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Effects of High Dose Intravenous Pamidronate on Disease Activity and Bone Metabolism in Patients with Active Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled Trial

To the Editor:

One single agent that decreases both disease activity and bone loss would be useful in the treatment of rheumatoid arthritis (RA). We assessed the effect of high dose intravenous pamidronate on disease activity and bone metabolism in patients with active RA.

Twenty six patients, recruited in outpatient rheumatology clinics between December 1999 and May 2002, were included in a randomized double-blind placebo-controlled trial and received a single intravenous infusion of 45 mg or 90 mg pamidronate or placebo as adjuvants to the conventional RA treatment. Patients with a recent change in disease modifying antirheumatic drugs (DMARD), unstable dosage of drugs known to interfere with bone metabolism (including glucocorticoids), intraarticular glucocorticoid injections, or bisphosphonate treatment before inclusion were excluded. Disease activity, markers of bone formation, and markers of bone and cartilage resorption were assessed at baseline and 1, 2, 4, and 6 weeks after infusion. To minimize the effects of changes in DMARD (allowed as of Day 14) on our results, Day 28 was chosen as endpoint. Data missing due to loss to followup were handled by a last-observation-put-forward approach. The changes in disease activity and markers of bone metabolism, expressed as area under the curve (AUC), between the 3 groups were compared by means of a test for linear trend across the groups within a one-way analysis of variance (ANOVA). Kruskal-Wallis tests, chi-square tests, or Fisher's exact tests were performed where appropriate. P values ¾ 0.05 (2 sided) were considered significant. The software used was SPSS for Windows v. 9.0 (Chicago, IL, USA).

Baseline characteristics of the 3 intervention groups were not significantly different (Tables 1 and 2). The disease variables and values of the markers of bone and cartilage metabolism at 4 weeks after infusion are shown in Table 2. The median [interquartile range (IQR)] AUC of change of Disease Activity Score from baseline to 4 weeks after infusion were –0.40 (–0.71 to –0.19), –0.30 (–0.62 to 0.16), and –0.46 (–0.73 to 0.28) in the 90 mg, the 45 mg, and the placebo group, respectively (nonsignificant in the intention-to-treat analyses). The per-protocol analyses did not change the significance of the results.

Table 1. Baseline demographic, disease, and therapy variables of the patients at randomization.

Table 2. Disease variables and markers of bone and cartilage at baseline and at 28 days after infusion with placebo (n = 8), 45 mg pamidronate (n = 8), or 90 mg pamidronate (n = 9). One patient out of 9 allocated to the placebo group was lost to followup after randomization.

The bone and cartilage resorption markers decreased significantly in a dose-dependent way — p values of test for linear trend within ANOVA: 0.002 for urine ß-isomerized carboxy terminal telopeptide of type 1 collagen (ß-CTx), 0.002 for urine type 2 collagen C-telopeptide breakdown products (CTxII), and 0.01 for serum ß-CTx. Bone formation markers showed inconsistent results (p = 0.14 for serum N-terminal peptide of type 1 procollagen synthesis; and p = 0.03 for test for linear trend within ANOVA for serum osteocalcin). In the per-protocol analyses, only the AUC of change of urine ß-CTx consistently showed a significant dose-dependent difference between the 3 groups. In all patients but one, side effects consisting of fever and flu-like symptoms that occurred in some of the patients treated with pamidronate disappeared within 24 hours. Six patients in the placebo group, 3 in the 45 mg group, and 9 in the 90 mg group underwent a change in (dose of) DMARD at any time during the study [median Day 14 (IQR 11.5 to 20)].

In summary, intravenous administration of a single high dose of pamidronate did not result in a statistically significant beneficial effect on RA disease activity, while markers of bone and cartilage resorption were significantly suppressed in a linear dose-dependent way. In accord with our results, 3 out of 4 controlled studies that used intravenous bisphosphonates (maximum dose of 60 mg) showed no consistent advantageous effect on disease activity^1-3. However, one study did find a significant decrease in tender and swollen joint counts as well as biochemical disease activity⁴. The apparent beneficial results of oral pamidronate in RA patients in one placebo-controlled study are difficult to interpret because of baseline disease activity differences in the groups⁵. Cantatore, et al found no favorable effect on clinical disease activity in their randomized controlled trial on the effects of oral alendronate in RA patients⁶. However, they did report a significant decrease in erythrocyte sedimentation rate and C-reactive protein in the active group in contrast to the placebo group after 3 months. The relatively small sample size of all studies, including our study, is likely to result in a lack of discriminatory power. Another explanation for the conflicting results remains a truly nonexistent effect of bisphosphonates on disease activity. However, ample evidence from in vitro studies as well as experimental animal models points toward a suppression of the inflammatory response by bisphosphonates^7,8.

In accord with our results, the controlled studies of the effects of bisphosphonates in RA showed a suppression of bone resorption markers^2-4,6. Whether our findings on the suppression of the cartilage degradation marker CTxII confirm recent suggestions of a chondroprotective effect of bisphosphonates^9,10 or indicate a lack of specificity of the marker remains uncertain. Thus, whether and how bisphosphonates influence RA disease activity remains a question to be answered by studies of sufficient sample size and duration that investigate effects of highly potent bisphosphonates in patients with active RA.

MARIETTE C. LODDER, MD; PHILOMINE A. VAN PELT, MD, Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands; WILLEM F. LEMS, MD, PhD, Department of Rheumatology, VU University Medical Center, Department of Rheumatology, Slotervaart Hospital, Amsterdam; PIET J. KOSTENSE, PhD, Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam; CEES H.W. KOKS, PhD, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam; BEN A.C. DIJKMANS, MD, PhD, Department of Rheumatology, VU University Medical Center, Department of Rheumatology, Slotervaart Hospital, Amsterdam, The Netherlands.

Address reprint requests to Dr. M.C. Lodder, Department of Rheumatology, Room 4A42, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: secr.reumatologie@vumc.nl

REFERENCES

1. Van Offel JF, Schuerwegh AJ, Bridts CH, Bracke PG, Stevens WJ, De Clerck LS. Influence of cyclic intravenous pamidronate on proinflammatory monocytic cytokine profiles and bone density in rheumatoid arthritis treated with low dose prednisolone and methotrexate. Clin Exp Rheumatol 2001;19:13-20.

2. Valleala H, Laitinen K, Pylkkanen L, Konttinen YT, Friman C. Clinical and biochemical response to single infusion of clodronate in active rheumatoid arthritis — a double blind placebo controlled study. Inflamm Res 2001;50:598-601.

3. Ralston SH, Hacking L, Willocks L, Bruce F, Pitkeathly DA. Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 1989;48:396-9.

4. Eggelmeijer F, Papapoulos SE, Van Paassen HC, Dijkmans BA, Breedveld FC. Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: a double blind placebo controlled study. J Rheumatol 1994;21:2016-20.

5. Maccagno A, Di Giorgio E, Roldan EJ, Caballero LE, Perez LA. Double blind radiological assessment of continuous oral pamidronic acid in patients with rheumatoid arthritis. Scand J Rheumatol 1994;23:211-4.

6. Cantatore FP, Acquista CA, Pipitone V. Evaluation of bone turnover and osteoclastic cytokines in early rheumatoid arthritis treated with alendronate. J Rheumatol 1999;26:2318-23.

7. Richards PJ, Williams BD, Williams AS. Suppression of chronic streptococcal cell wall-induced arthritis in Lewis rats by liposomal clodronate. Rheumatology Oxford 2001;40:978-87.

8. Ceponis A, Waris E, Monkkonen J, et al. Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits. Arthritis Rheum 2001;44:1908-16.

9. Konttinen YT, Salo T, Hanemaaijer R, et al. Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate. Matrix Biol 1999;18:401-12.

10. Valleala H, Friman C, Konttinen Y, Solovieva S, Teronen O, Sorsa T. Inhibition of collagenase by a bisphosphonate-group drug in patients with rheumatoid arthritis. J Rheumatol 2000;27:1570-2.

Therapeutic Benefits of Irsogladine Maleate on Aphthous Stomatitis Induced by Methotrexate in Rheumatoid Arthritis

To the Editor:

Methotrexate (MTX) is a generally well tolerated drug that has become a first-line agent in the treatment of rheumatoid arthritis (RA)^1-3. The development of aphthous stomatitis and/or oral ulcer will increase with high dose MTX treatment, as observed in 12% to 37% of patients followed in longterm studies⁴. This adverse effect is the most common cause of discontinuation of the treatment. Most examples of aphthous stomatitis are idiopathic, and effective treatment is limited. Some gastric mucosal protective agents have been reported to be effective for extragastric mucosal tissues, which promotes mucosal regeneration. Irsogladine maleate (Gaslon N, Nippon Shinyaku Co., Kyoto, Japan), which reinforces gap junctional intercellular communication in vitro, has been reported to be effective for treatment of aphthous stomatitis⁵.

We examined the effects of irsogladine maleate on transient and relapsing aphthous stomatitis during treatment with MTX in RA. Subjects in this study were 24 patients with RA (20 women, 4 men; mean age 49.9 ± 11.3 yrs) diagnosed as having RA as defined by the American College of Rheumatology, and treated as outpatients between July 2000 and July 2002 at our university hospital. Each patient was randomly assigned to treatment with only irsogladine maleate (4 mg/day PO, BID) or only folic acid (5 mg/day) for 6 months. Clinical and laboratory features of each patient were investigated with their consent. Efficacy was evaluated according to patients' subjective assessment of symptoms and the macroscopic findings of oral lesions.

The incidence of transient aphthous stomatitis in the irsogladine-treated group was 7.7%, whereas that in non-irsogladine group was 45.5% (p < 0.05; Table 1). The incidence in the non-irsogladine group was higher than in the Japanese population as a whole who are generally treated with lower doses of MTX. No adverse events were observed during the study period and no new abnormal laboratory data were noted. In addition, 4 patients with RA, whose lesions recurred 10 or more times per year and who had discontinued the MTX treatment, were also treated with irsogladine (4 mg/day PO, BID) with concomitant use of MTX for 12 months. Two of the 4 patients with relapsing aphthous stomatitis manifested marked improvement in their complaints and oral lesions after 3 and 5 days of irsogladine maleate treatment, whereas the period to healing before administration of irsogladine maleate was 10 to 14 days. The other 2 patients had no additional development of their stomatitis. All patients were free of recurrence of stomatitis for 12 months.

Table 1. The effects of irsogladine maleate (IM) on transient aphthous stomatitis with methotrexate therapy in RA.

MTX is a commonly prescribed disease-modifying antirheumatic drug (DMARD) for RA^1,2,6. With increasing use of DMARD, gastrointestinal toxicity including aphthous stomatitis seems to increase. Although the aphthous stomatitis lesions may be transient, it tends to recur, and patients suffer eating disability induced by the mucosal pain. They may refrain from MTX treatment even when its antirheumatic efficacy is established. Management in such a situation includes dosage reduction, temporary withdrawal, or the addition of folic acid supplementation.

Irsogladine maleate has been shown to inhibit the formation of various experimental gastric ulcers produced by different agents without suppression of gastric secretion⁷. Hara, et al reported the presence of connexins 26 and 32 in human oral mucosa, and demonstrated that administration of irsogladine maleate was effective for transient or relapsing aphthous stomatitis of different causes⁵. Irsogladine maleate can reinforce the gap junction in the gastric mucosa to repair damaged epithelium in the stomach. Saitoh, et al experimentally confirmed that gap junction was associated with wound healing in cases such as glossitis, suggesting that such effect was not limited to the gastric mucosa only, and the wound healing seemed to be accelerated by intercellular communication through the gap junction⁸. It has been reported that irsogladine maleate reinforces the function of gap junction through phosphorylation of connexins mediated by increasing content of intercellular cAMP, maintaining intercellular pH mediated by Na+/H- exchange, stimulation of the M1 muscarinic acetylcholine receptor, and suppressing Ca2+ mobilization^9,10. It is difficult to separate the individual contributions of the factors contributing to aphthous stomatitis induced by MTX treatment. Because irsogladine maleate is effective in treatment of aphthous stomatitis and can reinforce the function of the gap junction, aphthous stomatitis might be partly induced by deteriorated intercellular communication through the gap junction.

Irsogladine maleate is a safe drug and seems effective to prevent the development of MTX-induced aphthous stomatitis in patients with RA.

TADASHI YOSHIDA, MD, Department of Pathophysiology, Faculty of Pharmaceutical Science, Hoshi University; MICHITO HIRAKATA, MD, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

REFERENCES

1. Furst DE. The rational use of methotrexate in rheumatoid arthritis and other rheumatic diseases. Br J Rheumatol 1997;36:1196-204.

2. Weinblatt ME, Kaplan H, Germain BF, et al. Methotrexate in rheumatoid arthritis: Effects on disease activity in a multicenter prospective study. J Rheumatol 1991;18:334-8.

3. Gispen JG, Alarcon GS, Johnson JJ, Acton RT, Barger BO, Koopman WJ. Toxicity to methotrexate in rheumatoid arthritis. J Rheumatol 1987;14:74-8.

4. Kremer JM, Phelps CT. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum 1990;35:138-45.

5. Hara A, Murata H, Uemura R, et al. Identication of connexins in human oral mucosa and therapeutic effect of irsogladine maleate on aphthous stomatitis. J Gastroenterol 1999;34:1-6.

6. Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann Intern Med 1987;107:358-66.

7. Ueda F, Aratani S, Mimura K, Nomura A, Enomoto H. Effect of 2,4-diamino-6-(2,5- dichlorophenyl)-s-triazine maleate (MN-1695) on gastric mucosal damage induced by various necrotizing agents in rats. Arzneimittelforschung 1984;34:478-84.

8. Saitoh M, Oyamada M, Oyamada Y, Kaku T, Mori M. Changes in the expression of gap junction protein (connexins) in hamster tongue epithelium during wound healing and carcinogenesis. Carcinogenesis 1997;18:1319-28.

9. Ueda F, Watanabe M, Hirata Y, Kyoi T, Kimura K. Changes in cyclic AMP content of rat gastric mucosa induced by ulcerogenic stimuli — In relation to the antiulcer activity of irsogladine maleate. Jpn J Pharmcol 1991;55:493-9.

10. Kameda Y, Ueda F. Irsogladine inhibits ionomycin-induced decrease in intercellular communication in cultured rabbit gastric epithelial cells. Jpn J Pharmcol 1995;69:223-8.