Coexistence of immune-mediated diseases in sarcoidosis. Frequency and clinical significance in 1737 patients.

OBJECTIVE: To analyze whether immune-mediated diseases (IMDs) occurs in sarcoidosis more commonly than expected in the general population, and how concomitant IMDs influence the clinical presentation of the disease. METHODS: We searched for coexisting IMDs in patients included in the SARCOGEAS-cohort, a multicenter nationwide database of consecutive patients diagnosed according to the ATS/ESC/WASOG criteria. Comparisons were made considering the presence or absence of IMD clustering, and odds ratios (OR) and their 95% confidence intervals (CI) were calculated as the ratio of observed cases of every IMD in the sarcoidosis cohort to the observed cases in the general population. RESULTS: Among 1737 patients with sarcoidosis, 283 (16%) patients presented at least one associated IMD. These patients were more commonly female (OR: 1.98, 95% CI: 1.49-2.62) and were diagnosed with sarcoidosis at an older age (49.6 vs. 47.5years, P<0.05). The frequency of IMDs in patients with sarcoidosis was nearly 2-fold higher than the frequency observed in the general population (OR: 1.64, 95% CI: 1.44-1.86). Significant associations were identified in 17 individual IMDs. In comparison with the general population, the IMDs with the strongest strength of association with sarcoidosis (OR>5) were common variable immunodeficiency (CVID) (OR: 431.8), familial Mediterranean fever (OR 33.9), primary biliary cholangitis (OR: 16.57), haemolytic anemia (OR: 12.17), autoimmune hepatitis (OR: 9.01), antiphospholipid syndrome (OR: 8.70), immune thrombocytopenia (OR: 8.43), Sjögren syndrome (OR: 6.98), systemic sclerosis (OR: 5.71), ankylosing spondylitis (OR: 5.49), IgA deficiency (OR: 5.07) and psoriatic arthritis (OR: 5.06). Sex-adjusted ORs were considerably higher than crude ORs for eosinophilic digestive disease in women, and for immune thrombocytopenia, systemic sclerosis and autoimmune hepatitis in men. CONCLUSION: We found coexisting IMDs in 1 out of 6 patients with sarcoidosis. The strongest associations were found for immunodeficiencies and some systemic, rheumatic, hepatic and hematological autoimmune diseases.

Autoimmune diseases induced by biological agents. A review of 12,731 cases (BIOGEAS Registry).

INTRODUCTION: Biological drugs are therapies designed to target a specific molecule of the immune system that have been linked with the development of autoimmune diseases. Areas covered: The BIOGEAS Registry currently collects information about nearly 13,000 reported cases of autoimmune diseases developed in patients exposed to biologics, including more than 50 different systemic and organ-specific autoimmune disorders, of which psoriasis (n=6375), inflammatory bowel disease (n=845), demyelinating CNS disease (n=803), interstitial lung disease (n=519) and lupus (n=369) were the most frequently reported. The main biologics involved were anti-TNF agents in 9133 cases (adalimumab in 4154, infliximab in 3078 and etanercept in 1681), immune checkpoint inhibitors in 913 (ipilimumab in 524 and nivolumab in 225), B-cell targeted therapies in 741 (rituximab in 678), and growth factor inhibitors in 549 cases (bevacizumab in 544). Even though targeting a particular immune molecule may be associated with an excellent clinical response in most patients, an unexpected autoimmune disease may arise in around 8 out of 10,000 exposed patients. Expert opinion: Following the increased use of biologics, the number and diversity of induced autoimmune diseases is increasing exponentially. Management of these disorders will be an increasing clinical challenge in the daily practice in the next years.

Infection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies.

INTRODUCTION: Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) are characterized by a wide range of etiologies, symptoms, and outcomes, but have a common etiopathogenic pathway leading to organ damage: an excessive inflammatory response. Biological therapies have been proposed as a therapeutic option for refractory HLH, but have also been related to the development of HLH in severe immunosuppressed patients. OBJECTIVES AND METHODS: The purpose of this study was to analyze the clinical characteristics and outcomes of adult patients who developed HLH after receiving biological therapies. RESULTS: We identified 30 patients (29 from the PubMed search and one unpublished case), including 19 women and 11 men, with a mean age of 46.5 years. Underlying diseases consisted of rheumatologic/autoimmune diseases in 24 patients and hematological neoplasia in the remaining 6. Biological agents received before the development of HLH were mainly anti-TNF agents (n = 19). Search for microorganisms confirmed systemic infection in 20 (67%) patients, including Mycobacterium tuberculosis (n = 5), cytomegalovirus (CMV) (n = 4), Epstein-Barr virus (EBV) (n = 3), Histoplasma capsulatum (n = 3), Escherichia coli (n = 2), Staphylococcus aureus, Leishmania amastigotes and Brucella melitensis (n = 1, respectively); viral infections were mainly reported in inflammatory bowel disease (IBD) patients. Patients with infections had more frequently received previous immunosuppressive therapies (p = 0.036) and had lower leukocyte counts (p = 0.020) in comparison with patients without associated infections. The outcome was described in 29 patients. After a mean follow-up of 6.3 months, 8 patients died (28%) and 6 had received anti-TNF agents. There was a high mortality rate in patients aged >65 years and those with tuberculosis (62% and 60%, respectively). CONCLUSIONS: In patients receiving biological therapies who develop HLH, searching for a concomitant infectious process is mandatory, and specific surveillance for EBV/CMV infections (in patients with IBD) and for bacteria, including mycobacteria (in elderly patients receiving anti-TNF therapy), is recommended.

Etiopathogenic role of surfactant protein d in the clinical and immunological expression of primary Sjögren syndrome.

OBJECTIVE: To analyze the etiopathogenic role of genetic polymorphisms and serum levels of surfactant protein-D (SP-D) in primary Sjögren syndrome (pSS). METHODS: We analyzed 210 consecutive patients with pSS. SFTPD genotyping (M11T polymorphism rs721917) was analyzed by sequence-based typing and serum SP-D by ELISA. RESULTS: Thirty-two patients (15%) had the Thr11/Thr11 genotype, 80 (38%) the Met11/Met11 genotype, and 96 (46%) the Met11/Thr11 genotype; 2 patients could not be genotyped. Patients carrying the Thr11/Thr11 genotype had a higher prevalence of renal involvement (13% vs 1% and 4% in comparison with patients carrying the other genotypes, p = 0.014). Serum SP-D levels were analyzed in 119 patients (mean 733.94 ± 49.88 ng/ml). No significant association was found between serum SP-D levels and the SP-D genotypes. Higher mean values of serum SP-D were observed in patients with severe scintigraphic involvement (851.10 ± 685.69 vs 636.07 ± 315.93 ng/ml, p = 0.038), interstitial pulmonary disease (1053.60 ± 852.03 vs 700.36 ± 479.33 ng/ml, p = 0.029), renal involvement (1880.64 ± 1842.79 vs 716.42 ± 488.01 ng/ml, p = 0.002), leukopenia (899.83 ± 661.71 vs 673.13 ± 465.88 ng/ml, p = 0.038), positive anti-Ro/SS-A (927.26 ± 731.29 vs 642.75 ± 377.23 ng/ml, p = 0.006), and positive anti-La/SS-B (933.28 ± 689.63 vs 650.41 ± 428.14 ng/ml, p = 0.007), while lower mean values of serum SP-D were observed in patients with bronchiectasis (489.49 vs 788.81 ng/ml, p = 0.019). CONCLUSION: In pSS, high SP-D levels were found in patients with severe glandular involvement, hypergammaglobulinemia, leukopenia, extraglandular manifestations, and positive anti-Ro/La antibodies. The specific association between SP-D levels and pulmonary and renal involvements may have pathophysiological implications.

Biologics-induced autoimmune diseases.

PURPOSE OF REVIEW: Biological agents are therapies designed to target a specific molecular component of the immune system, and are currently licensed for use in autoimmune rheumatic, digestive, dermatological and systemic diseases. However, their use has been linked with the paradoxical development of autoimmune processes. RECENT FINDINGS: More than 1500 cases of autoimmune diseases induced by biologics have been reported, including a wide variety of both systemic (lupus, vasculitis, sarcoidosis, antiphospholipid syndrome and inflammatory myopathies) and organ-specific (interstitial lung disease, uveitis, optic neuritis, peripheral neuropathies, multiple sclerosis, psoriasis, inflammatory bowel disease and autoimmune hepatitis) autoimmune processes. Although these processes are overwhelmingly associated with anti-TNF agents, recent cases have been associated with therapies directed against other cytokines, B or T-cells, illustrating that even though targeting a particular immune molecule may be associated with an excellent clinical response in most patients, an unexpected autoimmune response may arise in some cases. SUMMARY: As the use of biological therapies expands, the number and diversity of induced autoimmune disorders should be expected to increase. Paradoxically, for many of these drug-related processes, current treatment indications include the very biological agent producing the adverse event.

Classification and characterisation of peripheral neuropathies in 102 patients with primary Sjögren's syndrome.

OBJECTIVES: This paper aims to analyse the etiology, characterisation and outcomes of the different types of peripheral neuropathy in patients with primary Sjögren's syndrome (SS) and their association with clinical and immunological disease expression. METHODS: A total of 563 consecutive patients diagnosed with primary SS were evaluated. We retrospectively assessed the results of nerve conduction studies carried out in patients with suspected peripheral nervous system involvement. Peripheral neuropathies were classified into mononeuropathy, mononeuropathy multiplex, polyneuropathy and neuronopathy according to the patterns evidenced by electrodiagnostic studies. RESULTS: Nerve conduction studies were carried out in 158/563 (28%) SS patients. The results were normal in 49 and abnormal in 109 patients, in whom peripheral neuropathy was diagnosed in 102. After excluding patients with neuropathy associated with other diseases and patients with entrapment mononeuropathies, 55/563 (10%) patients were classified as having SS-related peripheral neuropathy, including axonal sensorimotor polyneuropathy (n=24), pure sensory neuronopathy (n=15), mononeuropathy multiplex (n=15) and demyelinating polyradiculoneuropathy (n=1). In spite of therapy, clinical progression measured by the MOHS scale was observed in 12% of patients with axonal polyneuropathy, 13% of those with mononeuropathy multiplex and 47% of those with neuronopathy. Survival was significantly reduced in patients with peripheral neuropathy (especially in those with mononeuropathy multiplex and axonal polyneuropathy) in comparison with the control group (log rank =0.001). CONCLUSIONS: We found a prevalence of SS-related peripheral neuropathy of 10%. Classification of neuropathy according to the clinical presentation and electrodiagnostic tests may be useful in determining the functional outcome, therapeutic response and survival.

Anti-Ro52 antibody testing influences the classification and clinical characterisation of primary Sjögren's syndrome.

OBJECTIVES: To evaluate how determination of antibodies against the Ro52 antigen influences the classification and clinical characterisation of patients with suspected primary Sjögren's syndrome (SS). METHODS: The cohort study included 187 patients who fulfilled at least four of the six 1993 SS classification criteria, including positive autoantibodies (antinuclear antibodies [ANA], rheumatoid factor [RF], anti-Ro/SSA and/or anti-La/SS-B antibodies) as mandatory criterium. Anti-Ro/SSA antibodies were tested by qualitative ELISA using a commercial assay. Anti-Ro52 antibodies were detected by a semiquantitative ELISA. RESULTS: Anti-Ro52 antibodies were found in 70/187 (37%) patients. A significant percentage of patients with anti-Ro/SSA antibodies were negative for anti-Ro52 antibodies (22%), while 13 patients (12%) were negative for anti-Ro/SSA antibodies but positive for anti-Ro52 antibodies, meaning that they fulfilled the 2002 SS criteria while avoiding the need for a salivary biopsy. Higher mean titers of anti-Ro52 antibodies were associated with severe scintigraphic involvement, positive salivary gland biopsy, parotid enlargement, anaemia, leukopenia and RF. A statistical correlation was found between anti-Ro52 titers and age, gammaglobulin levels, RF titers and serum IgA and IgG. Patients with positive anti-Ro/SSA and anti-Ro52 antibodies had a higher frequency of positive salivary gland biopsy, parotid enlargement and positive RF, and higher levels of serum IgG and IgA levels in comparison with patients with positive anti-Ro/SSA but negative anti-Ro52 antibodies. CONCLUSIONS: Anti-Ro52 antibodies were closely associated with the main clinical, histopathological and immunological features of primary SS. Anti-Ro52 autoantibody testing may help to identify a specific subset of SS patients with more aggressive disease, in whom a closer follow-up and earlier, more robust therapeutic management may be necessary.

Monoclonal gammopathy related to Sjögren syndrome: a key marker of disease prognosis and outcomes.

OBJECTIVE: To analyze the monoclonal expression of SS through the detection of serum monoclonal immunoglobulins (mIgs) in a large series of patients with Sjögren syndrome (SS), focusing on the etiology, characterization and evolution of the monoclonal band and the association with SS clinical expression and outcomes. METHODS: Serum immunoelectrophoresis (IE) was performed to 408 consecutive patients who were evaluated by our unit between 1992 and 2011: 221 patients who fulfilled the 2002 American-European criteria for primary SS, 122 primary SS patients who fulfilled exclusively the 1993 European criteria and 65 patients with SS-associated hepatitis C virus infection. IE was performed at diagnosis and every year during the follow-up. RESULTS: Of the 221 patients with primary SS, 48 (22%) had monoclonal gammopathy. In the control groups, the prevalence was 16% in patients with SS who fulfilled the 1993 criteria (p > 0.05) and 52% in SS-HCV patients (p < 0.001). Monoclonal bands were characterized in 47/48 patients with primary SS: IgG (n = 21), IgM (n = 16), IgA (n = 5) and free light chains (n = 5); the light chain was κ in 28 patients and λ in 19 (κ:λ ratio 1.5). Primary SS patients with monoclonal gammopathy had a higher prevalence of parotidomegaly (38% vs 20%, p = 0.021), vasculitis (21% vs 6%, p = 0.003), neurological involvement (42% vs 23%, p = 0.016), higher mean values of circulating gammaglobulins (23.4 vs 20.6%, p = 0.026), ESR (56.6 vs 37.6 mm/h, p = 0.003), a higher prevalence of RF (69% vs 50%, p = 0.022), low C3 levels (24% vs 11%, p = 0.028), low C4 levels (24% vs 7%, p = 0.003), low CH50 activity (28% vs 11%, p = 0.008) and cryoglobulins (23% vs 8%, p = 0.012) compared with those without monoclonal gammopathy. Of the 48 patients with primary SS and monoclonal gammopathy, 8 developed hematologic neoplasia after a mean follow-up of 10 years, a higher prevalence than observed in patients without monoclonal gammopathy (17% vs 5%, p = 0.009). Survival rates according to the presence or absence of monoclonal gammopathy were 83% and 97%, respectively (log rank 0.004). CONCLUSION: Monoclonal gammopathy was detected in 22% of patients with primary SS fulfilling the 2002 criteria, with mIgGκ being the most frequent type of band detected. In HCV-associated SS patients, the prevalence was higher (52%) with IgMκ being the most prevalent band detected. Monoclonal gammopathy was associated with a higher prevalence of parotid enlargement, extraglandular features, hypergammaglobulinemia, cryoglobulinemia and related markers (rheumatoid factor, hypocomplementemia), and with a poor prognosis (development of neoplasia and death).

Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases.

The emergence of tumor necrosis factor-α (TNF-α)-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in patients with hepatitis B virus (HBV) infection. We studied the current evidence on the use of anti-TNF agents in patients with HBV through a systematic analysis of cases reported in the MEDLINE and EMBASE databases using the MeSH term "hepatitis B virus" combined with the terms "infliximab," "etanercept," "adalimumab," "certolizumab," "golimumab," and "anti-TNF agents," and summarize the results here. We analyzed 257 patients with positive HBV markers who received anti-TNF therapy (255 identified in the search strategy and 2 new cases), 89 HBsAg+ carriers, and 168 anti-HBc+ persons. HBV reactivation was reported in 35 (39%) HBsAg+ carriers. The percentage of reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p=0.033) and lower in those who received antiviral prophylaxis (23% vs. 62%, p=0.003). Acute liver failure was reported in 5 patients, 4 of whom died. Infliximab was associated with a higher rate of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. In anti-HBc+ persons, reactivation was reported in 9 (5%) cases, including 1 patient who died due to fulminant liver failure.In summary, our search of the current evidence identified 257 reported HBV+ patients treated with anti-TNF agents, with a significant percentage of liver damage in HBsAg+ carriers, including raised transaminase levels (42%), signs and symptoms of liver disease (16%), reappearance of serum HBV-DNA (39%), and death related to liver failure (5%). The rate of reactivation in anti-HBc+ persons was 7-fold lower than in HBsAg+ carriers. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand specific preventive strategies.

Pulmonary disorders induced by monoclonal antibodies in patients with rheumatologic autoimmune diseases.

Monoclonal antibodies have emerged as a new class of agents causing drug-related pulmonary involvement in patients with systemic rheumatologic autoimmune diseases. The most frequently associated noninfectious pulmonary diseases are interstitial pneumonia (118 cases reported by August 2010), sarcoid-like disease and vasculitis (40 cases), and 97% of cases are associated with agents blocking tumor necrosis factor (TNF), a cytokine implicated in pulmonary fibrosis, granuloma formation, and maintenance. Drug-induced interstitial pneumonia has a poor prognosis, with an overall mortality rate of around one-third, rising to two-thirds in patients with pre-existing interstitial disease. Sarcoid-like disease has a better prognosis, with resolution or improvement in 90% of cases. Although the evidence comes overwhelmingly from case reports and case series, suggested recommendations for patient management include a detailed pre-therapeutic evaluation, early identification of symptoms suggestive of pulmonary disease, and tailored therapy. Mycobacterial infection should be exhaustively investigated, especially after anti-TNF administration. Large, prospective, postmarketing studies including nonbiological agents as controls may help elucidate the real risk of pulmonary disease in patients with rheumatologic autoimmune diseases receiving monoclonal antibodies.

Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases.

OBJECTIVES: To analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term "lung diseases, interstitial" as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy. RESULTS: There are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025). CONCLUSIONS: We found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-α, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD.

Outcomes in biopsy-proven lupus nephritis: evaluation of 190 white patients from a single center.

We describe the natural history of lupus nephritis (LN) in a historical cohort of 190 white patients with the diagnosis of biopsy-proven LN followed in a single reference center.We evaluated 670 patients with systemic lupus erythematosus (SLE) consecutively followed in our department from 1970 until 2006. All patients fulfilled the 1997 revised criteria for the classification of SLE. White patients (Spanish-born) with biopsy-proven LN were selected as the study population.The cohort included 190 patients (170 female patients and 20 male) with a mean age at LN diagnosis of 31 years. Renal biopsy revealed type I LN in 8 (4%) patients, type II in 33 (17%), type III in 46 (24%), type IV in 72 (38%), type V in 28 (15%), and type VI in 3 (2%) patients. Induction remission was achieved in 85% of patients with types I and II, 78% with type III, 70% with type IV, and 32% of patients with type V. After a mean follow-up of 2391 patient-years, 62 (33%) patients developed chronic renal failure and 18 (9%) evolved to end-stage renal disease. Adjusted multivariate Cox regression analysis identified male sex (hazard ratio [HR], 4.33) and elevated creatinine at LN diagnosis (HR, 5.18) as independent variables for renal failure. Survival was 92% at 10 years of follow-up, 80% after 20 years, and 72% after 30 years.Our results suggest that biopsy-proven LN in white patients has an excellent prognosis. Ethnicity should be considered a key factor when evaluating the prognosis and therapeutic response to different agents in patients with LN.

Clinical and prognostic significance of parotid scintigraphy in 405 patients with primary Sjogren's syndrome.

OBJECTIVE: To evaluate the association between the degree of involvement shown by parotid scintigraphy at diagnosis and the disease expression, outcomes, and prognosis of primary Sjögren's syndrome (SS). METHODS: All patients consecutively diagnosed with primary SS in our department between 1984 and 2008 were evaluated. The scintigraphic stages were classified into class 4 (severe involvement), class 2-3 (mild to moderate involvement), and class 1 (normal results). RESULTS: A total of 405 patients with primary SS underwent parotid scintigraphy at diagnosis (47 had class 1 involvement, 314 had class 2-3, and 44 had class 4). Patients with class 4 had a higher frequency of parotid enlargement (p < 0.001), systemic involvement (p = 0.007), high titers of antinuclear antibody (p = 0.016), positive rheumatoid factor (p = 0.002), anti-Ro/SSA (p = 0.001), anti-La/SSB (p = 0.001), low C4 levels (p = 0.001), and low CH50 (p = 0.001) in comparison with the other 2 groups. A higher rate of lymphoma development was observed in patients with class 4 involvement. Adjusted multivariate Cox regression analysis showed a hazard ratio (HR) of 10.51 (p = 0.002) and Kaplan-Meier analysis a log-rank of 0.0005. Mortality was 5-fold higher in patients with class 4 involvement. Adjusted multivariate Cox regression analysis showed an HR of 5.33 (p = 0.001) and Kaplan-Meier analysis a log-rank of 0.033. CONCLUSION: Patients with SS presenting with severe scintigraphic involvement at diagnosis had a more pronounced autoimmune expression, a higher risk of developing systemic features and lymphoma, and a lower survival rate. Study of the degree of salivary gland dysfunction at diagnosis by parotid scintigraphy offers valuable clinical information on the prognosis and outcome of primary SS.

Sjögren syndrome or sjögren disease? The histological and immunological bias caused by the 2002 criteria.

The current 2002 classification criteria do not cover the broad clinical and immunological heterogeneity of primary Sjögren syndrome (SS), since five of the six criteria focus exclusively on glandular involvement and the remaining criterion is the mandatory presence of anti-Ro/La antibodies. The aim of this study was to analyze the clinical features of patients with a well-established diagnosis of primary SS who do not fulfill the 2002 classification criteria. Five hundred seven patients diagnosed with primary SS (1993 criteria) were consecutively included and followed up. Two hundred twenty-one (44%) patients did not fulfill the 2002 criteria. These patients were older at diagnosis (p < 0.001) and had a lower frequency of parotid enlargement (p = 0.002), fever (p = 0.041), arthritis (p = 0.041), vasculitis (p = 0.050), peripheral neuropathy (p = 0.002), cranial nerve involvement (p = 0.015), raised erythrocyte sedimentation rate ( ESR) levels (p < 0.001), anemia (p < 0.001), leukopenia (p = 0.037), hypergammaglobulinemia (p < 0.001), positive rheumatoid factor ( RF; p = 0.002), and cryoglobulinemia (p = 0.049) in comparison with those fulfilling 2002 criteria. However, there were no significant differences in the prevalence of sicca features, diagnostic tests, overall systemic involvement, antinuclear antibodies , complement levels, development of B-cell lymphoma, or survival. Patients with anti-Ro antibodies had the highest frequencies of systemic features, hematological abnormalities, and altered immunological markers. In conclusion, patients fulfilling the 2002 criteria, who have either a specific histological diagnosis (lymphocytic infiltration) or highly specific autoantibodies (Ro/La), might well be considered to have Sjögren "disease." In contrast, etiopathogenic mechanisms other than lymphocytic-mediated epithelial damage could be involved in patients with negative Ro and negative biopsy, in whom the term Sjögren "syndrome" seems more adequate.

Chronic hepatitis B virus infection in Sjögren's syndrome. Prevalence and clinical significance in 603 patients.

OBJECTIVE: To analyze the prevalence and clinical characteristics of chronic hepatitis B virus (HBV) infection in a large series of patients with Sjögren syndrome (SS). METHODS: We investigated the prevalence of chronic HBV infection in 603 consecutive patients with SS diagnosed in our department between 1994 and 2008. There were 517 patients with primary SS (482 women and 35 men, with a mean age at the time of fulfillment of the classification criteria of 57 years) and 86 patients with SS associated with chronic HCV infection (66 women and 20 men, with a mean age at the time of fulfillment of the classification criteria of 65 years). All patients fulfilled 4 or more of the 1993 European Community Study Group criteria for SS. RESULTS: The presence of HBsAg+ was detected in five (0.83%) of the 603 patients with SS. All HBsAg+ patients had primary SS. No patient with HCV-related SS had HBV coinfection. There were 4 women and 1 man, with a mean age at diagnosis of primary SS of 65 years (range 31 to 89 years). All patients showed sicca and systemic involvement. The main extraglandular feature was articular involvement in 5 (100%) patients (including arthritis in two). The main immunologic features were RF in 4 (80%) patients and ANA in 3 (60%). No patient had hypocomplementemia, cryoglobulinemia, antimitochondrial or anti-LKM1 antibodies. Liver involvement was detected in two patients and consisted of slightly raised levels of transaminases. No patient showed clinical manifestations of liver disease such as hepatomegaly, splenomegaly, jaundice or clinical features of hepatic decompensation (ascites, encephalopathy or gastrointestinal bleeding). CONCLUSIONS: We found a prevalence of chronic HBV infection of 0.83% in SS, very similar to the prevalence in general population in Spain (0.7%). In contrast to the close association between SS and HCV, chronic HBV infection is not associated with SS in our geographical area, with a ratio SS-HBV/SS-HCV cases of 1:10.