Presence of autoimmune disease affects not only risk but also survival in patients with B‐cell non‐Hodgkin lymphoma

Abstract

Although autoimmune diseases (AIDs) are known to predispose to non-Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B-cell NHL onset by comparing AID history (determined by self-report and medication review and supplemented by chart review where possible) among 435 adult B-NHL patients in Hadassah-Hebrew University Medical Center, diagnosed 2009-2014, and 414 age-and-sex frequency-matched controls. We examined AIDs as a whole, B- and T-cell-mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan-Meier and Cox regression models to assess the association of AID with overall survival and relapse-free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup. Autoimmune diseases were associated with B-NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31-2.92), especially AIDs mediated by B-cell activation (OR = 5.20; CI, 1.90-14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59-80.9). We found that time to relapse for all B-NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HR ] = 1.69 (CI, 1.03-2.79). Specifically, in patients with diffuse large B-cell lymphoma, of whom 91.8% had received rituximab, a history of B-cell-mediated AIDs was associated with shorter relapse-free survival and overall survival, HR = 8.34 (CI, 3.01-23.1) and HR = 3.83 (CI, 1.20-12.3), respectively. Beyond confirming the well-known association between AIDs and B-NHL, we found that AID is an adverse prognostic factor in B-cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID-associated B-NHL. In the era of immunotherapy, these findings have particular relevance.

Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome

“…In other studies of AID in DLBCL populations varying figures have been reported [17,18]. In a recent study, and similar to our results, selfreported AID was present in 22.5% of 182 DLBCL patients compared to 13.8% in age-and sex-matched controls without lymphoma [21]. In this study, like in our study, all preexisting thyroid disorders were included as AID.…”

“…Similar analyses were performed in some of the previously mentioned studies of DLBCL and AID. In the Israeli study including 41 DLBCL cases with AID, a history of B-cell-mediated AIDs was associated with shorter relapse-free survival and OS compared to patients without AID [21]. The prospective study of 8 pre-defined AIDs by Kleinstern et al reported a non-significant trend toward inferior OS in DLBCL patients with AIDs primarily mediated by B-cell responses, while AIDs primarily mediated by T-cell responses were not associated with OS or EFS in any lymphoma subtype [20].…”

“…Data has been inconsistent between studies and it is not clear if this is an effect of differences in study designs, study population characteristics or the definitions and inclusion criteria that have been used. In some studies, AIDs have been self-reported by patients [20] and/or restricted to predefined AID diagnoses [12,21].…”

“…Some studies of AID-related lymphoma have categorized AIDs as primarily mediated by B-cell responses or by T-cell responses [6,12]. Recent studies have pointed out a correlation between DLBCL and several AIDs categorized as primarily mediated by B-cell responses such as RA, SLE and pSS and have also indicated an association between the group of primarily B-cell mediated AIDs and inferior outcomes [20,21,29].…”

Ocular adnexal marginal zone lymphoma (OAMZL)

“…In particular Sjögren disease and autoimmune thyroiditis showed a higher risk of periocular lymphomas (Wöhrer et al, 2007;Nutting et al, 2006). A recent study on patients with marginal zone lymphomas associated with autoimmune disorders showed a shorter median time to relapse and relapse-free survival in patients with autoimmune diathesis compared to patients without autoimmunity (Kleinstern et al, 2018).…”