Arthiritis

Use of Infopeptides as an Adjuvant Therapy for Rheumatoid Arthritis: A Clinical Trial

Rheumatoid arthritis (RA) is a disease in which autoimmunity and the cytokine network are clearly involved, and despite being the most extensively studied form of arthritis, all conventional therapeutic regimes are far from satisfactory in terms of clinical response. In 1996, Feldmann et al. (from the Mathilda and Terence Kennedy Institute of Rheumatology, London, UK), reported an open-label trial done in 1992-1993, where they attempted a new treatment for RA using a chimeric (mouse x human) monoclonal anti-TNF (antibody cA2). The treatment led to rapid improvement in every patient in all parameters of disease activity used.38 The proposed mechanism of action of Infopeptides, the specific protein derivatives obtained from bovine colostrum, is induction of anti-inflammatory cytokine-type activity by the organism, allowing the immune system to reorient or correct its response mechanism against autoimmune disease processes. Thus, this product is expected to work as a true immunomodulator. The initial clinical observations of the effects of Infopeptides in humans demonstrated marked reductions of inflammation, edema, pain and fever, apparently regardless of cause. Severe and active RA, unresponsive to conventional therapies, was chosen as a model disease to be managed with immunomodulators. Starting in March 1996, we initiated a small clinical trial with Infopeptides (Cytologª on 12 patients with RA, who despite adequate conventional therapy had clinical signs of active disease. At the same time we followed up 10 patients with Osteoarthrits (OA) who had no relief on conventional therapy. Because RA and OA have different ethiologic mechanisms, we must make it clear that the inclusion of OA patients in this study was incidental.

Method
Patients included in this trial had an established diagnosis of RA or OA, with clinical and laboratory evidence of active disease, despite adequate established conventional therapy (non-steroidal anti-inflammatory drugs (NSAIDs), chloroquine, steroids, methotrexate, azathioprine, gold salts). Patients were encouraged to comply with their conventional established treatment, and were started on Infopeptides as an adjuvant supplement. Treatment was not to be considered a failure before a three-month period. The administered dose was 5 mL orally per day, and patients were instructed to keep the product in contact with the oral mucosa for 2-3 minutes, and then swallow it. If no clinical response was observed after four weeks, the dose would then be doubled to 5 mL two times a day. All patients were evaluated clinically when they entered the trial and had a follow-up visit every four weeks. Records of clinical changes, as well as initial X-rays, laboratory exams and photographs were taken. Patients were also encouraged to report changes, or feel confident to call in case of need. RA patients were classified according to clinical severity of the disease, using the functional capacity classification: Class I: complete remission, or full capacity to develop Daily Life Activities (DLAs); Class II: moderate restriction, but still capable of handling DLAs; Class III: marked restriction, disabled to work, needs help for self care; Class IV: severe disability, bed or wheel chair confined.

RA Patients
Twelve patients (10 F, 2 M), with an average age of 52.5 years entered the trial. The average time of disease duration was 12.4 years. Patients were taking between one and five therapeutic drugs per day (average two drugs per day).

Results
After a minimum three-month follow-up, the results were outstanding. Clinical and subjective improvement (i.e., subjective and objective reduction or disappearance of pain, edema and inflammation, improvement in joint mobility and better tolerance to physical activity) was documented after two to six weeks of treatment in 10 out of 12 RA patients. Two patients were lost to follow-up. An objective reduction of inflammation and local joint edema, usually preceding reduction or disappearance of pain was observed between 7 and 35 days. The average response time was 21.3 days. Patients with longer disease courses took a longer time to respond. The dose was increased to 5 mL twice a day in five patients. In spite of being advised not to stop using their established therapies, patients decided to drop other agents on their own. At the end of the initial evaluation time, the medicine intake ranged from none to 3 drugs per day (average 1.5 drugs per patient-day). Six of the nine patients using NSAIDs at the time were not using them on a regular basis; since pain severity was markedly reduced, medicine intake was not as necessary as before. The RA patients with more severe conditions (functional class III-IV) have been followed for over one year, and have shown a slow but significant improvement in joint mobility, besides the initial reduction in pain, edema and inflammation (Table 2, Figure 1, below). With a prolonged course of treatment, we have observed dramatic changes in functional classification. In general, patients report improved quality of life, a state of well-being, better quality of sleep, increase in appetite and a noticeable reduction of frequency and severity of relapses.

OA Patients
During the initial phase of the RA trial, several patients with OA asked to be included, because of the excellent results they saw on their friends or relatives. Since the Infopeptides had initially shown to be very effective in pain control regardless of cause, and because of its general safety and tolerance, we decided to initiate a parallel observation including OA patients.
Ten patients, all female, (average age 58.4 years) agreed to participate in theclinical trials. Duration of disease ranged from six months to 11 years, averaging 5.6 years. All patients were on a NSAID, and two had other medications when they entered the trial. OA patients were evaluated based on a patient estimated scale of pain, where 0 would be total absence of pain, and 100 the worst pain.
Nine out of 10 patients reported a significant reduction of pain, and showed clinical reduction of inflammation, between 15 and 21 days after starting the therapy. The average response time was 16 days. After the initial three-month evaluation period, only five patients were taking NSAIDs, while the others were taking the Infopeptides as their only therapy. The only patient who did not report pain reduction or relief despite showing a clinically significant reduction of local edema and heat, had severe, deforming knee damage, where surgery was advised.

Comments
After the initial trials, we concluded that the colostrum derived product contains one or more immunomodulating agents that promote anti-inflammatory cytokine-type activity resembling the anti-inflammatory activity of cytokines 4,10,13,15,16. Longer follow-up and laboratory support data will be necessary to determine whether or not it is possible to stop, or even reverse the existent articular cartilage damage (this effect was described in vitro using cytokines 4 and 10 on mononuclear cells of RA patients).39
As expected from a biological response modifier, the effects of the Infopeptides are relatively non-specific, allowing the organism to recuperate normal functioning patterns. This hypothesis is supported by the good responses observed in both RA and OA. At present time, there are several other autoimmune processes that are already receiving benefit from this therapeutic alternative, with promising results.
The results of this initial clinical trial are very significant, not only because of the high level of clinical response of the whole group of patients, but also because of the sustained benefit and improvement on prolonged therapy. Its oral administration, its low cost when compared to other current experimental biological response modifiers, and the absence of side effects are remarkable as well. Nevertheless, to us, as clinicians, the most valuable aspect of this new therapeutic alternative is its profound effect on pain relief.