Roberta Priori

Infliximab Treatment for Ocular and Extraocular Manifestations of Behçet's Disease

PurposeTo assess the efficacy and safety of infliximab in the treatment of sight-threatening uveitis and extraocular manifestations in patients with Behçets disease.MethodsTwelve patients with Behçets disease and uveitis were treated with infliximab after unsuccessful therapy with other immunosuppressive drugs. The main outcome measures were as follows: the number of uveitis relapses, the number of Behçets disease-related extraocular lesions, and the amount of corticosteroids administered during the treatment as well as during an equal prior period of time while the patients were on other immunosuppressive agents. Visual acuity was recorded at the beginning of infliximab therapy and at the end of follow-up, and was defined as stable if it did not change from baseline, increased if it showed at least one line of improvement from baseline, and decreased if it showed at least a one line decrease from baseline.ResultsDuring an average follow-up of 16.67 ± 7.63 months (median, 15 months), 11 patients (91.6%) showed a reduction in the number of ocular relapses (relapse/month, from 0.35 ± 0.17 to 0.12 ± 0.17, P < 0.001). All of the patients (n = 11) who were taking corticosteroids before infliximab were able to reduce the amount of corticosteroids taken daily during infliximab treatment (from 24.33 ± 10.84 mg/prednisone per day to 8.97 ± 6.81 mg/prednisone per day, P < 0.001), and all presented with a reduced onset of extraocular manifestations of Behçets disease (mean total number, from 2.83 ± 3.61 to 1.51 ± 2.35, P = 0.039). One patient, who had to stop treatment 2 months after starting because of the onset of pulmonary tuberculosis, showed the same number of relapses during infliximab treatment but was able to reduce the mean daily corticosteroid dose. Visual acuity increased by one or more lines in three eyes (12.5%) and remained unchanged in 87.5% of the eyes. Infliximab-related side effects appeared in four patients (33.3%).ConclusionsInfliximab was effective in the treatment of uveitis in these Behçets disease patients, significantly reducing the number of ocular relapses and making possible a significant reduction in the daily dose of corticosteroids administered. Extraocular manifestations of Behçets disease were also controlled by infliximab. Nevertheless, side effects were not uncommon, and an extensive study of systemic conditions before infliximab administration had to be carried out to exclude systemic infection, particularly prior tuberculosis. Jpn J Ophthalmol 2007;51:191–196

Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis

We read with interest the debate about liver toxicity of infliximab in psoriatic arthritis (PsA).1,2 We describe the case of a 53 year old woman with a 4 year history of refractory PsA who developed transaminasitis during infliximab treatment. Despite combination treatment (ciclosporin 300 mg/day, fluocortolone 10 mg/day, and methotrexate (MTX)15 mg/week intramuscularly), disease activity was still high, and intravenous infliximab at 3 mg/kg was administered initially at weeks 0, 2, 6, 14 and then every 6 weeks. Ciclosporin was withdrawn. Within 3 weeks she improved, fluocortolone was gradually stopped while methotrexate (MTX) 20 mg/week intramuscularly, was continued. After the sixth infusion, she developed a mild transaminasitis and MTX, initially tapered, was stopped. After the eighth infusion transaminases continued to rise and in the absence of any other plausible cause, infliximab was withdrawn. She was admitted to our department with persistently high values of aspartate aminotransferase and alanine aminotransferase and a flare of PsA. …

Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjögren's syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate

IL-18, an immunoregulatory and proinflammatory cytokine, has been shown to play an important pathogenic role in Th1-driven autoimmune disorders. In this study, we evaluated the circulating levels and salivary-gland expression of IL-18 in patients with Sjögrens syndrome (SS), a mainly Th1-mediated disease. IL-18 serum levels were measured by ELISA in 37 patients with primary SS, 42 with rheumatoid arthritis, and 21 normal controls. We demonstrated high IL-18 serum levels in SS, similar to those in rheumatoid arthritis patients and significantly higher than in controls (P < 0.01). In addition, IL-18 serum concentrations were significantly higher in anti-SSA/Ro+ and anti-SSB/La+ than in anti-SSA/Ro- and anti-SSB/La- SS patients (respectively, P = 0.01, P < 0.01). Serum IL-18 correlated strongly with anti-SSA/Ro (P = 0.004) and anti-SSB/La (P = 0.01) titers. Salivary gland IL-18 expression was investigated by single/double immunohistochemistry in 13 patients with primary SS and in 10 with chronic sialoadenitis, used as controls. The expression of IL-18 was also examined in periductal inflammatory foci in relation to the acquisition of features of secondary lymphoid organs such as T–B compartmentalization, formation of follicular dendritic cell networks, and presence of germinal-center-like structures. IL-18 expression in SS salivary glands was detected in 28 of 32 periductal foci of mononuclear cells (87.5%), while no IL-18 production by infiltrating cells was detected in patients with chronic sialoadenitis. Within the inflammatory foci, IL-18 immunoreactivity co-localized almost exclusively with CD68+ macrophages. In addition, IL-18 was found in 15 of 19 foci (78.9%) with no evidence of T–B cell compartmentalization (nonsegregated) but in 100% of the segregated aggregates, both in T- and B-cell-rich areas. Strikingly, IL-18 was strongly expressed by CD68+ tingible body macrophages in germinal-centre-like structures both in SS salivary glands and in normal lymph nodes. IL-18 expression was observed in the ducts of all SS biopsies but in only 4 of 10 patients with nonspecific chronic sialoadenitis (P < 0.01). This study provides the first evidence of increased circulating levels and salivary gland expression of IL-18 in SS, suggesting an important contribution of this cytokine to the modulation of immune inflammatory pathways in this condition.

Ultrasonography of salivary glands in primary Sjögren's syndrome: a comparison with contrast sialography and scintigraphy

OBJECTIVE To compare ultrasonography (US) of salivary glands with contrast sialography and scintigraphy, in order to evaluate the diagnostic value of this method in primary SS (pSS). METHODS The diagnostic value of parotid gland US was studied in 77 patients with pSS (male/female ratio 3/74; mean age 54 yrs) and in 79 with sicca symptoms but without SS. The two groups were matched for sex and age. Imaging findings of US were graded using an ultrasonographic score ranging from 0 to 16, which was obtained by the sum of the scores for each parotid and submandibular gland. The sialographic and scintigraphic patterns were classified in four different stages. The area under receiver operating characteristic curve (AUC-ROC) was employed to evaluate the screening methods performance. RESULTS Of the 77 patients with pSS, 66 had abnormal US findings. Mean US score in pSS patients was 9.0 (range from 3 to 16). Subjects without confirmed pSS had the mean US score 3.9 (range from 0 to 9) (P < 0.0001). Results of sialography showed that 59 pSS patients had abnormal findings at Stage 1 (n = 4), Stage 2 (n = 8), Stage 3 (n = 33) or Stage 4 (n = 14), and 58 patients had abnormal scintigraphic findings at Stage 1 (n = 11), Stage 2 (n = 18), Stage 3 (n = 25) or Stage 4 (n = 4). Through ROC curves US arose as the best performer (AUC = 0.863 +/- 0.030), followed by sialography (AUC = 0.804 +/- 0.035) and by salivary gland scintigraphy (AUC = 0.783 +/- 0.037). The difference between AUC-ROC curve of salivary gland US and scintigraphy was significant (P = 0.034). Setting the cut-off score >6 US resulted in the best ratio of sensitivity (75.3%) to specificity (83.5%), with a likelihood ratio of 4.58. If a threshold >8.0 was applied the test gained specificity, at the cost of a serious loss of sensitivity (sensitivity 54.5%, specificity 97.5%, likelihood ratio 21.5). CONCLUSIONS Salivary gland US is a useful method in visualizing glandular structural changes in patients suspected of having pSS and it may represent a good option as a first-line imaging tool in the diagnostics of the disease.

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI)

Objectives To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögrens syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). Methods For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients’ satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. Results Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. Conclusions This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

CARDIAC INVOLVEMENT IN BEHCET'S DISEASE

To assess the prevalence and the extent of cardiac involvement in patients with Behçets disease and to investigate the possible causes that may predispose to this involvement, 30 patients affected by Behçets disease and 30 normal control subjects were submitted to M-mode, two-dimensional, and Doppler echocardiographic evaluation. Moreover, antinuclear and anticardiolipin autoantibodies were determined in the sera of both patients and control subjects. Finally, HLA-B51 positivity was assessed in the patients and in a historical control group. Mitral valve prolapse was observed in 50% and proximal aorta dilatation in 30% of the patients. There was a significant difference in the rate of these abnormalities in comparison with the control group. Left ventricular function parameters were similar between the two groups. The positivity rate of antinuclear and anticardiolipin autoantibodies was very low (7%), without differences between the groups. HLA-B51 was detected in 82.7% of the patients versus 21.7% in the control group (p < 0.00001). In conclusion, this study demonstrates a high rate of cardiac abnormalities in patients with Behçets disease.

Familial autoimmunity as a risk factor for systemic lupus erythematosus and vice versa: A case-control study

The objective of this multicentric case-control study was to investigate if a history of autoimmune disease (AD) in first-degree relatives (FDR) is a risk factor for systemic lupus erythematosus (SLE) and to evaluate the risk of AD among FDR of SLE patients. Cases were Italian SLE patients consecutively enrolled. Controls were orthopaedic inpatients without any autoimmune diseases.The strength of the association between family history of AD and SLE was measured as an odds ratio (OR) calculated from the coefficient of an unconditional regression model. To calculate the risk of AD among FDR of SLE patients, the extended generalized estimating equation technique was used. In total, 154 SLE cases and 140 controls were enrolled. A family history of AD was reported by 22.7% of SLE patients and by 5.7% of the controls. The risk of SLE increased with the number of FDR with AD (one FDR affected, OR 4.1; two or more, OR 11.3). The probability of having AD was higher among FDR of SLE cases in comparison to FDR of controls (RR 4.6; 95%CI 1.9-11.1). A female SLE patient conferred an increased risk of AD to her FDR; this risk is doubled in females (OR 10.3; 95% CI 3.1-34.4).

Biomarkers of lymphoma in Sjögren's syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study.

OBJECTIVES To define the biomarkers associated with lymphoproliferation in primary Sjögrens syndrome (pSS) by distinguishing in separate groups the two best-recognized non-malignant prelymphomatous conditions in pSS, i.e., salivary gland swelling and cryoglobulinemic vasculitis (CV). METHODS A multicenter study was conducted in 5 centres. Patients fulfilled the following criteria: (1) positive AECG criteria for pSS, (2) serum cryoglobulins evaluated, and (3) lack of hepatitis C virus infection. Four groups were distinguished and analysed by multinomial analyses: (1) B-cell non-Hodgkins lymphoma (NHL), (2) CV without lymphoma, (3) salivary swelling without NHL (SW), and (4) pSS patients without NHL or prelymphomatous conditions. RESULTS Six hundred and sixty-one patients were studied. Group 1/NHL comprised 40/661 (6.1%) patients, Group 2/CV 17/661 (2.6%), Group 3/SW 180/661 (27.2%), and Group 4/pSS controls 424/661 (64.1%). Low C4 [relative-risk ratio (RRR) 8.3], cryoglobulins (RRR 6.8), anti-La antibodies (RRR 5.2), and leukopenia (RRR 3.3) were the variables distinguishing Group 1/NHL from Group 4/Controls. As concerns the subset of patients with prelymphomatous conditions, the absence of these biomarkers provided a negative predictive value for lymphoma of 98% in patients with salivary swelling (Group 3/SW). Additional follow-up studies in patients with SW confirmed the high risk of lymphoma when at least 2/4 biomarkers were positive. CONCLUSIONS Lymphoma-associated biomarkers were defined in a multicentre series of well-characterized patients with pSS, by dissecting the cohort in the pSS-associated prelymphomatous conditions. Notably, it was demonstrated for the first time that among the pSS patients with salivary swelling, only those with positive biomarkers present an increased risk of lymphoma evolution.

Lymph node IL-18 expression in adult-onset Still's disease

IL-18 is a pleiotropic immunoregulatory cytokine that has been described and implicated in the pathogenesis of a variety of inflammatory diseases.1–4 Studies in murine models of arthritis and clinical studies suggest that dendritic cells, macrophages and synoviocites within the synovial membrane can produce IL-18.1 5–7 IL-18 expression has in turn been implicated in the reciprocal regulation of other pro-inflammatory cytokines, such as tumour necrosis factor alpha.8 Recent data clearly demonstrated that IL-18 serum levels were significantly elevated in adult-onset Still’s disease (AOSD) and correlated with disease activity and serum ferritin levels.2–4 AOSD is characterised by substantial and dysregulated …

Central nervous system involvement in systemic lupus erythematosus: a new therapeutic approach with intrathecal dexamethasone and methotrexate.

SummaryIn systemic lupus erythematosus (SLE), neurological involvement has been reported to occur with frequencies ranging from 14% (severe cases) to 83% (mild forms included). In spite of early diagnosis and aggressive treatment, neuropsychiatric SLE may represent a serious problem of management. We describe three cases, one with acute transverse myelitis, one with hemiparesis, and one with signs of focal and diffuse cerebral dysfunction, in whom improvement following intrathecal therapy with methotrexate and dexamethasone was observed.