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Aim: We investigated the clinical relevance of SLC19A1 genetic variability for methotrexate (MTX) toxicity in rheumatoid arthritis patients using a haplotype-based approach., Patients & Methods: Two hundred and twelve unrelated rheumatoid arthritis patients and 89 lymphoblastoid cell lines were used to investigate the effect of SLC19A1 SNPs and haplotypes on MTX adverse events and treatment discontinuation., Results: Two putatively functional SNPs in high linkage disequilibrium, rs1051266 and rs1131596, were associated with protection (hazard ratio: 0.33; 95% CI: 0.16-0.69; adjusted p = 0.021 and hazard ratio: 0.38; 95% CI: 0.17-0.27; adjusted p = 0.021, respectively) of discontinuation of MTX treatment owing to toxicity. These SNPs were also associated with protection from infections. SLC19A1 haplotype analysis found significant associations with MTX discontinuation owing to toxicity (p = 0.025). Quantification of SLC19A1 mRNA in cell lines suggested that rs1131596 was not a major causal variant., Conclusion: Individual SNP and haplotype analyses suggest that rs1051266 could be a functional variant altering MTX toxicity; however, validation in independent studies is needed.

Vaccines have undoubtedly brought overwhelming benefits to mankind and are considered safe and effective. Nevertheless, they can occasionally stimulate autoantibody production or even a recently defined syndrome known as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). There is scarce data regarding autoimmune response after seasonal/influenza A (H1N1) vaccine in patients with autoimmune inflammatory rheumatic disease (AIRD). The objective of our study was therefore to determine autoimmune response in a large group of AIRD patients vaccinated against seasonal and/or H1N1 influenza. We conducted a prospective cohort study with a 6-month follow-up. Two-hundred and eighteen patients with AIRD (50 vaccinated against seasonal influenza, six against H1N1, 104 against both, 58 non-vaccinated controls) and 41 apparently healthy controls (nine vaccinated against seasonal influenza, three against H1N1, 18 against both, 11 non-vaccinated controls) were included. Blood samples were taken and screened for autoantibodies [antinuclear antibody (ANA), anti-extractable nuclear antigen (anti-ENA), anticardiolipin (aCL) IgG/IgM antibodies, anti-beta 2-glycoprotein I (anti-β2GPI)] at inclusion in the study, before each vaccination, 1 month after the last vaccination and 6 months after inclusion. For non-vaccinated participants (patients and healthy controls) blood samples were taken at the time of inclusion in the study and 6 months later. We report that after the administration of seasonal/H1N1 vaccine there were mostly transient changes in autoantibody production in AIRD patients and in healthy participants. However, a small subset of patients, especially ANA-positive patients, had a tendency towards anti-ENA development. Although no convincing differences between the seasonal and H1N1 vaccines were observed, our results imply that there might be a slight tendency of the H1N1 vaccine towards aCL induction. Although seasonal and H1N1 vaccines are safe and effective, they also have the potential to induce autoantibodies in selected AIRD patients and healthy adults. Follow-up of such individuals is proposed and further research is needed.

Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 +/- 39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of

Objectives: Glutathione S-transferases (GST); GST-mu1 (GSTM1), GST-pi1 (GSTP1) and GST-theta1 (GSTT1) have peroxidase activity towards cytotoxic metabolites produced in inflammatory reactions, the main feature of rheumatoid arthritis (RA). Genetic polymorphisms in GSTM1, GSTP1 and GSTT1 modify the enzyme conjugation capacity and may be associated with the activity of RA., Methods: A genotyping approach was used to analyze GSTM1-0, GSTT1-0 and GSTP1 Ile105Val and Ala114Val polymorphisms in 213 RA patients. Disease activity was assessed by the disease activity score of 28 joint counts (DAS28) twice for each patient and mean DAS28 values were calculated., Results: The patients with GSTT1-0 genotype had a higher risk for developing high activity RA than the patients with GSTT1 genes present (p=0.028, OR=2.761, 95% CI=1.114-6.843). An interaction between the GSTT1 polymorphism and smoking was observed. In the group of smokers, the carriers of a homozygous deletion GSTT1 had an 8.5-fold higher risk for developing high disease activity than the patients with the GSTT1-1 genotype (p=0.004, OR=8.640, 95% CI=1.995-37.426). GSTM1 and GSTP1 polymorphisms were not associated with the disease activity., Conclusion: Our results suggest that the presence of the GSTT1-0 genotype contributed to higher disease activity in RA patients. The risk for developing highly active RA was the highest in smokers with the GSTT1-0 genotype.

Reactive oxygen and nitrogen species are involved in the pathology of rheumatoid arthritis (RA). Polymorphisms in genes coding for superoxide dismutases (SOD2 and SOD3), catalase (CAT), tumor necrosis factor-alpha (TNFA) and inducible NO synthase (NOS2A) may influence RA activity. We determined SOD2 Ala-9Val, SOD3 Arg213Gly, CAT C-262T, TNFA G-308A, TNFA C-857T and NOS2A (CCTTT) (n)polymorphisms in 327 RA patients. Carriers of CAT -262T and TNFA -308A allele had lower mean disease activity score of 28 joint count (DAS28) values than patients with CAT -262CC and TNFA -308GG genotypes (p = 0.014 and p = 0.046, respectively). Patients with the combination of CAT -262T and TNFA -308A allele had lower mean DAS28 values and a higher probability for low disease activity than non-carriers (p = 0.003, OR = 3.585, 95% CI = 1.538-8.357). Our results suggest that CAT and TNFA polymorphisms alone and in combination influence the activity of RA.

Objective: Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TS 2R-->3R), methionine synthase (MS A2756G) and methionine synthase reductase (MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response., Methods: A genotyping approach was used to determine the studied polymorphisms in 213 RA patients., Results: We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P = 0.039, OR = 3.574, 95% CI = 1.065-11.993 and P = 0.032, OR = 7.801, 95% CI = 1.194-50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P = 0.027, OR = 0.170, 95% CI = 0.035-0.820)., Conclusion: Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment.

Objective: Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic polymorphisms of CYP1A2, CYP2C19, and CYP2C9 influence leflunomide toxicity., Methods: A genotyping approach was used to determine CYP1A2*1F, CYP2C19*2, CYP2C19*17, CYP2C9*2, and CYP2C9*3 alleles in 105 RA patients., Results: Leflunomide treatment was well tolerated by 62 patients, whereas 43 patients discontinued the treatment within the first year due to toxicity. Patients with CYP1A2*1F CC genotype had a 9.7-fold higher risk for overall leflunomide-induced toxicity than did the carriers of CYP1A2*1F A allele [P = 0.002, odds ratio = 9.708, 95% confidence interval = 2.276-41.403]. No significant association between the CYP2C19 and CYP2C9 genotypes and the leflunomide toxicity was observed., Conclusion: Our results suggest that the CYP1A2*1F allele may be associated with leflunomide toxicity in RA patients.

With the broad employment of immunosuppressive therapy, the incidence of Pseudallescheria boydii infections is rising. We report a first case of the localized subcutaneous P. boydii infection in a patient with microscopic polyangiitis. Favorable outcome related to the treatment with voriconazole adds to the growing body of evidence supporting the use of this particular agent in P. boydii infections.

Objective: To develop response criteria for polymyalgia rheumatica (PMR) for monitoring treatment and comparing alternative treatments regimens., Methods: 76 patients, mean (SD) age 68.7 (7.7) years, were enrolled. Corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) were the only drugs allowed during the observation period. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), alpha(2) globulin, serum iron, pain, physician's global assessment (PGA), morning stiffness (MST), muscle tenderness (MT), myalgia, and the elevation of upper limbs (EUL) were determined regularly. The daily corticosteroid and NSAID doses as the corticosteroid response time were recorded. To ensure evaluation of an adequate number of patients (n = 57) week 24 was chosen for final analysis., Results: ESR, CRP, alpha(2) globulin, pain, PGA, MST, myalgia, MT, and EUL showed significant improvement (p<0.0001) at week 24 compared with week 0. Multiple regression analysis showed that changes of ESR (p = 0.08), CRP (p = 0.41), alpha(2) globulin (p = 0.13), MST (p = 0.1), and MT (p = 0.07) were independent of pain, but myalgia (p<0.001) and EUL (p = 0.003) were pain dependent. Consequently, a core set of PMR response criteria, comprising ESR or CRP, pain, PGA, MST, and EUL was established. Assessment of treatment responses with this core set resulted in 90%, 70%, 50%, and 20% improvement in 31/57 (54%), 46/57 (81%), 51/57 (89%), and 54/57 (95%) of the patients, respectively., Conclusion: These PMR response criteria are a promising tool for better monitoring of disease activity and treatment in PMR. It is proposed that these criteria should be used in clinical trials in the near future to explore alternative treatment options for PMR.

Objective: To analyse the influence of HLA-DR, DQ and corresponding DQA1 and DQB1 promoter alleles (QAP and QBP) on the anti-Ro alone autoantibody response in systemic lupus erythematosus (SLE)., Methods: Sixty-five unrelated anti-La antibody-negative SLE patients, 37 of them with and 28 without anti-Ro antibodies, were included. Anti-Ro antibodies were determined by both counter-immunoelectrophoresis and enzyme-linked immunosorbent assay. Seventy-four healthy individuals were selected as controls. The patients and controls were analysed for HLA-DRB1, QAP, DQA1, QBP and DQB1 alleles by DNA typing. The allelic frequencies of anti-Ro alone-positive and anti-Ro-negative SLE patients and healthy controls were compared using the chi(2) test or Fisher's exact test as appropriate., Results: The DQB1*0202 allele showed a significant positive correlation with anti-Ro alone antibodies [odds ratio (OR)=16.949, P=0.0015, corrected P=0.018], while the QBP5.11 allele and the combination of DQB1*0301 and its promoter QBP3.1 were under-represented in anti-Ro-alone-positive SLE patients (P=0.01, corrected P=0.048 and corrected P=0.048 respectively)., Conclusions: The above-mentioned alleles may contribute to the presence or absence of anti-Ro alone autoantibodies in SLE patients.

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. At this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10 y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of 1 y. Serious clinical signs or exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished.

Objective: Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE., Methods: Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up., Results: Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE., Conclusions: A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

In a sixty-one-year-old patient with chronic polyarthritis, two life-threatening septic events were observed over a period of 6 months. The patient also had a selective IgG3 deficiency. The susceptibility to infection and chronic polyarthritis observed in this patient were very likely a consequence of the selective IgG3 deficiency.

Objective: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr., Methods: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study., Results: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (

Objective: The aim of our study was to determine the prevalence of Sjögren's syndrome (SS) in Slovenia., Methods: A total of 889 randomly selected adults were invited to take part in our study. The classification of SS was based on the validated criteria reported by a multicentre study performed in Europe. The participants were asked six simple questions for assessing both ocular and oral involvement. Information on co-morbidities and related treatment was collected at the same time. All participants were subjected to a Schirmer-I test, an unstimulated salivary flow test, as well as serological studies (rheumatoid factor, antinuclear antibodies, anti-Ro/SS-A and anti-La/SS-B antibodies). When indicated, Rose Bengal score, salivary scintigraphy and histopathological investigation of the minor salivary glands were carried out until three out of the six European classification criteria for SS were shown to be negative or until SS was diagnosed., Results: Out of the 889 invited subjects, 332 (37.3%) participated in our study: 183 females, mean age (+/- S.D.) 52.2 +/- 13.7 yr (range 20-84) and 149 males, mean age (+/- S.D.) 56.3 +/- 12.9 yr (range 23-84). After the first visit, 244 of the 332 (73.5%) participants proved to be negative for three out of the six above-mentioned criteria, and were eliminated from further tests. The remaining 88 participants were consecutively subjected to Rose Bengal score, salivary scintigraphy and minor salivary gland biopsy. Fifteen participants refused to perform either one or more of the proposed tests at the second study stage. Two females of the 332 study participants [0.60% (exact 95% CI 0.07%, 2.16%)] fulfilled the criteria for primary SS., Conclusions: The estimated prevalence of definite SS in Slovenia is 0.60%.

Objective: The aim of this prospective 24-month follow-up study was to compare clinical features with radiological and magnetic resonance imaging (MRI) findings in evaluating synovial proliferation in the hand joints of 31 patients with rheumatoid arthritis (RA). A single joint was used for the follow-up of each patient., Methods: Thirty-one small hand joints were examined by conventional radiography and MRI before and after 24 months of treatment. MRI assessment of disease progression (volume and/or signal intensity of the synovial proliferation on T1 weighted precontrast, T1 weighted postcontrast and T2 weighted images) was compared with a clinical assessment of the chosen joints, and with a plain x-ray film evaluation (Larsen's score)., Results: Of 26 joints which clinically improved (14 markedly and 14 slightly) during the study, on MRI 16 showed improvement, 8 showed no change, and 2 showed deterioration. Four clinically unchanged joints appeared improved on MRI. One joint deteriorated clinically and on MRI. Overall, there was a 58% congruence between clinical and MRI findings. On x-ray 23 joints showed no change; nine of these were also unchanged on MRI, while 13 showed improvement and one deterioration. Only in 2 out of 8 joints showing deterioration on x-ray were the MRI findings in accordance. In the remaining six joints MRI showed improvement. The congruence between x-ray and MRI was therefore 36%., Conclusion: The long-term follow-up of rheumatoid synovial proliferation of the small joints in the hand using contrast enhanced MRI is feasible and may provide additional information regarding disease activity. Important advantages over conventional radiography methods are its ability to demonstrate qualitative differences of synovial proliferation within bone erosions, and demonstrate not only deterioration, but also the improvement of inflammatory disease.

Conventional radiograms have been used to quantitate the progression of rheumatoid arthritis, mainly through the assessment of bone erosions, but this approach has many limitations. It has been suggested that an advantage of contrast-enhanced Gd-DTPA MRI over radiography may be its prognostic value due to its ability to show the natural history of active destructive to inactive fibrous pannus. The aim of this study was to evaluate the possible prognostic value of MRI for future development of bone erosive changes in small hand joints in patients with RA. The results of the study confirm that in joints in which inflammatory active pannus is shown by contrast-enhanced MRI, progression of bone-destructive changes can be expected.

We report a 32-yr-old woman who suffered a stroke as a consequence of arteritis of both internal carotid arteries confirmed by selective carotid arteriography. Laryngeal inflammation and kidney biopsy proven focal crescentic glomerulonephritis were also present in this patient. Anti-neutrophil cytoplasmic autoantibodies with specificity for proteinase 3 were detected in high titre during the active phase of the disease. This overlap syndrome with features indicating both Takayasu's arteritis and Wegener's granulomatosis suggests a common pathogenesis for these diseases.

In an attempt to demonstrate whether clinically selected joints of the hand in active rheumatoid disease had consistent MRI findings, 45 patients were examined, in whom one joint in each was selected by both the referring clinician and patient as being active and symptomatic. Such joints, in order to be included in the study, were required to conform to ARA criteria of activity and usually mild to moderate X-ray changes. The joints were imaged using spin-echo sequences with T1W and T2W precontrast images, followed by T1W images after intravenous administration of Gd-DTPA. Different patterns of joint abnormalities were found. In 27 joints MRI findings suggested highly active synovitis and/or destructive pannus. In four, crescentic enhancement was thought to be compatible with simple synovitis, but in 23 rounded masses of synovial proliferation were characterized by marked, diffuse contrast enhancement on T1W postcontrast images, which corresponded well with high signal intensity on T2W images. Synovial proliferation in a further 12 joints was shown by only moderate stippled contrast enhancement and nonhomogeneous intermediate to high signal intensity on T2W images. These findings were thought to represent less active synovitis and pannus. MRI did not demonstrate inflammatory activity in six joints. In two of these pannus was of low signal intensity on T2W images, without contrast enhancement after Gd-DTPA infection presumed fibrotic and inert, and four were normal on all pulse sequences. These results suggest that clinical features of synovitis, even in carefully selected joints clinically, do not produce a homogeneous group when examined by MRI imaging. Indeed, a spectrum exists from presumed marked, active synovitis to total normality. If MRI is to be used as a clinical and research tool in the assessment of rheumatoid disease, and its therapeutic manipulation, these results are of some importance, since the variable findings indicate an appreciable heterogeneity of appearances in joints thought clinically to be of relatively uniform severity.

In spite of several articles questioning the general opinion that arterial hypertension in patients with systemic lupus erythematosus (SLE) is only the consequence of lupus glomerulonephritis (LGN), this still remains the usual pathophysiologic explanation. The purpose of this study was to explore the correlations between hypertension and LGN and to assess the importance of hypertension control for the prognosis of patients. A retrospective analysis of 173 patients with SLE over a period of 14 years was performed. For most of the patients, data were available from regular follow-up visits over an average of 6 years. Our results show a dissociation of hypertension and LGN and an association of hypertension and renal dysfunction. Severe hypertensive renal vascular lesions correlated well with a decrease of renal function. Successful treatment of hypertension is therefore essential in order to prevent deterioration of renal function in patients with LGN.

In view of the association of congenital heart block with maternal antibody to cellular antigen Ro (SSA), and one report linking anti-Ro with myocarditis in a patient with myositis an association between anti-Ro antibodies and cardiac disease was sought in adults with systemic lupus erythematosus (SLE). Among 67 patients with SLE, of whom 36 were anti-Ro positive, a significantly higher prevalence of myocarditis and conduction defects was found in the anti-Ro positive group (eight of 36) than in those who were anti-Ro negative (one of 31) and healthy controls (one of 50). Of the 36 anti-Ro positive patients with SLE, three had symptoms diagnostic of myocarditis, and an electrocardiogram showed first degree atrioventricular block and unifascicular block in three cases (including one with myocarditis), right bundle branch block alone (two cases), and first degree atrioventricular block alone (one case). Complete atrioventricular block was not seen. In the anti-Ro negative group there was no myocarditis and only one case of conduction defect (right bundle branch block). Among healthy controls only one of 50 had first degree atrioventricular block. It is concluded that myocarditis and conduction defects are reasonably common in adults with SLE and are associated with anti-Ro antibodies.