"Clinical trials testing the efficacy of vitamin E in the treatment of arthritis have been methodologically weak and have produced contradictory findings. Suggestions that there may be a positive effect on pain in some shorter-term studies of OA and inflammatory arthritis need to be replicated in RCTs using more methodologically robust protocols. In particular, there is a need for more clinical trials incorporating placebo control arms in order to avoid the difficulties inherent in interpreting the results in equivalence trials. There is presently no convincing evidence that selenium, vitamin A, vitamin C, or the combination product selenium ACE are effective in the treatment of any type of arthritis," Dr. Canter writes.
Interest in antioxidants in arthritis derives from the hope for effective, safer alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) and from an appreciation of the roles that reactive oxygen species and other free radicals play in inflammation [Table 1]. Low intake of dietary antioxidants has been linked to the incidence of RA and to increased incidence of OA or faster disease progression, according to Dr. Canter. In addition, there have been a number of reports on specific antioxidants or antioxidant diets in the treatment of arthritis.
Table 1. Oxidation and Reactive Oxygen Species (ROS) During Inflammation
|
Factor |
Effect |
|
Oxidation |
Modifies low-density lipoproteins; Inactivates α-1-protease inhibitor; Damages DNA; Causes lipid peroxidation |
|
ROS |
Damage cartilage; Damage extracellular matrix; Inhibit collagen synthesis; Inhibit proteoglycan synthesis |
The notable contribution of Dr. Canter's group was to review the evidence from randomized clinical trials (RCTs) for the effectiveness of the antioxidant vitamins A, C, and E and for selenium in the treatment of any type of arthritis. "Selenium is included because although it is not itself an antioxidant, it is an essential component of the endogenous antioxidant enzyme glutathione peroxidase," Dr. Canter explains.
The reviewers identified 22 RCTs: 11 in inflammatory arthritis, one in ankylosing spondylitis, one in psoriatic arthritis, and nine in OA. The reviewed studies included five of selenium for RA, five of vitamin E for inflammatory arthritis, and seven of vitamin E for OA, as well as one negative studies of vitamin A in inflammatory arthritis, plus isolated studies of the combination product selenium ACE in RA and in OA, of vitamin A in OA, and of vitamin C in OA.
"Of these, only the study of vitamin C reported any statistically significant differences favoring antioxidant treatment, but effect sizes were approximately half that of conventional treatments," Dr. Canter notes.
Quality of reporting was only "moderate." Only five studies adequately described the randomization procedure, and only four adequately described how double blinding was achieved. Many studies failed to use comparable treatment groups.
"The quality of these studies is generally poor and in particular, descriptions of randomization and double-blinding are inadequate," the reviewers write.
Possible analgesic effects of vitamin E
The RCTs of vitamin E suggested possible analgesic but not anti-inflammatory effects in inflammatory arthritis, according to Dr. Canter. Three of the five vitamin E trials used diclofenac as the comparator. None found any significant differences between the group treated with vitamin E and the group treated with diclofenac, and the researchers generally regarded these results as evidence of equivalence [Table 2]. However, Dr. Canter points out that this conclusion depends on the effectiveness attributed to diclofenac and that tests for statistical difference, which are designed to be conservative, are not suitable for establishing equivalence.
"Two of the equivalence studies had short-term treatment periods of only 3 weeks and apparently equivalent positive effects may be the result of placebo effect and/or regression to the mean in both groups. The third, which lasted 12 weeks, provides raw data for only two of the six outcomes, and neither are direct measures of pain. Equivalence can only be judged for finger-floor distance and morning stiffness, and for the latter diclofenac was clearly superior. Taken together, these studies provide very little convincing evidence of a positive effect of vitamin E in inflammatory arthritis," Dr. Canter writes. Trials of vitamin E versus diclofenac in OA had similar deficiencies. The reviewers conclude that the superiority reported for vitamin E by one measure of function "is consistent "with either a short-term effect of vitamin E on subjective measures of pain in OA that is not maintained longer term or a spurious finding resulting from methodological weaknesses in the placebo-controlled trials and/or regression to the mean in the equivalence trials."
Table 2. Summary of RCTs of Vitamin E in RA or OA
|
Study |
Diagnosis |
Intervention/Control |
Results |
|
Jäntti |
RA |
Selenium or vit A or vit E/ Placebo or fish oil |
No clear effect |
|
Springer |
RA |
Vit E/Placebo |
No difference in RAI, EMS, SJC, VAS for morning pain, evening pain, pain after activity favors vit E; investigator assessment but not patient assessment favors vit E |
|
Kolarz |
RA |
Vit E/Diclofenac |
No significant difference |
|
Wittenborg |
RA |
Vit E/Diclofenac |
No significant difference |
|
Petersson |
RA |
Selenium ACE/Placebo |
No significant difference |
|
Machtey |
OA |
Vit E/Placebo |
Significant improvement with vit E in patient self-reports of pain |
|
Blankenhorn |
OA |
Vit E/Placebo |
Significant improvement with vit E in physician global impression, pain during movement, pain at rest, pressure-induced pain, and analgesic use. No effect on restricted movement |
|
Wluka |
OA |
Vit E/Placebo |
No significant difference |
|
Brand |
OA |
Vit E/Placebo |
No significant difference |
|
Scherak |
OA |
Vit E/Diclofenac |
No significant difference |
|
Link |
OA |
Vit E/Diclofenac |
No significant difference in pain on pressure, pain on movement, range of motion, joint circumference. Keitel Function Test at 3 wk favors vit E |
Source: Adapted from Canter et al.
Reference
1. Canter PH, Wider B, Ernst E, et al. The antioxidant vitamins A, C, E, and selenium in the treatment of arthritis: a systematic review of randomized clinical trials. Rheumatology. 2007;46:1223-1233.
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