The use of intra-articular (IA) corticosteroids is often recommended when patients with osteoarthritis (OA) of the knee fail oral or topical analgesic therapy. However, the safety of IA steroid injections has been called into question as these agents can be associated with greater cartilage loss and an increased risk for septic arthritis. As a result, clinicians have attempted to use IM corticosteroids as an alternative route of administration. However, comparative data of the efficacy and safety of IA versus IM corticosteroids for OA of the knee are limited.

The KIS trial is a 24-week, multicenter, open-labeled, parallel, noninferiority, randomized clinical trial involving 80 general practices in the Netherlands that was designed to assess the effectiveness of IM glucocorticoid injections to standard IA glucocorticoid injections in patients with symptomatic knee OA in primary care.

To be included in the study, patients had to be aged older than 45 years; had to have been diagnosed in the past 5 years with knee OA by a general practitioner; had to have symptomatic knee osteoarthritis for at least 3 months prior to enrollment; and had to have moderate-to-severe pain over the past week based on a numeric rating scale score of >3 on a scale of 1 to 10.

The exclusion criteria were extensive and included patients who were receiving oral glucocorticoids; had an IA corticosteroid injection within the past 6 months; were allergic to glucocorticoids; had a local or systemic infection, or had received a live attenuated vaccine recently; had type 1 or poorly controlled type 2 diabetes; had inflammatory rheumatic disease such as rheumatoid arthritis, psoriatic arthritis or spondyloarthropathies; had a coagulopathy; were receiving anticoagulants; had gastric or duodenal ulcers or a history of them; had consulted an orthopedic surgeon for surgical management of their knee osteoarthritis; and if they could not complete the questionnaire in Dutch or give informed consent.

The IA group received a single, standard IA injection (superolateral approach) and the IM group received a single, standard IM injection (ipsilateral ventrogluteal region) of triamcinolone acetonide 40 mg (1 mL) in the index knee, which were administered without a local anesthetic.

The primary objective was the severity of knee pain at 4 weeks measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale, which ranges from 0 to 100, with 0 indicating extreme pain. The secondary outcome included KOOS pain scores at 2, 8, 12, and 24 weeks as well as other assessments of function, ability to engage in sports and recreation, and quality of life. Patient perceived recovery was defined by the OMERACT-OARSI criteria, which used a seven-point Likert scale to assess the degree of recovery. The percentage of responders was also determined.

Patients were excluded from the per-protocol (PP) analysis if those in the IM group received an additional IA injection within 8 weeks. An intention-to-treat analysis (ITT) was also performed.

For the primary objective—the KOOS pain score—noninferiority was assessed at all points by checking the lower limit of two-sided 95% confidence intervals for mean differences of IM minus IA with a noninferiority margin of -7. If the lower limit did not exceed the noninferiority range, noninferiority was established.

In total, 138 patients (95%) were in the PP analysis and all patients (145) were in the ITT. While both groups had KOOS pain scores that improved over the 24-week study period, the greatest improvement was seen in the IM group after 8 weeks and in the IA group after 4 weeks; noninferiority could not be declared between the two groups at Week 4, the primary time endpoint. Additionally, IM corticosteroids were found to be noninferior to IA corticosteroids at 8 and 24 weeks but not at 2 and 12 weeks.

There were no significant differences at the various time points between IM and IA corticosteroid injections for the secondary measures of joint symptoms, function, stiffness, ability to participate in sports, and quality of life. At 2 weeks, 33% in the IM group and 42% in the IA group had reported adverse events, which were mainly flushing and headache and were considered not to be serious. Oral analgesic use decreased in both corticosteroid groups.

Patients often seek advice from their pharmacist on the management of OA of the knee. This study provides pharmacists with information on the advantages and disadvantages of IM and IA glucocorticoid injections when nonprescription and oral topical agents are no longer effective.

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