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DOI: 10.1148/radiol.2211010095
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(Radiology. 2001;221:256-260.)
© RSNA, 2001

Technical Developments

Painful Multifocal Arthritis: Therapy with Rhenium 186 Hydroxyethylidenedi-phosphonate (186Re HEDP) after Failed Treatment with Medication—Initial Results of a Prospective Study1

Holger Palmedo, MD, PhD, Jürgen K. Rockstroh, MD, PhD, Michael Bangard, MD, Karin Schliefer, MD, Jörn Risse, MD, Christian Menzel, MD, PhD and Hans-Jürgen Biersack, MD, PhD

1 From the Departments of Nuclear Medicine (H.P., M.B., J.R., C.M., H.J.B.) and Internal Medicine (J.K.R., K.S.), University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Received December 6, 2000; revision requested January 18, 2001; revision received March 12; accepted March 22. Address correspondence to H.P. (e-mail: palmedo@mailer.meb.uni-bonn.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Eight patients (77 joints) with polyarthritis were treated systemically with 570 MBq (15.4 mCi) of rhenium 186 (186Re) hydroxyethylidenediphosphonate (HEDP). Pain and disease activity were assessed monthly. In six (75%) of eight patients, a single injection of 186Re HEDP led to an improvement in disease activity. Systemic low-dose treatment with 186Re HEDP can reduce pain and disease activity in patients with polyarthritis.

Index terms: Arthritis, psoriatic, 30.72, 40.72 • Arthritis, rheumatoid, 30.71, 40.71 • Lupus erythematosus, 30.612, 40.612 • Radionuclides, therapeutic, 30.1269, 40.1269 • Rhenium, radioactive • Therapeutic radiology, 30.1269, 40.1269


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Materials and Methods
Results
 Discussion
 REFERENCES
 
Chronic arthritis is very common and is associated with a variety of systemic diseases (1,2). Polyarthritis may appear in patients with rheumatoid arthritis (RA), psoriasis, and systemic lupus erythematosus, and it often affects distal joints of the extremities and, in some cases, the proximal joints, spine, and sacroiliac joints (2–5). In these patients, immunologic processes lead not only to destruction of joints and bones but also to proliferative alterations (6). Because complete remission of rheumatoid diseases is rare, the course of the disease is generally chronic and is accompanied in many patients by acute inflammatory phases (7). The major problems experienced by patients are progressive pain and increasing lack of mobility (7).

Drugs used to treat systemic inflammatory joint disease frequently cause side effects; therefore, alternative strategies are needed for such chronic treatment (8,9). In some cases, the disease does not respond well to drug therapy, and surgical treatment modalities or radiosynovectomy by means of intraarticular administration of radioisotopes may be performed (10–13). In patients with arthritis affecting multiple joints, these treatment options are not adequate.

Rhenium 186 (186Re) hydroxyethylidenediphosphonate (HEDP) and rhenium 188 HEDP are radiopharmaceuticals that have been used for palliation of painful bone metastases resulting from prostate and breast cancer (14–19). The 186Re HEDP can achieve noticeable pain relief in 70%–90% of patients after administration of local radiation doses of 10–100 Gy (14–17). The therapeutic effects of 186Re HEDP result from the beta emission, which has a maximal energy of 1.07 MeV and a maximal distance of 4.5 mm in soft tissue (15). The 186Re also has a 9% gamma emission (135 keV), which allows whole-body imaging, with a standard gamma camera, and dose estimations. The physical half-life of 186Re is 89.3 hours, which makes this radioisotope suitable for repetitive therapy within a short time. More than 50% of the administered activity is cleared through the kidneys within the first 24 hours (14). Similar to phosphonates such as technetium 99m (99mTc) dicarboxypropane diphosphonate (DPD), which is used for bone scanning, the 186Re HEDP adheres to the hydroxyapatite crystal mediated by the metabolic activity of osteoblastic cells. Therefore, hypermetabolic regions of the bone and joints will receive a significantly higher radiation dose than will regions of the skeleton that have normal metabolism (14).

The purpose of this study was to evaluate the effect of systemic radiation therapy with 186Re HEDP on pain and activity of patients with the polyarthritis of rheumatoid disease who do not respond to treatment with medication.


   Materials and Methods
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patients
Eight consecutive patients (four men, four women; mean age, 54.4 years; age range, 50–62 years) with a total of 77 diseased joints were included in this prospective study. The following joints were treated with 186Re HEDP (Mallinckrodt, St Louis, Mo): 22 metatarsophalangeal (feet), two tarsometatarsal, three proximal interphalangeal, and two ankle mortise joints; four wrist, 18 metacarpal, 11 proximal, and five distal interphalangeal joints; six shoulders, two sternoclavicular joints; and two sacroiliac joints (mean number of treated joints, 9.6; range, 3–21 joints).

The following inclusion criteria were used: (a) patient older than 50 years, (b) RA or rheumatic-related disease diagnosed according to the classification system of the American Rheumatism Association (20), (c) arthritis in a minimum of three joints, (d) high activity uptake by affected joints at 99mTc DPD scintigraphy, (e) disease duration of at least 5 years, (f) disease progression despite long-term treatment with antirheumatoid drugs or important side effects or contraindications to antirheumatoid treatment without further therapeutic options, (g) radiologic or clinical proof of affected joints, (h) pathologically increased erythrocyte sedimentation rate, and (i) disease activity scores of at least 4 on the visual analogue scale. The study exclusion criteria included (a) white blood cell count less than 4.0 x 109/L), (b) platelet count below 100 x 109/L, (c) age younger than 50 years, and (d) low disease activity (visual analogue scale, <4).

Approval for these studies was obtained from the ethical committee and the radiation safety committee, and all patients were informed about the experimental character of the study and possible side effects and provided written consent. If symptoms recurred, those patients showing a response to therapy with 186Re HEDP were considered for a second treatment. The same inclusion and exclusion criteria were used for subsequent therapy. Follow-up after a second treatment was completed in patients 3 and 7.

Therapy with 186Re HEDP
To prevent extravasation and excessive doses in the fingers, the radiopharmaceutical was administered by using an intravenous infusion system (Braun, Melsungen, Germany). The syringe was shielded to reduce the radiation dose. Each patient received at least one treatment with 555–740 MBq (15–20 mCi) of 186Re HEDP. The amount of required activity was estimated on the basis of results at pretreatment bone scintigraphy, with a maximum dose of 20 mCi. For patients to be admitted to therapy, dose estimations to the affected joints had to show a minimum radiation dose of 5 Gy (14). For this purpose, sequential bone scintigraphy was performed, and the accumulated activity of a reference joint was calculated. A radiograph was obtained to help determine the volume of the concerned joint. Multiplication of the radionuclide-specific S-value by the accumulated activity per mass unit equals the estimated radiation dose to the reference joint.

The patient was well hydrated after injection of the 186Re HEDP. Owing to local radiation protection laws, the patients remained in the isolation ward for 48 hours. Twelve hours after injection, whole-body scintigraphy was performed to document the accumulation of 186Re HEDP. The dose of 186Re HEDP for each patient was normalized to a standard body surface area of 1.73 m2. The body surface area (BSA) was calculated according to the following formula: BSA = 0.2025 x BW0.425 x H0.725, in which BW is body weight (in kilograms) and H is height (in meters). No therapeutic complications occurred.

Assessment of Pain and Disease Activity
Patient data assessed according to the core set of measurements of disease activity for RA obtained in clinical trials published by the American College of Rheumatology (21). We assessed the following five parameters: number of tender joints, number of swollen joints, patient’s global assessment of disease activity, physician’s global assessment of disease activity, and acute phase reactant value. Sixty-eight joints were examined by the physician during the physical examination to determine the number of tender and swollen joints (21). Global assessment of disease activity reflects not only the pain situation of the patient but also includes an anamnesis about daily activities and documentation of physical disabilities.

The global assessment of disease activity was scored by using a visual analogue scale that ranged from 0 to 10. The comparison of pre- and posttreatment values was categorized as one of the following scores: no improvement, moderate improvement (one score better on the visual analogue scale), clear improvement (two scores better on the visual analogue scale), and strong improvement (three or more scores better on the visual analogue scale). The erythrocyte sedimentation rate was used as a measure of the acute phase, and posttreatment values were compared with pretreatment values. Counts of thrombocytes, white blood cells, and erythrocytes were also measured before and after therapy as were creatinine levels.

All patient studies were assessed by consensus by two rheumatologists (J.K.R., K.S.) 1 week before therapy, during hospitalization, and monthly after treatment. The assessment results were documented with the help of standardized questionnaires and case report forms. During follow-up (at least 9 months), no new treatment (except for a second treatment with 186Re HEDP) was initiated unless the patient showed progressive disease and was considered a nonresponder. The patient was considered a responder if at least three of the five investigated parameters showed improvement.

Table 1 indicates the specific diseases, joints involved, and administered activities for the eight patients. One patient with psoriatic arthritis and one with RA received a second treatment with 186Re HEDP, which resulted in a total of 10 treatments (Table 1). Patients received a mean activity of 570 MBq of 186Re HEDP standardized to the body surface area (range, 496–688 MBq).


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  		TABLE 1. Administered Activity Normalized to Body Surface Area per Patient and per Treatment

 

   Results
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
Discussion
 REFERENCES
 
Six (75%) of eight single injections led to an improvement in disease activity (Figure). The duration of response after a single injection of 186Re HEDP ranged between 2 and 7 months (mean, 2.5 months). After the first injection in four patients, a pathologically elevated erythrocyte sedimentation rate decreased from a pretreatment mean of 57 mm/h (range, 44–71 mm/h) to a mean value of 30 mm/h. In one case, the erythrocyte sedimentation rate normalized completely (Table 2). Two or more joints became pain free after five (62%) of eight single injections of 186Re HEDP, (mean, 6.2 joints; range, 2–18 joints), and a decrease in the number of swollen joints was observed after four (50%) single injections (mean, 2.25 joints; range, 1–3 joints).



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  		Figure a. Patient 4. Bone scintigrams show hands with RA. (a) A Tc-99mDPD scintigram demonstrates intense tracer uptake (arrows) in multiple joints of both hands. The accumulation in the right wrist (arrowhead) and the carpal area is from an old fracture. After treatment with 186Re HEDP, the patient reported pain relief. (b) Posttreatment 186Re HEDP scintigram also shows high tracer accumulation (arrows) in the affected joints and wrist (arrowhead), which results in a locally high radiation dose, in comparison with normal bone.

 


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  		Figure b. Patient 4. Bone scintigrams show hands with RA. (a) A Tc-99mDPD scintigram demonstrates intense tracer uptake (arrows) in multiple joints of both hands. The accumulation in the right wrist (arrowhead) and the carpal area is from an old fracture. After treatment with 186Re HEDP, the patient reported pain relief. (b) Posttreatment 186Re HEDP scintigram also shows high tracer accumulation (arrows) in the affected joints and wrist (arrowhead), which results in a locally high radiation dose, in comparison with normal bone.

 

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  		TABLE 2. Response to Treatment with 186Re HEDP

 
The physician scored findings after three treatments as strong improvement, two as clear improvement, and one as moderate improvement. The patients scored findings after five treatments as clear improvement and after one treatment as moderate improvement. In all but patient 3, global assessment scores correlated with the decrease in the numbers of painful or swollen joints. Patients 4 and 8 scored pain relief in all affected joints.

There was no change in the number of painful and swollen joints for two patients with RA. The global assessment scores of both the physician and patients showed no improvement, and the erythrocyte sedimentation rates remained elevated.

Patients 3 and 7 underwent a second treatment 3 and 4 months later, respectively. After the second treatment, the duration of decreased disease activity was increased to 5 and 4 months, respectively. One of the patients reported a decrease in the number of painful and swollen joints, but the erythrocyte sedimentation rate remained elevated. In the other patient, the erythrocyte sedimentation rate normalized after the second treatment, but the number of painful joints did not decrease.

All patients experienced pain in the joints of either the fingers or feet, and five experienced pain in both. The sacroiliac and sternoclavicular joints, the wrist, the ankle, and the shoulder were also affected (Table 3). Painful joints of the feet and hands were successfully treated in 44% (12 of 27) and 35% (12 of 34) of joints, respectively. Pain reduction was also observed in other regions including the ankle, wrist, sacroiliac joint, and shoulder.


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  		TABLE 3. Success of Treatment with 186Re HEDP after Administration of a Single Injection

 
In a comparison with pretreatment values, no hematopoietic alterations or changes in creatinine levels were observed.


   Discussion
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
REFERENCES
 
Rheumatic diseases play an important role in the health systems of modern nations owing to the enormous costs resulting from the physical disabilities of such patients (4,22). The diagnosis of chronic polyarthritis is dramatic and can possibly lead to changes in employment and cause substantial alterations in private and family life (2).

In patients with multifocal arthritis, targeted therapy with phosphonates labeled with beta-emitting radioisotopes may be a useful approach. Our initial results show that an improvement in disease activity was achieved in six of eight patients who received a single injection of 186Re HEDP. A single injection of 186Re HEDP decreased the number of painful or swollen joints in five (62%) of eight patients, and this response lasted for 2–7 months (mean, 2.5 months).

Repetitive therapy was evaluated in two patients, and, in comparison with results after a single injection of 186Re HEDP, the effect on disease activity was similar. It seems possible, therefore, that repeated treatments can substantially increase the duration of response.

A response to therapy was observed in patients with polyarthritis due to psoriatic arthritis, RA, or systemic lupus erythematosus. Other types of arthritis were not found in these eight patients.

Limitations of this study are that the population was small and heterogeneous and there was no control group.

In the early stage of monarthritis or oligoarthritis, radiosynovectomy is an effective method to treat inflammatory processes of the synovia (10,11). Radiation doses of 70–130 Gy can be applied to the synovia with intraarticular injections of radionuclides (23). Depending on the location of the irradiated joint, radiosynovectomy results in noticeable pain reduction and improved mobility for 1–4 years (11). The effect of radiosynovectomy seems to be that immunologic reactions mediated mainly by cytokine-producing lymphocytes are suppressed, and synovitis is efficiently suppressed. Findings in radiobiologic experiments show that antiinflammatory radiation effects are based on modulation of the adhesion of white blood cells to activated endothelial cells and on induction of nitric oxide synthase by macrophages (24).

The treatment response after systemic administration of 186Re HEDP seems to be shorter in comparison with that after radiosynovectomy (11). The former response may be related to the higher radiation dose to the synovia achieved with radiosynovectomy.

By performing systemic therapy with 186Re HEDP for pain palliation of osseous metastases, Maxon et al (14) found that radiation doses of 10–100 Gy can be achieved in bone metastases. In our study, we administered half these levels of activity, and we calculated dose estimates to achieve doses of a minimum of 5 Gy per joint.

In four patients after a single treatment with 186Re HEDP, the erythrocyte sedimentation rate, which is used as a measure of the acute phase of disease, showed a mean decrease from 57 to 30 mm.

When a dose of 186Re HEDP between 496 and 688 MBq was administered systemically, the effective dose was about 200 mSv. This value was not much higher than the values of 80–155 mSv for whole-body radiation doses after radiosynovectomy, even if the treated joint was immobilized for 48 hours (23). Further treatment options were not available for the patients in this study, who were all older than 50 years, because their arthritis did not respond to treatment with medication or they experienced severe side effects of medication. We did not expect substantial changes in blood cell counts with a bone marrow dose of 0.4 Gy for each injection of 186Re HEDP, and none were seen.

In conclusion, our initial results show that systemic treatment with 186Re HEDP can reduce disease activity in patients with polyarthritis due to RA, psoriatic arthritis, and systemic lupus erythematosus. A single low-dose therapy with 186Re HEDP led to a response in six (75%) of eight patients that lasted 2–7 months. Further investigations with larger patient populations are required to confirm these encouraging results.


   FOOTNOTES
 
Abbreviations: DPD = dicarboxypropane diphosphonate, HEDP = hydroxyethylidenediphosphonate, RA = rheumatoid arthritis

Author contributions: Guarantors of integrity of entire study, H.P., J.K.R.; study concepts and design, all authors; literature research, H.P., J.K.R.; clinical studies, H.P., J.K.R., K.S., C.M.; data acquisition, K.S., H.P., M.B., J.K.R.; data analysis/interpretation, all authors; manuscript preparation and definition of intellectual content, all authors; manuscript editing, H.P., J.K.R.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 

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