M. Maset

A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis

OBJECTIVE To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV). METHODS Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. RESULTS Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [P < 0.0001]), 6 months (71.4% versus 3.5% [P < 0.0001]), and 24 months (60.7% versus 3.5% [P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated. CONCLUSION RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients.

BLyS upregulation in Sjögren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands

OBJECTIVE Primary SS is characterized by an increased risk of lymphoma in patients with prelymphomatous manifestations (i.e. myoepithelial sialadenitis or mixed cryoglobulinaemia). Serum B-lymphocyte stimulator (s-BLyS) levels in SS-related B-cell lymphoproliferative disorders were studied by integrating the results with the disease activity score and with molecular analyses of B-cell expansion in the salivary glands. METHODS Seventy-six primary SS patients (with or without lymphoma or prelymphomatous manifestations), 56 HCV-related cryoglobulinaemic vasculitis patients and 55 controls were studied. s-BLyS and molecular analyses of B-cell expansion in the salivary gland tissues were performed. Patients with SS and persistent parotid swelling underwent parotid biopsy. RESULTS s-BLyS differed between SS subgroups, higher levels being documented in patients with lymphoma or prelymphomatous manifestations vs SS without [1.85 (0.45-4.12) ng/ml vs 1.12 (0.56-1.98) ng/ml; P < 0.0001]. s-BLyS levels significantly correlated with the European League Against Rheumatism (EULAR) SS disease activity index (r = 0.62, P < 0.0001, Spearmans test). Clonal B-cell expansion in the salivary glands, but not polyclonal B-cell expansion, was associated with higher s-BLyS levels [1.98 (0.45-4.12) ng/ml vs 1.15 (0.56-3.25) ng/ml; P = 0.013)]. CONCLUSION Higher s-BLyS levels and tissue clonal B-cell expansion characterize SS with B-cell lymphoproliferative disorders, even at prelymphomatous stages. This subgroup of SS patients showed the highest EULAR SS disease activity index scores. This represents a biologic rationale for targeting both clonal B-cell expansion and s-BLyS overproduction in SS.

Biomarkers of lymphoma in Sjögren's syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study.

OBJECTIVES To define the biomarkers associated with lymphoproliferation in primary Sjögrens syndrome (pSS) by distinguishing in separate groups the two best-recognized non-malignant prelymphomatous conditions in pSS, i.e., salivary gland swelling and cryoglobulinemic vasculitis (CV). METHODS A multicenter study was conducted in 5 centres. Patients fulfilled the following criteria: (1) positive AECG criteria for pSS, (2) serum cryoglobulins evaluated, and (3) lack of hepatitis C virus infection. Four groups were distinguished and analysed by multinomial analyses: (1) B-cell non-Hodgkins lymphoma (NHL), (2) CV without lymphoma, (3) salivary swelling without NHL (SW), and (4) pSS patients without NHL or prelymphomatous conditions. RESULTS Six hundred and sixty-one patients were studied. Group 1/NHL comprised 40/661 (6.1%) patients, Group 2/CV 17/661 (2.6%), Group 3/SW 180/661 (27.2%), and Group 4/pSS controls 424/661 (64.1%). Low C4 [relative-risk ratio (RRR) 8.3], cryoglobulins (RRR 6.8), anti-La antibodies (RRR 5.2), and leukopenia (RRR 3.3) were the variables distinguishing Group 1/NHL from Group 4/Controls. As concerns the subset of patients with prelymphomatous conditions, the absence of these biomarkers provided a negative predictive value for lymphoma of 98% in patients with salivary swelling (Group 3/SW). Additional follow-up studies in patients with SW confirmed the high risk of lymphoma when at least 2/4 biomarkers were positive. CONCLUSIONS Lymphoma-associated biomarkers were defined in a multicentre series of well-characterized patients with pSS, by dissecting the cohort in the pSS-associated prelymphomatous conditions. Notably, it was demonstrated for the first time that among the pSS patients with salivary swelling, only those with positive biomarkers present an increased risk of lymphoma evolution.

Controversies on Rituximab Therapy in Sjögren Syndrome-Associated Lymphoproliferation

Sjögrens syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of salivary and lachrymal glands, and frequently accompanied by systemic symptoms. A subgroup of SS patients develops malignant B cell non-Hodgkins lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) type and very often located in the major salivary glands. Currently, there is a lack of evidence-based intervention therapy which may influence SS-related chronic inflammation and lymphoproliferation. B cells are involved in the pathogenesis of SS, and B cell downregulation may lead to a decrease of disease activity. Rituximab (RTX), a chimeric monoclonal antibody targeting the CD20 antigen on the B cell surface, has been successfully investigated in other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, ANCA-associated vasculitis, and mixed cryoglobulinemic syndrome. Preliminary experiences of RTX therapy in SS patients with or without a lymphoproliferative disorder suggest that SS patients with more residual exocrine gland function might better benefit from RTX. Efficacy of RTX in SS-associated B-cell lymphoma, mainly in low-grade salivary gland lymphomas, remains an open issue.

Role of oral cyclophosphamide in the treatment of giant cell arteritis

OBJECTIVE Glucocorticoid (GC)-related adverse events greatly contribute to the outcome in giant cell arteritis (GCA). CYC was investigated as a steroid-sparing agent in GCA. METHODS Nineteen patients treated with CYC were retrospectively analysed. CYC was administered in 15 of the 19 patients after failure of high doses of GC or relapse during medium to high doses of GC, with or without MTX, while CYC was used ab initio in 4 of the 19 patients, all with type 2 diabetes. Follow-up ranged from 1 month to nearly 9 years after the end of CYC treatment. RESULTS The efficacy of CYC was observed in 15 of the 19 patients, and remission was still present 6-12 months after CYC suspension in 12 of the 13 patients. GCs were suspended in 6 of the 15 patients, and they were continued at a dose ≤5 mg/day of prednisone in all the remaining responders. Relapse occurred in 4 of the 15 patients, usually >12 months after CYC suspension. Suspension of GC daily dose or reduction to ≤5 mg/day of prednisone occurred within the first 6 months of follow-up after the beginning of CYC in 10 of the 15 patients. Ten adverse events were registered in nine patients, with recovery usually soon after the suspension of CYC or dose reduction. However, one death occurred due to acute hepatitis. Disappearance of the inflammatory infiltrate could be demonstrated when temporal artery biopsy was repeated 3 months after CYC in one patient. CONCLUSION CYC may represent a useful option for patients requiring prolonged medium- to high-dose GC therapy and at high risk of GC-related side effects.

Outcome of pregnancy in Italian patients with primary sjogren syndrome

Objective. To investigate pregnancy and fetal outcomes in patients with primary Sjögren syndrome (pSS). Methods. An obstetric history of 36 women with established diagnosis of pSS at pregnancy was obtained from a multicenter cohort of 1075 patients. In a subgroup case-control analysis, 12 deliveries in patients with pSS were compared with 96 control deliveries. Results. Thirty-six women (31 with anti-SSA/Ro and/or anti-SSB/La antibodies) with an established diagnosis of pSS had 45 pregnancies with the delivery of 40 newborns. Two miscarriages, 2 fetal deaths, and 1 induced abortion were recorded. Mean age at the first pregnancy was 33.9 years; mean number of pregnancies was 1.25; 18/40 (45%) cesarean births were delivered; mean pregnancy length was 38.5 weeks (range 32–43), with 6 preterm deliveries. The mean Apgar score at 5 min was 8.9, mean birthweight was 2920 g (range 826–4060 g). Congenital heart block (CHB) occurred in 2/40 (5%) newborns. The reported rate of breastfeeding for at least 1 month was 60.5%. In 4/40 pregnancies (10%) a flare of disease activity was observed within a year from delivery. In the case-control subgroup analysis, 12 deliveries were compared with 96 controls and no significant differences were found. Conclusion. Patients with pSS can have successful pregnancies, which might be followed by a mild relapse. CHB was the only cause of death for offspring of mothers with pSS.

SAT0207 Correlation of clinical, serologic and histologic findings in a large cohort of primary sjögren’s syndrome patients: A multicentric cross-sectional study

Background Although primary Sjögren’s syndrome (pSS) is often a benign condition some patients develop systemic features. Identifying independent risk factors for pSS different clinical phenotypes would provide useful insights into patients’ assessment. Objectives to describe the clinical presentation of pSS in a large cohort of patients and to identify independent risk factors for severe disease manifestations. Methods Cumulative demographic, clinical, serological, histological and therapeutic data of 1115 pSS patients were retrospectively evaluated. Independent risk factors for disease manifestations were identified by logistic regression. Results The cohort included 1115 (1067 F:48M) pSS patients with a mean age of 51.6±13.8 yrs at diagnosis and 57.5±13.7 yrs at inclusion in the study (mean follow-up=5.8±6.5 yrs). Anti-Ro/SSA and anti-La SSB were detected in the 68% and 37% of the cases. Xerostomia (92%), xerophtalmia (94%) and articular involvement (61%) were the most commonly detected clinical manifestations. Salivary gland enlargement was detected in 346/1115 (31%) pSS patients while 475/1115 (42%) developed systemic extra-glandular involvement. Moderate to severe leukopenia (28%), peripheral arthritis (11%) and sensory-motor neuropathy (1.8%) were the most severe disease extra-glandular manifestations requiring immunosuppressive drugs. Independent risk factors for leukopenia were Raynaud’s phenomenon (RP) (p=0.008), low C3 (p=0.001), hypergammaglobulinemia (p=0.0006) and cryoglobulinemia (p=0.01). Arthritis was associated to RP (p=0.005) while sensory-motor neuropathy to purpura (p<0.0001), low C4 (p<0.0001) and cryoglobulinemia (p<0.0001). From the analysis, low C3/C4, hypergammaglobulinemia and cryoglobulinemia emerged as prognostic adverse laboratory abnormalities. Table 1 summarises patients’ clinical presentation according to the number of the laboratory abnormalities detected (“group A” = no abnormalities, “group B” =1 and “group C” ≥2 abnormalities). No factors 1 factor ≥2 factors p-value n=469 n=427 n=219 p-value Salivary gland enlargement 106 (22.6%) 150 (35.2%) 90 (41.1%) 0.000 Purpura 15 (3.2%) 35 (8.3%) 56 (25.7%) 0.000 Kidney 2 (0.4%) 12 (2.8%) 10 (4.6%) 0.001 Haematological manifestations 88 (19%) 152 (35.6%) 118 (54%) 0.000 Lung 20 (4.3%) 21 (4.9%) 19 (8.7%) 0.05 Peripheral nervous system 21 (4.5%) 18 (4.2%) 20 (9.1%) 0.01 Lymphoma 9 (1.9%) 10 (2.3%) 31 (14.2%) 0.000 Anti-Ro/SSA 239 (51.5%) 336 (79.4%) 187 (85.4%) 0.000 Anti-La/SSB 96 (20.7%) 200 (47.3%) 114 (52.1%) 0.000 Rheumatoid Factor 158 (36.3%) 264 (66%) 160 (73.7%) 0.000 Focus score ≥1 240 (77.9%) 226 (82.2%) 111 (88.8%) 0.03 Glucocorticoids 168 (36.3%) 166 (39.1%) 104 (47.9%) 0.01 Immunosuppressive drugs 42 (9.3%) 62 (14.7%) 69 (30.1%) 0.0001 Conclusions This study described the presentation of pSS in a large cohort of patients allowing us to identify independent risk factors which might help to predict the signs and symptoms of the disease. Patients with laboratory signs of B-cell hyperactivation should be more closely monitored since they may be at higher risk of severe extra-glandular involvement. Disclosure of Interest None Declared

SAT0212 Pregnancy and fetal outcome in patients with an established diagnosis of primary sjögren’s syndrome

Objectives To investigate pregnancy and fetal outcome in patients with an established diagnosis of primary Sjögren’s syndrome (pSS) Methods The clinical charts of 1073 women with pSS from four rheumatology centres were retrospectively evaluated. When a pregnancy has occurred after pSS diagnosis, the patient was personally interviewed to obtain more detailed information regarding obstetric history; obstetric clinical charts were reviewed as well. Results Patients’ mean age was 59 yr (17-89), mean age at diagnosis 51,4 yr; 138/1073 (12,8%) were diagnosed before 35 yr. Thirty-five women (31 with anti-SSA/Ro and/or anti-SSA/La antibodies) with an established diagnosis of pSS had 44 pregnancies which ended with the delivery of 39 newborns. Two miscarriages, 2 fetal death and one induced abortion were recorded. Mean age at the latest pregnancy was 34,6 yr (range 29-44), mean number of pregnancy 1,25 (1-3); 17/39 cesarean sections were performed, mean pregnancy length was 38,5 week (range 32-43) with 6 preterm delivery. The mean Apgar score at 5 minute was 8,9 (range 5-10), mean birth weight was 2934 mg (range 826-4060). Congenital heart block (CHB) occurred in 2 newborns of 31 mothers with anti-SSA and/or SSB antibodies (6,45%), with fatal outcome. Other 2 infants had cardial incontinence and a mild interatrial defect, respectively. During pregnancy one patient presented thrombocytopenia and another palpable purpura. In 4/39 pregnancies (10,2%) a flare of disease activity was observed (arthralgia/arthritis and central nervous system involvement) within a year from delivery. Conclusions Even if pSS generally starts after menopause, it can appear during the childbearing age. pSS can have successful pregnancies, which might be followed by a mild relapse. CHB is a fearful complication for women with anti-SSA/Ro and or anti-SSB/La antibodies. Disclosure of Interest None Declared

FRI0282 Serological biomarkers of b-cell lymphoproliferative disorders in patients with primary sjögren’s syndrome: retrospective study in a large italian cohort

Background primary Sjögren’s syndrome (pSS) is the autoimmune disease with the highest risk of lymphoma. Lymphoma and mixed cryoglobulinemic vasculitis (CV) occur in a minority of cases, but they are the most relevant clinical features characterizing the B cell lymphoproliferation in pSS. Objectives to provide serological biomarkers associated with lymphoproliferative complications (B-cell lymphoma, cryoglobulinemic vasculitis (CV) and non malignant major salivary gland swelling) in primary Sjögren’s syndrome (pSS). Methods data in 1170 patients with pSS diagnosis were retrospectively collected. The analyses were then performed in patients fulfilling the following criteria: 1. European or AECG criteria, 2. Hepatitis C virus infection antibody negative, 3. serum cryoglobulins tested. Multinomial analyses (P<0.05) were performed by distinguishing 4 groups: 1. lymphoma (including patients with lymphoma and CV associated), 2. CV without lymphoma, 3. Salivary gland swelling without lymphoma, 4. other pSS patients. Group 4 was assumed as “base outcome”. The following variables were considered: presence/absence of antinuclear antibodies, anti-Ro, anti-La, low C3, low C4, rheumatoid factor, hypergammaglobulinemia, monoclonal component, leucopoenia, and cryoglobulinemia. Results 661 patients were selected. Group 1 comprised 40/661 (6.1%), group 2 comprised 17/661 (2.6%), group 3 comprised 180/661 (27.2%), and group 4 comprised 424 (64.1%). Anti-La, hypergammaglobulinemia (IgG > 16 g/l), leucopoenia (<3000/mmc), rheumatoid factor, serum monoclonal component, low C3, low C4, and cryoglobulinemia were selected by univariate analyses. Low C4 [relative-risk ratio (RRR) 8.3, 95% CI 3.6-19.2], anti-La (RRR 5.2, 95% CI 2.3-11.9), cryoglobulins (RRR 6.8, 95% CI 2.1-22.1) and leucopenia (RRR 3.3, 95% CI 1.5-7.05) were the selected variables, by multinomial logistic analyses, that distinguished group 1 from group 4. At least one of the biomarkers selected by univariate analyses was present in all patients with lymphoma, and at least one of the biomarkers selected by multivariate analyses were present in 39/40 patients with lymphoma (97.5%). The majority of variables distinguishing Group 1 from Group 4 were shared with Group 2, while rheumatoid factor and hypergammaglobulinemia were shared with Group 3. Conclusions Serological biomarkers which raise the level of suspicion of lymphoma or suggest a close follow-up in pSS patients may be identified and confirmed. Rheumatoid factor and hypergammaglobulinemia may reflect the B-cell hyperactivation in patients with salivary gland swelling, which predisposes to lymphoma in pSS. The absence of all the lymphoma-associated biomarkers in pSS may identify patients at lower risk of lymphoma, when CV or salivary gland swelling are not present. Disclosure of Interest: None Declared

SAT0233 Characteristics of primary sjögren’s syndrome (PSS) patients with cryoglobulinemia in a large cohort of patients, and differences between hypergammaglobulinemic and cryoglobulinemic vasculitis in PSS

Background Vasculitis in primary Sjögren’s syndrome (pSS) may be related to cthe presence of cryoglobulins (cryos) or hypergammaglobulinemia. Cryos reflect a high grade of B-cell lymphoproliferation, possibly leading to malignant lymphoma. Objectives Patients with pSS with cryos with or without vasculitis, and pSS with hypergammaglobulinemic vasculitis (hypergammaV) were retrospectively compared in a large cohort of consecutive patients. Methods Clinical, laboratory and histopathologic data in 1170 patients with pSS (1118 females, and 52 males, age at diagnosis 51±14 years) were collected. Univariate analyses were performed. Results cryos were tested in 850/1170 patients (72.6%), and detected in 59/850 (6.9%). Cryos were significantly associated with male sex (p=0.02), purpura (p<0.0001), renal involvement (p=0.002), haematologic abnormalities (p<0.0001), peripheral neuropathy (p<0.0001), fibromyalgia (p=0.007), lymphoma (p<0.0001), low C3 or C4 complement (p<0.0001 for both), leukopenia (p<0.0001), serum M-component (p<0.0001), hypergammaglobulinemia (p=0.04), anti-SSB (p=0.005), and rheumatoid factor (RF) (p<0.0001). Lip or parotid biopsy was positive in 36/37 pSS patients with cryos who underwent salivary biopsy, and the grade of lymphoid infiltrate in the target tissue correlated with an increased risk of cryos (p<0.0001; OR 2.8, 95%CI 1.8-4.6). Cryoglobulinemic vasculitis (CV) (1), was reported in 3.9% (33/850). CV was significantly associated with renal involvement (p=0.02), with haematologic abnormalities (p<0.0001), peripheral neuropathy (p<0.0001), lymphoma (p=0.001), low C3 or C4 complement (p<0.0001 for both), leukopenia (p<0.0001), serum M-component (p<0.0001), and RF (p<0.0001). Lip or parotid biopsy was positive in all pSS patients with CV who underwent salivary biopsy, i.e. 20/20 and the grade of lymphoid infiltrate correlated with an increased risk of CV (p=0.033; OR 1.67, 95%CI 1.04-2.70). Hypergammaglobulinemia was present in 403/839 (48.0%). HypergammaV without cryos was reported in 48/839 (5.7%). HypergammV was associated with Raynaud’s phenomenon (p=0.005), haematologic abnormalities (p<0.0001), fibromyalgia (p=0.02), but not with other extraglandular involvement. HypergammaV was associated with leukopenia (p=0.001), serum M-component (p=0.02), antinuclear antibodies (p=0.02), anti-SSA (p<0.0001), anti-SSB (p=0.002), RF (p<0.0001). Lip or parotid biopsy was positive in 27/33 pSS patients with hypergammaV, without correlation with the grade of lymphoid infiltrate (p=0.07). Conclusions pSS with cryos showed both a high grade of activation of peculiar B-cell clones and a high grade of B-cell organization into ectopic salivary MALT. By contrast, hypergammaV was not associated with MALT lymphoid infiltrate. Both cryos alone and CV but not hypergammaV were associated with lymphoma in pSS, indicating that cryos itself represents a red flag for lymphoma in pSS, while hypergammaV did not. References De Vita S, et al. Ann Rheum Dis 2011. Disclosure of Interest None Declared