Reply to the letter by Prof. Rothschild. DOI: 10.1007/s10067-019-04560-y
Dear Editor in Chief, We would like to thank Professor Rothschild for his interest in our article and the opportunity to respond to his letter, where he describes Btwo fundamental methodologic flaws^ with regard to our GLUTEAL study, evaluating the role for glucocorticoid injections in the greater trochanteric pain syndrome (GTPS) [1]. His first point relates to betamethasone being water soluble. As described in our publication, the glucocorticoid preparation utilized was Diprophos®, which consists of a mixture of betamethasone disodium phosphate and betamethasone dipropionate. The betamethasone disodium phosphate is indeed water soluble, whereas the betamethasone dipropionate has poor water solubility as it forms local crystal deposits, which explains the prolonged clinical effect of this substance. The second point addresses the number of bursa in the region of the greater trochanter, and Professor Rothschild suggests that there are a total of four. Indeed, we could have been more specific, but generally when one describes the grater trochanteric bursa, it implies the deep subgluteus maximus bursa, which lies beneath the gluteus maximus muscle and iliotibial band, and superficial to the gluteus medius tendon. In the paper by Williams et al. cited in his letter, the authors in fact describe nine different bursae in the region of the greater trochanter that have been potentially implicated in the GTPS, although in most cases either the deep subgluteus maximus bursa or the subgluteus medius bursa is involved [2]. In our experience, the identification of the majority of these bursae with ultrasound is extremely difficult, unless there is a pathological collection of fluid within them. We are not aware of any publication suggesting that the injection of multiple bursae around the greater trochanter has a greater clinical efficacy compared with the injection of a single bursa. In a retrospective review including 65 ultrasound-guided glucocorticoid injections for the GTPS, there was a significantly greater efficacy of injections into the greater trochanteric (deep subgluteus maximus) bursa compared with the subgluteus medius bursa, and that injections into the subgluteus medius bursa were of no clinical benefit [3]. It should be highlighted that imaging evidence of a bursitis is only found in a minority of cases of the GTPS. For example, in the seminal paper by Bird et al., only 8% patients with GTPS demonstrated MRI evidence of bursitis [4]. Other publications have found imaging evidence of bursitis in 15 to 40% of cases of GTPS. Finally, Professor Rothschild states that Ball four bursae are inflamed, or at least sources of clinical symptoms, in almost all individuals^ with GTPS and in the World Journal of Orthopedics, he describes the immediate elimination of pain in 49/50 individuals from his own practice with trochanteric pain in whom four bursae were injected with triamcinolone, with pain relief persisting for greater than 6 months in 47 individuals [5]. It would indeed be very interesting to test this hypothesis in a randomized controlled trial. See related article, https://doi.org/10.1007/s10067-019-04560-y.
Ultrasound-guided corticosteroid injections for treatment of greater trochanteric pain syndrome: greater trochanter bursa versus subgluteus medius bursa.
OBJECTIVE
The purpose of this study was to evaluate the effectiveness of corticosteroid injections into the greater trochanteric bursa as opposed to the subgluteus medius bursa in patients with greater trochanteric pain syndrome.


MATERIALS AND METHODS
We retrospectively reviewed 183 injections (149 performed in women, 34 performed in men; age range 23-90 years; median, 53 years) performed for treatment of greater trochanteric pain syndrome. A 10-cm visual analog scale survey was used to assess pain level before the procedure and 14 days after the procedure. A 3-mL corticosteroid solution was injected into either the greater trochanteric bursa or the subgluteus medius bursa under direct ultrasound guidance. Procedure images were retrospectively reviewed to determine the site of injection. Diagnostic images obtained at the time of the procedure were also reviewed for findings of tendinopathy, bursitis, and enthesopathy. Statistical analysis of differences in pain reduction was performed, as was analysis for association between pain relief and demographic variables of age, sex, previous injections, and ultrasound findings.


RESULTS
Sixty-five injections met the inclusion criteria; 56 performed in women and nine performed in men (age range, 30-82 years; median, 53 years). Forty-one injections were into the greater trochanteric bursa and 24 into the subgluteus medius bursa. There was a statistically significant difference in pain reduction between greater trochanteric bursa and subgluteus medius bursa injections with a median pain reduction of 3 as opposed to 0 (p < 0.01). There was no statistically significant association between pain relief and demographic variables or ultrasound findings.


CONCLUSION
Corticosteroid injections into the greater trochanteric bursa may be more effective than injections into the subgluteus medius bursa for treatment of greater trochanteric pain syndrome.
Sources of Information on Lymphoma Associated with Anti-Tumour Necrosis Factor Agents
AbstractBackground: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems.
 Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents.
 Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma.
 Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p< 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn’s disease were more prevalent in published cases than in pharmacovigilance reports (p< 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001).
 Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.