Rheumatoid Arthritis: Brito-Zerón P

Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA. · Laboratory of Autoimmune Diseases Josep Font, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Spain. · Best Pract Res Clin Rheumatol. · Pubmed #19028367 No free full text.

Abstract: Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (www.biogeas.org). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.

Brito-Zerón P, Ramos-Casals M. · Laboratorio de Enfermedades Autoinmunes Josep Font, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, España. · Med Clin (Barc). · Pubmed #18261383 No free full text.

Abstract: The natural history of primary Sjögren's syndrome has been little studied. Some studies agree that, although it is not a benign disease, it is characterized by a steady evolution of the predominant symptoms (sicca and general manifestations). However, there are 2 main exceptions to this chronic course: the development of vasculitic manifestations, and the high incidence of lymphomas, both processes being related to the excess of mortality in patients with primary Sjögren's syndrome. Recent studies have prospectively analyzed the outcome of this disease in a large series of patients and identified those factors present at diagnosis prospectively associated with an adverse outcome. The main prognostic factors identified are severe involvement of the exocrine glands, vasculitis, hypocomplementemia and cryoglobulins at diagnosis. These features identify a specific subset of patients diagnosed with primary Sjögren's syndrome in whom a closer follow-up, and probably an earlier and more robust therapeutic management, should be mandatory.

Ramos-Casals M, Brito-Zerón P, Font J. · Servei de Malalties Autoimmunes, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain. · Clin Rev Allergy Immunol. · Pubmed #17992594 No free full text.

Abstract: Sjögren's syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes because of functional impairment of the salivary and lacrimal glands. The histological hallmark is a focal lymphocytic infiltration of the exocrine glands, and the spectrum of the disease extends from an organ-specific autoimmune disease (autoimmune exocrinopathy) to a systemic process with diverse extraglandular manifestations. In the absence of an associated systemic autoimmune disease, patients with this condition are classified as having primary SS. The differential diagnosis includes processes that specifically involve the exocrine glands. On the one hand, some chronic viral infections may induce lymphocytic infiltration of the exocrine glands, in some cases indistinguishable from that observed in primary SS. On the other hand, some processes may mimic the clinical picture of SS through nonlymphocytic infiltration of the exocrine glands. This review focuses on these two groups of diseases that mimic SS (infections and infiltrating processes).

Ramos-Casals M, Brito-Zerón P. · Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain. · Rheumatology (Oxford). · Pubmed #17586555 No free full text.

Abstract: Sjögren's syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes. SS primarily affects white perimenopausal women, with an incidence of 4-5 cases per 100 000. Recent studies have analysed new therapeutic approaches, focusing mainly on the use of biological agents. B-cell targeted therapies seem to be the most promising agents in primary SS, especially rituximab, which has been used in more than 50 reported cases. Other promising B-cell targeted therapies include epratuzumab and belimumab, while T-cell targeted agents (efalizumab, abatacept, alefacept) should currently be considered as possible future options. In the near future, biological agents will play key roles in the treatment of severe involvement, broadening the therapeutic options in primary SS and offering a more optimistic point of view of the treatment of this disease, which, at present, is often considered to lack adequate specific therapy. However, the possible risks and benefits of using these agents should be carefully balanced, and a reasonable assessment of the risk of serious adverse events versus the benefits of treatment should be made. The use of biological agents targeting molecules and receptors involved in the aetiopathogenesis of primary SS opens a new era in the therapeutic management of patients with primary SS.

Ramos-Casals M, Brito-Zerón P, Font J. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. · Semin Arthritis Rheum. · Pubmed #16996579 No free full text.

Abstract: OBJECTIVE: To analyze the main diagnostic problems caused by the overlap between Sjögren's syndrome (SS) and other systemic autoimmune diseases (SAD). METHODS: We performed a MEDLINE search for articles published between January 1966 and December 2005 that specifically analyzed the overlap between SS and other SAD. We identified a list of diagnostic problems in patients with primary SS who had features considered typical of other SAD. RESULTS: Clinically, the main diagnostic problems occur in SS patients presenting with arthritis, Raynaud phenomenon, cutaneous features (subacute cutaneous lupus erythematosus, purpura, livedo reticularis, erythema nodosum), interstitial pulmonary disease, and cytopenias (leukopenia, thrombocytopenia). Immunologically, antiphospholipid antibodies (aPL) and antineutrophil cytoplasmic antibodies (ANCA) are the most frequent atypical autoantibodies found in primary SS, with a prevalence ranging between 10 and 20%. However, coexisting antiphospholipid syndrome or systemic vasculitis is only detected in around 10% of SS patients with aPL or ANCA. Anti-DNA and anticentromere antibodies have a prevalence of 5 to 10%, but are more closely related to clinical and/or laboratory data suggestive of associated systemic lupus erythematosus and limited systemic sclerosis, respectively, leading to the fulfillment of classification criteria for these diseases in more than 25% of cases. CONCLUSION: The wide variety of clinical and immunological manifestations of patients with primary SS often overlap with other SAD, making the differentiation between primary SS, SS associated with SAD, and SS-like presentations of some other SAD difficult. This overlap suggests that the current classification criteria are useful in differentiating between autoimmune and non-autoimmune processes but fail to clearly differentiate among SAD.

Ramos-Casals M, López-Guillermo A, Brito-Zerón P, Cervera R, Font J, Anonymous00425. · No affiliation provided · Lupus. · Pubmed #15645755 No free full text.

This publication has no abstract.

Ramos-Casals M, Brito-Zerón P, García-Carrasco M, Font J. · Department of Autoimmune Diseases, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Hospital Clínic, Barcelona, Spain. · Medicine (Baltimore). · Pubmed #15028962 No free full text.

Abstract: We present 5 new cases of coexisting sarcoidosis and Sjögren syndrome (SS) and review the literature for additional cases in order to analyze the clinical, immunologic, and histologic characteristics that may help physicians differentiate the mimicry of SS by sarcoidosis from a true coexistence of both autoimmune diseases. We considered the coexistence of sarcoidosis with SS to be when patients presented specific histologic patterns of both diseases, simultaneously or at different times.Fifty-nine patients were included in the analysis (54 identified in the literature search plus our 5 unpublished cases): 49 (83%) patients were female and 10 (17%) were male, with a mean age at diagnosis of 50 years. According to the histopathologic examination of the exocrine glands performed in 53 cases, we defined coexistence of sarcoidosis and SS in 28 cases, while in the remaining 25 patients, sarcoidosis mimicked SS. Clues to identifying when sarcoidosis coexists with SS were a higher prevalence of systemic manifestations (arthritis and uveitis) and positive immunologic parameters (antinuclear antibodies, rheumatoid factor, and anti-Ro/SS-A), as well as the existence of a focal sialadenitis (Chisholm-Mason score grades III-IV, with a CD4+ lymphocytic infiltration) in the salivary gland biopsy. In patients first diagnosed with primary SS, the appearance of some clinical features such as hilar adenopathies, uveitis, or hypercalcemia leads to the diagnosis of coexisting sarcoidosis. A careful application of the new American-European consensus criteria had a sensitivity of 93% and a specificity of 92% in identifying when SS coexists with sarcoidosis.In conclusion, the association of sarcoidosis with SS leads to a true coexistence of both diseases in more than half the patients described in the literature, while in the remaining patients, sarcoidosis mimics SS. In light of these results, sarcoidosis should not be considered as an exclusion criterion for the diagnosis of SS, and in patients with a suspected overlap of the two diseases, application of the new American-European consensus criteria for diagnosis of SS should be mandatory.

Ramos-Casals M, Muñoz S, Medina F, Jara LJ, Rosas J, Calvo-Alen J, Brito-Zerón P, Forns X, Sánchez-Tapias JM, Anonymous00071. · Laboratory of Autoimmune Diseases Josep Font, Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036-Barcelona, Spain. · J Rheumatol. · Pubmed #19369460 No free full text.

Abstract: OBJECTIVE: To describe the clinical and immunologic characteristics of a large series of patients with systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus (HCV) infection. METHODS: The HISPAMEC Registry is a multicenter international study group dedicated to collecting data on patients diagnosed with SAD with serological evidence of chronic HCV infection. The information sources are cases reported by physicians of the HISPAMEC Study Group and periodic surveillance of reported cases by a Medline search updated up to December 31, 2007. RESULTS: One thousand twenty HCV patients with SAD were included in the registry. Patients were reported from Southern Europe (60%), North America (15%), Asia (14%), Northern Europe (9%), South America (1%), and Australia (1%). Countries reporting the most cases were Spain (236 cases), France (222 cases), Italy (144 cases), USA (120 cases), and Japan (95 cases). The most frequently reported SAD were Sjögren's syndrome (SS; 483 cases), rheumatoid arthritis (RA; 150 cases), systemic lupus erythematosus (SLE; 129 cases), polyarteritis nodosa (78 cases), antiphospholipid syndrome (59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases). Twenty patients had 2 or more SAD. Epidemiological data were available in 677 cases. Four hundred eighty-seven (72%) patients were female and 186 (28%) male, with a mean age of 49.5 +/- 1.0 years at SAD diagnosis and 50.5 +/- 1.1 years at diagnosis of HCV infection. The main immunologic features were antinuclear antibody (ANA) in 61% of patients, rheumatoid factor (RF) in 57%, hypocomplementemia in 52%, and cryoglobulins in 52%. The main differential aspect between primary and HCV-related SAD was the predominance of cryoglobulinemic-related markers (cryoglobulins, RF, hypocomplementemia) over specific SAD-related markers (anti-ENA antibodies, anti-dsDNA, anti-cyclic citrullinated peptide) in patients with HCV. CONCLUSION: In the selected cohort, the SAD most commonly reported in association with chronic HCV infection were SS (nearly half the cases), RA and SLE. Nearly two thirds of SAD-HCV cases were reported from the Mediterranean area. In these patients, ANA, RF and cryoglobulins are the predominant immunological features.

Ramos-Casals M, Brito-Zerón P, Soria N, Nardi N, Vargas A, Muñoz S, Bové A, Suárez B, Lozano F. · Department of Autoimmune Diseases, Laboratory of Autoimmune Diseases Josep Font, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. · Rheumatology (Oxford). · Pubmed #19056797 No free full text.

Abstract: OBJECTIVE: To investigate the association of mannose-binding lectin (MBL)-low genotypes with the clinical and immunological expression of primary SS. METHODS: Eighty-one patients with primary SS who fulfilled the 2002 classification criteria were included in the study. MBL2 polymorphisms were investigated by sequence-based DNA typing of the promoter and exon 1. Genotypes 0/0, 0/XA or XA/XA were considered as MBL-low and XA/A, A/0 and A/A as MBL-sufficient. Control groups included 46 patients who exclusively fulfilled the 1993 SS criteria, 114 SLE patients and 104 healthy individuals. RESULTS: Twelve (15%) SS patients had MBL-low genotypes, of whom six (7%) had genotype 0/XA, five (6%) had genotype 0/0 and one (1%) had genotype XA/XA. A higher prevalence of the XA/A genotype (32 vs 17%, P = 0.01) was found in primary SS patients in comparison with SLE patients. No patient with primary SS carrying MBL-low genotypes had purpura, glomerulonephritis or neurological involvement (0 vs 29%, P = 0.025). Immunologically, patients carrying MBL-low genotypes had a lower frequency of anti-Ro/SS-A antibodies (17 vs 55%, P = 0.014), anti-La/SS-B antibodies (8 vs 48%, P = 0.009) and low C4/C3 levels (0 vs 32%, P = 0.016). No patient with primary SS carrying the homozygous MBL-deficient genotype 0/0 had anti-Ro/SS-A or anti-La/SS-B antibodies, low C3/C4 levels or circulating cryoglobulins. CONCLUSION: SS patients with MBL-low genotypes have a less pronounced systemic and immunological disease expression in comparison with those carrying MBL-sufficient genotypes. In primary SS, MBL deficiency may represent a protective factor against the development of more aggressive autoimmune damage.

Brito-Zerón P, Soria N, Muñoz S, Bové A, Akasbi M, Belenguer R, Sisó A, Ramos-Casals M. · Laboratory of Autoimmune Diseases Josep Font, Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. · Semin Arthritis Rheum. · Pubmed #18378278 No free full text.

Abstract: OBJECTIVE: To analyze the prevalence of neutropenia in a large cohort of patients with primary Sjögren's syndrome (SS) and its association with clinical and immunological disease expression and adverse outcomes. METHODS: The study cohort included 300 patients diagnosed with primary SS in our department between 1984 and 2002. The outcomes measured after the first laboratory evidence of neutropenia (<2.5 x 10(9)/L) were first hospital admission caused by infection, development of systemic manifestations, neoplasia, and death. RESULTS: Ninety-nine (33%) patients had neutropenia during the follow-up, which was related to neoplasia or drugs in 9 (3%) patients and was considered idiopathic in the remaining 90 (30%). Patients with neutropenia had a lower mean age at diagnosis of SS (51.9 versus 59.4 years, P < 0.001) and a higher prevalence of anti-Ro/La antibodies (53% versus 22%, P < 0.001), rheumatoid factor (49% versus 32%, P = 0.009), and low C4 levels (17% versus 8%, P = 0.044) than those without neutropenia. Patients with neutropenia had a higher incidence of hospital admission caused by infection (24% versus 9%, P = 0.002), especially those with neutropenia <1 x 10(9)/L (50% versus 9%, P = 0.002), and a higher rate of admission (log rank = 0.0023) in comparison with those without neutropenia. Agranulocytosis was found in 7 (2%) patients, predominantly related to neoplasia (5 cases). One (1%) of the 90 patients with SS-related neutropenia developed large granular lymphocyte T-cell leukemia. CONCLUSION: Neutropenia should be considered a relevant hematologic finding of primary SS, due both to its elevated prevalence and to its clinical significance (close association with anti-Ro/La antibodies, coexistence with other cytopenias, and development of severe infections).

Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana D, Bertolaccini L, Cuadrado MJ, Khamashta MA. · Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Hospital Clínic, Barcelona, Spain. · Medicine (Baltimore). · Pubmed #17632266 No free full text.

Abstract: Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy found through a MEDLINE search of articles published between January 1990 and December 2006. We identified 233 cases of autoimmune diseases (vasculitis in 113, lupus in 92, interstitial lung diseases in 24, and other diseases in 4) secondary to TNF-targeted therapies in 226 patients. The anti-TNF agents were administered for rheumatoid arthritis (RA) in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. We found 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for systemic lupus erythematosus (SLE), which fell to one-third after discarding preexisting lupus-like features. One hundred thirteen patients developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). Leukocytoclastic vasculitis was the most frequent type of vasculitis, and purpura was the most frequent cutaneous lesion. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Twenty-four cases of interstitial lung disease associated with the use of anti-TNF agents were reported. In these patients, 2 specific characteristics should be highlighted: the poor prognosis in spite of cessation of anti-TNF therapy, and the possible adjuvant role of concomitant methotrexate. In conclusion, the use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, SLE, and interstitial lung disease.

Brito-Zerón P, Ramos-Casals M, Bove A, Sentis J, Font J. · Department of Autoimmune Diseases, School of Medicine, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain. · Rheumatology (Oxford). · Pubmed #17569749 links to  free full text

Abstract: OBJECTIVE: To identify features present at diagnosis that were prospectively associated with adverse outcomes in a large cohort of patients with primary Sjögren's syndrome (SS). METHODS: Two hundred and sixty-six patients diagnosed with primary SS in our department between 1984 and 2002 were consecutively included and followed up. Outcomes measured were vasculitis, B-cell lymphoma and death. Cox regression analysis was used to evaluate the effect of variables at diagnosis on outcomes. RESULTS: Twenty-five (9%) patients developed vasculitis. Multivariate analysis identified parotid scintigraphy grades III or IV (HR 3.55, P = 0.05) and C4 levels <0.11 g/l (HR 8.26, P < 0.001) as variables predicting the development of vasculitis. Nine (3%) patients developed B-cell lymphoma. Multivariate analysis identified C3 levels <0.82 g/l (HR 7.54, P = 0.016) as a predictive factor of lymphoma development. Twenty-five (9%) patients died during follow-up. Systemic involvement (HR 4.51, P = 0.022), vasculitis (HR 4.58, P = 0.042), C4 levels <0.11 g/l (HR 5.47, P = 0.027) and cryoglobulins (HR 4.58, P = 0.013) were independently associated with death. The presence of at least two of the above-mentioned predictive factors (parotid scintigraphy, vasculitis, hypocomplementaemia and cryoglobulinaemia) was associated with a lower survival in comparison with patients with no factor (log rank and Breslow tests <0.001). CONCLUSION: The main prognostic factors for an adverse outcome identified in our cohort of patients with primary SS were vasculitis, severe involvement in parotid scintigraphy, hypocomplementaemia and/or cryoglobulins at diagnosis. Patients with at least two of these factors need a closer follow-up.

Ramos-Casals M, Brito-Zerón P, Sisó A, Vargas A, Ros E, Bove A, Belenguer R, Plaza J, Benavent J, Font J. · Department of Autoimmune Diseases and the Lipid Unit, School of Medicine, University of Barcelona, Institut d'Investigacions BiomEdiques August Pi i Sunyer, Hospital Clínic, Spain. · J Rheumatol. · Pubmed #17309127 No free full text.

Abstract: OBJECTIVE: To analyze the prevalence and clinical significance of associated metabolic alterations [dyslipidemia, diabetes mellitus (DM), and hyperuricemia] in a large series of unselected patients with primary Sjögren's syndrome (SS). METHODS: We analyzed 254 consecutive patients with primary SS who had a complete analytical followup study for at least 5 consecutive years. The control group consisted of 254 age and sex-matched patients without systemic autoimmune diseases consecutively followed during the same period in a primary care center. RESULTS: In comparison with controls, patients with primary SS showed a higher frequency of dyslipidemia (47% vs 33%; p = 0.002), DM (28% vs 18%; p = 0.006), and hyperuricemia (9% vs 4%; p = 0.007). The mean age at SS diagnosis was 10 years greater in patients with DM (p < 0.001) and hyperuricemia (p = 0.009). Hypercholesterolemia was associated with a lower frequency of immunological markers such as anti-Ro/SSA antibodies (p = 0.001), anti-La/SSB antibodies (p = 0.005), low C3 (p = 0.047), and low C4 levels (p = 0.030), while hypertriglyceridemia and DM were associated with a higher prevalence of extraglandular features, especially renal, liver, and vasculitic involvement. A higher prevalence of DM was found in patients treated with corticosteroids (40% vs 19%; p = 0.001). CONCLUSION: Patients with primary SS showed a higher prevalence of associated dyslipidemia, DM, and hyperuricemia in comparison with an age and sex-matched control group. Metabolic alterations were associated with a differentiated pattern of clinical and immunological SS expression, but not with SS-related therapies (except for the higher frequency of DM observed in patients treated with corticosteroids).

Ramos-Casals M, Sánchez-Tapias JM, Parés A, Forns X, Brito-Zerón P, Nardi N, Vazquez P, Vélez D, Arias I, Bové A, Plaza J, Rodés J, Font J. · Department of Autoimmune Diseases and Hepatology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS, School of Medicine, University of Barcelona, Barcelona, Spain. · J Rheumatol. · Pubmed #16881116 No free full text.

Abstract: OBJECTIVE: To analyze the prevalence and clinical significance of liver involvement in patients with Sjögren's syndrome (SS), focusing on the characterization and differentiation of autoimmune versus chronic viral liver disease. METHODS: We investigated liver involvement (clinical signs, analytical data, chronic viral infections, and autoantibodies) in 475 consecutive patients with SS. All patients fulfilled 4 or more of the 1993 European Community Study Group criteria for SS. RESULTS: Liver involvement was detected in 129 (27%) patients. After ruling out chronic illnesses or use of hepatotoxic drugs, the main etiologies were chronic viral liver disease in 64 (13%) cases [chronic hepatitis C virus (HCV) infection in 63 and HBV infection in one] and autoimmune liver diseases in 24 (5%; primary biliary cirrhosis in 16 patients and type-1 autoimmune hepatitis in 8). The analytical liver profile was not useful in differentiating between viral and autoimmune liver disease. In contrast, patients with SS and autoimmune liver disease presented higher mean values of erythrocyte sedimentation rate (p = 0.044), circulating gammaglobulins (p = 0.007), and a higher prevalence of antinuclear antibodies (p < 0.001), antimitochondrial antibodies (p < 0.001), anti-smooth muscle antibodies (p = 0.026), anti-Ro/SSA (p < 0.001), and anti-La/SSB (p = 0.01), while patients with chronic viral liver disease had a higher frequency of cryoglobulinemia (p < 0.001) and hypocomplementemia (p < 0.001). CONCLUSION: Chronic viral liver disease (associated overwhelmingly with HCV) was the main cause of liver involvement in our patients with SS, with a prevalence of 13%, nearly 3-fold greater than that observed for autoimmune liver involvement. The immunological pattern played a key role in the differentiation of viral (predominance of cryoglobulins and low complement levels) and autoimmune (higher frequency of autoantibodies) liver involvement.

Brito-Zerón P, Ramos-Casals M, Nardi N, Font J. · No affiliation provided · Med Clin (Barc). · Pubmed #16759558 No free full text.

This publication has no abstract.

Ramos-Casals M, Nardi N, Brito-Zerón P, Aguiló S, Gil V, Delgado G, Bové A, Font J. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, Barcelona, Spain. · Semin Arthritis Rheum. · Pubmed #16616154 No free full text.

Abstract: OBJECTIVES: To analyze the clinical characteristics, follow-up, and fulfillment of classification criteria for other systemic autoimmune diseases (SAD) in patients with primary Sjögren syndrome (SS) and atypical autoantibodies. METHODS: We studied 402 patients diagnosed with primary SS seen consecutively in our Department since 1994. We considered anti-DNA, anti-Sm, anti-RNP, anti-topoisomerase1/Scl70, anticentromere (ACA), anti-Jo1, anti-neutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibodies (aPL), and lupus anticoagulant as atypical autoantibodies. The patients were prospectively followed after inclusion into the protocol, focusing on the development of features that might lead to the fulfillment of classification criteria for additional SAD. As a control group, we selected an age-sex-matched subset of patients with primary SS without atypical autoantibodies. RESULTS: Eighty-two (20%) patients showed atypical autoantibodies (36 had aPL, 21 anti-DNA, 13 ANCA, 10 anti-RNP, 8 ACA, 6 anti-Sm, 2 anti-Scl70, and 1 anti-Jo-1 antibodies). There were 77 (94%) women and 5 (6%) men, with a mean age of 57 years. Patients with atypical autoantibodies had no statistical differences in the prevalence of the main sicca features, extraglandular manifestations (except for a higher prevalence of Raynaud's phenomenon, 28% versus 7%, P=0.001), immunological markers, and in the fulfillment of the 2002 classification criteria, compared with the control group. After a follow-up of 534 patient-years, 13 (16%) of the 82 patients with atypical autoantibodies developed an additional SAD (systemic lupus erythematosus in 5 cases, antiphospholipid syndrome in 4, limited scleroderma in 3, and microscopic polyangiitis in 1) compared with none in the control group (P<0.001). CONCLUSIONS: This study shows an immunological overlap (defined by the presence of autoantibodies considered typical of other SAD) in 20% of our patients with primary SS. However, the clinical significance of these atypical autoantibodies varies widely depending on the autoantibodies detected, with a broad spectrum of prevalence and clinical patterns of disease expression, and a specific predilection for association with some SAD in preference to others.

Nardi N, Brito-Zerón P, Ramos-Casals M, Aguiló S, Cervera R, Ingelmo M, Font J. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, C/Villaroel 170, 08036 Barcelona, Spain. · Clin Rheumatol. · Pubmed #16249826 No free full text.

Abstract: The aim of this study was to analyze the prevalence and clinical significance of circulating auto-antibodies against nuclear and non-nuclear antigens in a large cohort of Spanish patients with primary Sjögren's syndrome (SS). We studied 335 patients diagnosed with primary SS seen consecutively in our department since 1994 and tested for anti-nuclear antibodies (ANA), anti-Ro/SS-A, anti-La/SS-B, anti-Sm, anti-ribonucleoprotein (anti-RNP), anti-smooth muscle antibodies (anti-SMA), anti-parietal cell antibodies (anti-PCA), anti-liver-kidney microsome type-1 (anti-LKM-1) antibodies and anti-mitochondrial antibodies (AMA). ANA were detected in 278 (83%) patients. The association of positive ANA with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies reached statistical significance at a titre of ANA >1/80 (p<0.001), while the presence of anti-Sm and anti-RNP was associated with positive ANA at a titre > or =1/320 (p=0.037 for Sm and p=0.016 for RNP). ANA titres correlated with the number of positive antibodies against specific nuclear antigens (p<0.001) but not with the number of positive antibodies against non-nuclear antigens. We found positive anti-Ro/SS-A antibodies in 111 (33%) patients, anti-La/SS-B in 78 (23%), anti-RNP in 8 (2%) and anti-Sm in 4 (1%). Anti-SMA antibodies were detected in 208 (62%) patients, with no significant associations with clinical or analytical SS features, while anti-PCA antibodies were found in 90 (27%) patients and were associated with a higher prevalence of thyroiditis and liver involvement. AMA were detected in 28 (8%) patients, although only 14 presented clinical and/or analytical evidence of liver involvement. No patient presented anti-LKM antibodies. ANA play a central role in the immunological expression of primary SS, due to their frequency and close association with the underlying presence of one or more anti-ENA antibodies. Positivity for antibodies against non-nuclear antigens such as anti-PCA and AMA suggests an association with some organ-specific autoimmune diseases (thyroiditis and primary biliary cirrhosis), while the presence of anti-SMA, in spite of their high prevalence, has no clinical significance in primary SS.

Belenguer R, Ramos-Casals M, Brito-Zerón P, del Pino J, Sentís J, Aguiló S, Font J. · Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Facultad de Medicina, Universitat de Barcelona, Barcelona, Spain. · Clin Exp Rheumatol. · Pubmed #15971423 No free full text.

Abstract: OBJECTIVE: To evaluate health-related quality of life (HR-QoL) in patients with primary SS patients using the SF-36 questionnaire and to analyse the association between the main clinical features and the SF-36 scales. METHODS: We studied 110 patients (105 women and 5 men, mean age of 56 years) with primary SS seen consecutively in the outpatient clinic of our Department. We used the population-based reference values for the Spanish version of the SF-36 health survey as control values for a healthy population. RESULTS: Comparison between patients with primary SS and the control population showed lower scores in all SF-36 scales (p < 0.001). Analysis of the SF-36 scales by gender showed a significant correlation between age and the values for physical functioning (p = 0.013) and bodily pain (p = 0.016) scores. No significant differences in SF-36 scores were found when comparing patients according to the presence or absence of sicca features. Women with vaginal dryness had lower scores for social functioning (61.9 vs. 74.4) and general health (37.2 vs. 44.7) than those without, although the differences were not statistically significant (p > 0.05). Patients with extraglandular involvement had lower scores for the vitality scale (40.8 vs. 54.5 p = 0.007), social functioning (67.0 vs. 79.8, p = 0.010), bodily pain (49.5 vs. 62.5, p = 0.018) and general health (38.6 vs. 49.4 p = 0.001) than those without. CONCLUSION: Patients with primary SS had clearly lower HR-QoL scores than the healthy population; with significantly lower scores in all SF-36 scales and in both summary measures. We identified several epidemiological and clinical SS features related to these lower SF-36 scores. Age at protocol correlated with physical functioning and bodily pain. Vaginal dryness was the sicca feature that most affected the HR-QoL of female SS patients, and a poor HR-QoL was also observed in those patients with a systemic expression of the disease, with pulmonary involvement being the extraglandular manifestation that most contributed to a poor HR-QoL. Our results highlight the importance of earlier diagnostic and therapeutic management of patients with primary SS, which, together with a close follow-up, may contribute to a significant improvement in their HR-QoL.

Brito-Zerón P, Ramos-Casals M, Nardi N, Cervera R, Yagüe J, Ingelmo M, Font J. · Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, Facultad de Medicina, Universitat de Barcelona, Barcelona, Spain. · Medicine (Baltimore). · Pubmed #15758838 No free full text.

Abstract: We conducted the current study to analyze the prevalence and clinical significance of circulating monoclonal immunoglobulins in patients with Sjögren syndrome (SS), focusing on the association with extraglandular features, immunologic markers, hematologic neoplasia, and hepatitis C virus (HCV) infection. We performed serum immunoelectrophoresis in 200 patients with primary SS and 37 patients with HCV-related SS. All patients fulfilled 4 or more of the 1993 European classification criteria for SS.Of the 200 patients with primary SS, 35 (18%) presented circulating monoclonal immunoglobulins. The monoclonal bands identified were 20 IgG (13 kappa, 7 lambda), 10 IgM (5 kappa, 5 lambda), 2 IgAkappa, and 3 free circulating light chains. Of the 37 SS-HCV patients, 16 (43%) had circulating monoclonal immunoglobulins. The monoclonal bands identified were 10 IgMkappa, 5 IgGlambda, and 1 free light lambda chain. Compared with primary SS patients, SS-HCV patients presented a higher frequency of monoclonal immunoglobulins (43% vs 18%, p = 0.001), with monoclonal IgMkappa being the most frequent monoclonal band. Six (12%) of the 51 SS patients with circulating monoclonal immunoglobulins presented hematologic neoplasia, compared with 3 (1.6%) of those without monoclonal immunoglobulins (p = 0.004; odds ratio = 8.13; 95% confidence intervals, 1.64-51.54). In 2 of the 6 patients with monoclonal immunoglobulins and lymphoproliferative disorders, a change of the monoclonal component was detected in previous immunoelectrophoresis determinations before the development of hematologic neoplasia.Circulating monoclonal immunoglobulins were detected in nearly 20% of patients with primary SS, with monoclonal IgG being the most frequent type of immunoglobulin detected. In SS-HCV patients, the prevalence of monoclonal immunoglobulins was higher (43%), with monoclonal IgM being the most frequent type found. SS-HCV patients presented a more restrictive monoclonal expression (limited to either monoclonal IgMkappa or monoclonal IgGlambda) than primary SS patients, who showed all types of heavy and light chains.

Ramos-Casals M, Brito-Zerón P, Yagüe J, Akasbi M, Bautista R, Ruano M, Claver G, Gil V, Font J. · Department of Autoimmune Diseases, Institut d'Investigacions Biomédiques Augst Pi i Sunyer (IDIBAPS) Hospital Clinic, School of Medicine, Univesity of Barcelona, Spain. · Rheumatology (Oxford). · Pubmed #15381790 links to  free full text

Abstract: OBJECTIVE: To analyse the prevalence and clinical significance of hypocomplementaemia in a large series of patients with primary Sjogren's syndrome (SS), focusing on the association of low complement levels with clinical manifestations, immunological features, lymphoproliferative disorders and mortality. METHODS: Complement determinations (C3 and C4 levels, CH50 activity) were made in 336 consecutive patients with primary SS (313 women and 23 men, mean age 58.5 yr). We also analysed complement levels in 46 patients with SS associated with hepatitis C virus (HCV) infection and 184 with HCV-related cryoglobulinaemia as control groups. RESULTS: Hypocomplementaemia was detected in 81 (24%) of patients with primary SS, low CH50 being detected in 51 (15%), low C3 values in 42 (12%) and low C4 values in 39 (12%). In the multivariate analysis, patients with low C4 levels showed a higher prevalence of peripheral neuropathy, cutaneous vasculitis, RF, cryoglobulins and lymphoma compared with those with normal C4 levels. The analysis of the 218 SS patients followed prospectively since 1994 showed a lower probability of survival in patients with hypocomplementaemia (with low C3, C4 or CH50 levels) at protocol entry. SS-HCV patients presented a higher frequency of hypocomplementaemia than patients with primary SS (76 vs 24%, P<0.001); nine (20%) of these patients had persistent, unquantifiable complement levels. CONCLUSION: Hypocomplementaemia is closely associated with systemic expression and adverse outcomes (lymphoma development and death) in patients with primary SS. Our results support the inclusion of complement determination at diagnosis as a predictor of the outcome of patients with primary SS and its routine determination in the clinical follow-up.