Effects of IL-6, JAK, TNF inhibitors and CTLA4-Ig on knee complaints in patients with rheumatoid arthritis

Factors that contribute to the relief of knee complaints

From January 2010 to August 2023, a total of 2,321 patients started b/tsDMARD treatment (Fig. 1). Of these, 573 had knee pain and/or swelling at the time of starting b/tsDMARDs (considered baseline). Six months later, 438 individuals returned for follow-up and swelling and/or tender joints were recorded. We excluded patients who had undergone total knee arthroplasty on the symptomatic side (N = 18) and those who had undergone TKA during the follow-up period (N= 7). As a result, 413 patients were included in the study (Supplementary Table S1). We then focused on patients who continued b/tsDMARDs for at least 3 months. Consequently, 295 cases were analyzed. The mean age at baseline was 60.9 years, ACPA positivity was 78.3%, RF positivity was 76.6%, females were 85.1%, and the mean RA duration was nine years (Table 1).

The symptom relief at 6 months in patients who continued b/tsDMARDs for 3 months was 78.2% for IL-6 inhibitors, 68.6% for JAK inhibitors, 65.9% for TNF inhibitors, and 57.6% for CTLA4-Ig (P< 0.01, Figure 2). The rates of knee joint symptom relief at 3 months were 66.3% for IL-6 inhibitors, 51.2% for JAK inhibitors, 61.4% for TNF inhibitors, and 55.6% for CTLA4-Ig, without statistical significance (P= 0.32, Supplementary Figure S1a). Significant differences were observed in the proportion of improvement in knee joint symptoms between 3 and 6 months for all b/tsDMARDs. Notably, further improvement in knee joint symptoms from 3 to 6 months was noted for both IL-6 and JAK inhibitors (Supplementary Figure S1b).

Three months after initiation, the continuation rate was 76.5% for IL-6 inhibitors, 74.5% for JAK inhibitors, 63.1% for TNF inhibitors, and 85.5% for CTLA4-Ig (P< 0.01; Figure 3a).

In patients who continued b/tsDMARDs after 3 months, disease activity (DAS28-ESR, disease activity score 28-joint count with erythrocyte sedimentation rate [DAS28-ESR]clinical disease activity index [CDAI]and simplified disease activity index [SDAI]) improved at 3 and 6 months compared to baseline (Fig. 3b–f). Although differences were observed in the values ​​of DAS28-ESR, CDAI and SDAI at 3 and 6 months, as well as differences from baseline, between these drugs, IL-6 inhibitors were not inferior to the other drugs in any of these indicators.

When examining treatments associated with relief of knee joint symptoms in patients who continued b/tsDMARD therapy beyond 3 months, the use of IL-6 inhibitors emerged as a significant contributing factor, surpassing TNF inhibitors in resolution of knee joint symptoms (Fig. 4, odds ratio [OR] 2.1, 95% confidence interval [CI] 1.1–4.3, P= 0.03) or CTLA4-Ig (OR 3.0, 95% CI 1.4–6.5, P= 0.005). The OR for relief of knee joint symptoms with b/tsDMARDs as first-line treatment was 1.72 (95% CI 0.99–2.99, P= 0.05). Methotrexate (MTX) or glucocorticoid use did not appear to be a significant risk factor.

Factors contributing to the inhibition of the destruction of the knee joint

Next, we focused on 141 patients who continued b/tsDMARD therapy for 3 months and underwent knee joint radiography at baseline and 2 years later. At baseline, there were no significant differences in disease activity as measured by DAS28-ESR, SDAI, and CDAI (Supplementary Table S2). At 3 months, DAS28-ESR was higher in patients using JAK inhibitors and CTLA4-Ig, 4.0 and 4.1, respectively, compared with 3.0 in patients using IL-6 inhibitors. MTX use was lower in CTLA4-Ig users; however, this difference was not statistically significant. In addition, the rate of use of JAK inhibitors as first-line b/tsDMARDs was lower.

At baseline, there were no significant differences in Larsen grade between the different drugs (Fig. 5a). Over two years, excluding progression from grade 0 to grade I, worsening of Larsen grade was observed in 5.2% of patients treated with IL-6 inhibitors, 6.3% with JAK inhibitors, 19.4% with TNF inhibitors and 28% with CTLA4-Ig (Fig. 5b, P< 0.01).

In line with this, when considering the use of MTX, glucocorticoids, the use of b/tsDMARDs as first-line treatment and the mode of action as covariates, the use of IL-6 inhibitors emerged as a protective factor against knee joint deterioration compared with CTLA4-Ig (OR 0.14, 95% CI 0.02–0.78, P= 0.02, Figure 5c).