The authors have declared that no competing interests exist.
Conceived and designed the experiments: AP MV DCZ CM. Performed the experiments: AP MV DCZ CM. Analyzed the data: DCZ EZ. Contributed reagents/materials/analysis tools: DCZ EZ. Wrote the paper: AT HM AP DCZ CM EZ MV.
‡ These authors contributed equally to this work.
Non-Hodgkin's lymphoma (NHL) development in Sjögren’s syndrome (SS) remains a potentially lethal complication and efforts should focus on the identification of predictors that could aid in appropriate therapeutic decisions.
In order to identify potential prognostic factors for outcome in SS-associated NHL, we retrospectively analyzed a cohort of 77 patients, diagnosed with NHL according to WHO classification criteria and meeting the American-European Consensus Classification (AECC) criteria for SS and examined the effect of SS-activity (defined as the EULAR SS disease activity index-ESSDAI) in the prognosis of SS-related NHLs, as defined in terms of overall and event-free survivals (OS and EFS). An event was defined as lymphoma relapse, treatment failure, disease progression, histological transformation or death. The effect of NHL clinical and laboratory characteristics was also investigated.
MALT lymphomas constituted the majority (66.2%) of lymphomas. During the follow-up (median = 57.93 months), the 5-year OS was 90.91% (95% CI: 82.14–95.80%) and the EFS was 77.92% (95% CI: 67.37–85.82%). Patients with high ESSDAI score at lymphoma diagnosis had a greater risk for death (OR = 5.241, 95% CI: 1.034–26.568) or for event (OR = 4.317, 95% CI: 1.146–9.699, p = 0.008). These patients had also significantly worse EFS (HR = 4.541, 95% CI: 1.772–11.637) and OS (HR = 5.946, 95% CI: 1.259–28.077). In addition, post-chemotherapy ESSDAI improvement was significantly lower in patients who had experienced an event (p = 0.005). An unfavorable International prognostic index (IPI) score (high-intermediate/high) was associated with high risk of death and event (OR = 13.867, 95% CI: 2.656–72.387 and OR = 12.589, 95% CI: 3.911–40.526, respectively), worse EFS (log-rank p<0.001, HR = 8.718, 95% CI: 3.477–21.858), as well as with worse OS (log-rank p<0.001, HR = 11.414, 95% CI: 2.414–53.974). After adjustment for identified risk factors, IPI score retained a significant prognostic role following by a strong effect of ESSDAI in survival outcomes.
At the point of NHL diagnosis, IPI and ESSDAI might be proved useful predictive tools in SS-associated lymphoma prognosis, directing to a more patient-tailored approach.
Primary Sjögren’s syndrome (SS) has been generally acknowledged as a chronic benign autoimmune disease characterized by slowly progressive signs and symptoms of a destructive, mainly salivary exocrinopathy. However, in more than 20–40% of patients the disease extends beyond the exocrine glands, manifested either by epithelial lymphocytic invasion of the lung, liver or kidney or by immune complex-mediated phenomena such as skin vasculitis, peripheral neuropathy, glomerulonephritis and low serum C4 levels, all of which have previously been shown to confer increased risk for non-Hodgkin’s lymphoma (NHL) development [
In the setting of SS, NHL is the most detrimental complication, affecting 5–10% of these patients [
We evaluated the medical records of all consecutive patients with an initial diagnosis of primary SS in the Department of Pathophysiology (School of Medicine, University of Athens) from 1993 to September 2013. Seventy-seven patients, diagnosed with NHL according to WHO classification criteria and meeting the American-European Consensus Classification (AECC) criteria for SS, were considered eligible for this study [
The following parameters at lymphoma diagnosis for all SS-associated NHL and SS-non lymphoma cases (where applicable) included: age, sex, NHL subtype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) [
All included lymphoma and control cases in our study had a salivary gland biopsy at SS diagnosis. A blinded pathologist quantified local inflammatory infiltration, based on the number of foci present in the glands, classified as the focus score (FS) [
In order to comprehensively describe the systemic manifestations and quantify the activity of primary SS, we used the European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI), the total score of which was estimated at lymphoma diagnosis as well as at SS diagnosis for SS-associated NHL cases and at SS diagnosis for SS-non lymphoma controls [
All analyses were done with use of data obtained until 30 September 2013. For categorical variables, data are presented as frequencies with their corresponding 95% confidence intervals (CI), and for continuous variables as means with standard deviation (SD) or as median with observed range (minimum-maximum). The 95% CIs of proportions were computed by modified Wald method. To compare categorical variables, we used the x2 test or the Fischer’s exact test where appropriate. To compare continuous variables, the Mann-Whitney (two-tailed) test was applied. Paired comparisons of over-time changes in continuous and categorical variables were performed with the Wilcoxon’s matched pairs test and the McNemar’s test, respectively. Survival curves were plotted and time-to-event analyses were estimated by the method of Kaplan-Meier; differences between curves were analyzed using the log-rank test. The median follow-up times were computed by the reverse Kaplan-Meier method. Unadjusted and adjusted hazard ratios (HR) with the respective 95% CIs were estimated using univariate and multivariate Cox regression analysis, respectively. The multivariate Cox regression analysis examined the effect on OS and EFS after adjustment for identified baseline (at lymphoma diagnosis) prognostic parameters. Also, unadjusted and adjusted odds ratios (OR) with the respective 95% CIs for examining the effects of OS and EFS without considering the time effect were estimated using logistic regression. Adjustment was performed for identified baseline (at lymphoma diagnosis) prognostic parameters.
To include total ESSDAI and IPI scores in our analysis, we grouped SS-associated NHL patients, using the median value of total ESSDAI score of our cohort as the dichotomous threshold: high SS disease activity group (High ESSDAI score>median value) and low SS disease activity group (low ESSDAI score<median value); and modifying the IPI risk subgroups as following: low/low-intermediate IPI risk group (= 0–2 points) and high-intermediate/high IPI risk group (= 3–4 points).
To address the realistic issue of missing data potentially emerging from the retrospective pattern of our study, frequent communication, wherever possible, was made with the patients themselves or their relatives by phone, email or fax thereby enabling us to complete our questionnaires and gather laboratory results. For all data-points collected, completeness of data exceeded 95%.
Statistical analyses were conducted using SPSS software package version 21 (Computing Resource Centre, Santa Monica, CA, USA) and GraphPad Prism software (GraphPad Software, Inc. La Jolla, CA, USA). Statistical significance was defined as a p-value of less than 0.05 for all comparisons.
Baseline characteristics of 77 SS-patients (5 males and 72 females) with confirmed histologic diagnosis of NHL, their first-line treatments and CR rates, according to lymphoma subtypes are presented in
Total SS-associated lymphoma patients | MALTL | NMZL | DLBCL | Other lymphomas | |
---|---|---|---|---|---|
Number (no) of patients | 77 | 51 | 8 | 12 | 6 |
Female sex, no | 72 | 47 | 7 | 12 | 6 |
Age, years | |||||
Median (range) | 58 (28–90) | 55 (28–76) | 56 (36–90) | 69 (44–81) | 62 (52–80) |
Mean (SD) | 56.16 (13.57) | 53.12 (12.55) | 56.25 (16.82) | 64.83 (13.12) | 64.50 (9.50) |
Median time from SS to lymphoma diagnosis, months (range) | 65.80 (0–456.2) | 61.53 (4.47–446.0) | 91.57 (0–251.3) | 97.54 (13.53–456.2) | 13.18 (2.2–72.97) |
Median follow-up, months |
57.93 | 59.20 | 30.17 | 47.52 | 90.42 |
ECOG PS≤1, no (%) | 72 (93.5) | 51 (100) | 4 (50) | 12 (100) | 5 (83.33) |
Skin, no (%) | 40 (51.9) | 23 (45.1) | 6 (75.0) | 9 (75.0) | 2 (33.3) |
Pulmonary, no (%) | 17 (22.1) | 12 (23.5) | 1 (12.5) | 4 (33.3) | 0 (0.0) |
Renal, no (%) | 19 (24.6) | 9(17.6) | 6 (75.0) | 3 (25.0) | 1 (16.7) |
Articular, no (%) | 74 (96.1) | 50 (98.0) | 7 (87.5) | 11 (91.6) | 6 (100) |
Muscular, no (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Peripheral neuropathy, no (%) | 20 (26.0) | 9 (17.6) | 4 (50) | 6 (50) | 1 (16.7) |
CNS involvement, no (%) | 1 (1.3) | 1 (2.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Salivary/parotid enlargement, no (%) | 52 (67.5) | 38 (74.5) | 4 (50) | 6 (50) | 4 (66.7) |
Constitututional, no (%) | 30 (39.0) | 14 (27.5) | 7 (87.5) | 7 (58.3) | 2 (33.3) |
Hematological, no (%) | 58 (75.3) | 35 (68.6) | 6 (75.0) | 12 (100) | 5 (83.3) |
Lymphadenopathy, no (%) | 47 (61.0) | 27 (52.9) | 8 (100) | 8 (66.7) | 5 (83.3) |
Biological, no (%) | 70 (90.9) | 46 (90.2) | 8 (100) | 12 (100) | 4 (66.7) |
Mean (SD) | 10.31 (4.02) | 9.49 (3.83) | 14.00 (3.12) | 12.17 (4.02) | 8.67 (3.20) |
Median (range) | 10 (4–20) | 9.00 (4–20) | 14.00 (9–19) | 12.50 (6–17) | 7.50 (6–13) |
B-symptoms, no (%) | 5 (6.5) | 0 (0) | 1 (12.5) | 2 (16.7) | 2 (33.3) |
Splenomegaly, no (%) | 12 (15.6) | 6 (11.8) | 6 (75) | 1 (8.3) | 3 (50) |
Palpable purpura, no (%) | 33 (42.9) | 22 (23.6) | 4 (50) | 7 (58.3) | 0 (0) |
Stage I | 31 (40.3) | 29 (56.9) | 0 (0) | 2 (16.6) | 0 (0) |
Stage II | 9 (11.7) | 3 (5.9) | 0 (0) | 4 (33.3) | 2 (33.3) |
Stage III | 6 (7.8) | 0 (0) | 4 (50) | 2 (16.6) | 0 (0) |
Stage IV | 31 (40.3) | 19 (37.3) | 4 (50) | 4 (33.3) | 4 (66.7) |
Low risk (0–1 points) | 30 (38.9) | 28 (54.9) | 0 (0) | 2 (16.6) | 0 (0) |
Low-intermediate risk (2 points) | 24 (31.2) | 14 (27.5) | 4 (50) | 3 (25) | 3 (50) |
High-intermediate risk (3 points) | 18 (23.4) | 5 (9.8) | 3 (37.5) | 7 (58.3) | 3 (50) |
High risk (4–5 points) | 5 (6.5) | 4 (7.8) | 1 (12.5) | 0 (0) | 0 (0) |
BM involvement, no (%) | 21 (27.3) | 15 (29.4) | 0 (0) | 2 (16.7) | 4 (66.7) |
Extranodal sites |
29 (37.7) | 25 (49) | 0 (0) | 2 (16.7) | 2 (33.3) |
Anemia (Hgb<12mg/dl), no (%) | 34 (44.2) | 20 (39.2) | 4 (50) | 7 (58.3) | 3 (50) |
Leucopenia (WBC<4000/mm3), no (%) | 18 (23.4) | 13 (25.5) | 3 (37.5) | 1 (8.3) | 1 (16.7) |
Lymphopenia (LYM<1000/mm3), no (%) | 32 (41.6) | 21 (41.2) | 4 (50) | 5 (41.7) | 2 (33.4) |
Elevated LDH (>220mg/dl), no (%) | 42 (54.5) | 25 (49.0) | 6 (75) | 7 (58.3) | 4 (66.7) |
Elevated β2-microglobulin, no (%) | 38 (49.4) | 24 (47.1) | 5 (62.5) | 5 (41.7) | 4 (66.7) |
Low C3 levels (<75 mg/dL), no (%) | 10 (13.0) | 8 (15.6) | 2 (25) | 0 (0) | 0 (0) |
Low C4 levels (<16 mg/dL), no (%) | 36 (46.8) | 24 (47.1) | 5 (62.5) | 6 (50) | 1 (16.7) |
PositiveANA, no (%) | 64 (83.1) | 46 (90.2) | 8 (100) | 8 (66.7) | 2 (33.4) |
Positive Ro, no (%) | 61 (79.2) | 43 (84.3) | 7 (87.5) | 9 (75) | 2 (33.4) |
Positive La, no (%) | 43 (55.8) | 31 (60.8) | 4 (50) | 7 (58.3) | 1 (16.7) |
Positive RF, no (%) | 51 (66.2) | 36 (70.6) | 7 (87.5) | 7 (58.3) | 1 (16.7) |
Hypergammaglobulinemia, no (%) | 35 (45.5) | 26 (51) | 4 (50) | 3 (25) | 2 (33.4) |
Hypogammaglobulinemia, no (%) | 7 (9.1) | 2 (3.9) | 2 (25) | 1 (8.3) | 2 (33.4) |
Monoclonal band, no (%) | 24 (31.2) | 16 (31.4) | 5 (62.5) | 1 (8.3) | 2 (33.4) |
Cryoglobulinemia, no (%) | 26 (33.8) | 18 (35.3) | 5 (62.5) | 3 (25) | 0 (0) |
Anti-CD20 monotherapy (Rituximab), no | 14 | 14 | |||
CR, no (%) | 10 (71.4) | 10 (71.4) | |||
Antibiotics, no | 4 | 4 | |||
CR, no (%) | 2 (50) | 2 (50) | |||
Single agent, no | |||||
-alkylating agent, CHL or C | 4 | CHL: 1 | C: 1 | CHL: 2 | |
CR, no (%) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
-purine analog, 2Cda | 3 | 1 | 1 | 1 | |
CR, no (%) | 3 (100) | 1 (100) | 1 (100) | 1 (100) | |
Polychemotherapy, no | 9 | COP: 2 | COP: 2 CHOP: 1 | CHOP: 1 | CHOP: 1 COP: 1 CHOP/ESHAP: 1 |
CR, no (%) | 4 (44.4) | 1 (50) | COP: 1 (50) CHOP: 0 | 1 (100) | CHOP: 0 (0) COP: 1 (100) CHOP/ESHAP: 0 (0) |
Rituximab plus Chemotherapy, no | 32 | RCHOP: 6 RF: 10 RCOP: 1 RC: 2 | RC: 1 RCHOP: 1 | RCHOP: 11 | |
CR, no (%) | 22 (68.8) | RCHOP: 5 (83.3) RF: 7 (70) RCOP: 1 (100) RC: 1 (50) | RC: 0 (0) RCHOP: 1(100) | RCHOP: 7 (63.6) | |
Irradiation, no (%) | 1 | 1 | |||
“Wait and see” policy, no (%) | 10 | 9 | 1, denied | ||
Total CR after first-line treatment, no (%) | 41 (61.2) | 28 (68.3) | 3(37.5) | 8 (66.7) | 2 (33.3) |
§Median follow-up times were computed by the reverse Kaplan-Meier method.
MALTLs constituted the majority (51/77, 66.2%) of NHL subtypes, followed by diffuse large B-cell lymphomas (DLBCL) (12/77, 15.6%) and nodal marginal zone lymphomas (NMZL) (8/77, 10.4%). Compared to patients with DLBCL, MALTL patients were significantly younger (median age was 55 versus 69 years respectively, p = 0.007), and developed lymphoma much earlier (median time from SS diagnosis to MALTL development was 65.80 versus 97.54 months respectively, p = 0.004).
At the time of NHL diagnosis, ECOG performance status of patients was fairly good (93% of patients had a PS≤1), 52% of patients had a limited disease (I and II), according to Ann Arbor staging, and 70.2% of patients belonged to the low-risk group and low-intermediate risk IPI groups (
Total ESSDAI score was used to quantify SS-activity. For SS-associated NHL patients mean total ESSDAI score (SD) was 10.31 (4.02) at lymphoma diagnosis, while at SS diagnosis was 3.12 (1.74). In comparison with the control group of 167 SS patients without lymphoma (8 males and 159 females, median age, range: 54, 29–79 years, mean total ESSDAI±SD: 2.86±1.74), the total ESSDAI score of our SS-associated lymphoma cohort at time of SS diagnosis, was similar to the ESSDAI score of SS patients that did not develop latterly NHL (p = 0.279). In the NHL subgroup analysis, MALTL patients had significantly lower total ESSDAI score (mean±SD, 9.49±3.83) compared with DLBCL patients (12.17±4.02) (p = 0.037) and NMZL patients (14±3.12) (p = 0.003) (
Skin vasculitis (51.9%, 40/77), articular involvement (98.7%, 76/77), parotid gland enlargement (70.1%, 54/77), hematological manifestations (75.3%, 58/77), lymphadenopathy (71.4%, 55/77) and biological parameters (90.9%, 70/77) were common (>50%) in SS-associated lymphoma patients compared to SS-non lymphoma matched controls. Furthermore, twenty NHL patients (26%) developed peripheral neuropathy and 33 NHL patients (42.9%) displayed palpable purpura. Among the hematological and biological findings, anemia, lymphopenia, the presence of monoclonal immunoglobulin and cryoglobulinemia were detected more often in NHL patients (
Six-months after NHL treatment, total ESSDAI score and biological parameters (such as cryoglobulinemia, hypergammaglobulinemia, RF, C3 and C4 levels) were re-assessed (
At lymphoma diagnosis | After lymphoma treatment | P-value |
|
---|---|---|---|
Positive RF, no (%) | 51 (66.2) | 18 (23.4) | <0.001 |
Low C3 levels (<75 mg/dL), no (%) | 10 (13.0) | 8 (10.4) | 0.774 |
Low C4 levels (<16 mg/dL), no (%) | 36 (46.8) | 20 (25.9) | 0.004 |
Hypergammaglobulinemia, no (%) | 35 (45.5) | 7 (9.1) | <0.001 |
Cryoglobulinemia, no (%) | 26 (33.8) | 8 (10.4) | <0.001 |
Skin | 40 (51.9) | 28 (36.4) | <0.001 |
Pulmonary | 17 (22.1) | 14 (18.2) | 0.250 |
Renal | 19 (24.6) | 17 (22.1) | 0.500 |
Articular | 74 (96.1) | 42 (54.5) | <0.001 |
Muscular | 0 (0.0) | 0 (0.0) | 1.000 |
Peripheral neuropathy | 20 (26.0) | 17 (22.1) | 0.375 |
CNS | 1 (1.3) | 1 (1.3) | 1.000 |
Glandular | 52 (67.5) | 44 (57.1) | 0.008 |
Constitutional | 30 (39.0) | 23 (29.9) | 0.016 |
Haematological | 58 (75.3) | 11 (14.3) | <0.001 |
Lymphadenopathy | 47 (61.0) | 17 (22.1) | <0.001 |
Biological | 70 (90.9) | 18 (23.4) | <0.001 |
Total ESSDAI score, mean (SD) | 10.31 (4.02) | 4.07 (3.02) | < 0.001 |
#For comparisons of proportions, P-value was calculated with McNemar’s test and for comparison of total ESSDAI scores (continuous variable)
P-value was calculated with Wilcoxon matched pairs test
During follow-up, 10 patients died, five suffered a relapse, two experienced progression/transformation, and five patients developed other hematological malignancies that included multiple myeloma (one), Hodgkin’s disease (one), T-cell NHL (two), and thymoma (one). Seven of the recorded deaths were attributed to treatment-related neutropenic sepsis; two deaths were the result of relapse after treatment failure, and one death was attributed to reasons that were not lymphoma or treatment-related.
A/a | Age/Sex | Type | Stage | IPI | First line TX | EFS (months) | Event | Second line TX | Outcome/Comment |
---|---|---|---|---|---|---|---|---|---|
1 | 48/F | DLBCL | IV | Inter/High | R-CHOP | 36.0 | Relapse | R-CHOP | CR |
2 | 75/F | DLBCL | III | Inter/High | R-CHOP | 42.3 | Death † | In CR, lymphoma related | |
3 | 61/F | MALTL | I | Low/Inter | R | 35.3 | Relapse | R-FMD | CR |
4 | 54/F | NMZL | IV | Inter/High | COP | 16.4 | Relapse | 2CDA | Death †, treatment related |
5 | 76/F | MALTL | IV | High | CHL | 0.3 | Death † | Death †, treatment related | |
6 | 62/F | LPL | IV | Inter/High | CHL/B | 85.3 | Progression | CHOP | Death †, treatment related |
7 | 57/F | MALTL | II | Low | RF | 29.9 | Death † | In CR, treatment related | |
8 | 58/F | NMZL | IV | Inter/High | C | 37.8 | Relapse | CHOP | Lost in follow-up |
9 | 60/F | NMZL | IV | High | COP | 80.1 | Relapse | CHOP | Death †, treatment related |
10 | 52/F | T-NHL | IV | Inter/High | CHOP/ ESHAP | 43.8 | Hodgkin’s disease | ABVD | CR |
11 | 36/F | NMZL | III | Low/Inter | R-CHOP | 61.7 | Relapse | RF | CR |
12 | 44/F | DLBCL | IV | Inter/High | CHOP | 19 | Relapse | R-ESHAP/ASCT | CR |
13 | 81/F | DLBCL | II | Inter/High | R-CHOP | 12.2 | Relapse | R-CHOP | Death †, treatment related |
14 | 57/F | MALTL | IV | Inter/High | R | 22.8 | Relapse | R-CHOP | CR |
15 | 72/F | MALTL | IV | High | RF | 70.9 | Multiple myeloma | No therapy | CR |
16 | 76/F | DLBCL | II | Inter/High | R-CHOP | 9.3 | Progression | R-ICE | Death †, treatment related |
17 | 63/F | MALTL | I | Low/Inter | CHOP | 41.7 | Transformation | RF | CR |
18 | 39/F | MALTL | IV | Low/Inter | R-CHOP | 78.3 | Thymoma | No therapy | CR |
19 | 59/F | DLBCL | I | Low/Inter | R-CHOP | 26.7 | Relapse | R-ESHAP | CR |
20 | 73/F | MALTL | IV | High | RF | 10.2 | Transformation | No therapy | T-LGL, Death †, lymphoma related |
21 | 43/F | MALTL | IV | Low/Inter | R-CHOP | 69.7 | Relapse | R-2CDA/BDR | T-NHL, R-ESHAP/ASCT, CR |
22 | 55/F | MALTL | IV | Low/Inter | R-CHOP | 7.8 | Death † | Death treatment-lymphoma-unrelated |
2Cda = 2-chlorodeoxyadenosine, CHL = chlorambucil, CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone, COP = cyclophosphamide, vincristine, prednisone
R = anti-CD20 (rituximab), C = cyclophosphamide, R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, RF = rituximab, fludarabine, ESHAP = etoposide, methylprednisolone, cytarabine, cisplatin, R-ICE = rituximab, ifosfamide, carboplatin, etoposide, R-FMD = rituximab, fludarabine, mitoxantrone, dexamethasone
ABVD = Adriamycin, bleomycin, vinblastine, dacarbazine, ASCT = autologous stem cell transplantation, BDR = Bortezomib, rituximab
T-LGL = T-large granular lymphocytic lymphoma
T-NHL = T-non-hodgkin lymphoma.
At 5 years, OS and EFS for the entire NHL cohort was 90.91% (95%CI: 82.14–95.80%) and 77.92% (95% CI: 67.37–85.82%), respectively (
Deaths | Overall survival | |||||||
---|---|---|---|---|---|---|---|---|
Parameters | OR (95%CI) | P-value | OR adjusted (95%CI) | P-value | HR (95%CI) | P-value | HR adjusted (95%CI) | P-value |
NHL subtype | 1.558 (0.865–2.804) | 0.139 | 1.177 (0.568–2.440) | 0.662 | 1.329 (0.806–2.193) | 0.265 | 0.920 (0.511–1.655) | 0.781 |
BM involvement (yes vs. no) | 1.961 (0.493–7.791) | 0.339 | 0.844 (0.168–4.234) | 0.836 | 2.457 (0.689–8.759) | 0.166 | 0.982 (0.243–3.967) | 0.980 |
Total ESSDAI score (high vs. total) | 5.241 (1.034–26.568) | 0.045 | 2.367 (0.368–15.237) | 0.364 | 5.946 (1.259–28.077) | 0.024 | 2.451 (0.442–13.601) | 0.305 |
IPI score (high/high-intermediate vs. low-intermediate/low) | 13.867 (2.656–72.387) | 0.002 | 9.628 (1.374–67.458) | 0.023 | 11.414 (2.414–53.974) | 0.002 | 8.529 (1.325–54.904) | 0.024 |
NHL subtype | 1.578 (0.983–2.533) | 0.059 | 1.230 (0.671–2.256) | 0.503 | 1.288 (0.919–1.804) | 0.142 | 0.845 (0.566–1.261) | 0.409 |
BM involvement (yes vs. no) | 3.333 (1.146–9.699) | 0.027 | 1.700 (0.467–6.187) | 0.421 | 3.789 (1.610–8.920) | 0.002 | 1.646 (0.632–4.288) | 0.308 |
Total ESSDAI score (high vs. total) | 4.317 (1.460–12.771) | 0.008 | 2.334 (0.641–8.500) | 0.199 | 4.541 (1.772–11.637) | 0.002 | 2.092 (0.722–6.064) | 0.174 |
IPI score (high/high-intermediate vs. low-intermediate/low) | 12.589 (3.911–40.526) | <0.001 | 6.996 (1.803–27.146) | 0.005 | 8.718 (3.477–21.858) | <0.001 | 6.002 (1.791–20.114) | 0.004 |
BM = Bone Marrow, OR = Odd ratio, HR = Hazard ratio, 95%CI = 95% confidence intervals.
Patients with high SS-disease activity (high total ESSDAI score >10) had greater risk to experience a death (OR = 5.241, 95%CI: 1.034–26.568, p = 0.045) or an event (OR = 4.317, 95%CI: 1.146–9.699, p = 0.008), and significantly worse EFS and OS compared to low total ESSDAI scored patients (score ≤10) (EFS: log-rank p = 0.001, HR = 4.541, 95%CI: 1.772–11.637; OS: log-rank p = 0.011, HR = 5.946, 95%CI: 1.259–28.077) (
A. and B. Kaplan-Meier for EFS and OS of SS-associated lymphoma patients, according to high or low total ESSDAI score groups (High total ESSDAI>10 and Low total ESSDAI≤10). High vs. Low total ESSDAI group for EFS: log-rank p = 0.001 and for OS: log-rank p = 0.011. C. and D. Kaplan-Meier for EFS and OS of the SS-associated NHL patients, according to IPI score groups: low/low-intermediate IPI group = 0–2 factors and high-intermediate/high IPI group = 3–4 factors. Log-rank test of low/low-intermediate vs. high-intermediate/high risk group curves for EFS: p< 0.001 and for OS: p<0.001. E. and F. Kaplan-Meier for EFS and OS of the SS-associated NHL patients, according to bone marrow involvement (log-rank test for EFS: p = 0.001 and for OS: p = 0.152).
Focusing further, we recognized additional predictors of lymphoma prognosis, such as an IPI score and BM involvement. In high/high-intermediate IPI group of patients, the risk of death was 13.867 times greater (95%CI: 2.656–72.387, p = 0.002) and the risk of event was 12.589 times greater (95%CI: 3.911–40.526, p<0.001) compared to low/low-intermediate IPI risk group (
After adjustment for identified independent prognostic parameters at the point of NHL diagnosis (lymphoma subtype, ESSDAI, IPI and BM involvement), only high IPI score retains a significantly increased risk for experiencing of event (adjusted OR = 6.996, 95%CI: 1.803–27.146, p = 0.005) or death (adjusted OR = 9.628, 95%CI: 1.374–67.458, p = 0.023). In our multivariate Cox regression model, high IPI score is associated with worse OS (adjusted HR = 8.529, 95%CI: 1.325–54.904, p = 0.024) and EFS (adjusted HR = 6.002, 95%CI: 1.791–20.114; p = 0.004) (
To our knowledge, this is the largest single center study so far to systematically evaluate the impact of SS disease activity on the clinical course of SS-associated lymphomas [
The primary objective of this study was to identify prognostic risk factors for an adverse outcome and especially death in SS patients after lymphoma diagnosis. Several previous studies focused on identifying predictive markers for lymphoma development in SS patients. Specifically, those presenting with parotidomegaly, vasculitic purpura, splenomegaly, lymphadenopathy, cryoglobulinemia, low C4 levels, neutropenia and lymphopenia at SS diagnosis were seen to have a much greater probability of developing lymphoma and are hence considered as high-risk patients [
Our prognostic analysis also incorporated clinical features that reflect the growth and invasive potential of the tumor. Since its implementation in1993 in patients with aggressive lymphoma, IPI has been extensively applied to all types of NHL, including indolent lymphomas [
Mainly because of its retrospective setting, our study had several limitations. ESSDAI was established relatively lately and published in 2010. In this respect, for the majority of patients, ESSDAI was estimated retrospectively at the time of SS and at the time of lymphoma diagnosis as well as 6 months after lymphoma treatment. Despite the high rate of data completeness of our study, the quality of ESSDAI has not been demonstrated yet when it is used retrospectively. Before lymphoma development, ESSDAI score was retrospectively evaluated in only one distant time-point, at SS diagnosis, affecting the dynamic character of disease activity scoring scale. In addition, some features included in the ESSDAI, such as hypocomplementemia, cryoglobulins, glandular swelling are known risk factors for lymphoma development and doubtlessly introduced further bias in the demonstration of a worse survival in those patients with original high ESSDAI score. On the other hand, at SS diagnosis, total ESSDAI score showed no significant differences between SS cases that latterly developed or not lymphoma. This finding is in agreement with a recent study by Risselada et al, where ESSDAI score could not clearly discriminate between patients with or without subsequent lymphoma development [
We detected that ESSDAI and IPI scores are valuable prognostic parameters of SS-associated NHL outcome. Validation of these prognostic factors through a prospective cohort will enable clinicians to treat SS-lymphoma patients with a more patient-tailored approach.