Intravenous Application of Omega-3 Fatty Acids in Patients with Active Rheumatoid Arthritis. The ORA-1 Trial. An Open Pilot Study

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1 ARTICLES Intravenous Application of Omega-3 Fatty Acids in Patients with Active Rheumatoid Arthritis. The ORA-1 Trial. An Open Pilot Study Burkhard F. Leeb*, Judith Sautner, Ingrid Andel, and Bernhard Rintelen Second Department of Medicine, Lower Austrian Center for Rheumatology, Humanisklinikum Lower Austria, Stockerau, Austria ABSTRACT: The objective of this work was to assess the therapeutic efficacy and tolerability of intravenously applied n-3-pufa in patients with active rheumatoid arthritis (RA). Thirty-four patients with active RA [identified as having a DAS28 (disease activity score including a 28 joint count) > 4.0] were enrolled into this 5-wk open pilot study (one group design). From the time of screening (visit 0, or V0), background therapy had to remain unchanged. Patients received 2 ml/kg (= g fish oil/kg) fish oil emulsion intravenously on 7 consecutive days (Visit 1 Visit 2, or V1 V2) in addition to their background therapy. A decrease of the DAS28 > 0.6 at day 8 (Visit 2) was the primary efficacy measure. Moreover, the DAS28 at day 35 (Visit 3, or V3), the modified Health Assessment Questionnaire, the American College of Rheumatology (ACR) response criteria (V2, V3) and the Short Form-36 (V3) were assessed. Thirty-three patients completed the trial. The mean DAS28 at V1 was 5.45;at V2, 4.51 (P <.001 V1 V2) and at V3, 4.73 (P <.001 V1 V3; V2 V3, not significantly different). Of the 34 patients, 56% achieved a reduction of the DAS28 > 0.6 at V2 (mean 1.52); 27% > 1.2. At V3, 41% of the patients showed a DAS28 reduction > 0.6 (mean 1.06), and 36% > 1.2. ACR 20 and 50% responses at V2 were seen in 29 and 12% of patients, respectively; at V3, the comparable values were 18 and 9%, respectively. Overall tolerability was excellent. Intravenous application of n-3-pufa (as an add-on therapy) was considerably well tolerated and led to improvement of the disease activity status in a reasonable number of RA patients. Future trials are warranted to answer whether the intravenous application of n-3-pufa constitutes a therapeutic option in RA patients. Paper no. L9843 in Lipids 41, (January 2006). *To whom correspondence should be addressed at Second Department of Medicine, Humanisklinikum Lower Austria, Lower Austrian Center for Rheumatology, Stockerau, Austria, A-2000 Stockerau, Landstrasse leeb.humanis@kav-kost.at Abbreviations: ACR, American College of Rheumatology; BMI, body mass index; CRP, C-reactive protein; DAS28, disease activity score including a 28-joint count; DMARD, disease-modifying antirheumatic drug(s); ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; EULARC, EULAR response criteria; ITT, intent-to-treat; M-HAQ, modified health assessment questionnaire; NS, not significantly different; NSAID. nonsteroidal antirheumatic drug(s); RA. rheumatoid arthritis; RF, IgM-rheumatoid factor; SF-36, Medical Outcomes Study Short Form 36; SJC, swollen joint count; TJC, tender joint count; V0, screening visit; V1, study entry visit; V2, visit after 1 wk; V3, final visit (4 wk after application of PUFA); VAS, visual analog scale; VAS-GH, visual analog scale of patient s general health; VAS pain, visual analog scale of patient s pain; VAS ph, visual analog scale of physician s global assessment; The habitual lifelong intake of fish and vegetables and dietary measures including the use of olive oil are supposed to exert independent protective effects on the development or severity of rheumatoid arthritis (RA) (1 3). These hypotheses are supported by epidemiological observations from selected geographical regions (4,5). The n-3 PUFA, EPA and DHA, are highly concentrated in oily fish and fish oils. These n-3 PUFA are structurally and functionally different from n-6 PUFA. In typical cases of human inflammation, the cells involved contain far higher concentrations of the n-6 PUFA arachidonic acid than of n-3 PUFA. Arachidonic acid is the precursor of prostaglandins and leukotrienes, which are known to be highly active mediators of inflammation. Consumption of fish oil causes partial replacement of arachidonic acid in inflammatory cell membranes by EPA (6). This exchange leads to a decrease of arachidonic acid-derived mediators, resulting in a potentially beneficial anti-inflammatory effect of n-3 PUFA. Moreover, a number of other effects may result from altered eicosanoid production or may be independent of this activity. For example, several animal and human studies demonstrated that the application of fish oil suppresses the synthesis of proinflammatory cytokines and is capable of reducing adhesion molecule expression (6). In clinical studies, oral supplementation with fish oil reduces signs and symptoms of RA in patients despite ongoing therapy with disease-modifying antirheumatic drug(s) (DMARD) (7). Also, fish oils have protective clinical effects in occlusive cardiovascular disease, for which patients with RA are at increased risk (8,9). Implementation of the clinical use of anti-inflammatory fish oil doses has been poor, in view of the sometimes only modest beneficial effect of oral supplementation or diets, however evident, and some problems concerning patients compliance. Secondly, the onset of dietary fish oil supplement efficacy is delayed up to 3 4 mon. To initiate a treatment with such a delayed effect requires belief in the efficacy of the prescriber and often difficult and time-consuming articulation to the patient (10). Therefore, we intended to assess the efficacy and tolerability of an intravenously administered fish oil emulsion in patients with active RA despite ongoing therapy with diseasemodifying agents and corticosteroids in hopes of achieving a rapid onset of efficacy. To our knowledge, this is the first investigation dealing with the intravenous application of highly Copyright 2006 by AOCS Press 29

2 30 B.F. LEEB ET AL. unsaturated FA in active RA patients. As this trial constituted the very first attempt, whether this treatment modality was worthwhile for further investigations the one group-design seemed to be one of the appropriate choices to be made in deciding. Here we report the results of this pilot study. PATIENTS AND METHODS All patients gave their written informed consent according to the Declaration of Helsinki. The design of the study has been approved by the local ethics committee. To be included, patients had to have active RA, according to the American Rheumatism Association criteria (11), defined as a DAS28 (disease activity score including a 28-joint count) (12) higher than 4.0 at the screening visit (visit 0, or V0) despite ongoing treatment, consisting of disease-modifying drugs, corticosteroids up to 10 mg prednisolone/d, and NSAID [nonsteroidal anti-inflammatory drug(s)] on demand. The intake of n-3- and n-6 PUFA and the average joule intake/d in the last week before inclusion were assessed. All patients were told not to change their usual diet until the end of the study (V3), to which they agreed. From V0, no change of the background therapy was allowed during the observation period. Exclusion criteria were changes in the DMARD regimen, relevant changes (exceeding ±2.5 mg prednisolone equiv/d) in the corticosteroid dosage, oral supplementation of unsaturated FA, and physiotherapy within the last 3 mon. After the screening visit (V0), patients were assessed before the first infusion (V1), after the last infusion at day 8 (V2), and 28 d thereafter (V3). Patients received 2 ml/kg (= g fish oil/kg) fish oil emulsion (Omegaven ; Fresenius-Kabi, Graz, Austria) intravenously over 4 h on 7 consecutive days in addition to their background therapy. One hundred milliliters of this preparation contains 6.56 g of n-3 PUFA, comprising 2.82 g EPA (20:5n-3), 3.09 g DHA (22:6n-3), 0.20 g a-linolenic acid (18:3n-3), and 0.45 g docosapentaenoic acid (22:5n-3). The change in the DAS28 at V2 constituted the primary efficacy criterion. A reduction of the DAS28 > 0.6 was regarded as a primary response (13). Secondary efficacy criteria comprised the DAS28 change at V3; the American College of Rheumatology (ACR) response rates (14), including the modified Health Assessment Questionnaire (M-HAQ) (15) at V2 and V3; the Medical Outcomes Study Short Form 36 (SF-36) (16) at V3; and the consumption of NSAID at V2 and V3. Tolerability was assessed by clinical examination; laboratory tests, comprising liver function tests, kidney function tests, complete blood cell count, neutral fat, total cholesterol, HDLand LDL-cholesterol, fasting blood glucose, and coagulation analysis (Quick-Test, aptt) and additionally by the reporting of side effects at V2 and V3. The body mass index (BMI) was calculated for each patient at every study phase. Statistical evaluation. The sample size estimation was based on the pilot data of 16 patients ( DAS28 V0 V1: mean = 0.37, SD = 1.0) and on the assumption that DAS28 V1 V3 will be 0.6 lower than DAS28 V0 V1. With a type I error of 5% (two-tailed) and a power of 90%, a sample size of 30 (valid cases for efficacy) was calculated. Analyses were carried out by applying the McNemar test and Student s t-test for dependent variables. For analyzing variables that were not normally distributed, the Wilcoxon-rank test was applied. Data evaluation was purely descriptive without adjustments of the P-values. Consequently, significances at P <.05 reflect the probability of differences, which can at best be used for generating hypotheses but not for proving them. RESULTS Thirty-four patients (27 81 yr; 29 female, 5 male; 25 IgMrheumatoid factor-positive) were enrolled into this open pilot study [intent-to-treat (ITT) population]. Personal data at baseline are given in Table 1. Thirty-three patients completed the trial; one patient dropped out between V2 and V3 (see Fig. 1). Three more patients were excluded from the per protocol efficacy analysis due to a DAS28 < 4.0 at V1, resulting in a per protocol population of 30 patients. Two-thirds of the patients were treated as in-patients during the 7-d treatment period, mostly for the distance between the hospital and their residence. No differences could be found between the in-patients and the group of outpatients. TABLE 1 Personal and Baseline Data of the Patient Population Investigated a ITT-population PP-population (V1 V2: n = 34) (n = 30) (V1 V3: n = 33) Age (yr; median ± 95% CI) 60 [± 4.6] 61 [± 4.2] Gender (M/F; %) 17/83 15/85 Body weight (kg; median ± 95% CI) 74.5 [± 5.5] 74[± 5.3] BMI (kg/m 2 ) (median ± 95% CI) 28.1 [± 4.73] 28.4 [± 4.64] Disease duration (mon; median ± 95% CI) 105 [± 44.0] 90 [± 45.6] DAS28 (V0; median ± 95% CI) 5.52 [± 0.27] 5.47 [± 0.26] M-HAQ (V1; median ± 95% CI) 1.4 [± 0.24] 1.4 [± 0.22] Morning stiffness (min; median ± 95% CI) 25 [± 26.5] 30 [± 25.3] Clinically active joint regions (n/patient; median ± 95% CI) 2 [± 0.4] 2 [± 0.4] Arthritis of the hand and finger joints (%) Symmetrical arthritis (%) Nodules (%) RF positivity (%) Erosions (%) a All metric variables are expressed as medians [95% CI in brackets]. PP, per protocol analysis; ITT, intent-to-treat analysis; CI, confidence interval; BMI, body mass index; DAS28, disease activity score including a 28-joint count; M-HAQ, modified health assessment questionnaire; RF, IgM-rheumatoid factor (determined by immunoturbidimetry); V0, screening visit; V1, study entry visit.

3 INTRAVENOUSLY ADMINISTERED N-3 PUFA IN RHEUMATOID ARTHRITIS PATIENTS 31 FIG. 1. Box-plots of the DAS28 in the ITT patient population (V1 V2: n = 34, V1 V3: n = 33; P <.001 V1 V2; P <.001 V1 V3; not significantly different V2 V3). DAS28, disease activity score including a 28-joint count; ITT, intent-to-treat analysis; VI, study entry visit; V2, second visit, 7 d after V1; V3, third visit, 35 d after V1. The mean values for the DAS28 in the ITT-population at the screening visit V0 (5.1, ) and at V1 (5.45; ) were not significantly different. At V2, immediately after the intervention, the mean DAS28 was 4.51 ( ); at V3, 28 d after the intervention, a reincrease to a mean of 4.71 ( ) was evident. A highly significant decrease in the DAS28 mean of 0.94 from V1 to V2 (P <.001) was apparent that could be maintained to V3 (DAS28 reduction to V1 0.72; P <.001), although a tendency to a reincrease [0.20; NS (difference not statistically significant) V2 to V3] indicated a relatively short treatment effect (see Fig. 1). In fact, 56% of the patients met the limit of a reduction of the DAS28 > 0.6 at V2, whereas at V3 in 41% of the patients this threshold could still be achieved. The 19 patients (17 female) achieving a reduction of the DAS28 > 0.6 at V2 were therefore regarded as primary responders; in 9 patients the DAS28 reduction was >1.2 (27%). At V3, 14 patients showed a DAS28 reduction >0.6, 12 patients >1.2 (36%). The mean DAS28 reduction in the responders amounted to 1.53 between V1 and V2 (P <.001) and to 1.06 between V1 and V3, respectively (P <.001). Even in the nonresponders a positive trend toward decreasing disease activity was noted. Indeed, only four patients experienced an increase of the DAS28 (mean 0.19; ) at V2, whereas at V3 eight patients faced such an increase (mean 0.46; ) compared with V2. Subgroup analysis of responders and nonresponders failed to demonstrate significant differences between the two groups or reveal predisposing factors for response. Changes of the single parameters of the DAS28 in the ITT population were as follows. The tender joint count (TJC) mean at V1 was 10 (1 25), decreased to 6 (0 25) at V2 (P =.015) and was 7 (0 26) at V3 (NS V1 V3; NS V2 V3). The mean value for the swollen joint count (SJC) was 7 (0 17) at V1, 5 (0 17) at V2 (P =.014), and 5 (0 14) at V3 (P =.043 V1 V3; NS V2 V3) see Table 2. The courses of C-reactive protein (CRP)-levels and the erythrocyte sedimentation rate (ESR) are shown also in Table 2. CRP values failed to demonstrate significant differences, whereas ESR showed a significant decrease (P =.007 V1 V2, P =.015 V1 V3). The patients global assessment (VAS-GH; visual analog scale of patient s general health) averaged 46 (16 82) at V1, decreased to25 (0 80) at V2 (P <.001) and rose to 39 (0 82) at V3 (NS V1 V3; P <.001 V2 V3). Physician s global assessment (VAS-ph) and patient s pain assessment (VAS pain) also were found to decrease significantly after the therapeutic intervention (VAS-ph: P <.001 V1 V2; P =.006 V1 V3; patient s pain: P <.001 V1 V2; P =.019 V1 V3), see also Table 2. Analysis of the per protocol population gave congruent results. The ACR response rates are given in Table 3. Whereas the M-HAQ did not change significantly throughout the observation period after the administration of the fish oil preparation (Table 2), general health as assessed by the SF-36 improved significantly from V1 to V3 (P =.015). NSAID consumption remained unchanged in 85% of the patients during the observation period; in 9% a reduction and in 6% an increase of the NSAID consumption were evident. Tolerability. Patients did not report spontaneously any of the unpleasant side effects usually associated with the oral intake TABLE 2 Disease Activity Parameters and DAS28 at V1, V2, and V3 a V1 mean (± SD) V2 mean (± SD) P-value V1 V2 V3 mean (± SD) P-value V1 V3 TJC 9.94 (7.19) 6.09 (5.82) (7.63).303 (NS) SJC 6.94 (4.22) 4.62 (3.58) (3.54).043 ESR (1st hour) (19.82) (18.00) (19.12).015 CRP (mg/dl) 2.47 (2.32) 2.12 (2.50).216 (NS) 2.18 (2.41).683 (NS) VAS GH (0 100) (17.72) (21.53) < (23.23).094 (NS) VAS ph (0 100) (22.38) (19.89) < (23.11).006 VAS pain (0 100) (20.08) (24.19) < (22.38).019 M-HAQ (0 3) 1.36 (0.68) 1.24 (0.76).09 (NS) 1.30 (0.71).531 (NS) DAS (1.05) 4.51 (1.05) < (1.33) <.001 a Values are expressed as means ± SD. TJC, tender joint count out of a 28-joint count; SJC, swollen joint count out of a 28- joint count; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; VAS-GH, visual analog scale of patient s general health; VAS ph, visual analog scale of physician s global assessment; VAS pain, visual analog scale of patient s pain; NS, not significantly different; for other abbreviations see Table 1.

4 32 B.F. LEEB ET AL. TABLE 3 ACR Response Rates in the Entire Patient Cohort a ITT-population PP-population (V1 V2: n = 34, (n = 30) V1 V3: n = 33) ACR 20 (V1 V2) (%) ACR 50 (V1 V2) (%) ACR 70 (V1 V2) (%) 7 6 ACR 20 (V1 V3) (%) ACR 50 (V1 V3) (%) 7 9 ACR 70 (V1 V3) (%) 3 3 a ACR, American College of Rheumatology; for other abbreviations see Table 1. of unsaturated FA such as fishy halitosis or fishy body odor (17). Among the measured blood parameters, no significant differences between V1 and V3 could be observed. Only LDLcholesterol changed significantly; an initial increase was followed by a final decrease at V3, matching well the experimental experience of the antihypercholesterolemic action of omega-6 FA (18). The BMI did not change significantly throughout the trial. Overall tolerability, including local reactions at the infusion site, was excellent. One patient dropped out because of a severe flare-up of the disease, another severe adverse event was caused by an acute lumbar disc herniation. Three upper respiratory tract infections and one case of local phlebitis were also observed. No adverse effect was assessed as being putatively drug-related. DISCUSSION To our knowledge, this pilot trial constitutes the first investigation dealing with the intravenous administration of n-3 PUFA, namely, a fish-oil emulsion containing high amounts of EPA and DHA, in patients with active RA. The preparation, Omegaven, is licensed for parenteral nutrition therapy. In contrast to the published trials applying capsules or diets (19,20), no problems with patients compliance, factors possibly influencing the absorption of the compounds, or gastrointestinal intolerance were to be expected in case of intravenous administration. Moreover, the doses applied during this trial were apparently higher than those that were used during preceding investigations. A major difference between oral and intravenous therapy is cost, with Omegaven treatment likely to be far more expensive on the basis of the actual price for the preparation. However, a formal costeffectiveness calculation needs to be performed on the assumption of reduced costs for Omegaven, if it is to be routinely administered in a larger patient population. As a first result we found a mean reduction of the DAS28 at V2 and V3 in the entire patient population exceeding 0.6, which represents the threshold of the European League Against Rheumatism response criteria (EULARC) (13) for a moderate therapeutic response in patients at medium disease activity. Moreover, a primary response in about 60% of the patients with a mean DAS28 reduction of about 1.5, which is considerably higher than a moderate response according to the EULARC (13), was observed. This response rate, as measured by the DAS28, which strongly reflects patient s satisfaction (21) and was just recently proposed for use in clinical trials (22), gives evidence for a mixed effect (drug + placebo) rather than for a simple placebo effect. Response as expressed by the ACR criteria was considerably lower, with an ACR 20% response in about 30% of the patients; although relatively low in this short-term observation, this response exceeds the placebo response rates in blinded RA trials (23,24). Interestingly, parameters such as the TJC, the SJC, the VAS pain, and the VAS-GH declined significantly, whereas the acute phase reactants, particularly CRP levels, did not change appreciably (Table 2). One explanation could be that the relatively short-term application of n-3 PUFA resulted in insufficient substitution of arachidonic acid within the cell membranes. This hypothesis is supported by a common feature of the patients nutrition, the consumption of a relatively high concentration of n-6 PUFA, prior to the investigation (25). The other explanation could be a placebo effect, which is inherent in open, noncontrolled trials. Considering the nature of the intervention, namely, intravenous infusion, the placebo effect could be higher than usually seen with oral interventions. Thus, the results of the study, while encouraging, have to be interpreted cautiously with regard to the placebo effect. However, a time-dependent reincrease of the disease activity parameters between V2 and V3 constituted a greater effect than is generally found with a placebo. Compared with a recently published trial dealing with the therapeutic efficacy of Mediterranean diet vs. ordinary Western diet, the mean DAS28 reduction in all patients in our investigation was almost twice as high and significant according to the EULARC (0.94 vs. 0.56) when compared with the DAS28 reduction in the Mediterranean diet group (20). Moreover, the decrease was achieved far more rapidly, namely, after 1 wk, whereas in the aforementioned trial the DAS28 decreased even after week 6. In both trials a significant amelioration of the patients general health, as expressed by the SF-36, was seen, whereas in our investigation the M-HAQ did not change significantly. It is doubtful, however, that the M-HAQ constitutes a tool for monitoring disease activity of RA (26). Two previous blinded trials compared the efficacy of oral fish-oil supplementation at dosages of 40 mg/kg/d for 15 wk and 130 mg/kg/d for 30 wk (27,28). As the DAS28 was not included in those trials a comparison can only be drawn on the basis of the single activity parameters. In both investigations the TJC and patient s global assessment decreased significantly throughout the observation period, yet much slower as in the case of intravenous administration. Thus, the primary question whether intravenous administration of n-3 PUFA leads to a significantly earlier treatment effect could be answered positively. As in preceding trials with oral preparations or diets, a positive treatment effect could be achieved, but it was far more pronounced as measured by the EULARC and occurred far earlier (20,27,28). Moreover, even in the nonresponders a positive trend to a decrease of RA activity was observed. Regardless of the consequences on RA

5 INTRAVENOUSLY ADMINISTERED N-3 PUFA IN RHEUMATOID ARTHRITIS PATIENTS 33 activity, an additional advantage of n-3 PUFA substitution (10) for RA patients is that it reduces the risk of cardiovascular disease (29), to which they are more susceptible. Given the excellent tolerability of the intravenously administered fish oil emulsion, as shown here, it seems worthwhile to investigate further the therapeutic potential of such preparations in RA patients. As the treatment effect of the intravenous application was relatively short, but occurred rapidly, the administration of repeated treatment cycles should be carefully investigated including blinded study designs. Another possibility to be evaluated would be an initial intravenously applied loading dose of n-3 PUFA followed by sustained long-term oral administration. However, the efficacy of all dietary or orally administrable therapeutic interventions depends far more on the patient s compliance and nutritional habits than intravenously applicable therapeutic regimes. In summary this pilot trial of intravenous administration of n-3 PUFA revealed moderate short-term efficacy with rapid onset and excellent tolerability. Besides the great progress in the treatment of RA during the last decade (30,31), the therapeutic administration of n-3 PUFA may constitute another possibly effective and presumably safe option for treating RA, for treating other inflammatory rheumatic diseases, and perhaps for reducing patients cardiovascular risk (17,32). COMPETING INTERESTS Study medication was supplied and statistical evaluation was financially supported by Fresenius-Kabi, Austria. 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