Background/Purpose: Rheumatoid arthritis (RA) is intrinsically associated with an increased incidence of lymphoproliferative disorders (LPDs). Although treatment with immunosuppressive agents, such as methotrexate, tacrolimus, or biological disease-modifying antirheumatic drugs (bDMARDs) is highly efficient, development of immunodeficiency-associated LPDs is becoming a more important issue. However, previous reports have come mainly from university or flagship hospitals, where the patient populations might differ from average RA patients. Furthermore, those studies have focused on the pathological features and regression of LPDs after withdrawal of methotrexate (MTX), and information that could allow earlier diagnosis of LPDs has been scant. Here we surveyed the clinical course of RA patients who developed LPDs seen at our hospital, focusing especially on the clinical features at LPD onset.

Methods:  RA patients who had been treated at Niigata Rheumatic Center between October 2006 and April 2016 were analyzed. The patients’ data were obtained retrospectively from their medical records. Data indicated are median (IQR_1/4–_3/4) values.

Results:  Among 2,986 RA patients, 26 patients with pathologically identified LPDs were analysed. The median patient age at the time of LPD diagnosis was 71 (62.5-78.3) years, and the duration of RA was 181 (106.5-238.3) month. Twenty-two patients were treated with MTX, 8 with bDMARDs (infliximab in 6 cases, etanercept in 1 case and golimumab switched from infliximab in 1 case), and 8 with tacrolimus. Ten patients were diagnosed as having diffuse large B cell lymphoma, 7 as having Hodgkin lymphoma, and 3 as having T cell lymphoma. The primary site of LPDs was extranodal in 11 (42.3%), and only 7 patients complained of lymph node swelling. Furthermore, even computed tomography image could not detect lymph node swelling in 6 cases. Although the C-reactive protein level (CRP) significantly rose from 0.2 (0.1 – 0.4) mg/dL at 6 months before LPD diagnosis to 2.1 (1.4 – 5.2) mg/dL after LPD diagnosis (p<0.001, Wilcoxon signed-rank test), neither the number of tender and swollen joints nor the matrix metalloproteinase-3 level showed any significant change (0.0 (0.0 – 0.5) vs 0.0 (0.0 – 1.3), p＝0.389, 1.0 (0.0 – 2.0) vs 0.0 (0.0 – 2.0), p=0.309, and 64.2 (54.7- 108.1) to 90.3 (55.8 -125.2) ng/mL, p=0.482, respectively). Lactate dehydrogenase (LDH) level and total lymphocyte count changed significantly from 198.0 (184.0 – 230) to 270.5 (209.3 – 384.8) IU/L, p=0.005, and 1365.0 (1101.8 – 1758.0) to 1008.5 (692.8 – 1628.0) /mm³,p＝0.032, respectively. By June 2016, 9 patients had died, and the median survival period was 27.0 (9.0 – 45.5) months. Among the 9 patients who died, 7 had diagnosed as LPDs with poor performance status (i.e. 3 to 4).

Conclusion:  Twenty-two out of 26 patients who developed LPDs were receiving MTX. MTX users might have a higher incidence of LPDs in our hospital. Patients with poor performance status had poor prognosis, and over the half of patients develops LPDs without subjective symptoms of lymph node swelling. CRP elevation that is disproportionate to RA activity, LDH elevation, and decrease of lymphocyte count might be the signs of underlying LPDs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-features-at-the-onset-of-lymphoproliferative-disorder-in-patients-with-rheumatoid-arthritis/