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The impact of intra-articular injection of diprospan at the knee joint on blood glucose levels in diabetic patients.

Introduction

Both diabetes mellitus and osteoarthritis of the knee joint (OAK) are relatively common in the general population, particularly among elderly patients (1). Intra-articular (IA) corticosteroid injection (IACI) is a very popular procedure for pain reduction in patients with OAK (2). It is usually used after failure or unsatisfactory response to painkillers and physical therapy. There are different preparations of IA corticosteroids. Methylprednisolone acetate is the most popular worldwide, betamethasone preparations are popular in Europe, and triamcinolone preparations are popular in the United States (3).

IACI could be associated with a wide range of systemic effects (4-8). These effects reflect a substantial amount of steroids reaching the circulation from the knee joint cavity following IACI (9). There are few reports on the effect of IACI on glucose levels in diabetic patients (10-12). In these studies, it has been shown that IACI at the knee joint in patients with symptomatic OAK is associated with significantly increased blood glucose levels in all controlled diabetic patients (10-12). These studies included methylprednisolone acetate (Depo-Medrol), triamcinolones, and betamethasone acetate/betamethasone sodium phosphate (Celestone Chronodose) (10-12). In contrast to triamcinolones and methylprednisolone acetate, following 1 mL Celestone Chronodose IACI (3 mg of betamethasone acetate + 3 mg of betamethasone sodium phosphate), there was a uniform pattern in all patients with a brisk increase in blood glucose levels within the first hour. The significantly increased blood glucose levels lasted for 2-3 days. In the Depo-Medrol group, there was a completely variable pattern between different patients, and the significantly increased glucose levels lasted for up to 5 days. The triamcinolones, particularly triamcinolone hexacetonide, had a more modest effect on blood glucose levels.

Betamethasone dipropionate/betamethasone sodium phosphate (Diprospan) is also a popular depot steroid compound. However, 1 mL of this preparation contains a lower dose of the rapid-acting compound betamethasone sodium phosphate and a higher dose of the long-acting compound betamethasone dipropionate. This difference in composition might have a different effect on blood glucose levels.

Methods

Patients with type 2 diabetes and glycated hemoglobin (HbAIC) levels of <7.5 during the previous 3 months, as determined using modern versions of blood glucose-monitoring devices, and with knee pain due to OAK for more than 3 months without sufficient response to medical treatment were administered 1 mL Diprospan IACI (Shering-Plough, Belgium) at the knee joint (13). Patients were reguested to monitor their blood glucose levels before and 2 h following breakfast, lunch, and dinner every other day for 1 week prior to IACI and daily for 5 days and every other day for 1 week following IACI using the same glucose-monitoring devices. In addition, patients were reguested to document blood glucose levels 1 h following IACI. Prior to IACI, all patients had to undergo the following tests: blood chemistry, complete blood count, antinuclear antibodies test, rheumatoid factor test, C-reactive protein test, essential sedimentation rate, and knee X-ray.

All injections were administered 1 h following breakfast, with patients in a supine position with straight legs. The insertion was performed using 23-G needle at the medial aspect of the knee, following local cleaning using chlorhexidine and ethyl chloride spray as a local anesthetic. Prior to IACI, the maximal aspiration of knee fluid, if any, was attempted following the needle insertion. Immediately after IACI, patients were reguested to step down and ambulate as usual.

Thereafter, controlled diabetic patients with symptomatic OAK, who were offered 1 mL of hyaluronic acid (20 mg of Suplazyn, Bioniche, Ireland) under the same regimen as the study group, were considered as the control group.

Exclusion criteria included patients who received any type of knee injection, who started or stopped any type of antidiabetic treatment during the previous 3 months, who changed their antidiabetic diet during the previous month, and who started or stopped any type of treatment, such as steroids or thiazides, which may affect glucose metabolism.

For statistical analysis, a significant increase in blood glucose level following IA injection was considered if the level was higher by at least 2-standard deviations than the mean comparable (in reference to meals) glucose level prior to the injection. The Mann-Whitney's U and Fisher's exact tests were used to compare between the continuous and categorical parameters, respectively, of the epidemiologic and clinical data between the two groups.

The study was approved by the Helsinki Committee of the Nazareth Hospital and all the patients signed a consent form.

Results

Fifteen and seven patients were recruited in the Diprospan and control groups, respectively. Twelve patients in the Diprospan group and six in the control group completed the study. No patient had used or abandoned any medication that could affect blood glucose levels, and no patient reported symptom/s or sign/s suggestive of acute infection.

Table 1 summarizes the epidemiologic and clinical parameters of the patients.

There was no significant difference between the epidemiological and clinical variables of the patient and control groups. Most patients had normal to moderate radiographic changes on X-rays.

All patients in the Diprospan group had a significant increase in blood glucose levels compared with levels prior to injection on several occasions (Table 2 and Figure 1). However, patients administered hyaluronic acid showed no significant increase in blood glucose levels, except on one occasion in two patients: in one patient, it occurred 1 h following the injection and in the second patient, on the third day (data not shown). On both occasions, the increased levels were very marginal.

Discussion

Diprosan IACI at the knee joint was associated with significantly increased blood glucose levels in every diabetic patient with symptomatic OAK, regardless of the duration and severity of osteoarthritis or duration and type of diabetes treatment. The increase in blood glucose levels in the Diprospan group could be attributed to only the steroids, since in the control group with IA injection of hyaluronic acid, there was no significant increase in blood glucose levels, except only on one occasion with marginal levels in two patients.

The median number of occasions of significantly increased blood glucose levels was six, with most of the levels seen on day 1.

The pattern of significantly increased blood glucose levels obtained in the Diprospan group is closer to that seen following Celestone Chronodose IACI at the knee joint. However, there are some differences, particularly in the time to early significantly increased glucose levels: with Celestone, it was seen within the first hour in all patients, while with Diprospan, there was some delay wherein for most of the patients, it was seen 3-5.5 h following IACI. The earliest significantly increased level was seen after 21 h in one exceptional case.

Peak levels were approximately 300 mg% and the last significantly increased glucose levels were seen aftera relatively short period of time: 1-3 days.

Hence, for diabetic patients who are candidates for IACI, especially when a betamethasone preparation is considered, Diprospan might be a better choice than Celestone Chronodose due to the gradual increase in glucose levels following Diprospan IACI. Other argument that might provide an advantage for its use over Celestone is the longer duration of the favorable effect in terms of pain relief, following IACI (14).

The main limitation of this study is the small number of patients. However, the consistent findings in either group, the Diprospan or control group, strengthen our conclusions.

Ethics Committee Approval: Ethics committee approval was received for this study from the Ethics Committee of the Nazareth Hospital.

Informed Consent: Written informed consent was obtained from all the patients who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - G.H., F.K.; Design - G.H., F.K., G.H., S.A.; Supervision G.H., F.S., F.K.,; Resources - G.H., G.H., S.A.; Materials - G.H., F.S,. G.H., S.A.; Data Collection and/or Processing -.G.H., F.S., G.H., S.A.; Analysis and/or Interpretation - G.H., F.K., F.S., G.H., S.A.; Literature Search - G.H., F.K.; Writing Manuscript -G.H., F.K., F.S., SA.; Critical Review-G.H., F.K., F.S., G.H., S.A.

Conflict of Interest: The authors have no conflict of interest to declare.

Financial Disclosure: The authors declared that this study has received no financial support.

References

(1.) Van den Bussche H, Koller D, Kolonko T, Hansen H, Wegscheider K, Glaeske G, et al. Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross- sectional study in Germany. BMC Public Health 2011; 11: 101 [Cross Ref]

(2.) Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2005; 2: CD005328. [CrossRef]

(3.) Centeno LM, Moore ME. Preferred intraarticular corticosteroids and associated practice; a survey of members of the American college of rheumatology. Arthritis Care Res 1994; 7: 151-5. [CrossRef]

(4.) Weitof T, Ronnblom L. Glucocorticoid resorption and influence on the hypothalamic-pituitary-adrenal axis after intra-articular treatment of the knee in resting and mobile patients. Ann Rheum Dis 2006; 65:955-7. [CrossRef]

(5.) Gondwe JS, Davidson JE, Deeey S, Sills J, Cleary AG. Secondary Cushing's syndrome in children with juvenile idiopathic arthritis following intra-articular triamcinolone acetonide administration. Rheumatology (Oxford) 2005; 44: 1457-8. [CrossRef]

(6.) Weitoft T, Larsson A, Saxne T, Ronnblom L. Changes of cartilage and bone markers after intra-articular glucocorticoid treatment with and without postinjection rest in patients with rheumatoid arthritis. Ann Rheum Dis 2005; 64: 1750-3. [CrossRef]

(7.) Gladman DD, Bombardier C. Sickle cell crisis following intraarticular steroid therapy for rheumatoid arthritis. Arthritis rheum 1987; 30: 1065-8. [CrossRef]

(8.) Steer JH, Ma DT, Dusci L, Garas G, Pedersen KE, Joyce DA. Altered leukocyte trafficking and suppressed tumor necrosis factor alpha release from peripheral blood monocytes after intra-articular glococorticoid treatment. Ann Rheum Dis 1998;57:732-7. [CrossRef]

(9.) Gless KH, Klee HR, Vecsei P, Weber M, Haack D, Lichtwakd K. Plasma concentration and systemic effect of betamethazone following intraarticular injection. Disch Med Wschr 1981; 106: 704-7. [CrossRef]

(10.) Habib G, Bashir M, Jabbour A. Increased blood glucose levels following intra-articular injection of methylprednisolone acetate in controlled diabetic patients with symptomatic osteoarthritis of the knee. ARD 2008; 67; 1790-1.

(11.) Habib GS, Miari W. The effect of intra-articular triamcinolone preparations on blood glucose levels in diabetic patients. A controlled study. J Clin Rheum 2011; 17:302-5. [CrossRef]

(12.) Habib GS, Safia A. The effect of intra-articular steroid injection of betamethasone acetate/betamethasone sodium phosphate on blood glucose levels in controlled diabetic patients with symptomatic osteoarthritis of the knee. Clin Rheum 2009; 28:85-7. [CrossRef]

(13.) Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American rheumatism association Arthritis Rheum 1986; 29:1039-49. [CrossRef]

(14.) Husby G, Kass E, Spongsveen KL. Comparative double-blind trial of intra-articular injections of two long- acting forms of betamethasone. Scand J Rheumatol 1975;4:118-20. [CrossRef]

George Habib (1,2), Fadi Khazin (3), Fahed Sakas (4), Geries Hakim (5), Suheil Artul (6)

(1) Rheumatology Unit, Laniado Hospital, Netanya, Israel

(2) Rheumatology Clinic, Nazareth Hospital, Israel Institute ofTechnology School of Medicine, Haifa, Israel

(3) Department of Orthopedics, Carmel Medical Center, Haifa, Israel

(4) Department of Medicine, Rambam Medical Center, Haifa, Israel

(5) Department of Orthopedics, Nazareth Hospital, Bar-llan University Gallile School of Medicine, Israel

(6) Department of Radiology, Nazareth Hospital, Bar-llan University Gallile School of Medicine, Israel

Address for Correspondence: George Habib, Rheumatology Unit, Laniado Hospital, Netanya, Israel & Rheumatology Clinic, Nazareth Hospital, Israel Institute of Technology School of Medicine, Haifa, Israel

E-mail: gshabib@gmail.com

Submitted: 16 September 2017

Accepted: 6 November 2017

Available Online Date: 13 February 2018

DOI:10.5152/eurjrheum.2018.17133
Table 1. Demographic and clinical parameters of patients in different
groups

Type of preparation
Parameter                           Diprospan     HA            P

- Age, years (median, range)        48,40-71      52,46-59      0.651
- Female:male                       8:4           4:2           0.988
- Duration of DM, years             7,2-14        6,1-17        0.725
  (median, range)
- Duration of knee symptoms,        6,4-9         5,2-8         0.264
  years (median, range)
- Knee effusion                     3,2-5         3,1-7         0.351
- Kellgren & Lawrence grading       1.5 (0-3)     2 (0-3)       0.407
- HbAIC levels (median, range)      6.4, 6.1-6.8  6.2, 5.8-6.7  0.312
- Oral hypoglycemic treatment only  5             3             0.764
- Diet only for DM                  1             0             0.666
- Insulin only                      3             1             0.755
- Combination therapy               3             2             0.737

DM: diabetes mellitus; HbAIC: glycated hemoglobin; HA: hyaluronic acid

Table 2. Time-relation of glucose levels following Diprospan IACI

Parameter                           Result

Median time to earliest               4.75, (3-21)
significantly increased
glucose levels, h (range)
Median earliest significantly       187.5, (128-326
increased glucose levels,
mg% (range)
Median time to peak                  11.5 (3-33)
significantly increased
glucose levels, h (range)
Median significant peak             310 (227-328)
glucose levels, mg% (range)
Median time to last                  45 (22-56)
significantly increased
glucose levels, h (range)
Median no. of occasions of            6 (5-8)
significantly increased glucose
levels in each patient (range)
No. of patients with a significant    8 (~72%)
clinical response (%)
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Title Annotation:Original Article
Author:Habib, George; Khazin, Fadi; Sakas, Fahed; Hakim, Geries; Artul, Suheil
Publication:European Journal of Rheumatology
Date:Jun 1, 2018
Words:2181
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