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1 From the School of Sport, Health, and Exercise Sciences, University of Wales, Bangor, United Kingdom (SMM, KRC, ABL, and PJM), and the Rheumatology Department, Gwynedd Hospital, Bangor, United Kingdom (GM and PJM)
2 Supported by Wyeth Pharmaceuticals and the North West Wales National Health Service (NHS) Trust R&D Committee. 3 Address reprint requests to SM Marcora, School of Sport, Health, and Exercise Sciences, University of Wales, Bangor, George Building, Holyhead Road, Bangor LL57 2PZ, United Kingdom. E-mail: s.m.marcora{at}bangor.ac.uk.
ABSTRACT
Background: Tumor necrosis factor (TNF) is an important mediator of cachexia, and its blockade prevents catabolism in animal models. However, little evidence shows that anti-TNF therapy is effective in treating cachexia in humans.
Objective: The main aim of this study was to investigate the effect of etanercept, a synthetic soluble TNF receptor, on body composition in patients with early rheumatoid arthritis (RA).
Design: Twenty-six patients were randomly assigned to 24 wk of treatment with etanercept or methotrexate; the latter is the first-line therapy for RA. Body composition, physical function, disease activity, systemic inflammation, and the circulating insulin-like growth factor (IGF) system were measured at baseline (week 0) and at follow-up (weeks 12 and 24). Twelve patients in each treatment group (9 F, 3 M) completed the study.
Results: Overall, no important changes in body composition were observed, despite a transient increase in IGF-I at week 12 (P < 0.01). However, the secondary analysis of those patients (6/treatment group) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained: 44% of weight gained in the etanercept group was fat-free mass, as compared with only 14% in the methotrexate group (P = 0.04). Etanercept and methotrexate were equally effective in controlling the disease and improving physical function.
Conclusions: Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo. However, TNF blockade seems to normalize the anabolic response to overfeeding and, if these findings are confirmed, may be useful in conditions characterized by anorexia and weight loss.
Key Words: Cachexia • tumor necrosis factor • rheumatoid arthritis • body composition • weight gain
INTRODUCTION
Cachexia, defined as an accelerated loss of skeletal muscle in the context of a chronic inflammatory response (1), is common to several systemic diseases, including AIDS, cancer, end-stage renal disease, chronic obstructive pulmonary disease, congestive heart failure, and rheumatoid arthritis (RA) (1, 2). Because cachexia is associated with reduced physical function and premature death, considerable effort has been made to understand its pathophysiology and to develop effective therapies to counter it (1, 2).
Currently, inflammatory cytokines such as tumor necrosis factor (TNF) are considered the main mediators of cachexia (1, 2). TNF, formerly named cachectin, can induce muscle loss directly by both stimulating muscle protein breakdown (3) and reducing the sensitivity of skeletal muscle cells to anabolic stimuli (4). TNF also down-regulates the systemic and local expression of anabolic hormones and growth factors, such as insulin-like growth factor I (IGF-I) (4), and induces the anorexia and physical inactivity (the so-called "sickness behavior") that exacerbate cachexia (1, 2). Consequently, it is not surprising that, in animal models, biological therapies aimed at neutralizing the activity of TNF have shown significant anticachectic effects (5–7).
On the basis of this evidence, anti-TNF therapy was proposed for the treatment of cachexia in a variety of cachectic diseases (1, 2, 8, 9), but to date little evidence exists for its efficacy in humans. In 1998, Clark et al (10) reported the effects of administering a monoclonal antibody against TNF to 28 patients with severe sepsis. Compared with the placebo group (n = 28), the treated group showed no significant effects on total-body protein loss and hypermetabolism. These negative results are not surprising, considering that this anti-TNF therapy had little effect on the overwhelming cytokine response characteristic of severe sepsis. More recently, Briot et al (11) conducted a 1-y prospective study on the effects of anti-TNF therapy with either etanercept (a synthetic soluble TNF receptor) or infliximab (a monoclonal antibody) on body composition in 19 patients with spondyloarthropathy, a chronic inflammatory disease complicated by cachexia (12). It is interesting that a significant increase in weight and total lean mass was observed in those 19 patients without any change in fat mass in response to treatment. A significant but transient increase in circulating IGF-I was also measured. Unfortunately, this study was uncontrolled; therefore, it is not clear whether these anabolic effects are specific to anti-TNF therapy or are merely a generic response to improved well-being, appetite, and physical activity secondary to reductions in systemic inflammation and symptoms. Two large randomized controlled trials of etanercept and infliximab for the treatment of cancer cachexia-anorexia syndrome are ongoing.
We present here the results of a randomized controlled trial of etanercept for the treatment of cachexia in patients with early RA. A placebo-controlled study was not feasible because withholding treatment in early RA is not ethical. Therefore, we compared etanercept with methotrexate, a disease-modifying antirheumatic drug (DMARD) commonly used for the treatment of RA. Comparative studies of etanercept and methotrexate in early RA have been published (13), but this is the first clinical trial to include measures of body composition, the main outcome variable in clinical trials for the treatment of cachexia (14). Secondary outcomes were physical function, disease activity, systemic inflammation, and the circulating IGF system, a potential mediator of the putative anabolic effects of anti-TNF therapy.
SUBJECTS AND METHODS
Subjects
Twenty-six patients were recruited by one of the investigators (GM) from the Early Synovitis Clinic at the Rheumatology Department of Gwynedd Hospital. The main inclusion criteria were age 18 y, a diagnosis of RA according to the 1987 revised criteria of the American Rheumatism Association (15), <6 mo history of RA, and active disease classified as a disease activity score on 28 joints (DAS28) of >3.2 (16). Potential participants were excluded from the study if they had previously received any DMARD (including biologics) or corticosteroid therapy, had a recent history of important infection, had any concurrent disease that prevented safe participation in the required physical function tests (eg, uncontrolled hypertension or musculoskeletal injury), had cognitive impairment, or had any other cachectic disease (eg, cancer or chronic heart failure). Patients were also excluded if they were taking drugs or nutritional supplements known to affect skeletal muscle mass or were participating in regular and intense physical training. Twelve subjects in each patient group (9 F, 3 M) completed the study.
All volunteers gave written informed consent before beginning the study. The study protocol was approved by the North Wales Health Authority Research Ethics Committee.
Study design and treatment
After baseline assessment (pretest), participants were assigned to a 24-wk regimen of etanercept or methotrexate on the basis of a computer-generated list of random numbers. Both the patients and the clinician responsible for their management (GM) were aware of treatment allocation. However, the investigators involved in the assessment of body composition and physical function (SMM and KRC) were blinded to treatment allocation until after statistical analysis was completed. Patients were assessed again at the end of week 12 (midtest) and week 24 (posttest) of follow-up.
Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75-kDa TNF receptor linked to the Fc portion of human immunoglobulin G1. This TNF-blocking agent is approved for the management of RA and other rheumatic diseases (17) and was supplied by Wyeth Pharmaceuticals (Madison, NJ) in 25-mg single-use vials. The contents of the vials were reconstituted with bacteriostatic water and injected subcutaneously twice a week as recommended by the manufacturer. Methotrexate is an antimetabolite commonly used as first-line therapy for RA because of its antiinflammatory and immunosuppressive effects (18). Patients assigned to treatment with methotrexate were given an oral dose of 7.5 mg/wk for a month. If deemed necessary, this dose was increased to a maximum of 15 mg/wk for the second month and 20 mg/wk for the subsequent 4 mo. Patients taking methotrexate also received the recommended folic acid supplementation (10 mg/wk taken the day of methotrexate administration). Symptomatic use of nonsteroidal antiinflammatory drugs and analgesics, but not corticosteroids, was allowed in both treatment groups. All participants were also instructed not to start regular and intense physical training and to maintain their usual dietary habits throughout the study period.
Outcome measures
Body mass and composition
Body mass and composition and physical function were measured at baseline and during follow-up by the same investigators (SMM and KRC) in the School of Sport, Health, and Exercise Sciences, University of Wales, Bangor, at approximately the same time of the day and under standard laboratory conditions. On each occasion, subjects were fasting when they came to the laboratory and were asked to void and to remove all metallic objects. Subjects were also instructed beforehand to avoid strenuous exercise in the 24 h before testing and were questioned as to whether they had orthopedic metal or silicone implants. During testing, subjects were allowed to wear only socks, shorts, underpants (no bra), and a tee-shirt.
Body mass was measured to the nearest 0.1 kg with the use of a calibrated balance scale (Seca, Hamburg, Germany). Total and regional (left and right arms, left and right legs, trunk, head) body composition was assessed by using dual-energy X-ray absorptiometry (DXA) with the use of a pencil-beam scanner (QDR1500; Hologic, Bedford, MA) that calculates the masses (in g) of 3 compartments: bone mineral content, fat mass, and lean mass. The sum of total bone mineral content and total lean mass corresponds to fat-free mass (FFM). Percentage body fat was calculated by using the following equation:
RESULTS
Patient characteristics and course of treatment
We screened 39 patients. Six patients declined to participate, and 7 others were excluded for various reasons (Figure 1). The remaining 26 patients were randomly allocated to treatment with etanercept (n = 12) or methotrexate (n = 14). One subject withdrew because she lost interest in the study when allocated to methotrexate, and another patient in the methotrexate group violated the protocol by starting an intense and regular physical training program during the study period. Therefore, the final analysis included a total of 24 patients (ie, 12/treatment group).
FIGURE 1.. Flow of participants through each stage of the trial.
With the exception of the HAQ score (P = 0.02), no significant between-group differences were observed at baseline in sex distribution (9 women and 3 men in each treatment group), age (etanercept: 54 ± 11 y; methotrexate: 50 ± 15 y; P = 0.48), height (etanercept: 165 ± 7 cm; methotrexate: 163 ± 7 cm; P = 0.52), body mass index (etanercept: 28 ± 7; methotrexate: 28 ± 4; P = 0.89), body mass and composition, physical function, disease activity, CRP, and IGF system (Tables 1, 2, and 3). Seven patients in each treatment group were positive for rheumatoid factor. At baseline, the average appendicular (arms plus legs) lean mass was 14.0 ± 2.1 kg for women and 21.0 ± 5.0 kg for men, which suggests that a significant loss of skeletal muscle mass had already occurred in these patients (24).
View this table:
TABLE 1. Effects of 24 wk of treatment with etanercept or methotrexate on body mass and composition in patients with early rheumatoid arthritis1
View this table:
TABLE 2. Effects of 24 wk of treatment with etanercept or methotrexate on disease activity, systemic inflammation, and physical function in patients with early rheumatoid arthritis1
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TABLE 3. Effects of 24 wk of treatment with etanercept or methotrexate on the circulating insulin-like growth factor system in patients with rheumatoid arthritis1
The methotrexate dose was escalated to 20 mg/wk in all but 2 patients, who required only 17.5 and 10 mg/wk, respectively, to control disease activity. Two subjects in the methotrexate group did not respond to treatment as defined by the criteria of the European League Against Rheumatism for a response with respect to RA (16). Similarly, 3 patients did not respond to treatment with etanercept. The only significant adverse event occurring during the study was a mild skin reaction at the injection site in 1 patient in the etanercept group.
Effects on body mass and composition
Body mass and composition at baseline and follow-up are shown in Table 1. Neither a significant treatment x time interaction nor a significant main effect of time on body mass (Table 1) was observed. Individual pretest-posttest changes in measured body mass were highly correlated to changes in body mass by DXA (P < 0.01) (Figure 2), which confirms the internal validity of our main body-composition measure as recommended by Lohman et al (25).
FIGURE 2.. Pearson's product-moment correlation between change (posttest score –pretest score) in body mass by scale and change in body mass by dual-energy X-ray absorptiometry (DXA) in 24 patients with early rheumatoid arthritis treated for 24 wk with etanercept or methotrexate.
With the exception of arm lean mass (P = 0.05), no significant treatment x time interaction was observed in any of the measured body compartments (Table 1). Tukey's tests on arm lean mass showed no significant changes over time within the methotrexate group, but a significant increase at week 12 (P < 0.05) and no further significant change at week 24 was observed in the etanercept group. No significant main effects of time were observed on leg lean mass, total lean mass, total bone mineral content, total FFM, trunk fat mass, percentage body fat, ICW, extracellular water, TBW, FFM hydration, or total body protein. However, a trend was seen for an increase in total fat mass in the treatment groups combined (main effect of time: P = 0.06).
The secondary analysis within the subgroup of patients who gained >3% of their baseline body mass over the 6 mo follow-up period (6/treatment group) found a significant effect of treatment. Although the amount of weight gained by these subjects did not differ significantly between the methotrexate (3.3 ± 1.7 kg) and the etanercept (4.4 ± 2.4 kg) groups (P = 0.37), a significant difference was observed in the composition of the body mass gained (Figure 3): the patients in the etanercept group gained a significantly (P = 0.04) greater proportion of FFM than did the patients in the methotrexate group (Figure 3). It is important that baseline percentage body fat (etanercept: 40.7 ± 7.9%; methotrexate: 39.8 ± 8.7%; P = 0.86) and energy balance (etanercept: 94 ± 42 MJ; methotrexate: 108 ± 45 MJ; P = 0.60) over the 6-mo follow-up did not differ between the treatment groups.
FIGURE 3.. Mean (±SE) effect of treatment with etanercept or methotrexate on the composition of body mass gained [% of fat-free mass (FFM)] in the 12 patients with early rheumatoid arthritis who had a significant increase in body weight over the 6-mo follow-up period. , Fat mass; , FFM. Data were analyzed by unpaired t test.
Effects on physical function
Performance on the various physical function tests and the HAQ scores at baseline and follow-ups are shown in Table 2. No significant treatment x time interaction was observed in any of the measured functional variables. However, significant main effects of time were observed for hand-grip strength (P < 0.01), arm-curl test performance (P < 0.01), walking velocity (P < 0.01), sit-to-stand test performance (P < 0.01), and HAQ (P < 0.01). Hand-grip strength increased significantly between pretest and midtest (P < 0.01), but no further improvements were measured at week 24 (P = 0.43). The number of repetitions performed during the arm-curl test was significantly (P < 0.01) greater at week 12 than at baseline, and a smaller but still significant (P = 0.01) improvement also occurred between weeks 12 and 24. Similar to arm-curl test performance, walking velocity increased significantly from baseline to midtest (P < 0.01); only a small further improvement was seen at week 24 (P = 0.07). Finally, a significant (P < 0.01) improvement was observed in sit-to-stand test performance at week 12 compared with baseline, and a smaller increase was seen between weeks 12 and 24 (P = 0.01). Overall, these objective improvements in physical function were also perceived by the patients who reported significantly less difficulty in performing activities of daily living after the initial 12 wk of treatment (P < 0.01), albeit no further improvements in HAQ were seen between weeks 12 and 24 (P = 0.34).
Effects on disease activity and systemic inflammation
Disease activity and CRP at baseline and follow-up are shown in Table 2. No significant treatment x time interaction was observed in DAS28. However, a significant (P < 0.01) main effect of time was observed. This was secondary to a large decrease in disease activity between baseline and week 12 and a further, smaller improvement between weeks 12 and 24 (both: P < 0.01). A significant decrease also was observed in systemic inflammation as measured by serum CRP concentration (main effect of time: P < 0.01), but no significant treatment x time interaction was seen (Table 2). The decrease was significant after the first 12 wk of treatment (P < 0.01), and no further improvement was seen between weeks 12 and 24 (P = 0.99).
Effects on the insulin-like growth factor system
Serum concentrations of IGF-I, IGF-II, and IGFBP-3 at baseline and follow-up are shown in Table 3. No significant treatment x time interaction was observed in any component of the IGF system (Table 3). However, a significant (P < 0.01) main effect of time on serum IGF-I was observed. Post hoc analysis showed an increase between baseline and week 12 (P < 0.01) and a return to baseline values by week 24 (P < 0.01). A similar trend was observed for serum IGFBP-3 (main effect of time: P = 0.06) but not for serum IGF-II (Table 3).
DISCUSSION
This is the first randomized controlled trial of anti-TNF therapy for cachexia of chronic disease. Because irreversible erosion of articular cartilage and bone occurs early in RA, the provision of placebo to a control group of patients would be unethical, and, consequently, any such patients could not be included in the study. Furthermore, we wanted to separate the specific effects of complete TNF blockade from the generic effects of reducing systemic inflammation and symptoms, because the generic effects may stabilize cachexia by improving well-being, appetite, and physical activity. Therefore, the control group was treated with methotrexate, an immunosuppressant and antiinflammatory agent commonly used as first-line therapy for RA (18).
As previously found in larger clinical trials comparing etanercept with methotrexate in patients who had early and active RA, both treatments induced a significant and sustained reduction in disease activity and systemic inflammation and a concomitant improvement in subjective measures of disability (13). We extended these findings by providing evidence that both etanercept and methotrexate are effective in improving objective measures of upper- and lower-body function. This finding is important because the measurement of global physical function was recently recommended in patients with RA (26).
Contrary to our expectations, however, our primary analysis did not show etanercept to be superior to methotrexate in the treatment of rheumatoid cachexia. Although a significant increase was observed in arm lean mass in the etanercept group, that increase had occurred by week 12, and no further gains were observed at week 24. In addition, this effect was isolated, and neither etanercept nor methotrexate induced significant increases in leg lean mass, total lean mass, FFM, ICW, or total body protein. Also no evidence was found for a differential effect of etanercept on joint tenderness and swelling in the arms (data not shown). Therefore, we believe that the apparent anabolic effect of etanercept in upper-limb musculature is likely to be a type I error and of no important clinical significance. Overall, if we make the reasonable assumption that untreated patients with active disease would have lost a significant amount of muscle mass over the same period (27), etanercept and methotrexate seem equally effective in stabilizing rheumatoid cachexia in the short term. Although this positive effect may simply be mediated by improvements in well-being, appetite, and physical activity secondary to reductions in systemic inflammation and symptoms, it is also possible that not only etanercept, but also methotrexate, has a direct anticatabolic effect. This possibility has been suggested by Rall et al (28), who found no evidence of accelerated whole-body protein breakdown, a cardinal feature of cachexia, in a small group of patients with RA who were treated with methotrexate. However, numerous cross-sectional studies of patients with long-standing RA (average disease duration, 10 y) treated with methotrexate and other DMARDs have consistently shown a significant, 12% reduction in muscle mass and a concomitant increase in fat mass, as compared with healthy control subjects (29–37). Thus, it is likely that methotrexate and other DMARDs are not totally effective in preventing rheumatoid cachexia in the long term. The long-term effects of anti-TNF therapy on body composition in patients with RA are unknown at present. However, continued treatment with etanercept is more effective than is continued treatment with methotrexate in slowing structural damage and ameliorating disability over 2 y in patients with early RA (13). Because both structural damage and disability are significantly associated with low muscle mass (31, 35), it is plausible that etanercept is superior to methotrexate in the long-term management of rheumatoid cachexia. This hypothesis deserves further research because our study was not large or long enough to detect the slow but relentless loss of skeletal muscle that is characteristic of cachexia of chronic disease. What seems clear from our results and these cross-sectional studies is that adjunct anabolic therapies such as progressive resistance training (28, 38) or nitrogen supplementation (39) are needed to reverse rheumatoid cachexia.
In contrast, Briot et al (11) measured a significant increase in total lean mass in 19 patients with spondyloarthropathy after the first 6 mo of anti-TNF treatment. Differences from the current study in disease, treatment (17 patients received infliximab, and only 2 received etanercept), sex (all their patients were men), and statistical power (better in the study by Briot et al) may explain this discrepancy in results. Certainly, differences in the IGF response to etanercept cannot explain the difference in anabolic response between patients with spondyloarthropathy and patients with RA. Briot et al (11) found a significant, 15% increase in serum IGF-I concentration after 3 mo of anti-TNF therapy; the concentration returned to baseline at 6 mo. We noted a similar response: a 19% increase at 3 mo, which was followed by a return to baseline at 6 mo. Furthermore, these changes do not seem specific to anti-TNF therapy, because patients in the methotrexate group showed an identical IGF-I response. The observed changes in the circulating IGF system at the 3-mo follow-up are likely to reflect a reduction in the growth hormone (GH) resistance associated with systemic inflammation (4). This contention is supported by the observation that only GH-dependent IGF proteins—ie, IGF-I and IGFBP-3—were affected by both etanercept and methotrexate, whereas the GH-independent IGF-II was not. The return to lower concentrations at 6 mo may be due to a state of mild GH insufficiency that is possibly associated with low levels of physical activity and excess body fat (40). A similar biphasic response (GH resistance followed by GH insufficiency) was seen in critically ill patients (41), but further studies of the effects of antirheumatic treatment on the GH and IGF axis are necessary to directly test this hypothesis.
Although our primary analysis did not prove a specific effect of anti-TNF blockade on overall body composition, the secondary analysis of those patients who gained a significant amount of weight during the 6-mo follow-up suggests the interesting hypothesis that etanercept may be able to restore the normal anabolic response to positive energy balance in cachectic patients. When healthy humans with a body-fat content similar to that of our patients with RA are overfed, 30–40% of the body mass gained is FFM (42). However, in catabolic conditions such as sepsis, chronic infection, cancer, and burns, this anabolic response to positive energy balance is impaired, and increased feeding leads to fat accumulation with little or no gain in FFM (43–46). In the current study, a similar phenomenon was observed in the 6 patients with RA who were treated with methotrexate, in whom only 14% of the body mass gained was FFM. On the contrary, TNF blockade with etanercept normalized the anabolic response to overfeeding, and 44% of the body mass gained by the 6 patients receiving etanercept was FFM (Figure 3). The clinical response of patients who gained weight did not differ significantly from that of patients who did not, and nor were differences in DAS28 and CRP reductions found in the patients in either arm of the study who were on positive energy balance (data not shown). Therefore, the effect of anti-TNF therapy is independent from a generic reduction in systemic inflammation and may be mediated by the positive effect of anti-TNF therapy on insulin resistance in skeletal muscle tissue but not adipose tissue (47).
Insulin, together with increased plasma concentrations of certain amino acids, is the main mediator of postprandial protein anabolism in humans (48), and specific restoration of its anabolic actions in skeletal muscle by anti-TNF therapy could be useful in diseases such as RA, in which systemic inflammation promotes insulin resistance and protein catabolism (49). TNF blockade with etanercept in patients with RA may also improve the sensitivity of skeletal muscle tissue to IGF-I (4), another hormone that is key to the regulation of the anabolic response to overfeeding (50). Given this biological rationale, the hypothesis generated by our secondary analysis warrants further testing by larger, confirmatory, randomized controlled trials of etanercept combined with overfeeding. However, even if proven effective, this combination would not be particularly relevant for the treatment of rheumatoid cachexia because most patients with RA are not anorexic, and they present with excessive body fat, a condition termed "cachectic obesity" (49). Therefore, an intervention that induces a concomitant increase in FFM and fat mass, while treating cachexia, would increase obesity, which would lead to detrimental effects on cardiovascular and metabolic health and increased passive load on damaged joints (49). However, the combination of hypercaloric diets or appetite stimulants with etanercept could be useful in patients affected by cachectic diseases such as cancer, which are often complicated by profound anorexia and weight loss. In these conditions, as in RA, TNF is an important mediator of catabolism (1, 2), and specific modulation of its biological activity may overcome the anabolic block to overfeeding that has frustrated clinical nutritionists over the years. Larger randomized controlled trials of etanercept combined with overfeeding in cancer anorexia-cachexia and other wasting syndromes are needed to confirm this interesting hypothesis.
In summary, over a period of 6 mo, no important changes in body composition were observed in patients with early RA treated with either etanercept or methotrexate. Whether etanercept is superior to methotrexate in the long-term treatment of rheumatoid cachexia is still unknown. Additional phase 3 trials, larger and longer than this trial, are needed to explore this possibility. In addition, experimental investigations should seek to replicate in other cachectic conditions the anabolic effect of etanercept that we observed in patients with RA on positive energy balance, because confirmation of this response would have profound implications for clinical nutrition practice.
ACKNOWLEDGMENTS
We thank Jeff Holly and the staff of his laboratory for performing the insulin-like growth factor system assays.
SMM designed the study, collected the body composition and functional data, analyzed the data, and wrote the manuscript. KRC collected the body composition and functional data and analyzed the data. GM recruited the patients and collected the clinical data. ABL and PJM supervised the study. All authors revised and approved the manuscript. None of the authors had a personal or a financial conflict of interest.
REFERENCES