B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE), so the safety and activity of anti-B cell immunotherapy with the humanized anti-CD22 antibody epratuzumab was evaluated in SLE patients. An open-label, single-center study of 14 patients with moderately active SLE (total British Isles Lupus Assessment Group (BILAG) score 6 to 12) was conducted. Patients received 360 mg/m2 epratuzumab intravenously every 2 weeks for 4 doses with analgesic/antihistamine premedication (but no steroids) prior to each dose. Evaluations at 6, 10, 18 and 32 weeks (6 months post-treatment) follow-up included safety, SLE activity (BILAG score), blood levels of epratuzumab, B and T cells, immunoglobulins, and human anti-epratuzumab antibody (HAHA) titers. Total BILAG scores decreased by ≥ 50% in all 14 patients at some point during the study (including 77% with a ≥ 50% decrease at 6 weeks), with 92% having decreases of various amounts continuing to at least 18 weeks (where 38% showed a ≥ 50% decrease). Almost all patients (93%) experienced improvements in at least one BILAG B- or C-level disease activity at 6, 10 and 18 weeks. Additionally, 3 patients with multiple BILAG B involvement at baseline had completely resolved all B-level disease activities by 18 weeks. Epratuzumab was well tolerated, with a median infusion time of 32 minutes. Drug serum levels were measurable for at least 4 weeks post-treatment and detectable in most samples at 18 weeks. B cell levels decreased by an average of 35% at 18 weeks and remained depressed at 6 months post-treatment. Changes in routine safety laboratory tests were infrequent and without any consistent pattern, and there was no evidence of immunogenicity or significant changes in T cells, immunoglobulins, or autoantibody levels. In patients with mild to moderate active lupus, 360 mg/m2 epratuzumab was well tolerated, with evidence of clinical improvement after the first infusion and durable clinical benefit across most body systems. As such, multicenter controlled studies are being conducted in broader patient populations.
To determine the tolerability and serum concentration of epratuzumab, a humanized monoclonal antibody targeting CD22, administered alone and in combination with reinduction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL), and to preliminarily assess tumor targeting and efficacy.
Patients and Methods
Therapy consisted of a single-agent phase (epratuzumab 360 mg/m2/dose intravenously twice weekly × four doses), followed by four weekly doses of epratuzumab in combination with standard reinduction chemotherapy. Morphologic and minimal residual disease (MRD) responses were determined at the end of this 6-week period. Serum concentrations of epratuzumab were determined before and 30 minutes after infusions, and CD22 targeting efficiency was determined by quantifying changes in CD22 expression after epratuzumab administration.
Fifteen patients (12 fully assessable for toxicity) with first or later CD22-positive ALL marrow relapse enrolled on the feasibility portion of this study from December 2005 to June 2006. Two dose-limiting toxicities occurred: one grade 4 seizure of unclear etiology and one asymptomatic grade 3 ALT elevation. In all but one patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration, indicating effective targeting of leukemic cells by epratuzumab. Nine patients achieved a complete remission after chemoimmunotherapy, seven of whom were MRD negative.
Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and acceptably tolerated in children with relapsed CD22-positive ALL. CD22 targeting was efficient, and the majority of patients achieved favorable early responses.
B-cells play an important role in the diagnosis and to some extent the pathogenesis of many autoimmune diseases. Specific B-cell directed antibodies are now gaining an increasing role in the management of these diseases. The first antibody target in this regard was CD20, with the development and introduction of rituximab in the management of B-cell malignancies as well as rheumatoid arthritis. A second candidate target is CD22, and the first antagonistic antibody to this B-cell marker is epratuzumab, which appears to function, in contrast to CD20 antibodies, more by modulation of B-cells than by their depletion capacity. Originally developed for the treatment of non-Hodgkin lymphoma, epratuzumab has now been reported to be effective, with a very good safety profile, in two prototype autoimmune diseases, systemic lupus erythematosus and primary Sjögren’s syndrome. As such, this new investigational antibody may provide distinct therapeutic effects and may be complementary to the known effects and role of CD20 antibodies.
autoimmune diseases; CD22; B-cells; epratuzumab
Epratuzumab, a humanized anti-CD22 monoclonal antibody, is under investigation as a therapeutic antibody in non-Hodgkin's lymphoma and systemic lupus erythematosus (SLE), but its mechanism of action on B-cells remains elusive. Treatment of SLE patients with epratuzumab leads to a reduction of circulating CD27negative B-cells, although epratuzumab is weakly cytotoxic to B-cells in vitro. Therefore, potential effects of epratuzumab on adhesion molecule expression and the migration of B-cells have been evaluated.
Epratuzumab binding specificity and the surface expression of adhesion molecules (CD62L, β7 integrin and β1 integrin) after culture with epratuzumab was studied on B-cell subsets of SLE patients by flow cytometry. In addition, in vitro transwell migration assays were performed to analyze the effects of epratuzumab on migration towards different chemokines such as CXCL12, CXCL13 or to CXCR3 ligands, and to assess the functional consequences of altered adhesion molecule expression.
Epratuzumab binding was considerably higher on B-cells relative to other cell types assessed. No binding of epratuzumab was observed on T-cells, while weak non-specific binding of epratuzumab on monocytes was noted. On B-cells, binding of epratuzumab was particularly enhanced on CD27negative B-cells compared to CD27positive B-cells, primarily related to a higher expression of CD22 on CD27negative B-cells. Moreover, epratuzumab binding led to a decrease in the cell surface expression of CD62L and β7 integrin, while the expression of β1 integrin was enhanced. The effects on the pattern of adhesion molecule expression observed with epratuzumab were principally confined to a fraction of the CD27negative B-cell subpopulation and were associated with enhanced spontaneous migration of B-cells. Furthermore, epratuzumab also enhanced the migration of CD27negative B-cells towards the chemokine CXCL12.
The current data suggest that epratuzumab has effects on the expression of the adhesion molecules CD62L, β7 integrin and β1 integrin as well as on migration towards CXCL12, primarily of CD27negative B-cells. Therefore, induced changes in migration appear to be part of the mechanism of action of epratuzumab and are consistent with the observation that CD27negative B-cells were found to be preferentially reduced in the peripheral blood under treatment.
Sjögren’s syndrome can involve the central nervous system; however, spontaneous intracranial hemorrhage has rarely been reported as the initial manifestation.
We report a 39-year-old woman with primary Sjögren’s syndrome presenting with intracranial hemorrhage. The diagnosis of primary Sjögren’s syndrome was based on the presence of ocular dryness, salivary gland secretory and excretory dysfunction confirmed with dynamic tracer emission CT, and positive anti-Sjögren’s syndrome A and anti-Sjögren’s syndrome B antibodies.
Primary Sjögren’s syndrome can present with variable central nervous system signs, which may precede the classic sicca symptoms. Therefore, Sjögren’s syndrome-associated indicators should be investigated in patients without the common risk factors for stroke who present with spontaneous intracranial hemorrhage.
Sjögren’s syndrome; Vasculitis; Intracranial hemorrhage; Internal carotid artery; Moyamoya disease; Anti-Sjögren’s syndrome A antibody; Anti-Sjögren’s syndrome B antibody
OBJECTIVES--In 1985 and 1988 a positive effect of treatment of primary Sjögren's syndrome with hydroxychloroquine was reported in two small open studies. To investigate further the clinical and laboratory effects of hydroxychloroquine in primary Sjögren's syndrome a two year study was performed. METHODS--The design of the study included a prospective, placebo controlled, two year double blind crossover trial in 19 patients. RESULTS--A significant decrease in IgG and IgM and a tendency for a decrease in the erythrocyte sedimentation rate (ESR) during treatment with hydroxychloroquine compared with treatment with placebo were found. No beneficial clinical effect of the use of hydroxychloroquine as expressed in preference for treatment with hydroxychloroquine or placebo with regard to symptoms and signs of primary Sjögren's syndrome could be shown, however, nor any relevant change in tear gland activity and sequelae of peripheral tear function deficiency, nor salivary gland scintigraphy. CONCLUSIONS--The use of hydroxychloroquine at a dose of 400 mg daily taken over a 12 month period does not have a worthwhile clinical benefit in patients with primary Sjögren's syndrome despite an improvement of hyperglobulinaemia and slight changes in the ESR and IgM.
Sjögren’s syndrome is a systemic autoimmune disease in which lymphatic cells destroy the salivary and lacrimal glands. Glomerulonephritis is thought to be a rare occurrence in primary Sjögren’s syndrome. Furthermore, concurrent glomerular involvement and lymphoma in patients with Sjögren’s syndrome has seldom been reported.
A 52-year-old woman with primary Sjögren’s syndrome developed membranous glomerulonephritis and Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL). She was diagnosed with Sjögren’s syndrome based on the dry eyes, dry mouth, positive anti-nuclear antibody test, anti-Ro (SS-A) antibody, salivary gland biopsy, and salivary scintigraphy. Moreover, renal biopsy confirmed the diagnosis of membranous glomerulonephritis. Three months later, her small bowel was perforated with pneumoperitoneum, and the biopsy revealed Epstein-Barr virus-positive DLBCL.
We observed the first case of primary Sjögren’s syndrome associated with Epstein-Barr Virus-positive DLBCL and membranous glomerulonephritis. Because of the possibility of malignancy-associated membranous glomerulonephritis in patients with primary Sjögren’s syndrome, we should be careful and examine such patients for hidden malignancy.
Primary Sjögren’s syndrome; Membranous glomerulonephritis; EBV-positive diffuse large B-cell lymphoma
To clarify the clinicopathological characteristics of primary Sjögren's syndrome (pSS) with anti-centromere antibody (ACA).
Characteristics of 14 patients of pSS with ACA were evaluated. All patients were anti-SS-A/Ro and SS-B/La antibodies negative (ACA+ group) without sclerodactyly. The prevalence of Raynaud's phenomenon (RP), titer of IgG and focus score (FS) in the minor salivary glands (MSGs) were determined. Quantification analysis of Azan Mallory staining was performed to detect collagenous fiber. Forty eight patients in whom ACA was absent were chosen as the conventional (ACA-) pSS group.
Prevalence of ACA+ SS patients was 14 out of 129 (10.85%) pSS patients. RP was observed in 61.5% of the patients with ACA. The level of IgG in the ACA+ group was significantly lower than that of the ACA- group (p = 0.018). Statistical difference was also found in the FS of MSGs from the ACA+ group (1.4 ± 1.0) as compared with the ACA- group (2.3 ± 1.6) (p = 0.035). In contrast, the amount of fibrous tissue was much higher in the ACA+ group (65052.2 ± 14520.6 μm2 versus 26251.3 ± 14249.8 μm2 ) (p = 1.3 × 10-12).
Low cellular infiltration but with an increase in fibrous tissues may explain the clinical feature of a high prevalence of RP and normal IgG concentration in ACA+ pSS.
Antibody engineering has made it possible to design antibodies with optimal characteristics for delivery of radionuclides for tumour imaging and therapy. A humanised divalent-Fab′ cross-linked with a bis-maleimide linker referred to as humanised divalent-Fab′ maleimide was produced as a result of this design process. It is a humanised divalent antibody with no Fc, which can be produced in bacteria and has enhanced stability compared with F(ab′)2. Here we describe a clinical study in patients with colorectal cancer using humanised divalent-Fab′ maleimide generated from the anti-carcinoembryonic antigen antibody A5B7 radiolabelled with iodine-131. Ten patients received an i.v. injection of iodine-131-labelled A5B7 humanised divalent-Fab′ maleimide, and positive tumour images were obtained by gamma camera imaging in eight patients with known lesions, and one previously undetected lesion was identified. True negative results were obtained in two patients without tumour. Area under the curve analysis of serial blood gamma counting and gamma camera images showed a higher tumour to blood ratio compared to A5B7 mF(ab′)2 used previously in the clinic, implying this new molecule may be superior for radioimmunotherapy. MIRD dose calculations showed a relatively high radiation dose to the kidney, which may limit the amount of activity that could be administered in radioimmunotherapy. However the reduction in immunogenicity was also a major advantage for A5B7 humanised divalent-Fab′ maleimide over murine versions of this antibody suggesting that humanised divalent-Fab′ maleimide should be a useful vehicle for repeated therapies.
British Journal of Cancer (2002) 86, 1401–1410. DOI: 10.1038/sj/bjc/6600198 www.bjcancer.com
© 2002 Cancer Research UK
humanised antibody; divalent-Fab′ maleimide; fragments; hDFM; imaging; colorectal cancer; phase I/II trial
Saliva diagnostics has become an attractive field utilizing nanotechnology and molecular technologies for pSS (primary Sjögren's syndrome). However, no specific methods have been established. To refine the diagnostic power of the saliva peptide finger print for the early detection of pSS, we screened the expression spectrum of salivary peptides in pSS patients by using mass spectrometry MALDI-TOF-MS (matrix-assisted laser-desorption ionization-time-of-flight MS) combined with magnetic bead. The present study was comprised 12 pSS patients and 13 healthy controls and broken down to two different phases. In the initial ‘exploratory phase’, we enrolled seven pSS patients with eight age- and sex-matched healthy volunteers. Proteomics analysis of the unstimulated salivary samples was conducted to generate proportional peptide mass fingerprints. A diagnostic model was established. The testing cohort of the second ‘validation phase’ was represented by five pSS patients and five age- and sex-matched healthy controls. The diagnostic power of this diagnostic panel was then validated. The results showed seven m/z (mass-to-charge) ratio peaks with significant differences. Five peptides were up-regulated and two down-regulated in the pSS patients compared with matched healthy subjects. In the validation phase, four out of five pSS patients were diagnosed as pSS, and four of the five healthy controls were diagnosed as healthy controls, respectively. Potential biomarkers were also primarily predicted. The novel diagnostic proteomic model with m/z peaks 1068.1 Da, 1196.2 Da, 1738.4 Da, 3375.3 Da, 3429.3 Da, 3449.7 Da and 3490.6 Da is of certain value for early diagnosis of pSS.
mass spectrum; peptidomics; salivary diagnostics; Sjogren’s syndrome (SS); weak cation exchange beads; MALDI-TOF-MS, matrix-assisted laser-desorption ionization-time-of-flight MS; PRP, proline-rich protein; pSS, primary Sjögren’s syndrome; sSS, secondary SS; WS, whole saliva; WCX, weak cation exchange
For invalidating symptoms in primary Sjögren's syndrome (pSS), there is still a need for easy‐to‐administer, cost‐effective and well‐tolerated systemic treatment. Leflunomide (LEF) is structurally unrelated to other immunomodulatory drugs and might be efficacious in pSS, given its characteristic immunoregulatory modes of action.
To investigate the safety and efficacy of LEF in pSS in a phase II open‐label pilot study.
15 patients with pSS with early and active disease received LEF 20 mg once daily for 24 weeks. Tolerability, safety and efficacy of LEF were evaluated every 8 weeks. Additional safety visits were performed every fortnight.
Mild gastrointestinal discomfort (including diarrhoea) and hair loss were mainly reported. Five patients developed lupus‐like skin lesions on the face, arms or trunk, responding well to topical corticosteroids, nevertheless causing the withdrawal of one patient. Two patients with pre‐existing hypertension had to increase dosages of anti‐hypertensive drugs. Increased levels of alanine aminotransferase normalised after dose reduction in two patients. A decrease in general fatigue and an increase in physical functioning were observed after 24 weeks. Serum IgG levels decreased from 8 weeks onwards. Schirmer test values increased, not reaching statistical significance, whereas sialometry values did not change. In four of five repeated biopsies, the lymphocytic focus score decreased at the rate of 1 focus/4 mm2. A remarkable amelioration of leucocytoclastic vasculitis was observed in three patients.
Although the safety profile seems fairly acceptable, the observed indications for efficacy were modest and may be doubtful in justifying a randomised controlled trial of LEF in pSS.
OBJECTIVE—To assess the prognosis of patients with sicca symptoms and to identify the clinical and immunological factors that most sensitively predict the later development of primary Sjögren's syndrome (SS) or other connective tissue diseases.
METHODS—Eighty seven patients (72 female, 15 male) with sicca symptoms were re-evaluated after a median follow up time of 11 years (range 8-17). The clinical examination included ophthalmological examination (Schirmer's test, break up time and Rose-Bengal staining). Labial salivary gland biopsy was performed and histological findings graded according to the Chisholm-Mason scale. The immunoserological tests included determination of rheumatoid factor (RF), antinuclear antibodies (ANA), anti-extractable nuclear antigen-antibodies (ENA), serum immunoglobulins IgA, IgG, and IgM, and serum β2-microglobulin (β2m).
RESULTS—At follow up 31 patients (36%) fulfilled modified Californian criteria (salivary flow measurements were not performed and Chisholm-Mason grades 3-4 were regarded as diagnostic histological findings) for possible or definite SS. Likewise, a significant progression of the histological findings was observed. Labial salivary gland re-biopsy was performed in 42 patients with grade 0-2 findings at baseline, progression to grades 3-4 being observed in 21 (50%) at follow up. The patients who later developed SS were at baseline significantly older (mean (SD) 52 (9) v 44 (14) years, p⩽0.005) compared with those not fulfilling the SS criteria at follow up; they also had significantly higher serum β2m (p⩽0.0005) and IgG concentrations (p⩽0.005), and they had positive ANA more frequently (p⩽0.01).
CONCLUSION—These results suggest that high age, increased values of serum β2m, ANA positivity and increased concentrations of serum IgG, might be useful indicators for the subsequent development of SS in patients with sicca symptoms. The prognosis of patients with these symptoms was favourable, and the clinical course was benign even in the 36% of patients who developed SS. No cases of lymphoma were observed.
Purpose: To investigate the presence of anti-Ro/SSA and anti-La/SSB antibodies in the tear fluid and serum of patients with Sjögren’s syndrome and to evaluate the association of these autoantibodies with the severity of keratoconjunctivitis sicca.
Methods: Tear fluid and serum were obtained from 28 patients with Sjögren’s syndrome and 17 age matched normal control subjects. Evaluation of tear fluid and sera anti-Ro/SSA and anti-La/SSB levels was done by using a quantitative enzyme linked immunosorbent assay kit designed for the quantitative measurement of IgG class autoantibodies directed against highly purified SSA and SSB antigens. Tear function and ocular surface were evaluated by Schirmer I test, tear break up time, and rose bengal staining. Dry eye symptom scores were recorded.
Results: Increased levels of anti-Ro/SSA and anti-La/SSB antibodies were detected in sera of 57.1% and 50% of SS patients, respectively. Six patients had increased levels of anti-Ro/SSA in the tear fluid, in one case anti-Ro/SSA being detected in tear fluid when it was negative in serum. Ten patients had positive anti-La/SSB titres in tear fluid and in four of these patients, anti-La/SSB titres were not elevated in serum. A positive correlation was observed between serum and tear fluid titres of anti-Ro/SSA (r = 0.43, p = 0.02), but not of anti-La/SSB. Serum anti-Ro/SSA and anti-La/SSB concentrations correlated positively with dry eye symptom scores (r = 0.42, p = 0.02 and r = 0.48, p = 0.01, respectively) and negatively correlated with Schirmer I test scores (r = −0.39, p = 0.04 and r = −0.40, p = 0.03, respectively). Significant correlations were found between tear anti-La/SSB concentrations and dry eye symptom score (r = 0.56, p = 0.02) and also rose bengal staining scores of the ocular surface (r = 0.44, p = 0.02).
Conclusion: This study shows that autoantibodies against Ro/SSA and La/SSB antigens are present in the tear fluid of some patients with SS and their presence in serum or tear fluid is associated with the severity of keratoconjunctivitis sicca. Additional measurement of tear fluid levels of anti-Ro/SSA and anti-La/SSB may serve as a valuable diagnostic indicator of SS.
Sjögren’s syndrome; anti-Ro/SSA; anti-La/SSB autoantibodies; tear fluid; keratoconjunctivitis sicca
A humanised bispecific monoclonal antibody (bsMAb) with binding specificity for carcinoembryonic antigen (CEA) on one arm and a radiolabelled chelate (DTPA-90Y) on the other arm was generated by consecutively transfecting the humanised genes of an anti-CEA MAb and the chimerised genes of an anti-chelate MAb into eucaryotic BHK cells using the calcium-phosphate coprecipitation technique. The antibodies secreted were of IgG3 isotype with a shortened hinge region (delta gamma 3) and light chains. Double transfectomas were screened for the secretion of bsMAbs using a double determinant enzyme-linked immunosorbent assay (ELISA) based on solid phase attached HSA-benzyl-DTPA and an anti-idiotypic MAb selective for the CEA-specific arm. After purification on two immunoaffinity chromatography columns, the humanised bsMAbs were characterised by SDS-PAGE and a quantitative binding assay in antigen excess. The purification procedure resulted in 95% reactive bispecific MAb. This humanised bsMAb may be employed in two phase radioimmunotherapy, binding to the tumour via the anti-CEA arm and localising a radiolabelled chelate with the other arm, without inducing a strong immune response observed sometimes with murine MAbs.
AIM--To establish a definitive set of diagnostic criteria in a multicentre European study a selected number of oral and ocular tests were performed on a large number of patients with Sjögrens Syndrome (SS) and controls. The diagnostic accuracy of each test for patients with primary and secondary SS and for controls at different ages, was studied. METHODS--Each centre received a clinical chart describing the series of tests to be conducted. The tests included: questionnaires for dry eye and dry mouth symptoms, Schirmer's-I-test (ScT), tear fluid lactoferrin level (TFLL), break-up time (BUT) and rose Bengal score (RBS) for the eye evaluation; unstimulated and stimulated whole saliva collection (UWSC and SWSC), salivary gland scintigraphy (SGS), parotid sialography (PS) and minor salivary gland biopsy (MSGB) for oral involvement. RESULTS--Data from 22 centres and 11 countries was collected on a total of 447 patients with SS (246 with primary SS and 201 with secondary SS) and 246 controls (of whom 113 had a connective tissue disease without SS). Among the ocular symptoms, the feeling of dry eye and 'sand in the eye' were the ones most commonly recorded in patients with SS. Similarly, the feeling of dry mouth, appearing either spontaneously or when the patient was eating or breathing, was the most frequent subjective oral symptom. Among the ocular tests, ScT showed the best balance between sensitivity and specificity (76.9% and 72.4% respectively), while RBS was the most specific test (81.7%). ScT and RBS gave also sufficiently concordant results. TFLL and BUT gave considerably less reliable results, which were not concordant with each other or with the other ocular tests. The quantitative lacrimal tests ScT and TFLL produced significantly different results in elderly controls, while RBS did not. Abnormal results for all of the ocular tests were less marked and less frequent in patients with secondary SS than in those with primary SS. The oral tests (except SWSC) were generally more reliable than the ocular tests in diagnosing SS. In particular, PS was the most specific diagnostic tools (100%), while MSGB (where the presence of at least one inflammatory focus was considered as indicative for the diagnosis) showed a good balance between sensitivity and specificity (82.4% and 86.2%, respectively). The tests showed a good degree of agreement, and, with the exception of UWSC, were not influenced by age. In the oral, as in the ocular tests, abnormal results were less frequent and less marked in patients with secondary SS. CONCLUSIONS--The results clearly show that ScT and RBS (for the eye evaluation), and SGS, PS, MSGB and UWSC (for salivary gland involvement) are the most reliable tests for the diagnosis of SS. The clinician should be aware, however, that the test results may vary depending on the age of the patient and the type of SS (primary or secondary).
A prospective study was carried out on 48 patients with HTLV I associated myelopathy/tropical spastic paraparesis (HAM/TSP) to assess the association between this entity and Sjögren's syndrome. Fourteen patients (29.1%) had chronic dacryosialadenitis confirmed by a positive Schirmer's test and salivary gland biopsy. None of these patients had evidence of collagen disease and tests for Ro, La, and rheumatoid factor were negative except in one case. Therefore, the dacryosialadenitis could not be classified as either primary or secondary Sjögren's syndrome. Ten of the 14 patients (71.4%) had other systems (haematological, articular, dermatological, or respiratory) involved apart from the neurological and exocrine gland pathology. The findings suggest that the dacryosialadenitis associated with HTLV I is a disease of viral origin distinct from Sjögren's syndrome.
Background: Retroviral infection has been implicated in the pathogenesis of primary Sjögren's syndrome.
Objective: To examine the efficacy of the reverse transcriptase inhibitor lamivudine in patients with this syndrome.
Methods: 16 patients with primary Sjögren's syndrome were randomised to receive either lamivudine 150 mg twice daily or placebo for three months. Measures of lacrimal and salivary function, including minor salivary gland biopsies, were obtained before and after treatment.
Results: Treatment with lamivudine did not result in significant improvement in the primary outcome measure of unstimulated whole salivary flow or other secondary measures, including minor salivary gland biopsy focus scores.
Conclusion: Lamivudine is not effective in patients with primary Sjögren's syndrome, suggesting either that a retroviral aetiology is not present or that it may be important only in early disease.
Patients with primary Sjögren's syndrome (pSS) produce functional IgG against cholinoreceptor of exocrine glands modifying their activity. The aim of the present work was to demonstrate pSS IgG antibodies (pSS IgG) interacting with M3 muscarinic acetylcholine receptors (mAChR) of rats submandibular glands that alter mucin release and production via phospholipase C (PLC) and cyclooxigenase-2 (COX-2) pathways.
Mucin release and production of prostaglandin E2 (PGE2), and total inositol phosphates (InsP) were measured in rat submandibular gland in the presence of pSS IgG auto antibodies.
The auto antibodies interacting with M3 mAChR decreased mucin release and production through stimulation of PLC and COX-2. This stimulation leads to an incremental increase in InsP production and in PGE2 generation, inducing signalling through the prostaglandin membrane receptors subtype 2 (EP2). Moreover, the decrease in mucin production had negative correlation with PGE2 generation and InsP accumulation.
IgG in patients with pSS could play an important role in the pathoetiology of dry mouth, decreasing the salivary mucin through the production of proinflammatory substances and leading to the reduction in the protection of the oral tissues.
Auto antibodies; InsP; mAChR; Mucin; PGE2; Submandibular gland
In recent years, therapies for follicular lymphoma (FL) have steadily improved. A series of phase III trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated significant improvements in progression-free survival (PFS) and overall survival. Recent studies have found that prolonged response durations and PFS were obtained with maintenance therapy using rituximab or interferon after completion of first line therapy. For patients with relapsed or refractory FL, phase II studies have assessed the effectiveness of combination therapies using a Toll-like receptor-9 agonist (1018ISS), oblimersen sodium (a Bcl-2 antisense oligonucleotide), bendamustine, and rituximab, as well as veltuzumab, a new humanized anti-CD20 antibody, and epratuzumab. In addition, the effectiveness of yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab as radioimmunotherapies has been reported. Furthermore, three phase III studies on an idiotype vaccine are near completion. Unfortunately, these vaccines, which appeared highly effective in phase I and II trials, do not appear to result in prolonged PFS. This report will summarize the current knowledge on therapies for treatment of FL, and will conclude with a brief discussion of feasible future options for effective treatments. Lastly, we added descriptions of the management of gastrointestinal FL, which is considered to be controversial because it is rare.
Anti-CD20 monoclonal antibody (rituximab); Follicular lymphoma; Idiotype vaccines; Immunoradiotherapy; Treatment strategies
Epratuzumab (anti-CD22) is a humanized monoclonal antibody that recognizes a pan-B-cell marker. It potentially downregulates B cell activity through negative signaling, as well as depleting B cells moderately. The uncontrolled series discussed by Dörner and colleagues in this issue of Arthritis Research & Therapy suggests that epratuzumab may be safe and efficacious for systemic lupus erythematosus. A randomized controlled trial is currently active to test this possibility.
The criteria for a clinical diagnosis of Sjögren's syndrome remain controversial and vary widely from study to study. With respect to the oral component it is considered necessary to use some form of objective test, but many of those available are not suitable for use in a busy clinical situation. The purpose of this study was to evaluate a simple method for measuring the whole unstimulated salivary flow. Twenty five patients with Sjögren's syndrome, 69 young control subjects, 20 age matched normal older control subjects and 20 patients with rheumatoid arthritis without Sjögren's syndrome had their salivary flows measured. Whole unstimulated salivary flows in the young control subjects were higher than in all other groups. Patients with primary Sjögren's syndrome had lower flows than either the older controls or the rheumatoid patients. Among the patients with Sjögren's syndrome 52% had a flow of 0.1 ml/min or less compared with only 8% of age matched controls. The positive predictive value of this low flow was 81%. It is concluded that whole unstimulated salivary flows of 0.1 ml/min or less are highly specific for xerostomia. When interpreted in the context of all the clinical findings whole unstimulated salivary flows are useful for diagnosing the oral component of Sjögren's syndrome.
The purpose of this study was to investigate the prevalence of cyclic citrullinated peptide antibodies (anti-CCP) in patients with primary Sjögren syndrome (pSS) and its correlation with clinical and laboratory data.
We analysed the clinical and serological data of 155 consecutive patients with pSS. Among these, 14 were excluded due to fulfillment of American College of Rheumatology criteria for rheumatoid arthritis (RA). So, 141 patients (27 males and 114 females; mean age 48 years, range 39 to 60) were clinically assessed for the presence of synovitis (objective swelling of one or more joints) and extra-glandular involvement. The anti-CCP antibodies were tested using a commercially available second-generation enzyme-linked immunosorbent assay. IgM rheumatoid factor (RF) was determined by nephelometry.
Fourteen patients (9.9%) had moderate to high levels of anti-CCP, and 94 (66.7%) were positive for RF. Eighty-one (57.4%) showed extra-glandular involvement, and 44 (31.2%) had synovitis without any radiographic sign of erosion. There was a close correlation between the presence of anti-CCP and synovitis (P < 0.001) but no association between anti-CCP and extra-glandular involvement (P = 0.77). Multivariate analysis confirmed the association between anti-CCP and an increased prevalence of synovitis (prevalence odds ratio for positive versus negative anti-CCP status 7.611, 95% confidence interval 1.475 to 74.870; P = 0.010).
Only a minority of patients with pSS are anti-CCP-positive, which seems to be closely associated with the prevalence of synovitis. Anti-CCP positivity in patients with pSS therefore may be a predictor of future progress to RA or an expression of the inflammatory process of synovial tissue.
A 65 year-old female with a history of xerostomia and xerophthalmia was presented with dyspnea on exertion (New York Heart Association class III). Echocardiography and cardiac catheterization demonstrated severe pulmonary hypertension (PH). Laboratory examinations showed positive anti-nuclear and anti-Ro/SS-A antibodies. Schirmer's test was positive and salivary gland scintigraphy revealed severely decreased tracer uptakes in both parotid and submandibular glands. By excluding other possible causes of PH during further examinations, she was diagnosed with severe PH associated with primary Sjögren's syndrome. Her dyspnea symptom was much improved with endothelin receptor antagonist and azathioprine.
Hypertension, pulmonary; Sjögren's syndrome
Thus far, none of the preclinically successful and promising immunomodulatory agents for type 1 diabetes mellitus (T1DM) has conferred stable, long-term insulin independence to diabetic patients. The majority of these immunomodulators are humanised antibodies that target immune cells or cytokines. These as well as fusion proteins and inhibitor proteins all share varying adverse event occurrence and severity. Other approaches have included intact putative autoantigens or autoantigen peptides. Considerable logistical outlays have been deployed to develop and to translate humanised antibodies targeting immune cells, cytokines, and cytokine receptors to the clinic. Very recent phase III trials with the leading agent, a humanised anti-CD3 antibody, call into question whether further development of these biologics represents a step forward or more of the same. Combination therapies of one or more of these humanised antibodies are also being considered, and they face identical, if not more serious, impediments and safety issues. This paper will highlight the preclinical successes and the excitement generated by phase II trials while offering alternative possibilities and new translational avenues that can be explored given the very recent disappointment in leading agents in more advanced clinical trials.
Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by sicca symptoms. Interstitial pulmonary fibrosis and tracheobronchial sicca are the most common symptoms of pulmonary involvement in primary SjS, and they are rarely accompanied by serositis such as pleuritis or pericarditis. We report a case of SS presenting initially with bilateral pleural effusions. A 63-year old man was admitted to our hospital with a one-month history of cough, dyspnea, and right chest pain. Chest-computed tomography revealed bilateral pleural effusions. Serum anti-SS-A antibody titer was 1 : 256. Ophthalmological examination revealed a positive Schirmer test. Lip biopsy showed atrophy and plasmacytic infiltration of the salivary gland. Corticosteroid treatment was initiated. Pleural effusions were almost completely resolved by day 30. The patient has not experienced any recurrence.