Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment.

The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility-both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.

Efficacy of wIRA in the treatment of sacroiliitis in male patients with ankylosing spondylitis and its effect on serum VEGF levels.

BACKGROUND: This study aimed to assess the efficacy of water-filtered infrared A (wIRA) in sacroiliitis in male patients with ankylosing spondylitis (AS) and the effect of wIRA therapy on serum vascular endothelial growth factor (VEGF). METHODS: One hundred twenty male AS patients with active sacroiliitis were randomly divided into wIRA group and control group. wIRA treatment was performed twice daily for 5 consecutive days with 24-h interval before switching the treatment (crossover design). Bath ankylosing spondylitis disease activity index (BASDAI) scores, pain visual analogue scale (VAS), and morning stiffness VAS were recorded prior to and after each treatment period. Additionally, C-reactive protein (CRP), serum VEGF, and resistance index (RI) of sacroiliac joints detected by ultrasonography were recorded at baseline and after the first and second treatment period, respectively. The efficacy was examined by using repeated measures analysis of variance (ANOVA). RESULTS: BASDAI, pain VAS, and morning stiffness VAS scores decreased significantly (P < 0.001) after wIRA treatment and no-wIRA treatment (control group), and the difference between the two groups was significant (P < 0.001). CRP declined and RI increased during the wIRA treatment as compared with the no-wIRA treatment (P < 0.001). The increase in RI was associated with improvement of pain VAS scores (P = 0.018), while serum VEGF was unaffected by the treatment. CONCLUSIONS: wIRA treatment achieved symptom and pain relief for AS patients with active sacroiliitis. wIRA treatment also improved RI revealed by ultrasonography, and this effect was associated with improved pain VAS scores.

LLLT for the management of patients with ankylosing spondylitis.

This study aimed to compare the effectiveness of the combined low-level laser therapy (LLLT) and passive stretching with combined placebo LLLT laser and the same passive stretching exercises in patients suffering from Αnkylosing spondylitis. Forty-eight patients suffering from Αnkylosing spondylitis participated in the study and were randomized into two groups. Group A (n = 24) was treated with a λ = 820 Ga-Al-As laser CW, with power intensity = 60 mW/cm(2), energy per point in each session = 4.5 J, total energy per session = 27.0 J, in contact with specific points technique, plus passive stretching exercises. Group B (n = 24), received placebo laser plus the same passive stretching exercises. Both groups received 12 sessions of laser or placebo within 8 weeks; two sessions per week (weeks 1-4) and one session per week (weeks 5-8). Pain and function scales were completed before the treatment, at the end of the fourth and eighth week of treatment, and 8 weeks after the end of treatment (follow-up). Group A revealed a significant improvement after 8 weeks of treatment in all pain and function scales. At 8-week follow-up, the improvement remained only for the pain, while for all other function outcomes the differences were not statistically significant. The results suggested that after an 8-week treatment and after a follow-up, the combination of LLLT and passive stretching exercises decreased pain more effectively than placebo LLLT along with the same passive stretching exercises in patients with Αnkylosing spondylitis. Future studies are needed to establish the relative and absolute effectiveness of the above protocol.

[Long-term investigation of the risk of malignant diseases following intravenous radium-224 treatment for ankylosing spondylitis]. / Langzeituntersuchung zum Risiko maligner Erkrankungen nach intravenöser Behandlung des Morbus Bechterew mit Radium-224.

BACKGROUND AND PURPOSE: In German-speaking countries, the intravenous treatment of ankylosing spondylitis (AS) with radium-224 ((224)Ra) was common between the late 1940s and 2005. In this long-term investigation, the risk of malignant diseases following intravenous (224)Ra treatment for AS was assessed. PATIENTS AND METHODS: In a prospective long-term study, 1,471 patients with AS who were treated with (224)Ra between 1948 and 1975 have been followed together with a control group of 1,324 AS patients treated neither with radioactive drugs nor with X-rays. Standardized questionnaires to evaluate the patients' health status were used. Observed numbers of malignant diseases were compared with those of the control group as well as with expected numbers for a normal population. RESULTS: After 26 years of follow-up, causes of death have been certified for 1,006 patients of the exposure group (control group: 1,072 patients). Significantly increased rates of myeloid leukemia (12 cases observed vs. 2.9 expected; p < 0.001), kidney cancer (18 vs. 9.1; p < 0.01), thyroid cancer (4 vs. 1.2; p = 0.03) and borderline significantly increased rates of cancer of female genital organs (10 vs. 5.6; p = 0.06) were found in the exposure group in contrast to no significant increases of these diseases in the control group. Rates of pulmonary and gastrointestinal malignancies were not increased. Lymphatic leukemia (exposure group: 8 vs. 2.7; p < 0.01; control group: 7 vs. 3; p = 0.03) was significantly elevated due to a high rate of chronic lymphatic leukemia in both, the exposure as well as the control group. CONCLUSION: Treatment of AS with (224)Ra led to increased incidences of myeloid leukemia and malignancies of kidneys, thyroid and female genital organs. Although this kind of therapy is now abandoned, there is a need for close follow-up of patients who received it.

Escalas de avaliação aplicadas à espondilite anquilosante pertinentes à fisioterapia / Ankylosing spondylitis evaluation scale related to physical therapy

A espondilite anquilosante (EA) é uma doença inflamatória crônica que acomete preferencialmente o esqueleto axial. A patologia evolui de forma insidiosa e é potencialmente debilitante, levando a redução da qualidade de vida dos indivíduos acometidos. Este estudo teve como objetivo realizar uma revisão literária das escalas de avaliação em EA (BASFI - Bath Ankylosing Spondylitis Functional Index, DFI - Dougado´s Functional Index, EVA – Escala Visual Analógica e BASDAI - Bath Ankylosing Spondylitis Disease Activity Index) pertinentes à fisioterapia, especificamente dos domínios: função, dor, mobilidade da coluna, rigidez e avaliação global do paciente, presentes na área SM-ARD/Fisioterapia. Foi abordada também uma escala de avaliação radiológica, SASSS (Stoke Ankylosing Spondylitis Spine Score). A revisão estendeu-se de outubro a dezembro de 2006, mediante pesquisas em livros de acervos particulares e públicos e em base de dados. Constatou-se neste estudo a necessidade da realização de pesquisas, metodologias ou complementos visando à validação de instrumentos no Brasil que sirvam de esclarecimento sobre o dinamismo e comportamento da EA diante da intervenção fisioterapêutica.

The Ankylosing Spondylitis (AS) is a chronic inflammatory disease that affects the axial skeleton. The pathology develops in an insidious way and it is potentially debilitated, taking reduction of the life quality. The objective of this study was to make a literature review of the evaluation scales in AS (BASFI - Bath Ankylosing Spondylitis Functional Index, DFI - Dougado´s Functional Index, VAS – Visual Analog Scale e BASDAI - Bath Ankylosing Spondylitis Disease Activity Index) related with physical therapy, specifically of the domains: function, pain, mobility of the column, rigidity and the patient's global evaluation, present in SM-ARD/ physical therapy area. This review showed also a scale of radiologic evaluation, SASSS (Stoke Ankylosing Spondylitis Spine Score). The literature revision was performed from October to December 2006, using books of private and public collections and data basis. It was verified, in this study, the need of researches, methodologies or complements aiming at the validation of instruments in Brazil in order to explain the dynamism and behavior of AS with physical therapy intervention.

Incidence of leukaemia and other malignant diseases following injections of the short-lived alpha-emitter 224Ra into man.

We performed an epidemiological study on 1,471 ankylosing spondylitis patients treated with repeated intravenous injections of the short lived alpha-emitter (224)Ra (excluding radiation therapy with X-rays) between 1948 and 1975. These patients have been followed together with a control group of 1,324 ankylosing spondylitis patients treated neither with radioactive drugs nor with X-rays. The mean follow-up time was 26.3 years in the exposed and 24.6 years in the control group. To date, causes of death have been ascertained for 1,006 exposed patients and 1,072 controls. Special emphasis was placed on the reporting of malignant diseases. Expected numbers of cases were computed for the age, sex and calendar year distribution of both groups using cancer registry incidence rates. In the exposed group 18 cases of kidney cancer (vs. 9.1 cases expected, P < 0.01) and 4 malignant thyroid tumours (vs. 1.2 cases expected, P = 0.03) were observed. In the control group the observed cases for these tumours were not significantly elevated. The most striking observation, however, were the 21 cases of leukaemia in the exposed group (vs. 6.8 cases expected, P < 0.001) compared to 12 cases of leukaemia in the control group (vs. 7.5 cases expected). Further sub-classification of the leukaemias demonstrated a high increase of myeloid leukaemia in the exposed group (12 cases observed vs. 2.9 cases expected, P < 0.001), and out of these, especially a high excess of acute myeloid leukaemias (7 cases observed vs. 1.8 expected, P = 0.003). In the controls the observed cases are within the expected range (4 myeloid leukaemias vs. 3.1 cases). This increase in total leukaemias as well as particularly in myeloid leukaemias is significant in direct comparison between the exposed and control groups too (P < 0.05). The enhanced leukaemia incidence in the exposed group is in line with the observation of increased leukaemia incidence in mice injected with (224)Ra.

Influence of the bystander phenomenon on the chromosome aberration pattern in human lymphocytes induced by in vitro alpha-particle exposure.

A recent publication on both chromosome-type and chromatid-type aberrations in lymphocytes of patients during treatment with radium-224 for ankylosing spondilitis has revived the question of whether the chromatid-type aberrations may be the consequence of factors released by irradiated cells. Therefore, the aim of the present study was to investigate the influence of such a bystander phenomenon on the chromosome aberration pattern of lymphocytes. Monolayers of human lymphocytes were irradiated with 1 Gy of alpha-particles from an americium-241 source in the absence or presence of whole blood, autologous plasma or culture medium. In the presence of any liquid covering the monolayer during irradiation, the chromatid-type aberrations were, contrary to expectation, elevated. Whereas the intercellular distribution of dicentrics was significantly overdispersed, the chromatid-type aberrations showed a regular dispersion. It can be concluded that the enhanced frequency of chromatid aberrations is the result of a damage signal or a bystander phenomenon released by irradiated cells.

[Radon within therapeutic strategies of ankylosing spondylitis]. / Radon im Behandlungskonzept der Spondylitis ankylosans.

For more than fifty years patients with rheumatic diseases have been treated in the thermal gallery of Bad Gastein, main indication is ankylosing spondylitis. Experiences of this kind of spa treatment on several hundred patients and randomised controlled clinical trials document the positive treatment effect of spa therapy with Radon which lasts for up to 40 weeks.

Increased risk of myeloid leukaemia in patients with ankylosing spondylitis following treatment with radium-224.

OBJECTIVE: To investigate long-term health effects in AS patients treated with (224)Ra. METHODS: A prospective epidemiological study has been carried out on 1471 AS patients treated with repeated intravenous injections of (224)Ra between 1948 and 1975. These patients have been followed together with a control group of 1324 AS patients not treated with radioactive drugs and/or X-rays. Numbers of malignancies expected in a normal population were computed from German and Danish cancer registry data. RESULTS: After a mean follow-up time of 26 yrs in the exposed group or 25 yrs in the control group, causes of death have been ascertained for 1006 exposed patients and 1072 controls. In particular, 19 cases of leukaemia were observed in the exposure group (vs 6.8 cases expected, P < 0.001) compared to 12 cases of leukaemia in the control group (vs 7.5 cases expected). Further subclassification of the leukaemia cases demonstrated a high increase of myeloid leukaemia in the exposure group (11 cases observed vs 2.9 cases expected, P < 0.001), especially a high excess of acute myeloid leukaemias (7 cases observed vs 1.8 cases expected, P = 0.003), whereas in the controls the observed cases are within the expected range (4 myeloid leukaemias vs 3.1 cases expected). CONCLUSIONS: The enhanced leukaemia incidence in the exposed group is in line with results from experiments in mice injected with varying amounts of the bone-seeking alpha-emitter (224)Ra. In these studies, in animals exposed to lower doses of (224)Ra, i.e. at doses lower than those found to induce osteosarcomas, an increased risk of leukaemia was observed.

[Cost-benefit analysis of [224Ra] radium chloride therapy for ankylosing spondylitis (Bekhterev's disease)]. / Kosten-Nutzen-Analyse einer Therapie der ankylosierenden Spondylitis (Morbus Bechterew) mit Radiumchlorid [224Ra].

BACKGROUND AND PURPOSE: Cost-benefit analyses are helpful in setting priorities for funding health-care programs. The authors studied the cost/benefit of treatment with radium-224 compared to the treatment without radium-224 in patients with ankylosing spondylitis (AS). MATERIAL AND METHODS: The data of a 2-year retrospective observational study were used to estimate cost/benefit of [224Ra] therapy. Twelve patients treated with [224Ra], complete recruit in AOK Saxony, matched (age, gender, employment status) with twelve patients receiving conservative treatment without [224Ra], were compared for lost productivity and direct medical costs, such as doctor visits, medication and hospitalization, 1 year before and after treatment. RESULTS: 1 year after the first i.v. injection of [224Ra], all cost factors in the case group were reduced compared to 1 year before treatment with [224Ra] (hospitalization 29.4%, doctor visits 23.5%, medication 9.4%, and lost productivity even 82.3%). The total costs decreased by an average of 3,870 Euros. Because of the small sample the differences showed a trend but were not significant. CONCLUSION: The use of [224Ra] in patients with AS seems to reduce lost productivity and direct medical costs, but additional studies based on more patients and long-term data are needed.

Leukaemia and aplastic anaemia in patients irradiated for ankylosing spondylitis. 1957.

Reported here is a seminal study of leukaemia among patients who had been treated with x-rays for ankylosing spondylitis. The findings were first published in a Medical Research Council (MRC) report in 1957. The report is now published in a scientific journal for the first time, 50 years after it first appeared.

The 1957 MRC report on leukaemia and aplastic anaemia in patients irradiated for ankylosing spondylitis.

The estimation of the carcinogenic effects of exposure to low doses of ionizing radiation has depended primarily on extrapolation from effects seen in two populations exposed to relatively high doses--the survivors of the atomic bomb explosions in Japan and patients treated in the UK with x-rays for the arthritic condition ankylosing spondylitis. The study of the leukaemia risk in over 14000 irradiated spondylitis patients was completed in an astonishingly short period of time in the mid-1950s. The full report of the original study has been difficult to access because it was not published in a journal but only as a Special Report of the UK Medical Research Council. To mark 50 years since this publication this full report is reproduced in this issue of the Journal. This accompanying review describes the background to the study, the principal findings and the further follow-up of the population that documented the risks of cancers in addition to leukaemia associated with the x-ray treatment. The architects of the study were a radiobiologist, Michael Court-Brown, and an epidemiologist, Richard Doll. Their very productive study of the leukaemia risk among spondylitics spawned a lifelong collaboration including further seminal studies of the carcinogenic effects of radiation exposure, which are also summarised in the review.

Estimation of cancer risks from radiotherapy of benign diseases.

BACKGROUND: The effective-dose method which was proposed by the ICRP (International Commission of Radiation Protection) for the estimation of risk to the general population from occupational or environmental, low-dose radiation exposure is not adequate for estimating the risk of cancer induction by radiotherapy of malignant or nonmalignant diseases. METHODS: The risk of cancer induction by radiotherapy of benign diseases should be based on epidemiologic data directly derived from follow-up studies of patients who had been given radiotherapy for nonmalignant diseases in the past. RESULTS: Risk factors were derived from epidemiologic studies of patients treated with irradiation for nonmalignant diseases to be used for selecting treatment options and optimizing treatment procedures. CONCLUSION: In most cases, cancer risks estimated by the effective-dose method may overestimate the true risks by one order of magnitude, yet in other cases even may underestimate it. The proposed method using organ-specific risk factors may be more suitable for treatment planning.

[Effectiveness and safety of radium chloride in the treatment of ankylosing spondylitis. Results of an observational study]. / Wirksamkeit und Verträglichkeit von Radiumchlorid in der Behandlung der ankylosierenden Spondylitis. Ergebnisse einer Anwendungsbeobachtung.

After radium chloride was approved for the therapy of ankylosing spondylitis (AS) in Germany on October 23, 2000, an open, non-comparative prospective observational study was planed. The assessment involved 308 patients with the diagnosis of AS and radiological evidence of spinal involvement who were treated with at least one injection of radium chloride. 278 of these patients received the full cycle of 10 injections (a total of 10 MBq radium-224) one injection one per week for a period of 10 successive weeks. Validated outcomes were measured before therapy and six months after therapy according to the recommendations of the "assessment in ankylosing spondylitis working group"(ASAS). The primary endpoint was disease activity assessed using the BASDAI ("Bath Ankylosing Spondylitis Disease Activity Index"). Secondary endpoints included the BASFI ("Bath Ankylosing Spondylitis Functional Index"), as well as self-reported pain and global patient ratings. Patients showed significant improvement in all of the parameters assessed (BASDAI, BASFI, pain, global patient rating) at 6-months post-treatment. At this time, the mean BASDAI and BASFI scores improved from 5.5 to 3.5 and from 5.6 to 3.7, respectively. Pain decreased from a mean of 7.3 to 4.1, and disease activity (as rated by patients) also decreased from 7.2 to 4.1 (p < 0.001 for all of them). Drug tolerance was good. Six adverse events were documented, none of which was serious and none led to discontinuation of treatment. According to the data provided here medical treatment with radium chloride seems to be effective and safe during an observation period of 6 months. Nevertheless, a randomized placebo-controlled study should be performed in the near future in order to safeguard the level of evidence.

Chromosomal aberrations in peripheral lymphocytes of patients treated with radium-224 for ankylosing spondylitis.

The aim of this study was to investigate the in vivo frequency of chromosomal aberrations (primarily dicentric chromosomes and chromatid breaks) potentially induced by (224)Ra alpha-radiation in peripheral lymphocytes. The study was designed to serve as a cytogenetic analysis along with the therapeutic procedure of ankylosing spondylitis patients who were undergoing a treatment with (224)Ra-chloride. The total administered activity was 10 MBq, and the treatment followed a schedule of 10 i.v. injections per week, each with a dose of 1 MBq of (224)Ra. The calculation of absorbed doses delivered to the blood used the models suggested by the ICRP and yielded a value of 4.7 mGy/MBq. The frequency of chromosomal aberrations observed during the course of therapy was related to the blood dose. The frequency of dicentric chromosomes induced in vivo was found to agree well with the corresponding value of dicentrics induced in vitro. However--given that peripheral lymphocytes are in the cell cycle's G(0) stage--an unexpected increase with dose in the yield of chromatid breaks was observed, with about 95% of them occurring in cells without any other chromosome-type aberrations. Reasons for the production of chromatid breaks are discussed.

Radon therapy for the treatment of rheumatic diseases--review and meta-analysis of controlled clinical trials.

OBJECTIVE: The aim of this study was to analyze the effect of radon therapy on pain in rheumatic diseases. METHODS: MEDLINE and MedKur databases were searched for the terms radon plus therapy, rheum, arthritis, and osteo. Radon therapy centers and experts in the field were contacted, proceedings hand-searched, and bibliographies checked for references of potential importance. Included were all prospective randomized controlled clinical trials that compared clinical effects of radon therapy with other interventions in patients with rheumatic diseases and studied pain intensity. Information concerning patients, interventions, results, and methodology were extracted in a standardized manner by all authors independently and summarized descriptively. Reports on pain reduction were pooled for meta-analysis. RESULTS: Five clinical trials with a total of 338 patients and comparing the effect on pain of radon baths (three trials) or radon speleotherapy (two trials) with control intervention in degenerative spinal disease (two trials), rheumatoid arthritis (one trial) and ankylosing spondylitis (two trials) met the inclusion criteria. In meta-analysis, the pooled data showed no difference immediately after treatment (P=0.13) but significantly better pain reduction in the radon group than the control group at 3 months (P=0.02) and 6 months (P=0.002) after treatment. CONCLUSIONS: The existing trials suggest a positive effect of radon therapy on pain in rheumatic diseases. With respect to the potential clinical effect and given the increasing public interest in radon therapy, there is an urgent need for further randomized controlled clinical investigations with long-term follow-up.

Evaluation of a freeze-dried kit for EDTMP-based bone-seeking radiopharmaceuticals.

A freeze-dried kit developed for formulation of ethylenediamine-tetramethylenephosphonic acid (EDTMP) chelates with "pain-palliation" radiolanthanides (e.g., 153Sm and 177Lu) or "diagnostic" 99mTc has been evaluated, meeting quality and safety criteria required for medicinal use. The EDTMP kit enables an instant one-step preparation of a radiopharmaceutical of high radiochemical purity (>99%) and has a sufficiently long shelf life. Comparative biodistribution studies of 177Lu-EDTMP and 99mTc-EDTMP prepared from the kit revealed similar tissue uptake and clearance to those obtained for pre-formulated 153Sm-EDTMP. The most significant difference was observed for 99mTc-EDTMP, which shows a high retention in kidney, reaching ca. 2% ID after 90min p.i.v.Although preliminary clinical evaluations suggest that 99mTc-EDTMP possesses limited value for bone scintigraphy, application of the radiopharmaceutical for specific diagnostic purposes may still be considered, e.g., investigation of bone metastases or ossification processes in inflammatory spondyloarthropathy.