous ctivtion of B cells nd eventully induce synovil lesions (2,3). Vitmin D (Vit D) decreses the production of IL-17, IL-6, IL-1 nd tumor necrosis fctor-α (TNF-α) by inhibiting the immune response of Th1 cells. In ddition, ctivted Vit D my inhibit the precursors of monocytes by immune modultion effects nd inhibit the poptosis of B-cells (4). It hs been previously demonstrted tht Vit D is ssocited with the ctivity of RA nd exerts therpeutic benefits (5,6). Although in previous studies the ssocition between Vit D nd RA ws investigted, to the best of our knowledge, no study hs investigted whether Vit D ffects the recurrence rte of RA or whether Vit D supplementtion hs vrious benefits for RA ptients through reduction of the recurrence of RA, thereby proving useful for the long-term remission of RA, or reducing the ppliction of slow-cting drugs. In this rndomized, open lbel clinicl study, we investigted the effect of Vit D on the recurrence rte of RA nd found tht decresed level of Vit D in the groups exmined in the present study is risk fctor for the recurrence rte of RA. Mterils nd methods Ptients chrcteristics. RA ptients, who were treted t the outptient service of the Deprtment of Rheumtism nd Immunology, Xuzhou Centrl Hospitl (Jingsu, Chin), between October 2010 nd Februry 2014, were enrolled. A questionnire ws used to collect generl dt including ge, gender, disese durtion, nd medicl history in the previous 2-3 months, visul nlogue scle (VAS) score, ptient globl ssessment nd number of swelling nd pin joints of the ptients. In ddition, levels of C-rective protein (CRP), blood sedimenttion rte (ESR), C, P nd 25(OH)D3 of ptients were lso mesured. The inclusion criteri tht pplied were: i) ptients met the Americn College of Rheumtology nd Europen Legue Aginst Rheumtism (ACR-EULAR)

2 YANG et l: EFFECT OF VITAMIN D ON THE RECURRENCE RATE OF RA 1813 Tble I. Demogrphic dt nd bseline disese chrcteristics. Vit D deficient group Norml Vit D Vit D tretment Control subgroup Chrcteristics group (n=168) subgroup (n=84) (n=88) P-vlue Age (yers) 43.1± ± ± Mle ptients, n (%) 20 (11.9) 12(14.2) 10 (11.3) 0.82 Disese durtion (yers) 5.2± ± ± Remission time (months) 8.2± ± ± Vit D level (ng/ml) 37.6± ± ± Comprison of the Vit D level between the Vit D tretment nd non-vit D subgroups. Vit D, vitmin D. clssi fiction criteri for RA issued in 2010 (7); ii) ptient ws in remission phse in the previous 2-3 months, ccording to the ACR-EULAR 2010 criteri (8), with <1 swelling joint nd 1 tender joint, CRP <1 mg/dl, nd ptient globl ssessment 1 (rnge 0-10); nd iii) ptient did not receive glucocorticoids or Vit D during the previous 2-3 months, lthough the ptients remined on mintennce tretments with slow-cting drugs. Ptients with one or more of the following fetures were excluded: i) other comorbid rheumtic diseses; ii) poor complince to previously used tretment method; or iii) serum clcium >2.75 mmol/l or serum phosphorus >1.61 mmol/l. The study ws pproved by the Ethics Committee of the Clinicl Tril Center of the Xuzhou Center Hospitl ( ). Written informed consent ws obtined from ll the ptients prior to entering the study. Tretment method. This rndomized, controlled, openlbel study ws conducted between October 2010 nd Februry The included RA ptients were first divided into the norml Vit D nd Vit D deficient groups ccording to their bseline Vit D levels (cut-off vlue, 30 ng/dl). Rndom numbers were generted by computer to llocte ptients in the Vit D deficient group, the Vit D tretment subgroup nd the non-vit D tretment subgroup (control group). For the ptients in the Vit D tretment subgroup, lfclcidol (0.25 µg, twice dy) ws dministered s the tretment, while for ptients in the control group nd non-vit D tretment subgroup the previously used tretment method ws continued (Tble II). Ptients were followed up every 2-3 months during the 24-month follow-up period, nd VAS nd the number of swelling or tender joints were recorded. In ddition, CRP nd ESR levels were mesured. The ctivity level ws clculted bsed on the disese ctivity score 28 (DAS28). When DAS it ws deemed s RA recurrence. The Vit D3 level of the ptients ws lso mesured t the end of follow-up. In ddition, C nd P levels were mesured for the ptients who received lfclcidol. If ptients receiving lfclcidol were found with serum clcium level >2.75 mmol/l or serum phosphorus >1.61 mmol/l, tretment of lfclcidol ws discontinued nd dditionl tretments were performed to reduce serum clcium nd phosphorus. Enzyme linked immuno sorbent ssy (ELISA) kits (Roche, Bsel, Switzerlnd) were used to determine Vit D3 levels, nd blood smples were preserved in the drk. Sttisticl nlysis. SPSS 16.0 softwre (SPSS, Inc., Chicgo, IL, USA) ws used for sttisticl nlyses. Anlysis of vrince nd the t-test (two-smple/group t test nd lest significnt difference test) were used for comprison of quntittive dt. The Chi-squre test ws used for comprison of qulittive dt. P<0.05 ws considered to indicte sttisticlly significnt result. Results Generl chrcteristics. A totl of 377 eligible ptients were included in the present study, of which 185 ptients hd norml Vit D levels nd 192 ptients hd Vit D deficiency, which indicted Vit D deficiency rte of 50.9%. The 192 ptients with Vit D deficiency were subdivided into the Vit D tretment subgroup (n=93, comprising 77 women nd 16 men) nd the non-vit D tretment subgroup (n=99, comprising 83 women nd 16 men). Tble I shows the demogrphic nd clinicl chrcteristics of the ptients t bseline. No significnt difference in ge, gender, disese durtion, nd remission time t study entry ws identified for the three groups. In ddition, the Vit D level ws not significntly different between the Vit D tretment nd non-vit D tretment subgroups. Tble II provides the tretment methods pplied t study entry for the ptients, nd the dt show there ws no sttisticlly significnt difference. Vit D levels t bseline were significntly different between the recurrent ptients in the Vit D tretment nd non-vit D tretment subgroups (Tble III). Recurrence rte. After 24 months of follow up, the number of ptients lost to follow up nd who filed to comply with tretment requirements in the norml Vit D group, Vit D tretment subgroup nd control subgroup ws 17, 9 nd 11, respectively. Thus the ctul number for the three groups of complete follow up ws 168 (comprising 149 women nd 19 men), 84 (comprising 72 women nd 12 men), nd 88 (comprising 78 women nd 10 men) for the the norml Vit D group, Vit D tretment subgroup nd non-vit D subgroup, respectively.

3 1814 Tble II. Tretment methods of ptients t study entry Norml Vit D Vit D tretment Control subgroup Tretment group (n=168) subgroup (n=84) (n=88) P-vlue Methotrexte >0.05 Leflunomide Tripterygium nd methotrexte Methotrexte nd hydroxychloroquine Leflunomide nd methotrexte P>0.05, compring ech tretment method for the three groups. Vit D, vitmin D. Tble III. Comprison of the generl chrcteristics of the ptients with recurrence Norml Vit D Vit D tretment Control subgroup Chrcteristics group (n=168) subgroup (n=84) (n=88) P-vlue Age (yer) 42.1± ± ± Disese durtion (yers) 5.0± ± ± Remission time (months) 8.1± ± ± Vitmin D level (ng/ml) 36.8± ± ± Comprison of Vit D level between ptients with disese recurrence in the Vit D tretment nd non-vit D subgroups. Vit D, vitmin D. Tble IV. Comprison of recurrence rte for the three groups. P-vlue Comprison between Comprison No. of ptient Comprison Vit D tretment between norml No. of ptients without between subgroup nd Vit D group nd Group with recurrence recurrence three groups non-vit D subgroup non-vit D subgroup Norml Vit D group (n=168) Vit D tretment subgroup (n=84) Non-Vit D subgroup (n=88) Vit D, vitmin D. RA recurrence ws identified in 28 of the 168 ptients with norml Vit D (recurrence rte of 16.7%) compred with 26 ptients in the non-vit D tretment subgroup (recurrence rte of 29.5%), nd the difference ws sttisticlly significnt (P=0.02). No ptient in the Vit D tretment subgroup discontinued becuse of high clcium or high phosphorus. However, 16 ptients in the Vit D tretment subgroup were identified s hving RA recurrence, yielding recurrence rte of 19.0%, which ws not sttisticlly different from the recurrence rte in the non-vit D tretment subgroup (29.5%) (P=0.11) (Tble IV).

4 YANG et l: EFFECT OF VITAMIN D ON THE RECURRENCE RATE OF RA 1815 Discussion Previous studies hve demonstrted tht Vit D supplementtion reduces the prevlence nd ctivity of RA (5,9 11). However, few studies hve investigted the effects of Vit D on the recurrence rte of RA. In this rndomized, open-lbel clinicl study, remission phse RA ptients with decresed Vit D levels were treted with or without Vit D, nd the recurrence rte of RA ws compred. The results showed tht the recurrence rte ws sttisticlly different between the norml Vit D nd Vit D deficient groups. The results suggest tht low Vit D level constituted risk fctor for RA recurrence. Tretment with lfclcidol incresed the Vit D levels in ptients; however, the recurrence rte ws not sttisticlly different between the Vit D tretment nd non-vit D tretment subgroups. RA is n utoimmune disorder with complex pthophysiology. Genetic nd environmentl fctors contribute to the development of RA. 1,25-Dihydroxyvitmin D3 hs been hypothesized to decrese chondrolysis by the IL-1A medited production of mtrix metlloproteinses, nd thus, deficiency is potentil trigger for crtilge dmge in RA (9). Epidemiologicl studies hve demonstrted tht reduced Vit D level ws ssocited with n incresed risk for the development nd progression of utoimmune diseses including RA, systemic lupus erythemtosus, nd type 1 dibetes (10-12). Incresed intke of Vit D hs lso been ssocited with reduced risk of developing RA. In study by Merlino et l, dt from 29,368 women ged between 55 nd 69 yers were nlyzed (13). Following dministrtion of Vit D dministered in these women for 11 yers, no RA ws found, suggesting tht Vit D reduces the incidence or RA. Merlino et l reported n inverse ssocition between Vit D levels nd the risk of RA (13). In bsl pretretment conditions, proportionl inverse reltionship mong the levels of 25(OH)D nd the tender joint counts, HAQ scores, CRP levels, nd the DAS28 scores ws observed. Ech increse of 10 ng/ml in the level of 25(OH)D ws ssocited with decrese in the DAS28 score of 0.3 nd in the CRP level of 25% (14). Kröger et l studied 143 Finnish women with RA nd found tht the lowest vlues of serum Vit D were identified in ptients with the highest disese ctivity (15). In study with 19 ptients with RA treted with trditionl disese modifying nti rheumtic drugs (DMARDs), orl supplementtion with high doses of lfclcidol for 3 months reduced the severity of the symptoms in 89% of the ptients, 45% of whom chieved complete remission, nd 44% hd stisfctory results. No significnt dverse effects were identified, nd the serum clcium levels were within norml limits for ll the ptients during the period of the study (16). Vit D, closely ssocited with RA, is cost-effective with few side effects. Vit D is recommended for the preventive tretment for high-risk individuls with RA (17). Therefore, lck of Vit D tretment recommendtions for ptients with RA in remission is due to the lck of studies vilble on the effect of Vit D on the RA recurrence rte. A single study focusin on Vit D nd the recurrence rte of RA ws performed in Irn, between October 2012 nd Februry 2013, with totl of 80 RA ptients with Vit D deficiency being enrolled nd rndomly llocted to receive Vit D or plcebo in the 6-month follow-up period. The study showed tht the flre rte ws not different between two groups (18). The min drwbcks of this study were the smll smple size, lck of controls with RA ptients of norml Vit D levels, nd the shorter observtion time period of 6 months. In the present study, the effect of Vit D on the recurrence rte of RA ws evluted in 340 RA ptients in remission fter follow-up period of 24 months. Bsed on this study, ~50.9% of RA ptients in remission hd Vit D deficiency. This finding ws consistent with findings by Dehghn et l (18). The results of the present study hve shown tht the recurrence rte ws 16.7, 19.0 nd 29.5% for ptients in the norml Vit D group, Vit D tretment subgroup, nd non-vit D tretment subgroup. The recurrence rte of the norml Vit D group ws lower, compred with tht of the non-vit D tretment subgroup, nd the difference ws sttisticlly significnt, suggesting tht decresed level of Vit D is risk fctor for RA recurrence. The findings of the present study demonstrte tht the recurrence rte of the norml Vit D group ws lower nd tretment of ptients with stndrd dose of Vit D potentilly incresed the level of Vit D nd reduced the recurrence rte of RA, lthough the difference ws not sttisticlly significnt. This finding my be due to the fct tht the Vit D level of the Vit D tretment subgroup following tretment remined below the norml rnge. Therefore, more studies re required to investigte whether incresing the dose of Vit D is beneficil to ptients in order to recover norml Vit D levels, nd thus ffect the recurrence rte of RA. Vit D my exert importnt effects on utoimmune diseses, nd the dverse effects of Vit D re substntilly lower thn slow-cting drugs. References 1. Pinls RS: Survivl in rheumtoid rthritis. Arthritis Rheum 30: , Turhnoglu AD, Guler H, Yonden Z, Asln F, Mnsuroglu A nd Ozer C: The reltionship between vitmin D nd disese ctivity nd functionl helth sttus in RA. Rheumtol Int 31: , Prietl B, Treiber G, Pieber TR nd Amrein K: Vitmin D nd immune function. Nutrients 5: , Chen S, Sims GP, Chen XX, Gu YY, Chen S nd Lipsky PE: Modultory effects of 1,25-dihydroxyvitmin D3 on humn B cell differentition. J Immunol 179: , Crig SM, Yu F, Curtis JR, Alrcón GS, Conn DL, Jons B, Cllhn LF, Smith EA, Morelnd LW, Bridges SL Jr, et l: Vitmin D sttus nd its ssocitions with disese ctivity nd severity in Africn Americns with recent-onset RA. J Rheumtol 37: , Wng M, Chen D, Lou Y nd Wn R: Assocition study between 25(OH) vitmin D nd erly RA. Lb Med Clin 7: , Aleth D, Neogi T, Silmn AJ, Funovits J, Felson DT, Binghm CO III, Birnbum NS, Burmester GR, Bykerk VP, Cohen MD, et l: 2010 rheumtoid rthritis clssifiction criteri: n Americn College of Rheumtology/Europen Legue Aginst Rheumtism collbortive inititive. Ann Rheum Dis 69: , Hque UJ nd Brtlett SJ: Reltionships mong vitmin D, disese ctivity, pin nd disbility in RA. Clin Exp Rheumtol 28: , Tetlow LC nd Woolley DE: The effects of 1 lph,25 dihydroxyvitmin D(3) on mtrix metlloproteinse nd prostglndin E(2) production by cells of the rheumtoid lesion. Arthritis Res 1: 63-70, Cutolo M, Ots K, Ls K, Yprus M, Lehtme R, Secchi ME, Sulli A, Polino S nd Seriolo B: Circnnul vitmin D serum levels nd disese ctivity in RA: Northern versus Southern Europe. Clin Exp Rheumtol 24: , My E, Asdullh K nd Zügel U: Immunoregultion through 1,25-dihydroxyvitmin D3 nd its nlogs. Curr Drug Trgets Inflmm Allergy 3: , 2004.

5 Andjelkovic Z, Vojinovic J, Pejnovic N, Popovic M, Dujic A, Mitrovic D, Pvlic L nd Stefnovic D: Disese modifying nd immunomodultory effects of high dose 1 lph (OH) D3 in RA ptients. Clin Exp Rheumtol 17: , Merlino LA, Curtis J, Mikuls TR, Cerhn JR, Criswell LA nd Sg KG; Iow Women's Helth Study: Vitmin D intke is inversely ssocited with RA: results from the Iow Women's Helth Study. Arthritis Rheum 50: 72-77, Ptel S, Frrgher T, Berry J, Bunn D, Silmn A nd Symmons D: Assocition between serum vitmin D metbolite levels nd disese ctivity in ptients with erly inflmmtory polyrthritis. Arthritis Rheum 56: , Kröger H, Penttilä IM nd Alhv EM: Low serum vitmin D metbolites in women with RA. Scnd J Rheumtol 22: , Andjelkovic Z, Vojinovic J, Pejnovic N, Popovic M, Dujic A, Mitrovic D, Pvlic L nd Stefnovic D: Disese modifying nd immunomodultory effects of high dose 1(OH)D3 in RA ptients. Clin Exp Rheumtol 17: , Hrel M nd Shoenfeld Y: Predicting nd preventing utoimmunity, myth or relity? Ann NY Acd Sci 1069: , Dehghn A, Rhimpour S, Soleymni-Slehbdi H nd Owli MB: Role of vitmin D in flre ups of rheumtoid rthritis. Z Rheumtol 73: , 2014.