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1.  Association of the Idiotype:Antiidiotype Antibody Ratio With the Efficacy of Intravenous Immunoglobulin Treatment for the Prevention of Recurrent Autoimmune-Associated Congenital Heart Block 
Arthritis and rheumatism  2011;63(9):2783-2789.
Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ~18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype: antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.
We studied 16 anti-Ro/SSA and anti-La/ SSB–positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349–364aa of La/SSB (idiotype) and its antiidiotypic antibodies.
Following IVIG treatment, serum titers of anti-La(349–364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349–364) was observed. The Id: anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P < 0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349–364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied.
This is the first study in humans to demonstrate that IVIG influences the Id–anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.
PMCID: PMC3551293  PMID: 21618202
2.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
3.  The contribution of epigenetics in Sjögren’s Syndrome 
Sjögren’s syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers.
PMCID: PMC3982050  PMID: 24765104
Sjögren’s syndrome; DNA methylation; HERV; epithelial cells; microRNAs
4.  Incidence and Prevalence of Major Central Nervous System Involvement in Systemic Lupus Erythematosus: A 3-Year Prospective Study of 370 Patients 
PLoS ONE  2013;8(2):e55843.
The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients.
370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage.
16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P≤0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P<0.001).
Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes.
PMCID: PMC3570560  PMID: 23424638
5.  Selective Screening of Secretory Vesicle-Associated Proteins for Autoantigens in Type 1 Diabetes: VAMP2 and NPY are New Minor Autoantigens 
Clinical Immunology (Orlando, Fla.)  2008;127(3):366-374.
The four major autoantigens (IA-2, I-2β, GAD65 and insulin) of type 1 diabetes are all associated with dense core or synaptic vesicles. This raised the possibility that other secretory vesicle-associated proteins might be targets of the autoimmune response in type 1 diabetes. To test this hypothesis 56 proteins, two-thirds of which are associated with secretory vesicles, were prepared by in vitro transcription/translation and screened for autoantibodies by liquid phase radioimmunoprecipitation. Two secretory vesicle-associated proteins, VAMP2 and NPY, were identified as new minor autoantigens with 21% and 9%, respectively, of 200 type 1 diabetes sera reacting positively. These findings add support to the hypothesis that secretory vesicle-associated proteins are particularly important, but not the exclusive, targets of the autoimmune response in type 1 diabetes. Selective screening of the human proteome offers a useful approach for identifying new autoantigens in autoimmune diseases.
PMCID: PMC3403618  PMID: 18359275
autoantibodies; autoantigens; GAD65; IA-2; protein tyrosine phosphatase; proteome; secretory vesicles; type 1 diabetes
6.  Efficacy and long-term follow-up of IL-1R inhibitor anakinra in adults with Still's disease: a case-series study 
To assess the efficacy and safety of the interleukin-1 receptor (IL-1R) inhibitor anakinra in adult patients with refractory Still's disease.
Twenty-five patients (13 males and 12 females, median age 32 years, median disease duration seven months) with Still's disease were treated with subcutaneous injections of anakinra (100 mg/day). Treatment was given as adjunct therapy in 16 patients and as standalone in 9 patients for a median time of 15 months (range 1.5-71). The clinical and laboratory parameters during follow-up were recorded.
In 84% of patients the clinical activity resolved completely within a few days (median time 0.2 months), and response was maintained until the last visit in all but one patient. A complete response of all disease-related symptoms (clinical and laboratory) occurred subsequently within a median time of three months in 80% of patients. A partial clinical and laboratory improvement was shown in 12% and 16% of patients, respectively. The Visualized Analogue Scale and Health Assessment Questionnaire scores significantly decreased during treatment. The proportion of patients achieving the American College of Rheumatology 20 (ACR20) score (20% improvement) was 82% at one month and improved to 100% at one year. The mean oral corticosteroid dose was significantly reduced at each visit. Anakinra was discontinued due to unresponsiveness in one patient and due to relapsing disease in another. Treatment was also withdrawn in three patients with severe skin reactions (urticaria). Seven patients experienced an infection during follow-up.
The rapid and sustained response in the majority of our patients encourages the use of anakinra in adults with Still's disease.
PMCID: PMC3218906  PMID: 21682863
7.  Current Aspects of Pathogenesis in Sjögren's Syndrome 
Sjögren's syndrome is a chronic autoimmune process that primarily affects the exocrine glands and leads to their functional impairment. The exocrine gland involvement is characterized by a focal, mononuclear cell infiltrate which is accumulated around ducts and, in some patients, extends and replaces the secretory functional units. The mechanisms of this autoimmune 'exocrinopathy' are not fully understood. The immune attack that follows activation or apoptosis of glandular epithelial cells exposing autoantigens in genetically predisposed individuals may drive the immune-mediated tissue injury. Abnormalities related to the upregulation of type I interferon-regulated genes (interferon signature), abnormal expression of B-cell-activating factor (BAFF) and activation of the IL-23/TH17 pathway are among the immune mediators implicated in the pathogenesis of autoimmune lesions within the salivary glands. Such abnormalities demonstrate the complex interplay between innate and adaptive immunity that contributes to autoimmune 'exocrinopathy'.
PMCID: PMC3383491  PMID: 22870458
Sjögren's syndrome; pathogenesis; cytokines; apoptosis; autoimmune exocrinopathy
8.  Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study 
Arthritis Research & Therapy  2010;12(6):R208.
While the role of mycophenolate mofetil (MMF) in the management of lupus nephritis has been increasingly recognized, limited information is available regarding its efficacy and safety as a long-term maintenance treatment. The aim of the present study was to evaluate the efficacy and safety profile of MMF as maintenance therapy for proliferative lupus nephritis.
Thirty-three consecutive patients with proliferative lupus nephritis received induction therapy with five to seven monthly intravenous (iv) pulses of cyclophosphamide (CYC) plus iv steroids followed by oral MMF 2 g/day as maintenance therapy for a median time of 29 months (range 9 to 71 months). Primary end points were the achievement of renal remission, complete renal remission, disease remission - renal and extrarenal -, the occurrence of renal relapse, chronic renal failure and death. Secondary end points were the extrarenal disease activity and drug adverse events. The clinical and laboratory parameters were compared during follow-up by means of nonparametric statistical tests. Time to event analysis was performed according to the Kaplan-Meier method.
A significant improvement of all renal parameters was observed at the end of the induction treatment and at the latest follow-up compared to baseline. The rate of patients achieving renal remission until the end of follow-up was 73%, whereas that of complete renal remission was 58%. The median survival times in the Kaplan-Meier analyses were 7 and 16 months, respectively. Remission was maintained in all but four (12%) patients who relapsed within 19 to 39 months after initial response. At the end of follow-up, 51% of the patients had reached disease remission. The median survival time of disease remission was 18 months. Extrarenal manifestations were well controlled in most of the patients. In one patient receiving MMF, extrarenal activity led to treatment discontinuation. Non life-threatening drug adverse events developed in 18 patients (58%) and included infections, amenorrhea, myelotoxicity, gastrointestinal complications, hypercholesterolemia, alopecia and drug intolerance. None of the patients developed chronic renal insufficiency or died from any cause.
MMF appeared to be efficacious and safe as maintenance treatment for proliferative lupus nephritis.
PMCID: PMC3046515  PMID: 21059275
9.  RNA Recognition Motif (RRM) of La/SSB: The Bridge for Interparticle Spreading of Autoimmune Response to U1-RNP 
Molecular Medicine  2009;16(1-2):19-26.
Systemic lupus erythematosus (SLE) is characterized by the production of grouped sets of autoantibodies targeting mainly the U1 ribonucleoprotein (RNP) and/or Ro/La RNP particles. Intraparticle diversification of the autoimmune response is believed to occur via epitope spreading. So far, it is not known how the autoimmune response “jumps” from one particle to another. To the extent that the majority of nuclear autoantigens in SLE are RNA binding proteins and major epitopes were previously mapped within their RRM (RNA recognition motifs), conserved sequences within RRM could be involved in the intermolecular and inter-particle diversification process of the autoimmune response. We investigated the potential of RRM of the La/SSB autoantigen to induce antibodies that cross-recognize components of the U1-RNP particle and therefore its capacity to produce interparticle epitope spreading. We immunized New Zealand white rabbits with a peptide corresponding to the epitope 145–164 of La/SSB (belonging to the RRM of La/SSB), attached in four copies on a scaffold carrier. Sera were drawn from 20 sera of patients with SLE and anti–U1-RNP antibodies and 26 sera of primary Sjögren syndrome patients with anti-La/SSB antibodies. All sera were evaluated for reactivity against the major epitope of La/SSB (pep349–364), the RNP antigen and the RRM-related epitope of La/SSB (pep145–164). Specific antibodies against pep145–164 were purified with immunoaffinity columns from selected sera. After the immunization of the animals with pep145-164, a specific IgG antibody response was detected, directed against the La/SSB autoantigen (wks 3–7), the immunizing peptide (wks 3–27), and the RNP autoantigen (wks 7–20). This response gradually decreased to low levels between postimmunization wks 27–42. Purified antibodies against pep145–164 recognized La/SSB and a 70-kD autoantigen in Western blot and exhibited significant reactivity in anti–U1-RNP ELISA. Depletion of anti-pep145–164 antibodies eliminated anti–U1-RNP reactivity from immunized rabbit sera but not from human sera. In addition, pep145–164 was recognized to a greater extent by autoimmune sera with anti-RNP reactivity compared with anti-La/SSB–positive sera, in contrast to pep349–364 of La/SSB, which was recognized almost exclusively by sera with anti-La/SSB reactivity. These data suggest that the RRM region of La/SSB can trigger interparticle B-cell diversification to U1-RNP-70 autoantigen via molecular mimicry. Identification of key sequences that trigger and perpetuate the autoimmune process is particularly important for understanding pathogenetic mechanisms in autoimmunity.
PMCID: PMC2762815  PMID: 19838329
10.  Properties and Function of Polyreactive Antibodies and Polyreactive Antigen-Binding B Cells 
Journal of autoimmunity  2007;29(4):219-228.
The advent of hybridoma technology has made it possible to study in depth individual antibody molecules. These studies have revealed a number of surprises that have and are continuing to change our view of the immune system. None of these was more surprising than the demonstration that many antibody molecules are polyreactive – that is they can bind to a variety of different and structurally unrelated self and non-self foreign antigens. These findings make it clear that self-reactivity is a common and not necessarily forbidden or pathogenic feature of the immune system and that the well known broad anti-bacterial activity of natural antibodies is largely due to polyreactive antibodies. In this brief review we will discuss these insights and their impact on basic and clinical immunology.
PMCID: PMC2100422  PMID: 17888628
Polyreactive antibody; Natural antibody; B cell; Autoantibody; Bacteria
11.  Unmasking the anti-La/SSB response in sera from patients with Sjogren's syndrome by specific blocking of anti-idiotypic antibodies to La/SSB antigenic determinants. 
Molecular Medicine  2002;8(6):293-305.
BACKGROUND: Autoantigen La/SSB is molecular target of humoral autoimmunity in patients with primary Sjogren's Syndrome (pSS) and systemic lupus erythematosus (SLE). In this study, we investigated the existence and possible influence of anti-idiotypic response to anti-La/SSB antibodies. MATERIALS AND METHODS: Synthetic peptide analogs (pep) of the major antigenic determinants of La/SSB (289-308 aa and 349-364 aa) were prepared. Based on "molecular recognition" theory, complementary peptides (cpep), derived by anti-parallel readings of the noncoding strand of La/SSB DNA encoding for its antigenic determinants, were constructed. Sera from 150 patients with anti-La/SSB antibodies, 30 patients without anti-La/SSB antibodies, and 42 normal individuals were tested against all four peptides. F(ab')(2) fragments from anti-peptide IgG were prepared and F(ab')(2) - IgG interactions were evaluated using a specific anti-idiotypic ELISA. RESULTS: All four peptides were recognized by anti-La positive sera (83% and 51% for pep and cpep 349-364 and 51% and 28% for pep and cpep289-308, respectively). Anti-cpep F(ab')(2 )bound to a common idiotype (Id) located within or spatially close to the antigen combining site of anti La/SSB (anti-pep) antibodies. Homologous and cross-inhibition experiments further confirmed this relation. The anti-idiotypic antibodies inhibited the anti-La/SSB antibody binding to recombinant La/SSB by 91%. To overcome the anti-idiotypic interference in anti-La/SSB detection, a specific assay was developed. Sera were heated for dissociation of Id-anti-Id complexes, anti-Id antibodies blocked with cpep, and anti-La/SSB reactivity was recovered. Application of this method to anti-Ro positive-anti-La/SSB "negative" sera showed that all anti-Ro/SSA positive autoimmune sera also possess anti-La/SSB antibodies. This reaction was not observed in 14 anti-Ro negative- anti-Sm/RNP positive sera from patients with SLE. CONCLUSIONS: Autoimmune sera from patients with pSS and SLE contain anti-idiotypic antibodies targeting a common anti-La/SSB idiotype. These antibodies can be detected using complementary peptides of La/SSB epitopes. The antiidiotypic antibodies mask the anti-La/SSB response. Hidden anti-La/SSB antibodies can be released and detected using complementary epitope analogs.
PMCID: PMC2039996  PMID: 12428060

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