Paraskevi V. Voulgari

Primary Sjögren syndrome in the paediatric age: a multicentre survey.

Abstract Primary Sjögren syndrome (SS) is very rare in childhood. We collected a series of primary paediatric SS cases from different centres. A data collection form was prepared and sent to rheumatologists who were willing to participate. Data on 40 cases of primary SS with onset before the 16th birthday were collected. Almost all patients (35/40) were females, age at onset varied from 9.3 to 12.4 years (mean 10.7 years). Signs and symptoms at disease onset were mainly recurrent parotid swelling followed by sicca symptoms. Abnormal laboratory tests were found in the majority of cases. Regarding treatment, 22 patients were treated at some time with oral corticosteroids, seven with non-steroidal anti-inflammatory drugs, and five with hydroxychloroquine; two patients needed cyclosporine and one cyclophosphamide. Follow-up varied from 0 to 7.5 years from onset, without major complications in the majority of patients. Conclusion: recurrent parotid swelling is a common feature of primary Sjögren syndrome in childhood and often occurs as a presenting feature. Sicca symptoms may be rarer.

Early Treatment Reduces the Cardiovascular Risk Factors in Newly Diagnosed Rheumatoid Arthritis Patients

OBJECTIVE To investigate subclinical atherosclerosis and the effect of treatment in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS Forty patients with early RA who met the revised American College of Rheumatology (ACR) criteria and disease duration of <1 year were included in the study. Smokers and patients with classical risk factors for atherosclerosis were excluded. The serum levels of total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol were determined in all patients before and after 1 year of therapy. Carotid artery intima-media thickness (IMT) and carotid plaque were measured before and after treatment. RA disease activity was measured using the 28 joint indices score (DAS-28) and clinical improvement was determined by the ACR response criteria. Forty-five age- and sex-matched nonsmoking volunteers were used as controls. All patients were treated with methotrexate and prednisone. RESULTS RA patients had a baseline mild dyslipidemia characterized by a decrease in serum HDL-C levels and a high TC/HDL-C atherogenic ratio compared with controls. Both lipid parameters were significantly improved after treatment (P<0.01). Common carotid artery IMTs at baseline were higher in RA patients compared with controls (P<0.05). After 1 year of therapy there was a significant decrease in the IMTs (P<0.001). Thirty-five patients (88%) achieved the ACR 20%, while 30 (75%) reached the ACR 50% response criteria. A significant decrease of DAS-28 was observed after treatment (P<0.03). CONCLUSIONS The atherogenic lipid profile and subclinical atherosclerosis are features of early RA, which improved after therapy. Early intervention and control of the disease activity may reduce the risk of atherosclerosis and cardiovascular events in patients with RA.

Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme

ER aminopeptidase 1 (ERAP1) customizes antigenic peptide precursors for MHC class I presentation and edits the antigenic peptide repertoire. Coding single nucleotide polymorphisms (SNPs) in ERAP1 were recently linked with predisposition to autoimmune disease, suggesting a link between pathogenesis of autoimmunity and ERAP1-mediated Ag processing. To investigate this possibility, we analyzed the effect that disease-linked SNPs have on Ag processing by ERAP1 in vitro. Michaelis–Menten analysis revealed that the presence of SNPs affects the Michaelis constant and turnover number of the enzyme. Strikingly, specific ERAP1 allele-substrate combinations deviate from standard Michaelis–Menten behavior, demonstrating substrate-inhibition kinetics; to our knowledge, this phenomenon has not been described for this enzyme. Cell-based Ag-presentation analysis was consistent with changes in the substrate inhibition constant Ki, further supporting that ERAP1 allelic composition may affect Ag processing in vivo. We propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity.

Demyelination and other neurological adverse events after anti-TNF therapy

Tumor necrosis factor (TNF) α inhibitors are an essential therapeutic option for several inflammatory diseases, like rheumatoid arthritis, spondyloarthropathies and inflammatory bowel diseases. As TNFα antagonists have become increasingly utilized, there have been a number of reports of neurological adverse events in patients receiving anti-TNFα therapy. The frequency of central nervous system adverse events after initiation of anti-TNFα therapy is unknown. However, questions have been raised about a possible causal association. Although several hypotheses have been proposed in an attempt to explain the possible relationship between TNFα antagonist and demyelination, none is considered to be adequate. Thus, in this report we deal with the implication of TNFα in multiple sclerosis and we discuss the possible relationship of TNFα antagonist and demyelinating diseases.

The role of microRNA-146a (miR-146a) and its target IL-1R-associated kinase (IRAK1) in psoriatic arthritis susceptibility.

MicroRNAs have shown different expression patterns in immune diseases. The present study explores the association of miRNA‐146a variant rs2910164 and of two IRAK1 (target of miR‐146a) polymorphisms rs3027898 and rs1059703 with psoriasic arthritis (PsA). Twenty‐nine PsA and 66 controls were enrolled in the study. To study if the statistical significant differences between patients with PsA and controls are independent to psoriasis, we expanded the study in 49 patients with ankylosing spondylitis (AS). Strong statistical significant difference was observed in IRAK1 rs3027898 polymorphism distribution between patients with PsA and controls (P = 0.003), as between patients with AS and controls (P < 0.001). Marginally significant difference was observed in distribution of IRAK1 rs1059703 genotypes between patients with PsA and controls (P = 0.058), but no difference was observed in miRNA‐146a rs2910164 distribution (P = 0.394). This is the first study that addresses IRAK1 rs3027898 polymorphism association with PsA susceptibility, but further studies could help to understand the extent of the proposed association.

Granuloma annulare induced by anti-tumour necrosis factor therapy

Objective: To describe granuloma annulare (GA) skin lesion development in patients during anti-tumour necrosis factor (TNF) therapy. Methods: 199 patients with rheumatoid arthritis and 127 suffering from spondyloarthropathies treated with anti-TNF antagonists were analysed to identify skin lesions suggesting GA. Results: Nine cases of GA during anti-TNF therapy (123 treated with infliximab, 57 with adalimumab and 17 with etanercept) for rheumatoid arthritis were identified. Two have been treated with infliximab, six with adalimumab and one with etanercept, and here the development of GA was 4.5%. No patient with spondyloarthropathies developed such skin lesions. All patients developed the generalised form of GA. None had or developed diseases, or conditions known to be associated with GA. In seven patients the skin eruptions developed during the first year of anti-TNF treatment, while they developed in two patients during the second year. Two patients had to stop anti-TNF therapy due to the extent of skin lesions. All patients responded well to the local corticosteroid therapy. Conclusions: Our series strongly supports a link between TNF inhibition and the development of GA in some patients. When dealing with patients on these agents physicians should be aware of possible adverse events and the potential development of such complications.

Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor alpha inhibitors

Objective: To describe immune-mediated skin lesion (IMSL) development in patients during anti-tumour necrosis factor (TNF) therapy. Methods: Two hundred and fifty-two patients with rheumatoid arthritis (RA) and 183 with spondyloarthropathies (SpA) treated with anti-TNF inhibitors were analysed to identify IMSLs. Results: Of the 252 patients with RA (146 treated with infliximab, 72 with adalimumab, and 34 with etanercept), 32 developed IMSLs. Eleven patients developed psoriatic skin lesions, 10 presented with granuloma annulare (GA), five had skin vasculitis, two alopecia areata, two discoid lupus erythematosus, one lichenoid eruption (lichen planus), and one vitiligo. Of the 183 patients with SpA (138 treated with infliximab, 37 with etanercept, and eight with adalimumab), 10 cases with IMSLs were identified. All were treated with infliximab. More specifically, six patients with ankylosing spondylitis (AS) developed psoriatic skin lesions, one developed GA, one lichen planus, and one alopecia areata. In addition, one patient with psoriatic arthritis (PsA) developed skin vasculitis. The occurrence of these IMSLs ranged from 3 to 36 months with a median of 20 months. Of all the patients with IMSL development, two with psoriatic skin lesions, two with GA, and one with vasculitis stopped anti-TNF therapy because of the extent and severity of the skin lesions. Conclusions: Our results on patients treated with TNF antagonists strongly support a link between TNF inhibition and IMSL development. Although these clinical complications are rare, clinicians should be aware of their occurrence and should recognize them.

Gender and age differences in systemic lupus erythematosus. A study of 489 Greek patients with a review of the literature

We investigated whether gender and age influence the clinical course and outcome in systemic lupus erythematosus (SLE) patients. Thus, we analyzed the clinical and laboratory data of 489 SLE patients at presentation and during follow-up. In addition, disease activity score (using the European Consensus Lupus Activity Measure, ECLAM) and organ damage index (using the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index, DI) were measured. Furthermore, data from both sexes were analyzed according to the following age groups: < 55 years (younger group) and > 55 years (older group). There were 68 men and 421 women, giving a ratio of 1:7. We found no differences in the mean age, mean age at diagnosis, disease duration as well as duration of follow-up between men and women. Young men presented more frequently with serositis and discoid lesions, while women presented with Raynauds phenomenon (RP) and malar rash. Regarding the laboratory findings, young women presented more often with anti-Ro(SSA) and anti-La(SSB) antibodies, while increased levels of erythrocyte sedimentation rate (ESR) were found in old women. During follow-up, men had serositis and renal disease more frequently, while the womens group were found to complain of RP, photosensitivity and mucosal ulcers more frequently, especially in young women. Anemia, leukopenia, thrombocytopenia and elevated levels of ESR were also found more frequently in young women during follow-up. However, there were no significant differences concerning ECLAM and DI scores between the two gender groups. Using multiple logistic regression analysis, a statistically significant association of malar rash, discoid lesions, serositis, RP, anti-Ro(SSA)= La(SSB) and increased ESR with sex was found independently of age, while only malar rash showed a statistically significant association with age independentlyof sex. Thus, we conclude that gender influences the clinical expression of the disease independentlyof age, while both gender and age do not affect the overall damage score.

Increased incidence of anti-cardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to anti-phospholipid syndrome

Objective Chronic infection with hepatitis C virus (HCV) has been found to be associated with various diseases known as extra‐hepatic manifestations of HCV. Recently, HCV has been implicated as a cause of the anti‐phospholipid syndrome (APLS). We conducted a study in a well‐characterized area for epidemiological and prospective studies in the north‐western part of Greece in order to address whether an aetiopathogenesis exists between HCV and APLS. Design Seventy‐five patients with chronic hepatitis C were investigated for the presence of anti‐cardiolipin antibodies (anti‐CL) and for a past medical history supportive to the diagnosis of APLS. In addition, 24 patients with well‐defined APLS (primary or secondary) and 12 patients with systemic lupus erythematosus (SLE) were tested for the presence of markers of HCV infection (anti‐HCV and HCV RNA). The SLE patients were anti‐CL‐positive but none of them had developed any of the known clinical features of APLS. In addition, 267 healthy subjects were investigated for the presence of anti‐CL. Methods IgG and IgM anti‐CL were determined by a quantitative isotype‐specific solid phase enzyme‐linked immunosorbent assay set up in our laboratory. Anti‐HCV was determined using a third‐generation enzyme immunoassay and a confirmatory third‐generation recombinant immunoblot assay. Active virus replication was defined by the detection of HCV RNA using a combination assay based on a reverse transcriptase polymerase chain reaction and a DNA enzyme immunoassay. Results Of the HCV patients, 37.3% had IgG and/or IgM anti‐CL (P < 0.00005 compared to healthy controls (2.25%)). However, the mean titres of each specific isotype were significantly lower in HCV patients compared with those found in the APLS patients (P < 0.05 for IgM and P < 0.001 for IgG isotypes). The mean titres of IgG anti‐CL were also significantly lower in HCV patients compared with those found in the SLE patients (P < 0.01). All patients with APLS or SLE (n = 36) tested negative for HCV infection markers. In addition, neither thrombotic events nor thrombocytopenia were associated with a positive anti‐CL test in HCV patients. Conclusions A significant proportion of HCV patients (37.3%) had detectable anti‐CL of low titre. However, this finding was not associated with the development of APLS. On the other hand, none of the APLS patients was positive for HCV. Taken together, our data rather failed to reveal an aetiopathogenetic link between HCV and APLS. For this reason, testing for HCV in patients with APLS or follow‐up for the possibility of the development of APLS in HCV patients cannot be suggested, at least in Greek patients. More prospective studies of longer duration are required in order to address whether HCV is involved or not in the aetiopathogenesis of APLS. Eur J Gastroenterol Hepatol 12:67 ‐ 74

Ear involvement in systemic lupus erythematosus patients: a comparative study

Ear damage in systemic lupus erythematosus (SLE) patients has been occasionally reported but the frequency and the mechanisms of ear involvement are not well documented. In an attempt to investigate the presence of hearing loss and the possible causes for it we prospectively evaluated 43 SLE patients. All patients underwent a complete ear-nose-throat physical examination and audiological evaluation with pure tone, impedance and speech audiometry. In addition, systemic manifestations of the disease and drug therapy were recorded. Finally, all patients were tested for the presence of autoantibodies. The results were compared with those of 50 age-matched healthy subjects. Hearing loss (HL) was found in nine patients (22.5 per cent). More specifically, eight patients presented sensorineural hearing loss (SNHL) (21.5 per cent) and only one had conductive hearing loss (CHL) (2.63 per cent). From the patients with SNHL, one had bilateral symmetrical damage, four had bilateral but no symmetrical damage and three patients showed unilateral SNHL. Finally, the patient with CHL had unilateral involvement. There were no statistically significant differences between patients with HL and those without regarding age, disease duration, clinical disease manifestations, autoantibody profile and drug therapy. In conclusion, one fourth of our SLE patients presented HL, expressed as SNHL affecting mainly the middle and high frequencies, while only one patient had CHL. This is a lower percentage of ear involvement in SLE than that reported by other investigators. The mechanism of ear damage remains unknown. Thus, additional prospective studies are needed to elucidate its pathogenesis.