SHORT REPORT

Double Blind Radiological Assessment of Continuous Oral Pamidronic Acid in Patients with Rheumatoid Arthritis

A. Maccagno’, E. Di Giorgio’, E. J. A. Roldan2, L. E. Caballero2 and A. Perez Lloret2

’Department of Rheumatology, French Hospital, and *Department of Clinical Pharmacology Gador S.A., Buenos Aires, Argentina

Maccagno A, diGiorgio E, Roldan EJA, Caballero LE, Perez Lloret A. Double Blind Radiological Assessment of Continuous Oral Pamidronic Acid in Patients with Rheumatoid Arthritis. Scand J Rheumatol 1994; 23: 21 1-4.

Continuous oral pamidronate (APD), 1000 mg/day, was administered to 14 patients with rheumatoid arthritis. A control group of 13 patients with similar conditions received placebo under a double blind randomized study design. Periarticular erosion scores were significantly higher in the control group after 12 months treatment. This was attributed to a deterioration in this group rather than to an improvement in the APD treated one. By contrast, intraarticular narrowing score was not influenced by APD. Tolerance to oral APD was acceptable in all patients.

Key words: rheumatoid arthritis, periarticular erosion, pamidronate, bisphosphonates

Management of rheumatoid arthritis (RA) involves the use of several drugs as NSAID’s, corticosteroids or DMARD’s. However, these compounds are unable to prevent the periarticular or systemic osteoporosis asso- ciated with inflammatory factors found in the joints of RA patients, which increase bone resorption inde- pendently of osteopenia due to disuse itself (1).

Oral pamidronic acid (APD) has proved to be effec- tive in the treatment of systemic or focal osteolytic diseases (2-9).

As APD soft capsules proved to be tolerable (9,13), we decided to perform a double blind, placebo-con- trolled trial with patients treated continuously through 1 year with a high oral dose, focussing the evaluation on the ra&ological assessment of periarticular erosion, where benefits from the bisphosphonate treatment would be expected.

Materials and Methods

This study design was approved by the Scientific Com- mittee of the Buenos Aires French Hospital. Twenty- seven eligible patients with RA diagnosis fulfilling the ARA criteria of functional stage I1 disease, who were willing to participate, were randomly divided in two groups. Pregnant patients and those with history of drug hypersensitivity or digestive, renal or hematolog- ical severe disorders (i.e. those who had undergone previous hospitalization or chronic treatments) were excluded.

E. RoldBn, Darwin 429, (1414) Buenos Aires, Argentina

Received 14 May 1993 Accepted 21 March 1994

One group of 14 patients received oral APD, 2 soft enteric-coated gelatin capsules (IG-7913) with 250 mg pamidronate each, b.i.d., over 12 months. Under dou- ble blind conditions, the control group (13 patients) received the same number of placebo capsules (only soybean oil and lecithin). Piroxicam, 20 mg enteric coated tablets, or prednisone at a maximum daily dose of 7.5 mg, were administered when required.

Monthly clinical evaluations were performed by the same observer by means of Ritchie articular index, pain visual analogue scale, grip strength for active hand and morning stiffness. Baseline radiological as- sessment was performed and repeated at the 6th and 12th month, using the Genant et al. (14) evaluation of erosion and intraarticular narrowing in hands and feet. Genant’s scale is based on the presence of erosion signs in 16 anatomic areas in each hand and 6 areas in each foot, and the presence of intraarticular narrowing in 11 sites in each hand and 6 sites in each foot. Individual scores for each member are obtained as the sum of affected areas. Data presented as global the score means the sum of individual scores obtained with two or more blinded observers agreeing. Hematolog- ical measurements and urinalysis were performed monthly and erythrocyte sedimentation rate (ESR) and rheumatic factor titration quarterly. They were all car- ried out in accordance to standardized methods, nor- mally performed by the Central Laboratory of the Hos- pital. Side effects were assessed and categorized as “mild” if symptoms were transient and did not require dosage modification; “moderate” when palliative medication was needed or “severe” if treatment had to be discontinued. Basal status matching and intra and intertreatment variations were analyzed through Stu-

0 1994 Scandinavian University Press on license from Scandinavian Rheumatology Research Foundation 21 1

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A. Maccugno et al. Table I. Clinical, biochemical and radiological variables in RA patients treated during 12 months with oral APD 1000 mglday (n:14) or placebo (n:13)

Variables Units Basal 6th month 12th month Signif. ( P 4 12th Month vs Basal

Placebo ADP Placebo ADP Placebo ADP Placebo ADP

CLINICAL Pain (VAS) mm

Morning stiffness minutes

Ritchie Index score

BIOCHEMICAL ESR mm/h

Rose Ragan dilut.

Latex test dilut.

EROSION Active hand (1) score (3)

Inactive hand (2) score

Right foot (4) score

Left foot (5) score

INTERARTICULAR NARROWING Active hand score

Inactive hand (4) score

Right foot (4) score

Left foot (5) score

37.4 (5.4) 74.0 (11.5) 13.9 (1.91

54.0 (5.7)

168.9 (44.7) 455.3 (86.5)

8.9 (0.9)

(0.91 3.6 (0.5) 4.1 (0.6)

11.2 (0.9)

(1.3) 4.6

10.5) 5.5

(0.71

8. 1

10.8

68.9 (4.9)

120.0 (12.7) 24.5 (4.0)

73.3 (4.0)

(44.3) 424.2

228.3

(84.71

11.1 (1.3) 10.6 (1.5) 4.6 (0.6) 4.1

(0.7)

11.3 (0.8) 10.4 (1.1) 5.1 (0.6) 5.1 (0.7)

30.1 (3.4) 59.3 (7.31 11.9 (1.4)

48.9 (3.41

167.3 (32.01 356.9 (48.4)

11.1 (1.1) 10.4 (1.2) 4.7 (0.7) 4.6

(0.8)

12.8 (1.0) 12.4 (1.7) 5.3 (0.4) 6.5 (0.8)

41.0

71.0 (5.6) 12.5 (1.7)

53.7 (1.9)

169.1

377.1 (49.2)

10.5 (1.51 9.6

(1.5) 4.3 (0.5) 4.1

(1.1)

11.6

11.2 (1.1) 5.6

(0.6) 5.6 10.6)

(18.5)

(0.8)

21.9 (2.91 49.3

19.3 (4.81

(0.8)

43.3 (2.4)

(12.1) 406.2 (46.1)

12.0 (1.3) 12.7 (1.8) 5.6

(0.8) 5.6 (0.9)

13.5 (1.1) 13.8 (1.7) 6.3

(0.7) 6.1

(0.7)

128.4

20.3 (2.71 47.3 (4.2) 5.4 (0.9)

40.3 (2.2)

(11.4) 291.4 (45.2)

9.7 (1.71 9.0 (1.5) 3.5 (0.6)

(0.6)

12.1 (0.9) 11.7 (0.9) 5.1

(0.71 5.5 (0.6)

84.5

3.8

.0011

ns.

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ns .

,005’

,005’

,001’

.02’

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,027

n.s.

.001(

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,011

.0011

,011

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.03T

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Figures express mean (SE); I = decrease; = increase (1) Usually right; (2) usually left; (3) according to Genant et al. 1983; (4) n:12 at 12th month, (5) n:ll at 12th month; (61 pc0.03 comparing placebo vs APD at 12th

month

dent T or ANOVA test for parametric or ANOVA non-parametric technique, depending on the nature of data (see table), with a computerized program, TAD- POLE I11 for IBM PC. Data is provided as mean (SE) or median (range). Statistical significance was defined when p<O.O5 with a p power of 0.8.

Results

Table I shows the most descriptive results obtained from clinical, laboratory and radiological evaluations. The APD patients group mean age was 44.6(+.2.8) years, 13/14 were females, with a illness mean duration time of 5.3 (+ 1.6) years for the entire group. Mean prednisone consumption in the previous month in 9/14 patients of this group was 5.0 mg/day. The placebo patients group was 48.5 (2 2.4) years old, 12/13 were females, with 3.9 (+ 0.7) years of disease duration and

mean prednisone consumption in 7/13 patients of 5.0 mg/day respectively. Differences between groups were not significant. Some variables, such as clinical and pain indexes and ESR, showed baseline differences. While total radiological score showed comparable baseline status, both for periarticular erosion and intra- articular narrowing scores, after one year of treatment the periarticular erosion score was significantly higher in the placebo group than in the APD treated one. By contrast, intraarticular narrowing score was not influ- enced. Each point of the figure shows the relation between the initial and final radiological score in each patient.

Radiological scores are discriminated by hand or foot in the table. Significant deteriorations were ob- served in both hands and feet in the placebo group, while no changes were registered in the APD treated group except in the right foot where a significantly (p < 0.03) decreased score was found. Intra-articular

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Pamidronate in rheumatoid arthritis

Petinrliculnr Eroslon

n.ii.9

-’ 10 IF& _._---

fo f5 z0 25 3~ 35 do 45 50 65 60 lnilial score

~ ~ I ~ - W W A A r . r ” F 3

Fig. 1.Global radiological evaluation of RA patients treated with oral APD (A) or placebo (0) continuously, during 12 months. Each point represents the intersection between initial and final score in each patient. Points on the diagonal line indicate absence of chang- es. Points over the diagonal indicate worsening and under ameliora- tion. Radiological score as Genant et al. (14).

narrowing score in hands showed significant deteriora- tion in both groups.

Discussion

Patients treated with APD showed clinical and bio- chemical improvement as compared to controls. They also experienced a lower consumption of additional drugs than those treated with placebo. Nevertheless, the presence of baseline differences between the treated and control groups requires some caution about attributing clinical and biochemical results to an APD effect. Furthermore, these patients received antiinflam- matory drugs concomitantly. Therefore our conclu- sions have not been focussed on clinical or biochem- ical data.

With respect to the described differences in the peri- articular erosion score observed after treatments, these effects should be attributed to a progression of the bone-deteriorating process in the placebo group rather than to an improvement in APD treated patients. Nevertheless, one may speculate on the possible role of APD in the protection of bone from erosion (and defor- mity‘?) in RA.

The two publications mentioned earlier have failed to show radiological changes in RA patients treated with i.v. APD. However, relevant differences in trial design do not allow comparisons with our results. Oral APD, as other bisphosphonates is absorbed at an esti- mated rate of 1-2%; that is, our patients would have effectively received 300 to 600 mg per month continu- ously over one year, while Ralston’s patients only received a monthly intravenous infusion of 30 mg (lo), and Tan’s patients received 0,25 mgkg daily in courses of 5 days per month which i.e. about 70 to 100 mg monthly (1 1). Consequently much lower dosages and shorter follow-up periods were used in both trials as compared to ours. In our opinion, this should be con- sidered relevant, since high dosages of APD may be needed to achieve the erosion-protective effect in RA patients (12).

Mild to moderate digestive disturbances appeared in some of the patients treated with APD; but, a dosage as high as 1000 mg of oral APD administered in enteric dissolution soft capsules to our trial population did not seem to induce higher incidence of GI adverse effects than the 600 mg in the same galenic preparation given to Paget’s patients (3,13). No severe intolerances were reported. Although the present results should be con- firmed in a wider population, perhaps using more so- phisticated methodology, they have to be considered as promising with regards to the therapy with oral amino- bisphosphonates against periarticular erosive disease in RA patients. Moreover, lower oral doses of APD ad- ministered in earlier stages of the disease should be investigated as a preventive therapy for RA erosions.

Although systemic osteoporosis in RA patients has not been evaluated in this trial, it should be counter- acted by APD, as has been recently suggested (15).

Acknowledgements This study was supported by Gador S.A. - Buenos Aires. Soft capsules of IG-7913, its placebo and enteric coated piroxicam were kindly provided by Dr. E. Montuori. Prednisone was purchased from a commercial source.

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2.

3.

4.

5.

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14. Genant HK. Methods of assessing radiographic change in rheu- matoid arthritis. Am J Med 1983; 75: 35-47.

15. Eggelmeijer F, Papapoulos SE, Valkema R, Hermans J, Land- man JO, Pauwels EKJ, et al. Double blind placebo controlled trial of continuous oral pamidronate in rheumatoid arthritis: effects on bone mass after 1 year. Bone Miner 1992; 17(S I): 31.

1193-204.

EUROPEAN RHEUMATOLOGISTS IN TRAINING (EULAR Standing Committee for Education & Training

EURORITS was established to improve the interaction between junior rheumatologists in different European countries and increase their awareness, knowledge and experience of rheumatology as practiced throughout Europe. To enable this, EURORITS will help arrange visits of one to two weeks to centres in other European countries and, if possible, offer a travel bursary. These have been made available by EULAR, national rheumatological societies and the pharmaceutical industry. These visits can be to any centre of choice, but we have identified several departments in various European countries who we know are prepared to occadionally host such visits. Their details are available on request. If you are a trainee or junior rheumatologist and would like to apply for a travel bursary, please request an application form and further details from Dr A.D. Woolf, Chairman, European Rheumatologists in Training, Duke of Cornwall Rheumatology Unit, Royal Cornwall Hospital (City), Truro, TR1 2HZ, England.

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