Clinical and laboratory characteristics of lymphoproliferative diseases in primary Sjogren's syndrome associated with anticentromere antibodies

Purpose of the study. To study the characteristics and frequency of lymphomas in patients with Sjogren's disease (SD) and anticentromere antibodies (ACA); to evaluate the predictors of the development of lymphoproliferative diseases (LPD) in this group of patients. Material and methods. Over the period from 1998 till 2019, 131 ACA-positive patients were under medical supervision at the Research Institute of Rheumatology named after Nasonova V.A. Isolated SD was diagnosed in 82 patients (62.6%), isolated limited form of SSc — in 12 patients (9.2%), combination of SD and limited form of SSc — in 37 patients (28.2%). Lymphoproliferative diseases (LPD) were diagnosed in 20 ACA-positive patients: in 15 — with SD, in 5 — with SD and SSc; no lymphomas were found in the group of patients with isolated SSc. All lymphomas were diagnosed on the basis of histological, immunohistochemical and PCR examination with of B-cell clonality determination in the tissue, and were classified on the base of haematopoietic and lymphoid tissue tumors classification by the World Health Organization. Further analysis included 15 ACA-positive patients with isolated SD and lymphomas. Results. In our study, 18.3% of patients with isolated ACA-positive SD were diagnosed with LPD, represented by MALT lymphomas of the salivary glands (subsequent transformation into aggressive diffuse large B-cell lymphoma (DLBCL) was noted in one patient) in most cases. The course of SD before the diagnosis of LPD was characterized by a gradual progression of dental manifestations of SD with the development of late stages of parenchymal parotitis, severe xerostomia, and significant enlargement of the salivary glands with a minimum number of systemic manifestations of the disease. Significant enlargement of salivary glands, severe infiltration of minor salivary glands, severe xerostomia, decreased level of C4-complement component, monoclonal secretion, low content of CD19+B-cells in peripheral blood, positive B-cell clonality in biopsy material were the main signs of LPD in this study. When diagnosing MALT lymphomas, a focal damage of the salivary glands with no signs of dissemination, no symptoms of B-cell intoxication, and minimal changes in laboratory assessment were found in patients with ACA-positive SD. Conclusion. The natural course of ACA-positive SD and the absence of pathogenetic therapy at an early stage contribute to the development of salivary gland lymphomas in the first 10 years of the disease. Persistent enlargement of the salivary glands in SD, especially in the presence of other predictors of lymphoproliferation, is a direct indication for biopsy followed by the research to exclude the presence of lymphoma.

A Japanese Patient with Anti-PM/Scl and Centromere Antibody-Positive Scleroderma-Amyopathic Dermatomyositis Overlap Syndrome Who Developed Renal Crisis

Anti-PM/Scl antibodies are associated with the overlap syndrome of systemic sclerosis and dermatomyositis/polymyositis (SSc-DM/PM), and are found in 50% of SSc-DM/PM cases in Europe and the United States, whereas they are rare in Japan. We report a case of an 80-year-old Japanese female with SSc-amyopathic dermatomyositis (ADM) overlap syndrome, who developed scleroderma renal crisis (SRC), a complication of SSc. She had positive antinuclear antibodies in a discrete-speckled and nucleolar pattern and anticentromere antibodies and anti-PM/Scl antibodies were confirmed by ELISA and immunoprecipitation, respectively. The incidence rate of SRC in SSc patients varies significantly depending on the specificity of autoantibodies, with the highest incidence of ~50% in anti-RNA polymerase III antibody positive patients, followed by ~10% in anti-PM/Scl and lower incidence of 0.45% in anticentromere antibody-positive cases. Anti-PM/Scl antibodies are uncommon in Japanese patients presumably due to its strong association with certain HLA haplotype that is rare in Japanese. Clinical significance of anti-PM/Scl antibodies in Japanese patients will need to be clarified with accumulation of cases in future studies.

AB0451 TO EVALUATE THE PREVALENCE OF INTERSTITIAL LUNG DISEASE (ILD) AND/OR PULMONARY ARTERIAL HYPERTENSION (PAH) IN PATIENTS AFFECTED BY SYSTEMIC SCLEROSIS (SSC) AND TO DETERMINE THE FACTORS ASSOCIATED WITH ILD

Background:Systemic sclerosis (SSc) is a chronic autoimmune disease that carries significant mortality. Despite diagnostic and therapeutic advances in recent years, there is still a significant percentage of patients who do not present a complete clinical response, with the associated increase in morbidity and mortality. Specifically, pulmonary disease is frequent and entails a poor prognosis, with interstitial lung disease (ILD) and pulmonary hypertension (PAH) being the two most important complications, the first and second cause of mortality, respectively.Objectives:To evaluate the prevalence of ILD and/or PAH in patients affected by SSc and to determine the factors associated with ILD.Methods:Cross-sectional observational study of 102 patients diagnosed with SSc (Limited, Diffuse, SSc without scleroderma or Pre-scleroderma), treated between 1975 and 2020 at the Reina Sofia University Hospital in Cordoba. A descriptive study of the cohort was carried out and factors independently associated with ILD were evaluated using a multiple logistic regression model.Results:102 patients were included, 87.3% of these were female with an average age of 50.8 (14) years. There were 20 deaths (19.8%), from which 55% died because of SSc and the main reason was ILD and/or PAH. Respiratory complications (as ILD or as PAH) were present in 59 patients (57.8%), of whom 52 were diagnosed with ILD (90.4% with a pattern of non-specific interstitial pneumonia) and 25 PAH, whose mean pulmonary artery systolic pressure was 47.16 (18.54) mmHg. Anti-topoisomerase I antibodies were positive in 34.6% of patients who developed ILD, while anticentromere antibodies were more frequent in SSc without interstitial lung disease (80%). Independent factors associated with ILD were type of SSc, proximal skin involvement, anticentromere antibodies, current treatment with corticoids and the death.Conclusion:Just over half of the patients with SSc have lung disease (as ILD or as PAH). The main risk factors associated with ILD are proximal skin involvement and treatment with glucocorticoids, probably in the context of more severe forms that require more treatment. Anticentromere antibodies are more prevalent in patients with Limited SSc and their expression decreases the risk of developing ILD in these patients.References:[1]Orlandi M, Barsotti S, Lepri G, et al. Clin Exp Rheumatol 2018 Jul-Aug; 36 Suppl 113: 3-23[2]Hao Y, Hudson M, Baron M, et al. Arthritis Rheumatol. 2017;69(5):1067-1077.[3]Furue M, Mitoma C, Mitoma H, et al. Immunol Res. 2017 Aug; 65: 790-7.[4]Nihtyanova SI, Schreiber BE, Ong VH, et al. Arthritis Rheumatol. 2014 Jun; 66: 1625-35.Disclosure of Interests:None declared.

Comparative characteristics of the clinical and laboratory features of the primary Sjogren’s syndrome associated with anticentromere antibodies and the “classic” subtype of the disease

Objective: to compare clinical and laboratory manifestations in 2 groups of patients with primary Sjogren’s syndrome (pSS): with and without anticentromere antibodies (ACA); compare the incidence, clinical and laboratory characteristics of lymphomas in these two groups.Materials and methods. We examined 119 patients with ACA-positive pSS (pSS-ACA+). pSS was diagnosed based on Russian 2001 criteria, systemic sclerosis (SSc) – criteria ACR/EULAR 2013. To diagnose liver diseases, the level of transaminases, alkaline phosphatase and antimitochondrial antibodies (AMA) was determined, as well as liver biopsy. The diagnosis of primary biliary cholangitis (PBC) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. Lymphomas were diagnosed according to histological, immunohistochemical and molecular studies of affected organs biopsies, according to the classification of the World Health Organization. A combination of pSS and SSc was diagnosed in 37 patients, and they were excluded from further analysis. We compared clinical and laboratory features in patients with pSS-ACA+ (n=82) and ACA-negative pSS (pSS-ACA–, n=64) and characterized lymphomas in the pSS-ACA+ (n = 14) and pSS-ACA– (n=10) groups.Results and discussion. In patients with pSS-ACA+, a later age of disease onset was revealed, the duration of the disease before lymphoma development did not differ. In patients with pSS-ACA+, we found a lower frequency of rheumatoid factor (RF), antibodies to Ro (anti-Ro) and La (anti-La), decreased C3-complement, hypergammaglobulinemia, increased IgG concentration, CRP, increased ESR, leukopenia and anemia. 51.2% of patients with pSS-ACA+ were seronegative for anti-Ro, anti-La and RF. Patients with pSS-ACA+ had a higher frequency of AMA and elevated IgM. The incidence of cryoglobulinemia and paraproteinemia did not differ. The frequency of recurrent parotitis in pSS-ACA+ was significantly lower, there were no differences in the frequency and severity of other signs of salivary and lacrimal gland damage. PBC and epitheliitis of the biliary ducts in patients with pSS-ACA+ were detected significantly more often. Damage to the peripheral nervous system, lungs, hypergammaglobulinemic purpura, arthralgia and autoimmune thyroiditis were significantly more often detected in the group of patients with pSS-ACA–. In the pSS-ACA+ group, Raynaud’s phenomenon was significantly more frequent, mainly with scleroderma-type capillaroscopic abnormalities. There was no difference in the frequency of other signs characteristic of SSc. MALT lymphomas were diagnosed in the study groups with the same frequency. Patients with lymphomas in the pSS-ACA+ group were characterized by significantly higher laboratory activity. All patients with lymphomas in both groups showed persistent parotid salivary gland enlargement. Lymphomas in both groups developed in patients with late stage salivary and lacrimal gland damage, systemic manifestations of pSS in both groups were rare.Conclusion. pSS-ACA+ is an independent subtype of pSS, which has a number of significant clinical and laboratory differences from the “classic” variant of the disease. ACA in pSS are associated with a low frequency of anti-Ro, anti-La, and RF, as well as an increased risk of PBC and limited SSc. MALT lymphomas in the pSS-ACA+ and pSS-ACA– groups developed with the same frequency and were associated with the progression of glandular damage, regardless of the presence of systemic manifestations.

Thoracic lymphadenopathy as possible predictor of the onset of interstitial lung disease in systemic sclerosis patients without lung involvement at baseline visit: A retrospective analysis

Objective: To evaluate clinical, laboratory, or radiographic predictors of the onset of interstitial lung disease in systemic sclerosis. Methods: Sixty-five out of 220 systemic sclerosis outpatients, without interstitial lung disease at baseline and with ⩾3 chest high resolution computed tomography scans during follow-up were recruited. Thoracic lymphadenopathy and interstitial lung disease were assessed by chest high resolution computed tomography. Hazard ratio (95% confidence interval) of interstitial lung disease occurrence was assessed by Cox regression models, adjusting patient’s demographics and disease characteristics. Sensitivity, specificity, and accuracy of the interstitial lung disease predictors were evaluated by receiver operating characteristic analysis. Results: The development of interstitial lung disease was observed in 44/65 (68%) patients. Thoracic lymphadenopathies was detected in 40/65 (61%) patients, of whom 36 (82%) developed interstitial lung disease, but only four patients with thoracic lymphadenopathies did not develop ILD at last visit of follow-up (19%) (p = 0.0001). Adjusted hazard ratio of systemic sclerosis-interstitial lung disease onset was 5.8 (95% confidence interval, 2.0–16.5) for thoracic lymphadenopathy, which preceded by 108 ± 98 weeks the systemic sclerosis-interstitial lung disease detection. Thoracic lymphadenopathy had 84% specificity, 81% sensitivity, and 0.82 accuracy to predict interstitial lung disease. In particular, anticentromere antibodies or limited cutaneous subset of systemic sclerosis patients with thoracic lymphadenopathy showed earlier interstitial lung disease onset than those without lymphadenopathy. In addition, patients who developed interstitial lung disease had higher frequency of anti-Scl-70 (57% vs 19%; p = 0.009) and diffuse cutaneous subset (29% vs 3%; p = 0.02) than those who did not. Conclusions: Thoracic lymphadenopathy was the strongest independent predictor of systemic sclerosis-interstitial lung disease, mostly in anticentromere antibodies and limited cutaneous subset of systemic sclerosis patients. Further prospective studies are needed to confirm our preliminary data and to understand whether thoracic lymphadenopathies may have a pathogenetic role in interstitial lung disease development.

Overall mortality in combined pulmonary fibrosis and emphysema related to systemic sclerosis

ObjectivesThis multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease—ILD, emphysema or neither).MethodsChest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ² test assessed the differences between groups. P<0.05 was considered statistically significant.ResultsWe enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6).ConclusionsCPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD.