A Retrospective Review of Intra-articular Methylprednisolone Hip Injection and Development of Rapidly Progressive Idiopathic Arthritis in Adults

Abstract

Background:

Rapidly progressive idiopathic arthritis (RPIA) of the hip is a rare, poorly understood, destructive hip disease. Etiologies are understudied; however, recent literature suggests a causal relationship between intra-articular corticosteroid hip injections and the development of RPIA. This study's primary objective was to identify the prevalence of RPIA following methylprednisolone intra-articular hip injections (IAHI) and assess these cases' baseline characteristics.

Methods:

Patients who received at least 1 fluoroscopy-guided methylprednisolone IAHI into a native hip between January 2010 and December 2019, had available preinjection and postinjection images, and met inclusion criteria were enrolled. Demographic variables, injection dose and laterality, and number of injections per hip were collected from electronic medical records. Postinjection RPIA was determined through imaging review.

Results:

The total was 1,402 unique hips. The mean age at the time of first injection was 63 (SD = 12.65), and 54% (n = 752) of patients were female. Review of preinjection and postinjection imaging revealed 31 cases of RPIA, thus 2.2% overall prevalence. The mean number of methylprednisolone injections per hip was 1.67 (SD = 1.72), with a mean cumulative dose of 74.91 mg (SD = 84.58). Conditional logistic regression showed each 100 mg increase in cumulative dose was associated with an odds ratio of 0.90 (95% confidence interval 0.59-1.37; p = 0.62). Thus, increasing dose was not significantly associated with the risk of RPIA.

Conclusion:

To our knowledge, this is the first study to exclusively analyze methylprednisolone IAHI, which found a lower prevalence of postinjection RPIA than most previous studies. Importantly, cumulative methylprednisolone dose was not significantly associated with an increased risk of RPIA, suggesting that repeat dosing within the studied ranges is unlikely to substantially increase the risk of this complication.

Level of Evidence:

Level II. See Instructions for Authors for a complete description of levels of evidence.

Introduction

Rapidly progressive idiopathic arthritis (RPIA) of the hip is characterized by rapid degeneration and destruction of the femoral head and acetabulum, leading to substantial functional impairment and morbidity¹. The progression of hip joint destruction, defined as greater than 2 millimeters per year of joint space narrowing or loss of more than 50% of the total joint space, occurs within 12 months². Despite being first described in 1957 by Forestier³ and subsequently defined by Lequesne et al.⁴, the literature lacks consistency and consensus with respect to the nomenclature, etiologies, and risk factors associated with RPIA. The Society of Skeletal Radiology Subchondral Bone Nomenclature Committee sought to clarify the condition in 2019 by proposing diagnostic guidelines, naming the condition RPIA, and denoting the condition as subchondral bone destruction and resorption that is rapid and extensive and not a result of septic arthritis, osteonecrosis, neuropathic joint, or rheumatologic disease⁵.

Recent retrospective studies proposed a causal relationship between intra-articular hip injections (IAHI) and the subsequent development of RPIA⁶. Hess et al.⁷ found up to 21% of patients who underwent a corticosteroid IAHI develop RPIA. Other researchers found a 7% incidence⁸. One recent study refuted postinjection RPIA, criticizing other studies for failing to consider preexisting disease severity⁹. With disagreement in the literature regarding the relationship between corticosteroid IAHI and RPIA, comprehensive studies evaluating the true nature of RPIA ought to be conducted.

Objective

The primary objective was to assess the incidence of postinjection RPIA by evaluating radiographic changes of the hip joint following steroid injections. The secondary objective was to determine if other variables, including age, sex, body mass index (BMI), and cumulative total doses of intra-articular corticosteroids, were associated with the development of RPIA.

Methodology

Participants

Adult patients, 18 years or older, who received at least 1 fluoroscopy-guided intra-articular methylprednisolone injection into a native hip between January 2010 and December 2019 were selected. Patients included had available preinjection and postinjection images. Patients were excluded from the study if they did not have baseline imaging and follow-up imaging within 1 year of injection, if fluoroscopy images of the IAHI were missing, or if they had previous known trauma, inflammatory arthropathy, systemic glucocorticosteroid use, alcohol abuse, advanced osteoarthritic disease at baseline, or hardware in the proximal femur or hemipelvis of the injected side. Patients who did not develop RPIA and had surgery of their affected hip within 1 year of injection or before postinjection images were excluded. Incomplete documentation of the study variables resulted in exclusion.

Hip Injection Technique

All injections were performed by musculoskeletal radiologists with fluoroscopic guidance between January 2010 and December 2019. Informed consent was obtained following standard procedure. Using fluoroscopy, the location of the hip joint was confirmed. A 20-gauge or 22-gauge spinal needle was used. Iodinated contrast, Isovue, was injected to confirm penetration into the hip joint. Then 1 to 2 cc of local anesthetic (1% lidocaine) and methylprednisolone 40 mg/ml, 80 mg/ml, or 120 mg/ml were injected. Repeat injections were not administered for 90 days.

Study design

This study was conducted in 2 parts. The first was a retrospective cohort to determine the rate of RPIA. The second was a matched case-control analysis to determine if other variables contributed to the development of RPIA. Cases were defined as patients diagnosed with RPIA, as determined during the cohort analysis. A control group was selected from patients who did not develop RPIA. Control patients were matched to cases based on age (±2 years), sex, and laterality of hip injection. Controls were matched to cases on a 2:1 ratio.

Data Collection

Diagnostic imaging was accessed through the Picture Archiving and Communication System (PACS). The dose of methylprednisolone at each injection was recorded, along with the laterality of the hip injection and the number of total injections performed. Demographic information, such as age, sex, BMI, and smoking status, was collected. For each hip, the presence or absence of RPIA following injection was determined.

Diagnosis of RPIA

The retrospective search was performed through PACS, using keywords “hip injection” and “fluoroscopy” during the study time frame. Preinjection, fluoroscopic, and postinjection images were analyzed for patients meeting inclusion criteria. For each positive case, the images were reviewed and confirmed by 2 orthopaedic surgeons and 1 musculoskeletal radiologist. Discrepancies were resolved by consensus.

Statistical Analysis

Baseline characteristics were analyzed using descriptive statistics. The rate of postinjection RPIA was calculated by dividing the number of positive cases by the number of hips that received methylprednisolone injection. For the unmatched cohort, univariate logistic regression models were used to examine the associations between baseline factors and RPIA. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.

For the matched case-control analysis, controls were matched to cases on age (±2 years), sex, and hip laterality. Associations between cumulative methylprednisolone dose and RPIA were then examined using conditional logistic regression, stratified by matched set, to account for the individual matching. Cumulative dose was evaluated both in grouped form (tertile categories) and as a continuous variable. To explore potential nonlinear associations, fractional polynomial modelling was applied, comparing linear and higher-order transformations of cumulative dose. The most parsimonious model was selected based on likelihood ratio testing. The final model expressed cumulative dose in 100 mg increments.

Sensitivity analyses were performed using unconditional logistic regression (adjusting for the matched variables) and quartile-based dose categories. All analyses were two-sided, with p < 0.05. Analyses were conducted in R-4.5.1.

Ethics

Ethics was approved by the Health Research Ethics Board. There was no external funding source for the study.

Results

Retrospective Cohort Study

In the retrospective cohort analysis, 2,348 injections were performed in 1,402 hips of 1,183 patients. Bilateral injections were administered in 18.5% (n = 219) of patients. Fifty-four percent were women. The mean age at the time of first injection was 63 years (SD = 12.65). The mean number of injections per hip was 1.67 (SD = 1.72). The mean cumulative dose was 74.91 mg (SD = 84.58).

Thirty-one cases of postinjection RPIA were identified, yielding a prevalence of 2.2% (Fig. 1). The mean age of RPIA cases was 66.5 years (SD = 11.97), and 61% (n = 19) were female (Table I). Neither age (OR = 1.02, 95% CI 0.99-1.06; p = 0.104) nor sex (OR = 1.45 95% CI 0.56-3.08; p = 0.336) were associated with RPIA. Of the 31 cases, 1 developed contralateral hip destruction without injection, and 3 developed bilateral RPIA following injections. Twenty-six total hip replacements were performed, accounting for 86.2% of the cases (Fig. 2). The 5 patients who did not receive a total hip arthroplasty had their surgery outside of the study timeframe, were lost to follow-up, or had expired.

Fig. 1.

A 60-year-old woman with right hip pain secondary to osteoarthritis. Fig. 1-A Baseline anteriorposterior pelvis radiograph demonstrating right hip osteoarthritis taken in December 2017. Fluoroscopic-guided intra-articular hip injection was performed in February 2018. Fig. 1-B Follow-up AP pelvis radiograph taken in July 2018 demonstrating destruction of the right femoral head, acetabulum, and joint space.

Fig. 2.

A 57-year-old woman with right hip pain secondary to osteoarthritis. Fig. 2-A Baseline AP pelvis radiograph demonstrating right hip osteoarthritis. Fig. 2-B Fluoroscopic image confirming penetration into the right intra-articular location. Fig. 2-C Follow-up radiograph 4 months postinjection demonstrating destruction of the right femoral head, acetabulum, and joint space. Fig. 2-D Postoperative AP pelvis radiograph at the 6-week follow-up visit for her right total hip arthroplasty.

TABLE I.

Summary of Patient Demographic Characteristics

		Matched Case-Control Cohort (n = 93)
Variable	Retrospective Cohort (n = 1,402)	No RPIA (n = 62)	RPIA (n = 31)
Age at first injection, years	63.0 (12.7)	66.6 (11.9)	66.5 (12.0)
Female sex	752 (53.6%)	38 (61.3%)	19 (61.3%)
Right hip	784 (55.9%)	46 (74.2%)	23 (74.2%)
Cumulative dose, mg	74.9 (84.6)	83.2 (129.6)	70.3 (75.0)
Injections	1.67 (1.72)	1.85 (2.69)	1.74 (1.86)

RPIA = rapidly progressive idiopathic arthritis.

Values are presented as n (%) or mean (SD).

Retrospective Matched Case-Control Study

The matched case-control analysis included 93 hips (31 cases and 62 matched controls). The mean age of the matched cohort was 66.6 years (SD = 11.83). Women accounted for 61% (n = 57) of hips, and 74% (n = 69) were right hips. Smoking history was present in 24.1% of cases and 32.3% of controls. The mean BMI was 33.90 kg/m² (range 22.47-63.72, SD = 8.86) in cases and 30.73 kg/m² (range 20.96-68.38, SD = 8.34) in matched controls (OR = 3.244, 95% CI 0.583-7.07; p = 0.0956).

The mean cumulative dose of methylprednisolone was 70.32 mg (SD = 74.99) in cases and 83.23 mg (SD = 129.62) in controls (Fig. 3). In the primary analysis, conditional logistic regression with fractional polynomial modelling indicated the relationship between cumulative dose and RPIA was best represented as linear. Each 100 mg increase in cumulative dose was associated with an odds ratio of 0.90 (95% CI 0.59-1.37; p = 0.62), and this association was not statistically significant (Fig. 4). No evidence of nonlinear or threshold effects was identified. As a sensitivity analysis, cumulative dose was categorized into quartiles and re-evaluated with conditional logistic regression. The results were consistent with the main analysis, showing no significant association with RPIA and no consistent dose-response pattern.

Fig. 3.

Seventy-two-year-old man with right hip pain secondary to right hip osteoarthritis. Fig. 3-A Baseline AP pelvis radiograph in 2017. Fig. 3-B Fluoroscopic image demonstrating penetration of the intra-articular space for corticosteroid injection in 2017. Fig. 3-C Fluoroscopic image demonstrating penetration of the intra-articular space for corticosteroid injection 6 months later in 2018. Fig. 3-D Fluoroscopic image demonstrating penetration of the intra-articular space in 2019. Fig. 3-E Right femoral head and acetabulum destruction on AP pelvis radiograph 5 months after the third corticosteroid injection.

Fig. 4.

Predicted odds ratios for RPIA across cumulative methylprednisolone dose. RPIA = rapidly progressive idiopathic arthritis.

Discussion

The incidence of RPIA following a corticosteroid IAHI is disputed in the literature. Okike et al.¹⁰ and Boutin et al.¹¹ found an incidence of RPIA in 5.4% and 7.2% of cases, respectively. Serhal et al.¹² found a postinjection prevalence of 13.7%. The rate of RPIA has been quoted as high as 21%⁷. The lowest reported rate of hip RPIA in the literature is 0.6%¹³. However, 57% of their study population received a total hip arthroplasty by 6 months postinjection, with a 10-month average interval between injection and total hip arthroplasty. The shortened time frame may have missed RPIA cases. Our study included patients who developed RPIA and had a hip arthroplasty, those who underwent a hip arthroplasty within 12 months of injection and did not develop RPIA were excluded.

Previous studies failed to control for preexisting disease. Simeone et al.¹⁴ compared postinjection results to baseline severe osteoarthritis. Doing so may have inflated the number RPIA cases. Selection bias may also contribute to the high prevalence previously reported, as patients with more severe disease may be more likely to receive intra-articular injections. In our study, patients were excluded if there was evidence of advanced osteoarthritic changes on baseline imaging, therefore removing a potential selection bias and confounding variable. Conversely, Boutin et al.¹¹ reported an association between high degree of osteoarthritis at baseline and increased risk of RPIA. The cases they captured may represent the natural progression of those individuals' disease.

Abraham et al.⁹ controlled for preexisting disease by excluding patients with baseline avascular necrosis or subchondral insufficiency fracture. Hips that received injections were matched to controls by osteoarthritic severity on baseline imaging. Abraham et al. found a rate of osteoarthritic progression to be similar between both patients with and without an injection (3.2%). However, the authors neither identified RPIA as an outcome, compared preinjection and postinjection radiographs, nor investigated patients who received more than 1 intra-articular injection.

Our matched case-control analysis demonstrated no increased risk of RPIA with higher cumulative doses of intra-articular methylprednisolone. These findings contrast with those of Okike et al.¹⁰, who reported an increase in RPIA cases with high-dose steroids and multiple doses. Their study used an unmatched case-control design—controls were defined as any adult patient who underwent a primary total hip replacement during their study time frame. Fifty-five percent of these controls had never received an IAHI. This approach may have introduced selection bias, with respect to baseline disease severity. In addition, 40% of hips in their study had severe osteoarthritis at baseline. Streck et al.¹³ had similar results to ours: They found no significant cumulative dose-dependent effect, reporting a comparable mean cumulative dose of 75 mg.

While we found a low incidence of postinjection RPIA, the relationship between RPIA and intra-articular injections is still unknown. This may be the first study specifically assessing methylprednisolone injections. Previous studies assessed RPIA in hips following triamcinolone injections or do not present their results by type of corticosteroids.

Definitions of RPIA are inconsistent in the literature. Okike et al.¹⁰ used the definition outlined by Zazgyva et al.¹⁵ of “complete disappearance of the joint space, deformed femoral head and acetabulum, and ascension of the femoral head.” Streck et al.¹³ defined RPIA as “hips with >50% joint space width showing progression to bone-to-bone OA” or “hips with <50% joint space width showing >3 mm bone loss of femoral head.” By contrast, Hess et al.⁷ and Boutin et al.¹¹ used the Lequesne classification of “cartilage loss greater than 2 mm or 50% joint space narrowing over 12 months postinjection.” In our study, cases of postinjection RPIA were characterized as rapidly progressive joint-space narrowing, osteolysis, partial or complete collapse of the femoral head, and destruction of the acetabulum within 12 months of injection.

Discordant results may also be due to smaller sample sizes. Our study included 1,402 hips for analysis. Sanguino et al.¹⁶ yielded a similar rate of RPIA with a sample size of 924. In comparison, Simeone et al.¹⁴ examined 70 hips, Hess et al.⁷ 109 hips, Serhal et al.¹² 163 hips, and Streck et al.¹³ 682 hips. Smaller sample sized studies—possibly underpowered—may overestimate the incidence of RPIA.

Limitations

As this is a retrospective study, information available in PACS and the electronic medical record may be incomplete. Patients who did not undergo injections were not analyzed, so their RPIA rates are unknown. Imaging quality and patient positioning varied between baseline and follow-up—potentially introducing interpretation errors. Only 31 unique cases of postinjection RPIA were identified, leaving the matched case-control analysis underpowered. As a result, small-to-moderate dose-response effects could not be excluded. Residual confounding by unmeasured patient or disease characteristics may exist. Finally, because this study exclusively examined methylprednisolone injections, the results may not be generalizable to other IAHI.

Conclusion

To our knowledge, our study was the first to exclusively assess RPIA after methylprednisolone injections. Strict inclusion and exclusion criteria determined the incidence and possible risk factors of postinjection RPIA. We found an RPIA rate of 2.2%, which is lower than most previously published studies. In the matched case-control analysis, higher cumulative doses were not significantly associated with RPIA, and sensitivity analyses supported this finding. Although the limited number of cases restricts the ability to exclude small effects, repeat dosing of methylprednisolone within the studied ranges is unlikely to meaningfully increase the risk of this catastrophic complication. These results suggest intra-articular methylprednisolone can be used in the nonoperative management of hip osteoarthritis; further studies are needed to confirm these findings in larger cohorts.