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We read with interest the article by Paran and colleagues on a pilot study of a long acting somatostatin analogue for the treatment of refractory rheumatoid arthritis (RA).1 The role of peptidergic sensory neurons and the “neurogenic inflammation” in RA and, particularly, in the involvement of substance P (SP) in the articular destruction in experimental arthritis has been demonstrated.2 High levels of SP have been detected in synovial fluid3 and plasma4 samples of patients with RA. It has also been shown that somatostatin inhibits SP release from sensory nerves.5 Matucci-Cerinic et al have demonstrated that intra-articular somatostatin induces clinical improvement in patients with RA.6
We would like to report our experience, based on a pilot study of treatment for RA with somatostatin analogue (sandostatin). Eleven female patients with classical or definite RA according to American Rheumatism Association criteria were selected for this study with a mean age of 57.4 years and average duration of disease period of 14.5 years. All the patients had previously received multiple disease modifying antirheumatic drugs, but complete remission could not be achieved. Patients who had received any drug except non-steroidal anti-inflammatory drugs during the eight weeks before the start of the study, who had severe cardiovascular, pulmonary, renal, or hepatic disease, and who were hypersensitive against penicillin analogue were not included in the study group. During this treatment, patients were allowed to receive piroxicam and indometacin group NSAIDs.
Sandostatin (Sandoz) is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. Sandostatin 0.1 mg was injected subcutaneously every day for eight weeks.
Clinical evaluations, such as joint tenderness, grip strength, duration of morning stiffness, 15 m walking time, and visual analogue scale for pain, were performed by the same investigator at baseline and at two, four, six, and eight weeks. Sedimentation rate, C reactive protein (CRP), alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, fasting plasma glucose, leucocytes, thrombocytes, and erythrocyte levels were measured at two, four, six, and eight weeks. Additionally, abdominal ultrasound was carried out at the fourth and eighth week of treatment.
Table 1 shows the patients' characteristics at the beginning of the study.
Eleven patients were enrolled in the study. The data from two patients were not included in the statistical analyses. One of them had severe diarrhoea and abdominal cramps within the first week of the somatostatin treatment and treatment was stopped. A persistent increase in fasting plasma glucose level was seen in the other patient and she also left the study.
In comparison with the values recorded at the beginning of the study, pain intensity and walking time had decreased and the left hand grip strength had increased by the fourth week; these differences were not statistically significant. There was a significant reduction in the duration of morning stiffness and in joint sensitivity (p<0.05). Two female patients were withdrawn from the follow up at the end of the fourth week. At the end of the eighth week, the remaining seven patients had a reduced duration of morning stiffness, a decrease in walking time, and an increase in the grip strength of both hands. The laboratory variables CRP and erythrocyte sedimentation rate (ESR) were reduced. None of these differences were significant (p>0.005). In comparison with entry values, a significant decrease was found in pain intensity and joint sensitivity (p<0.05). Neither adverse clinical effects nor changes in laboratory values were serious enough to stop the treatment with somatostatin in any patient.
Our results are similar to those of Paran and colleagues1; a significant improvement (p<0.05) was noted in the mean visual analogue scales of pain, doctor's and patient's global assessment of disease activity, and in the mean number of swollen joints, but no statistically significant improvements were seen in the mean number of tender joints. Although there was a trend towards reduction of the mean ESR and CRP values of the 10 patients as a group, this did not reach statistical significance. However, these findings are insufficient to conclude that somatostatin is useful and effective in RA treatment. We hope that the results of these studies will stimulate further research on the use of somatostatin in RA, particularly in determining the appropriate effective dose.
We read with interest the letter by Drs Koseoglu and Koseoglu, in which they report a pilot study on the effect of somatostatin analogue treatment in refractory rheumatoid arthritis (RA). Their study is similar to our study in size and patient characteristics but differs in three major points: the dose of somatostatin analogue and the preparation used; the length of the study; and the criteria employed to assess a therapeutic response.
The dose of octreotide (sandostatin) used in their study was low (100 μg once a day). When using subcutaneous octreotide 100 μg/day injections to treat other conditions, such as acromegaly, the accepted dose is 100 μg three times a day owing to the peptide's short half life. A dose of subcutaneous octreotide 100 μg/day may not be sufficient to achieve a significant effect. This may explain the more marked effect seen in our study, where octreotide was given as a long acting preparation that produces therapeutic doses of octreotide (equivalent to 100 μg subcutaneously three times a day) for a period of four weeks after injection.
Koseoglu and Koseoglu conducted a shorter study of only eight weeks as compared with our 14 week study, where we saw continued improvement after eight weeks.
Moreover, accepted American College of Rheumatology criteria for the evaluation of response to treatment in patients with RA were not used, making it difficult to compare the results. Despite the different methodology Koseoglu and Koseoglu showed a similar, significant beneficial effect of somatostatin analogue treatment on the assessment of pain: “pain intensity”, and “joint sensitivity”, with only mild adverse effects.
This pilot study supports our conclusion that treatment with a somatostatin analogue may be beneficial in the treatment of RA, and that further large, placebo controlled studies are required to evaluate this drug as a potential disease modifying antirheumatic drug for patients with RA.
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