Unguided intra-articular betamethasone injections provide rapid and enduring control of inflammation in both small and large peripheral joints when used as a component of a treat-to-target strategy in patients with early rheumatoid arthritis, according to findings from the randomized, placebo-controlled trial.
The findings are among the first to systematically demonstrate efficacy and feasibility of intra-articular glucocorticoid injections when used in combination with disease-modifying antirheumatic drugs (DMARDs) in the setting of early rheumatoid arthritis (RA), Dr. Merete Lund Hetland of Copenhagen University Hospital and her colleagues wrote in a report published online in the Feb. 1 issue of Annals of Rheumatic Diseases.
Dr. Merete Lund Hetland
The 160 DMARD-naive patients who participated in the CIMESTRA (Ciclosporin, Methotrexate, Steroid in RA) study had early active RA of less than 6 months duration. They were randomized to receive either 7.5 mg-20 mg of methotrexate weekly plus 2.5 mg/kg per day of ciclosporin or methotrexate plus placebo-ciclosporin. Both groups were given intra-articular injections of 7 mg/mL of betamethasone in up to four swollen joints at baseline and at weeks 2, 4, 6, and 8, and then every 4 weeks thereafter for up to 2 years. Since the combination and monotherapy groups had similar clinical and radiographic outcomes, as well as a similar number of injections and cumulative betamethasone dose after 5 years, data from both treatment arms were pooled for the current analysis.
A total of 2,166 injections were given, including 1,373 first injections, 531 second injections, and 262 third injections. The median dose of betamethasone decreased from 28 mg at baseline to 0 mg at the following visits, and the cumulative dose after 2 years was 77 mg, which corresponds to less than 1 mg prednisolone daily. The median cumulative number of injections per patient was 13.
Within 2 weeks of the initial joint injections, the median 28-joint count Disease Activity Score (DAS28) had decreased from 5.5 to 3. By 6 weeks, the DAS28 had decreased to 2.6, the investigators wrote (Ann. Rheum. Dis. 2012 Feb. 1[doi:10.1136/annrheumdis-2011-200632]).
"Thus, the median number of swollen and tender joints had decreased sharply to 0 and 3, respectively, and remained low. By weeks 2, 4, and 6, respectively, 50%, 58.1%, and 61.7% of patients had achieved a good EULAR response, and 39%, 42%, and 47% were in DAS28 remission," they said.
The injections also provided good long-term efficacy. After 1 and 2 years, 62.3% and 55.5%, respectively, of the swollen joints injected at baseline had not relapsed.
An analysis by joint area showed that benefits of joint injection persisted at 2 years was 51.2% for elbows, 60.1% for ankles, 54.8% for wrists, 55.3% for knees, 52.3% for metacarpophalangeal (MCP) joints, 53.6% for metatarsophalangeal (MTP) joints, 49.5% for shoulders, and 73.7% for proximal interphalangeal (PIP) joints. Persistence of join injection benefits was significantly higher for first-time injections.
For example, the 1-year survival was 63.6% for first-time injections, compared with 48.7% and 32.4% for second and third injections, respectively. The 2-year survival for first-time injections was 56.6%, compared with 43.4% and 31.3% for second and third injections, respectively.
Both the magnetic resonance imaging synovitis score of MCP joints and anticyclic citrullinated peptide (anti-CCP) positivity each were significantly associated with persistence of joint injection benefits (hazard ratios, 1.078 per synovitis score unit, and 0.661, respectively). The anti-CCP finding "may reflect the emerging pattern of different pathogenesis and treatment responses in anti-CCP–positive and –negative disease," the investigators noted, adding: "The increased joint injection survival in our anti-CCP–positive patients with RA may indicate that the local immunosuppressive effect of joint injections targets specific processes in these patients. To this end, it is of particular interest that antibodies against citrullinated proteins seem locally to enhance the inflammatory process in experimental murine autoimmune arthritis."
In contract, serum C-reactive protein and immunoglobulin M–rheumatoid factor (IgM-RF) were not associated with persistence of joint injection benefits in this study, they noted.
Patients in CIMESTRA had at least two swollen joints at baseline and had not received glucocorticoid treatment within 4 weeks prior to enrollment. All patients received calcium and vitamin D supplementation, and those with a Z score of less than 0 in the femoral neck or lumbar spine also received 10 mg/day of alendronate.
Treatment was well tolerated. No cases of septic arthritis or aseptic necrosis occurred. One patient had a spontaneous spinal fracture, but other adverse events occurred only rarely and were mild and transient.
The findings indicate that unguided intra-articular injections of betamethasone in patients with early RA result in rapid, effective, and long-lasting inflammatory control in both small and large peripheral joints and that these injections are a well tolerated component in a treatment strategy aimed at remission, the investigators said.