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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.

Objective: The objective of this paper is to evaluate the prevalence and characterize the main epidemiological, clinical and immunological features of annular erythema (AE) in non-Asian patients with primary Sjögren's syndrome (SS)., Methods: We carried out a retrospective study searching for AE in 377 Spanish patients with primary SS fulfilling the 2002 American-European criteria. In addition, we searched PubMed (1994-2012) using the MeSH terms "annular erythema" and "primary Sjögren's syndrome" for additional cases. All cases with AE reported in patients with SS associated with systemic lupus erythematosus were excluded., Results: In our Spanish cohort, we found 35 (9%) patients diagnosed with AE. All were white females, with a mean age of 47 years at diagnosis of AE. AE preceded diagnosis of SS in 27 (77%) patients. Cutaneous AE lesions involved principally the face and upper extremities. All patients reported photosensitivity, with cutaneous flares being reported during the warmest months in 93% of patients. Immunological markers consisted of anti-Ro/La antibodies in 31 (89%) patients. In the literature search, we identified eight additional non-Asian patients with primary SS diagnosed with AE. In comparison with 52 Asian patients, the 43 non-Asian patients with AE related to primary SS were more frequently women (100% vs 78%, p=0.008), and cutaneous lesions were less frequently reported in the face (55% vs 81%, p=0.045) and more frequently in the neck (40% vs 14%, p=0.041). Immunologically, non-Asian patients had a lower frequency of anti-Ro antibodies and a higher frequency of negative Ro/La antibodies, although the differences were not statistically significant., Conclusion: AE is not an exclusive cutaneous feature of Asian patients with primary SS. In addition to the characteristic cutaneous expression, AE has a very specific clinical and immunological profile: often presenting before the fulfillment of SS criteria, overwhelmingly associated with anti-Ro antibodies but weakly associated with other immunological markers and the main systemic SS-related features.

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.

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.

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)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To describe the main characteristics of patients with primary Sjögren syndrome (SS) and white matter abnormalities (WMA) seen by a specialist SS unit., Methods: The study cohort included 321 consecutive patients fulfilling the 2002 classification criteria for primary SS. We retrospectively analyzed the results of neuroimaging studies performed in patients who presented with neurological symptoms. Patients were further evaluated by three neurologists to determine fulfillment of the McDonald criteria for the diagnosis of multiple sclerosis (MS)., Results: Fifty-one (16%) patients had at least one neuroimaging study, and 25 of these had WMA. WMA were classified as vascular pathological changes in 21 patients: 10 had multiple small focal lesions, 7 had beginning confluence of lesions and 4 had diffuse involvement of the entire region. WMA were classified as inflammatory/demyelinating lesions (MS-like) in 4 patients who fulfilled the MRI Barkhof criteria. Patients with inflammatory/demyelinating lesions were younger (53.7 vs. 73.5 years, P = 0.001) and had a lower frequency of hypertension (25% vs. 86%, P = 0.031) and altered glomerular filtration rate (0% vs. 70%, P = 0.047) in comparison with patients with vascular lesions. The multivariate age-sex adjusted model including the seven variables which were statistically significant in the univariate analysis (antimalarial therapy, leukopenia, anti-La/SSB antibodies, diabetes, hypertension, metabolic syndrome and HDL-c levels) identified hypertension (P = 0.019) and HDL-c levels (P = 0.032) as independent predictors of WMA in primary SS patients., Conclusion: Neuroimaging studies disclosed WMA in 49% of patients with primary SS and suspected neurological involvement. WMA were identified as vascular pathological changes in 80% of the patients, and hypertension and HDL-c levels as predictive factors for this association.

The treatment of primary Sjögren's syndrome (SS) is based principally on the management of sicca features and systemic manifestations. Sicca manifestations are treated symptomatically through administration of topical therapies, such as saliva substitutes and artificial tears; in patients with residual salivary gland function, stimulation of salivary flow with a sialogogue is the therapy of choice. The management of extraglandular features must be tailored to the specific organ or organs involved; however, limited data have been obtained from controlled trials in SS to guide the treatment of systemic symptoms using therapies including antimalarials, glucocorticoids, immunosuppressive drugs and biologic agents. Nevertheless, randomised controlled trials of biologic agents that target molecules and receptors involved in the aetiopathogenesis of primary SS have initiated a new era in the therapeutic management of the disease, although the potential risks and benefits of these agents must be carefully considered. In this Review, we analyse the evidence regarding the efficacy of the therapeutic agents currently available to treat the manifestations of SS. On the basis of this evidence, we provide guidance on the use of these agents in different clinical scenarios.

Context: A variety of topical and systemic drugs are available to treat primary Sjögren syndrome, although no evidence-based therapeutic guidelines are currently available., Objective: To summarize evidence on primary Sjögren syndrome drug therapy from randomized controlled trials., Data Sources: We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010., Study Selection: Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source., Results: The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline., Conclusions: In primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab.

Objective: To evaluate the prevalence of cytoplasmic (c) and perinuclear (p) antineutrophil cytoplasmic antibodies (ANCA) in patients with primary Sjogren's syndrome (SS), and to correlate the presence of ANCA with extraglandular and immunological manifestations related to SS., Methods: In a cross-sectional study, we included 82 consecutive patients (75 female and seven male; mean age 61 yr; range 33-87 yr) attending our unit. All patients fulfilled four or more of the diagnostic criteria for SS proposed by the European Community Study Group in 1993. Extraglandular manifestations such as arthralgia and/or arthritis, Raynaud's phenomenon, autoimmune thyroiditis, peripheral neuropathy, renal involvement and cutaneous vasculitis were also recorded. Serum samples were examined by indirect immunofluorescence (IIF) and by ELISA using as substrates myeloperoxidase (MPO) and proteinase 3 (PR3)., Results: ANCA were detected in nine (11%) patients: seven had pANCA and two an atypical pattern. These two atypical ANCA became cANCA when paraformaldehyde fixation was applied. ELISA findings showed that two patients had antibodies against MPO, and no patient had antibodies to PR3. The most common extraglandular manifestations in the ANCA-positive patients were articular involvement in six (66%) patients, peripheral neuropathy in five (55%), Raynaud's phenomenon in four (44%) and cutaneous vasculitis in four (44%). Of the four patients with cutaneous vasculitis and ANCA, two had a mononuclear inflammatory vascular disease (MIVD) in the biopsy specimen. When compared with patients without ANCA, those with these antibodies had a higher prevalence of cutaneous vasculitis (44% vs 8%, P = 0.01), Raynaud's phenomenon (44% vs 8%, P = 0.01) and peripheral neuropathy (55% vs 7%, P < 0.001)., Conclusion: ANCA positivity can be found in patients with primary SS and its detection is associated with the presence of clinical manifestations attributable to vascular involvement (cutaneous vasculitis, peripheral neuropathy and Raynaud's phenomenon).

We report two patients with a definite diagnosis of primary Sjögren's syndrome who developed Hodgkin's disease. Clinical and laboratory features of this transformation comprised prolonged fever, the appearance of lymphadenopathy together with loss of serum autoantibodies and a reduction in serum gammaglobulin levels. We know of only one well documented case of such an association. From these observations, it seems reasonable to include Hodgkin's disease in the clinical spectrum of the lymphoproliferative disorders that may occur in the course of primary Sjögren's syndrome.

Objective: To describe the main characteristics of patients with primary Sjögren syndrome (SS) and white matter abnormalities (WMA) seen by a specialist SS unit.Methods: The study cohort included 321 consecutive patients fulfilling the 2002 classification criteria for primary SS. We retrospectively analyzed the results of neuroimaging studies performed in patients who presented with neurological symptoms. Patients were further evaluated by three neurologists to determine fulfillment of the McDonald criteria for the diagnosis of multiple sclerosis (MS).Results: Fifty-one (16%) patients had at least one neuroimaging study, and 25 of these had WMA. WMA were classified as vascular pathological changes in 21 patients: 10 had multiple small focal lesions, 7 had beginning confluence of lesions and 4 had diffuse involvement of the entire region. WMA were classified as inflammatory/demyelinating lesions (MS-like) in 4 patients who fulfilled the MRI Barkhof criteria. Patients with inflammatory/demyelinating lesions were younger (53.7 vs. 73.5 years, P = 0.001) and had a lower frequency of hypertension (25% vs. 86%, P = 0.031) and altered glomerular filtration rate (0% vs. 70%, P = 0.047) in comparison with patients with vascular lesions. The multivariate age–sex adjusted model including the seven variables which were statistically significant in the univariate analysis (antimalarial therapy, leukopenia, anti-La/SSB antibodies, diabetes, hypertension, metabolic syndrome and HDL-c levels) identified hypertension (P = 0.019) and HDL-c levels (P = 0.032) as independent predictors of WMA in primary SS patients.Conclusion: Neuroimaging studies disclosed WMA in 49% of patients with primary SS and suspected neurological involvement. WMA were identified as vascular pathological changes in 80% of the patients, and hypertension and HDL-c levels as predictive factors for this association. [ABSTRACT FROM PUBLISHER]