Costantino Botsios

Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate

Infliximab, a humanised, mouse derived, genetically engineered, monoclonal antibody to tumour necrosis factor α (TNFα), is successfully used in association with low dose methotrexate in the treatment of rheumatoid arthritis (RA).1 Serious infections have been reported to be associated with infliximab treatment.1,2 However, the safety of infliximab is unknown or has not been yet established in chronic viral infections, including human immunodeficiency virus, hepatitis B virus (HBV) or hepatitis C virus infections. We describe a case, from our cohort of 102 patients treated with infliximab plus methotrexate, who carried hepatitis B surface antigen (HBsAg) and subsequently developed acute hepatitis due to HBV reactivation after 16 months of treatment with infliximab. A 49 year old man was diagnosed as having RA in January 1990. HBsAg, and HBe and HBc antibodies were positive, while HBe antigen and HBs …

Infections and autoimmunity: the multifaceted relationship

Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. This review focuses on the pivotal role of infection in the induction of autoimmune disorders. Although the development of autoimmune phenomena linked to infections is a common finding, the onset of autoimmune diseases is a rare event, arising from a combination of genetic susceptibility and environmental factors. There are several mechanisms through which pathogens can initiate or perpetuate autoimmunity. Some of them are antigen‐specific, including molecular mimicry, expression of modified, cryptic, or new antigenic determinants, and superantigens. Others are nonspecific and collectively known as “bystander activation.” They include enhanced processing and presentation of self‐antigens, immune cell activation, cytokine release, and cell apoptosis/necrosis. Infections may also trigger organ‐specific autoimmune diseases, but studies carried out until now have provided conflicting and inconclusive results regarding the role of viral and bacterial agents. Infections and autoimmune diseases have multifaceted and multidirectional relationships. It has been suggested recently that infections cannot only induce or precipitate autoimmune diseases, but they may also protect from autoimmunity or even abrogate an ongoing autoimmune process depending on the interaction between microorganisms and host. Therefore, we should look at microorganisms, not only as causes of infections but also as potential agents able to modulate the immune system. On the other hand, numerous evidences have emerged regarding the higher susceptibility of autoimmune patients to infections, possibly as a result of immunosuppressive therapy and treatment with biologic agents.

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: Comparison of adalimumab, etanercept and infliximab in the GISEA registry

OBJECTIVE To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

Longterm Retention of Tumor Necrosis Factor-α Inhibitor Therapy in a Large Italian Cohort of Patients with Rheumatoid Arthritis from the GISEA Registry: An Appraisal of Predictors

Objective. To evaluate 4-year retention rates of tumor necrosis factor-α (TNF-α) inhibitors adalimumab, etanercept, and infliximab among patients with longstanding rheumatoid arthritis (RA), as derived from an Italian national registry. Methods. The clinical records of 853 adult patients with RA in the GISEA (Gruppo Italiano Studio Early Arthritis) registry were prospectively analyzed to compare drug survival rates and the baseline factors that may predict adherence to therapy. Results. In 2003 and 2004, 324 patients started treatment with adalimumab, 311 with etanercept, and 218 with infliximab. After 4 years, the global retention rate of anti-TNF-α therapy was 42%. Etanercept survival (51.4%) was significantly better than that of infliximab (37.6%) or adalimumab (36.4%; p < 0.0001). Accordingly, the mean duration of therapy was significantly longer for etanercept (3.1 ± 2 yrs) than for adalimumab (2.6 ± 2 yrs) or infliximab (2.7 ± 2 yrs; p < 0.05). The use of concomitant disease-modifying antirheumatic drugs, mainly methotrexate, and the presence of comorbidities significantly predicted drug continuation (p < 0.01), whereas a high Disease Activity Score did not. Conclusion. The 4-year global drug survival of adalimumab, etanercept, and infliximab was lower than 50%, with etanercept having the best retention rate. The main positive predictor of adherence to anti-TNF-α therapy was the concomitant use of methotrexate. Our study provides further evidence that the real-life treatment of patients with RA may be different from that of randomized clinical trials.

Fibromyalgia in Italian patients with primary Sjögren's syndrome

OBJECTIVE To assess the prevalence of fibromyalgia in primary Sjögrens syndrome and to evaluate the clinical differences between patients affected with both primary fibromyalgia and primary Sjögrens syndrome and those affected only with primary fibromyalgia. METHODS Clinical features of fibromyalgia were evaluated in 100 consecutive outpatients with primary Sjögrens syndrome and, as controls, in 90 patients with non-insulin-dependent diabetes mellitus, in 75 patients with primary fibromyalgia and in 30 healthy subjects. RESULTS Fibromyalgia was recorded in 22% of patients with primary Sjögrens syndrome, in 12.2% with diabetes and in 3.3% of healthy controls. In the primary Sjögrens syndrome group the prevalence was significantly higher than in healthy controls (P < 0.01), but not significantly different than in diabetes. Moreover, primary Sjögrens syndrome with fibromyalgia and primary fibromyalgia patients did not differ with respect to the number of tender points, while the mean pain threshold was lower in the latter (P = 0.05). Purpura, hypergammaglobulinemia, rheumatoid factor, and a focus score > or = 1 on lip biopsy were significantly more frequent in primary Sjögrens syndrome patients without than with fibromyalgia. CONCLUSIONS As recently reported by other authors, our study confirms the moderate increase of fibromyalgia prevalence in primary Sjögrens syndrome. Typical fibromyalgic findings are quite similar to those of primary fibromyalgia, but surprisingly, primary Sjögrens syndrome patients with fibromyalgia show a less severe global involvement than those with primary Sjögrens syndrome alone.

Adult-onset Still’s disease with myocarditis successfully treated with the interleukin-1 receptor antagonist anakinra

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 30 octobre 2010

Cost-effectiveness of etanercept treatment in early active rheumatoid arthritis followed by dose adjustment.

OBJECTIVES To explore the cost-effectiveness of early biologic treatment, followed by dose-reduction in the case of remission, of active rheumatoid arthritis (RA), compared with standard treatment with methotrexate (MTX) in Sweden. METHODS Effectiveness (function, disease activity, erosions) in early RA for both alternatives was taken from a clinical trial comparing etanercept (ETA) combined with MTX to MTX alone. Patients discontinuing treatment can switch to another or their first biologic treatment. For patients in remission (Disease Activity Score [DAS28] < 2.6), ETA is reduced to half the dose. Return to full dose occurs when DAS28 reaches ≥ 3.2 again. Costs and utilities by level of functional capacity from an observational study are used. The model is analyzed as a micro-simulation and results are presented from the societal perspective for Sweden, for 10 years; costs (€2008) and effects are discounted at 3 percent. Sensitivity analysis was performed for the perspective, the time horizon, switching, and dose-reduction. RESULTS The main analysis conservatively assumes 50 percent switching at discontinuation. The cost per quality-adjusted life-year (QALY) gained with early ETA/MTX treatment is €13,500 (societal perspective, incremental cost of €15,500 and incremental QALYs of 1.15). With 75 percent switching, the cost per QALY gained was €10,400. Over 20 years, the cost per QALY gained was €8,200. Results were further sensitive to the time patients remained on half dose and the perspective. CONCLUSIONS AND POLICY IMPLICATIONS: This study combines clinical trial and clinical practice data to explore cost-effective treatment scenarios in early RA, including the use of biologics. Our results indicate that a situation where a considerable proportion of patients achieve remission, dose-adjustments will increase the cost-effectiveness of treatment.

Non‐complementaemic urticarial vasculitis: successful treatment with the IL‐1 receptor antagonist, anakinra

Urticarial vasculitis (UV) is a clinical and pathological entity characterized by recurrent episodes of urticaria with the histopathological features of leucocytoclastic vasculitis (1). This condition is idiopathic in many patients but can also occur in the context of autoimmune disorders, infections, drug reactions, or as a paraneoplastic syndrome. The variability in the clinical presentation may be due to the presence or absence of hypocomplementaemia (2). Here we describe a case of noncomplementaemic UV (NUV) successfully treated with anakinra. A 54-year-old man was referred to our department for a second opinion because of fever of 3 years’ duration. The patient also complained of recurrent urticaria for approximately 4 years. Prior to presentation at our clinic, he had been treated for 6 months with cyclosporin (5 mg/kg/day) and for the past 2 months with up to 40 mg of daily prednisone without improvement. The urticarial lesions were located on the trunk and extremities. No arthritis or splenomegaly was evident. Laboratory data were significant for elevated erythrocyte sedimentation rate (70 mm/h) and C-reactive protein (83 mg/L). Cryoglobulins and circulating immune complexes were absent, serology for hepatitis C was negative, and complement profile was normal. Biopsy of an urticarial lesion revealed swelling of endothelial cell nuclei with disruption of the vessel wall, extravasation of red blood cells, fibrin deposition, and an infiltrate of neutrophils and lymphocytes with occasional eosinophils. Bone marrow biopsy was unremarkable. Multiple cultures of blood, urine, and sputum were negative. A diagnosis of NUV was made and the patient was started on methotrexate (15 mg/weekly i.m.), prednisone (25 mg/daily), and naproxen (500 mg twice a day). After 6 months of this regimen, fever and urticaria were reduced but persisted. The patient reported a dramatic remission in all symptoms following the initiation of anakinra (100 mg/daily s.c.). After 2 weeks of anakinra, methotrexate and naproxene were stopped, and

Elderly onset of primary Sjögren’s syndrome: Clinical manifestations, serological features and oral/ocular diagnostic tests. Comparison with adult and young onset of the disease in a cohort of 336 Italian patients

OBJECTIVES To study and compare the clinical and serological features of patients with elderly versus adult and younger onset of primary Sjögrens syndrome (pSS). METHODS We analyzed retrospectively 336 consecutive pSS patients followed at our unit. They were subdivided into three groups according to the age at disease onset: elderly (>65 years), adult (>40 and ≤65 years), and young (≤40 years). Clinical and immunological features of the disease, labial salivary glands biopsy, ocular and oral tests were collected at time of diagnosis and then compared among the three groups. RESULTS In 21 (6%) patients, disease onset occurred after the age of 65 years. At the time of diagnosis, 15 (71.4%) of these patients reported symptoms of dry mouth and 16 (76.1%) of dry eye. The most common extraglandular manifestation were arthralgias in 14 (66.7%), Raynauds phenomenon in five (23.8%) and purpura in three (14.2%) cases. Ocular diagnostic tests (Schirmers I and Rose-Bengal staining) were positive respectively in 17 (80%) and nine (44.4%) patients. In eight (38%) cases, unstimulated whole salivary flow showed normal values, while 12 patients (57.1%) showed positivity for salivary sialography. A focus score greater or equal to 1 per 4mm(2) was demonstrated in 11 (53.3%) of the 21 cases. CONCLUSION Elderly onset of pSS was associated with similar incidence of the diagnostic tests positivity (parotid sialography, ocular tests, minor salivary gland biopsy) in comparison with adult and younger onset. Moreover, no statistical differences were found among the three groups concerning sex, disease duration, as well as ocular and oral symptoms.

Serum and salivary neopterin and interferon‐γ in primary Sjögren's syndromeCorrelation with clinical, laboratory and histopathologic features

Objective: To investigate serum and salivary neopterin and interferon‐γ as possible markers of immune system activation in primary Sjögrens Syndrome (pSS). Methods: Serum and salivary neopterin and interferon‐γ concentrations were determined in 30 untreated patients with pSS and matched with several other clinical and laboratory parameters. Results: The mean concentration of neopterin was significantly higher in pSS patients (8.12±3.36 nmol/L in serum and 9.50±7.61 nmol/L in saliva) than in normal controls (p<0.05). Significant correlations were found between serum neopterin and β2‐microglobulin, serum IgG as well as lip biopsy score. Salivary neopterin concentration was inversely related to Shirmer‐I test, tear break‐up time and stimulated salivary flow rate. Serum and salivary levels of interferon‐γ were normal and no correlation with the other parameters was found. Conclusion: In pSS patients serum neopterin may represent a useful marker of cell‐mediated immunity. On the other hand, salivary neopterin seems to reflect the glandular damage.