Background/Purpose:

Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Cytokines involved in lymphocyte development, function and homeostasis are known to signal through JAK. Here we characterize changes in absolute lymphocyte counts (ALC) following tofacitinib treatment and evaluate the relationship between ALC and rates of infection. These data were presented previously.¹

Methods:

ALC and adverse event data of treated (requiring antimicrobial therapy or surgical intervention; TIs), serious (SIs), and opportunistic infections (OIs) were analyzed from 5 randomized controlled Phase 3 (P3), and 2 open-label long-term extension (LTE) studies in patients (pts) with RA. Lymphopenia was defined by OMERACT criteria (ALC ×1000/mm³) as mild, ≥1.5 to <2; moderate to severe, <1.5 to ≥0.5; and potentially life threatening, <0.5. Confirmed lymphopenia was defined as lymphopenia in 2 consecutive measurements. Cox analysis was applied to evaluate the relationship between “time-varying” ALC and rates of infection. Threshold values of ALC were evaluated by calculating the percentage of correct decisions (POCD), based on the sum of pts falling below a specific threshold (e.g. 0.5 or 1.0) and experiencing an SI, and those with ALC above threshold and without an SI.

Results:

Across treatment groups, at baseline 35-39% of pts in P3 (N = 3252) had ALC of <1.5. Pooled analysis of P3 data showed mean increases in ALC from baseline with tofacitinib at Month (Mo) 1 followed by a gradual decrease of approximately 10% from baseline after 12-mo of therapy. Further decreases in mean ALC were not seen in the LTE studies. Lymphopenia frequency in the P3 studies was similar between tofacitinib and placebo pts at Mo 3 and 6; all placebo pts were advanced to tofacitinib at Mo 6. Lymphocyte subset analyses from P2 dose‑ranging studies (6 and 24 weeks [wks]) showed increases in B cell counts (~40%; 1‑24 wks), decreases in NK cell counts (~40%; Wks 2-24) and a transient increase in T cell counts (Wks 1-2). Subset analyses from LTE studies (median exposure 22 mo) showed that NK cell counts were similar to baseline counts, B cell counts remained elevated and T cell counts decreased slightly (<20%). For pts with ALC ≥0.5, there was no increase in the frequency of TI, SI or OI. Although confirmed lymphopenia of <0.5 was infrequent (5/2430 pts (0.2%) in P3; 10/3219 (0.3%) in the LTE), 11, 4, and 1 of these pts experienced a TI, SI, and OI, respectively. The SI in this group included 1 case each of pneumonia, cellulitis, tuberculosis (an OI), and pyelonephritis. Cox analysis using all available P2, P3 and LTE data showed a significant trend (p<0.05) for increased risk for infection (SI and OI) with decreased ALC. The POCD decreased from ~94% for an ALC threshold of 0.5 ×1000/mm³ to 66% for 1.0 ×1000/mm³.

Conclusion:

Tofacitinib treatment in patients with moderate to severe RA is associated with modest mean decreases in ALC over 12-mo of therapy. Confirmed ALC <0.5 ×1000/mm³ occurred rarely and may be the optimum threshold for defining increased risk of SI. These data could inform appropriate risk mitigation strategies.

References:    1.   van Vollenhoven RF et al.  Ann Rheum Dis 2013; 72: 250-251.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/relationship-between-lymphocyte-count-and-risk-of-infection-in-rheumatoid-arthritis-patients-treated-with-tofacitinib/