High plasma C5a and C5b-9 levels during quiescent phases are associated to severe antiphospholipid syndrome subsets.

OBJECTIVES: High plasma C5a and C5b-9 levels are considered a clear sign of complement activation. We aimed to evaluate the clinical significance of these two complement activation products during quiescent phases of thrombotic antiphospholipid syndrome (APS) by comparing their plasma levels in the different clinical subsets and relating them to the clinical characteristics and antiphospholipid antibody profile of the patients. METHODS: The three patient subsets studied were: i) thrombotic patients responsive to anti-vitamin K therapy (TAPS); ii) patients with refractory to vitamin K antagonists recurrent thrombosis (RAPS); iii) patients diagnosed with catastrophic APS (CAPS). Plasma C5a and C5b-9 levels were assessed using commercial ELISA assays. RESULYTS: Sixty-two quiescent APS patients were recruited: 40 were affected by TAPS, 13 by RAPS and 9 by CAPS. Data analysis showed that the TAPS patients had significantly lower levels of both complement activation products with respect to the RAPS and CAPS patients. In addition, C5a and/or C5b-9 significantly prevailed in the patients with small-vessel thrombosis, just as C5b-9 did in the triple antiphospholipid antibody positive patients. The ROC curve showed that the best cut-offs for C5a and C5b-9 levels had a higher sensitivity, specificity and likelihood ratio in the CAPS and RAPS groups than they did in the TAPS subset. CONCLUSIONS: These results suggest that the persistence of high plasma C5b-9 and C5a levels during quiescent phases identifies APS patients with more severe disease who may develop rethrombosis and benefit from complement inhibition treatment during an acute disease phase.

SFRP4 Expression Is Linked to Immune-Driven Fibrotic Conditions, Correlates with Skin and Lung Fibrosis in SSc and a Potential EMT Biomarker.

Secreted Frizzled Receptor Protein 4 (SFRP4) has been shown to be increased in Scleroderma (SSc). To determine its role in immune-driven fibrosis, we analysed SSc and sclerotic Chronic Graft Versus Host Disease (sclGVHD) biosamples; skin biopsies (n = 24) from chronic GVHD patients (8 with and 5 without sclGVHD), 8 from SSc and 3 healthy controls (HC) were analysed by immunofluorescence (IF) and SSc patient sera (n = 77) assessed by ELISA. Epithelial cell lines used for in vitro Epithelial-Mesenchymal-Transition (EMT) assays and analysed by Western Blot, RT-PCR and immunofluorescence. SclGVHD skin biopsies resembled pathologic features of SSc. IF of fibrotic skin biopsies indicated the major source of SFRP4 expression were dermal fibroblasts, melanocytes and vimentin positive/caveolin-1 negative cells in the basal layer of the epidermis. In vitro studies showed increased vimentin and SFRP4 expression accompanied with decreased caveolin-1 expression during TGFß-induced EMT. Additionally, SFRP4 serum concentration correlated with severity of lung and skin fibrosis in SSc. In conclusion, SFRP4 expression is increased during skin fibrosis in two different immune-driven conditions, and during an in vitro EMT model. Its serum levels correlate with skin and lung fibrosis in SSc and may function as biomarker of EMT. Further studies are warranted to elucidate the role of SFRP4 in EMT within the pathogenesis of tissue fibrosis.

Complement activation in the plasma and placentas of women with different subsets of antiphospholipid syndrome.

PROBLEM: As antiphospholipid antibody-positive women with adverse pregnancy outcomes have higher plasma complement activation product levels, and the placentas of women with antiphospholipid syndrome (APS) exhibit C4d complement component deposition, complement activation involvement has been hypothesized in APS pregnancy complications. METHOD OF STUDY: Plasma levels of C5a and C5b-9 complement components of 43 APS non-pregnant patients and 17 pregnant APS women were measured using enzyme-linked immunosorbent assay. The results were compared with those of 16 healthy non-pregnant women and eight healthy pregnant women, respectively. Placenta samples of five APS patients at high risk of pregnancy complications and of five healthy controls were subjected to immunoblotting analysis with specific antibodies to C5b-9 and CD46, CD55, CD59 complement regulators. RESULTS: The mean plasma C5a and C5b-9 levels were significantly higher in the non-pregnant APS patients with previous thrombosis ± pregnancy morbidity (P = .0001 and P = .0034, respectively) and in the pregnant APS women with adverse outcomes (P = .0093 for both). Similarly, C5b-9 amounts were significantly higher in the adverse pregnancy outcome placenta (P = .0115) than in those associated to a favorable outcome. The mean CD46, CD55 and CD59 amounts were, instead, lower, although not always significantly, in the placentas of all the high-risk APS women with respect to the control placentas. CONCLUSION: Data analysis demonstrated that there was significant complement activation in the more severe subset of APS patients and in only the adverse pregnancy outcome APS women. Further studies will clarify whether the lower CD46, CD55, and CD59 expressions in the APS placentas are limited to only high-risk APS patients.

Postural counseling represents a novel option in pain management of fibromyalgia patients.

BACKGROUND: Chronic pain is a key symptom in fibromyalgia (FM), and its management is still challenging for rheumatologists in daily practice. FM patients show psychological and psychiatric manifestations, going from mood and emotional disorders to depression and alexithymia that negatively impact their quality of life, limiting their daily activities. Since pharmacological strategies have a limited efficacy in FM pain, alternative or complementary non-pharmacological approaches have been introduced in the clinical management of FM. PATIENTS AND METHODS: This is a retrospective study on FM patients (n=52) treated with a novel integrated postural counseling (PC) rehabilitation program carried out by a counselor physiotherapist. The clinical impact of PC was evaluated by 1) a semi-structured interview using an ad hoc modified questionnaire McGill Illness Narrative Interview (MINI) 1 to obtain data on pain management by highlighting everyday experience of living with pain and 2) an FM impact questionnaire (FIQ) total score. RESULTS: Two main structures of narrative emplotment of FM illness were recognized: 1) the cumulative life narrative structure (46.15%) and 2) the broken life (53.85%) narrative structure. Baseline FIQ score was 77.38±7.77, and it was significantly reduced after PC to 39.12±13.27 (P<0.0001). Although well-being still requires further definition as outcome in pain management, it is important for FM patients, dealing with pain-related sensations, thoughts and feelings and limiting their daily activities. In our study, 87.5% of interviewed FM patients reported an improvement in their well-being after PC. CONCLUSION: Our data suggest that an integrated PC program positively impacts chronic pain and fatigue based on self-management strategies. PC allows FM patients to resume their own life and regenerate their own image. Finally, we propose the introduction of the evaluation of the ability to resume daily activities as the target of rehabilitation programs in FM.

Rituximab increases peripheral natural killer cells in patients with rheumatoid arthritis.

OBJECTIVES: The clinical response of rituximab (RTX) is related to the degree of B cell depletion, although other circulating lymphocytes may be affected. We investigated the changes in lymphocyte sub-populations in rheumatoid arthritis (RA) patients treated with RTX and their relationship with the therapeutic response, with attention to natural killer (NK) cells. METHODS: In fifty-one RA patients peripheral blood B and T lymphocytes and NK cells subtypes were counted by flow cytometry before and 3, 6 and 12 months after RTX administration. Patients were evaluated for disease activity with DAS28-CRP and EULAR response criteria at each visit. RESULTS: RTX significantly increased from baseline values CD56+3- cells (28 %, 19 % and 25 %; p<0.001, p=0.009 and p=0.004 respectively for month 3, 6 and 12) and CD56dimCD16+ cells (41%, 24% and 36%; p<0.001, p=0.001 and p<0.001 respectively for month 3, 6 and 12). CD56bri16- cells were unaffected by RTX treatment. The increase in both CD56+3- and CD56dimCD16+ cells was significantly greater in patients who were re-treated with another course of RTX at month 6 (p=0.046 and p=0.010 respectively). An inverse correlation between disease activity score and increase in NK cells was demonstrated. No significant changes were observed in CD3+, CD4+ and CD8+ cells during the whole observation period. CONCLUSIONS: In RA patients, RTX treatment is associated with significant and persistent increase in CD56+3- and CD56dimCD16+ NK cells. A correlation with disease activity is probable, although the association with clinical response remains to be proved.

Bone Metabolism in a Large Cohort of Patients with Systemic Sclerosis.

The aim of this study was to evaluate in a large size cohort of SSc patients bone mineral density (BMD) and to analyze its possible determinants. 106 consecutive outpatients affected by SSc were enrolled and completely evaluated for bone metabolism and SSc characteristics. For the statistical analysis, we preferred Z score to BMD or T score since the population was composed of patients of different ages and of both sexes. Mean neck Z score was significantly lower than 0. No significant differences were found for other sites. Female patients were shown to have a total femur and neck Z score significantly lower than 0 (p = 0.028 and p < 0.001, respectively). 13 % of patients had at least one morphometric non-clinical vertebral fracture. In univariate analysis, total femur Z score was lower in female (p = 0.050) and positively correlates with BMI (p = 0.001), neck Z score positively correlates with age (p = 0.016), and whole body Z score positively correlates with BMI (p < 0.001). No correlations were found for lumbar Z score. The multivariate analysis confirmed the positive correlation between BMI and total femur and whole body Z score and between age and neck femur Z score (p = 0.005, p < 0.001 and p = 0.040, respectively). Lung involvement was shown to correlate with a lower whole body Z score in multivariate analysis (p = 0.037). We found a modest risk of low BMD in patients with SSc and the important protective role of BMI. Patients with lung involvement showed lower whole body Z score.

Cutaneous manifestations of adult-onset Still's disease: a case report and review of literature.

Adult onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology and pathogenesis characterized by high spiking fever, arthralgia or arthritis, sore throat, lymphadenopathy, hepatosplenomegaly, serositis, and transient cutaneous manifestations. Although more common in children, cases are seen also in adults. Cutaneous involvement is common and may be suggestive for the diagnosis. A case of AOSD in a 35-year-old man is reported here, presenting with urticarial maculopapular rash of trunk, high spiking fever, acute respiratory distress syndrome, and myopericarditis. Skin biopsy showed interstitial and perivascular mature CD15(+) neutrophils. A comprehensive review of literature showed that cutaneous involvement occurs in about 80 % of patients, with various clinical presentations. The most common skin manifestation is an evanescent salmon pink or erythematous maculopapular exanthema, predominantly on the trunk and proximal limbs, with rare involvement of face and distal limbs. Less common manifestations include persistent erythematous plaques and pustular lesions. A constant histopathologic finding is the presence of interstitial dermal neutrophils aligned between the collagen bundles. This pattern may provide an easy accessible clue for the definitive diagnosis of AOSD and exclude other diagnosis such as drug eruptions or infectious diseases.

The local complement activation on vascular bed of patients with systemic sclerosis: a hypothesis-generating study.

OBJECTIVE: The role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region. METHODS: C5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method. RESULTS: Even though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases. CONCLUSIONS: Our results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation.

Cost-effectiveness analysis of two rituximab retreatment regimens for longstanding rheumatoid arthritis.

OBJECTIVE: Rituximab (RTX) is licensed for second-line treatment of rheumatoid arthritis (RA) after first tumor necrosis factor (TNF) inhibitor failure. RTX is generally administered intravenously at 1 gm 2 weeks apart, and the retreatment is scheduled at the time of clinical relapse (regimen 1). A more intensive regimen is proposed with a fixed full cycle after 6 months (regimen 2) if remission is not reached. A cost-effectiveness analysis (CEA) compared these 2 regimens of RTX administration in patients with longstanding RA based on data provided by an observational study. METHODS: An observational retrospective study was conducted on 102 patients, enrolled in 3 hospitals and followed for ≥12 months. Forty-seven patients followed regimen 1, while 55 patients followed regimen 2. A CEA based on a Markov model was conducted. A lifelong and social perspective was adopted. CEA was conducted for the entire cohort and for the 2 subgroups separately (patients with positive rheumatoid factor and/or anti-cyclic citrullinated peptide and failures to TNF inhibitors). RESULTS: Results for the overall sample show at 10, 20, and 30 years that regimen 1 is less costly and associated with a higher quality of life compared to regimen 2. Probabilistic sensitivity analysis at 10 years estimated a probability of 95.1% for regimen 1 to be cost effective given a willingness to pay of €35,000/quality-adjusted life year, while for seropositive patients and for TNF failures it was estimated to be 92% and 92.7%, respectively. CONCLUSION: In longstanding RA, cost effectiveness of RTX retreatment at clinical relapse was found to be at least equivalent to the more intensive regimen proposed.

The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study.

OBJECTIVE: The polymorphism 158V/F of Fc fragment of IgG (FCGR) type 3A may influence the response to rituximab (RTX) in rheumatoid arthritis (RA). We investigated the FCG3A polymorphism in a large cohort of RA patients treated with RTX, also by considering the possible loss of response from month +4 to +6 after RTX and the presence of established predictors of response. METHODS: The study analysed 212 RA patients. European League Against Rheumatism (EULAR) response was evaluated at months +4 and +6 after the first RTX infusion. The FCGR3A polymorphism was analysed by PCR followed by Sanger sequencing. RESULTS: The FCGR3A genotypes were associated with EULAR response (good or moderate) at month +6 (response in 34/38 (89.5%) VV vs 70/106 (66%) VF and in 51/77 (66.2%) FF patients; p=0.01), but not at month +4 (response in 32/37 (86.5%) VV vs 69/102 (67.6%) VF and 53/73 (72.6%) FF patients; p=0.09). Loss of response was observed only in VF and FF carriers ((VV vs VF vs FF: 0/37 (0%) vs 11/102 (10.8%) vs 12/73 (16.4%); p=0.02)). Probability of response at month +6 was very high when at least two of the three following items selected by multivariate analysis were present: positive rheumatoid factor and/or anticyclic citrullinated peptide antibodies, previous treatment with ≤ 1 anti-tumor necrosis factor (TNF) agent, and 158VV FCGR3A genotype (p<0.0001; OR 7.9, 95% CI 4.1 to 15.1). CONCLUSIONS: The 158VV FCGR3A genotype was associated with response to RTX in a large cohort of RA patients. Patient genotyping may be helpful to plan RTX treatment, and may be integrated with clinical predictors.

Relationship between body composition and both cardiovascular risk factors and lung function in systemic sclerosis.

The aims of this study were to evaluate body composition in systemic sclerosis (SSc) and to assess its association with the traditional risk factors for atherosclerosis and parameters of lung function. Eighty-six patients affected by SSc (13 men and 73 women, mean age 58.5 years, mean disease duration 10.7 years, 31 with diffuse form and 55 with limited pattern) underwent evaluation of body composition using a dual-energy X-ray (DXA) fan beam densitometer (GE Lunar iDXA) in order to assess total and regional body fat mass and fat-free mass. Clinical features, pulmonary function parameters, and the concomitant presence of the traditional cardiovascular risk factors were recorded. Android fat resulted to be higher in SSc patients with coexistence of hypercholesterolemia (P = 0.021), hypertension (P = 0.028), and overweight/obesity (P < 0.001) and positively correlated with body mass index (P < 0.001). Forced vital capacity (FVC) was inversely correlated with android fat (P = 0.034) and with the android fat/gynoid fat ratio (P = 0.013) and positively correlated with android lean (P = 0.041); the correlations were improved when FVC data were adjusted for sex, age, disease duration, and smoking habits (P = 0.010 for android fat, P = 0.010 for android fat/gynoid fat ratio, P = 0.011 for android lean). In this study, we showed that visceral abdominal fat, measured by DXA, is correlated with the main cardiovascular risk factors and lung volumes in SSc patients. Longitudinal studies are needed to evaluate if decrease of abdominal fat would improve lung function.

The co-occurrence of Hashimoto thyroiditis in primary Sjogren's syndrome defines a subset of patients with milder clinical phenotype.

To evaluate in a cohort of 100 consecutive patients affected by primary Sjogren's syndrome (pSS) the incidence of Hashimoto thyroiditis (HT) and to compare the clinical features and the laboratory parameters of patients affected by pSS with and without concomitant HT. In 100 consecutive patients affected by pSS, the occurrence of other autoimmune diseases was recorded and a full examination of thyroid function obtained. HT was associated with pSS in 27 cases. The comparison between pSS cases with and without HT showed that only patients with isolated pSS had low C4 level [p = 0.032, OR (IC 95 %) 230 (13.13-4,046)]. In addition, only patients affected by pSS without HT had evidence of cryoglobulins, cutaneous vasculitis with palpable purpura, peripheral neuropathy, and development of lymphoma, although all these manifestations were observed in a 4.1-8.2 % of the cases, without reaching statistical significance. The association of HT in patients suffering from pSS defines a subset of patients with milder disease and normal C4 levels.

The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers.

OBJECTIVE: To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA). METHODS: The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation-maximization algorithm, and BLyS serum levels were analyzed using enzyme-linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). RESULTS: The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti-cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti-tumor necrosis factor (anti-TNF) agents had previously failed. In the whole series of seropositive patients in whom anti-TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77-117.39], P=0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7-152.5], P=0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2-7.8], P=0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear. CONCLUSION: BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti-TNF agents have failed.

Osteonecrosis in systemic lupus erythematosus: an early, frequent, and not always symptomatic complication.

Osteonecrosis may complicate the course of systemic lupus erythematosus and may contemporaneously affect multiple joints. The major risk factor associated with the development of osteonecrosis is the use of glucocorticoid at high doses. Recent studies using serial MRI, which represents the "gold standard" for the early detection of osteonecrosis, yielded some interesting findings about the natural history of this clinical entity. Osteonecrosis in the majority of the cases is asymptomatic and occurs early in the course of the disease. Its later occurrence is associated with lupus flare that requires the increase of corticosteroid dose. The optimal treatment of osteonecrosis is controversial. In case of silent osteonecrosis involving a small area conservative strategy is usually adequate. When lesions are symptomatic surgical treatment as core decompression or free vascularized fibular grafting is required; extracorporeal shockwave treatment may represent an alternative therapeutic approach. When the lesion has a medium-large dimension or involves a weight-bearing area bone collapse is a common complication requiring total joint replacement. Coadministration of bisphosphonate or warfarin with high doses of corticosteroid might be a promising preventive strategy of osteonecrosis.

The early psoriatic arthritis screening questionnaire: a simple and fast method for the identification of arthritis in patients with psoriasis.

OBJECTIVE: Dermatologists usually see patients with psoriasis before arthritis develops, making them well placed to diagnose early PsA (ePsA). This study aimed to develop a rapid and robust screening questionnaire for predicting PsA in patients with psoriasis referred to a specialized joint dermatology-rheumatology combined clinic. METHODS: In all, 228 psoriasis patients naïve to DMARD treatment were administered two screening questionnaire: the new Early ARthritis for Psoriatic patients (EARP) questionnaire and the existing Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire. The diagnostic accuracy of the two questionnaires for the diagnosis of ePsA was compared by receiving operating characteristics curves. RESULTS: After psychometric analysis, a simplified questionnaire of 10 items was found to have good internal reliability (Cronbach's α = 0.83) and was much faster and simpler to administer than the PASE. Both the EARP and PASE questionnaires presented similar receiving operating characteristics curves (specificity 91.6 and 67.2 and sensitivity 85.2 and 90.7, respectively) in identifying ePsA patients by using the cut-off value of 3 for EARP-10 and the standard cut-off value of 44 for PASE. The CASPAR criteria for PsA were present in 61 (26.7%) of the patients at clinical presentation and in 32.9% at 1-year follow-up, and the EARP score of ≥3 correlated with clinically determined arthropathy by a rheumatologist. CONCLUSION: The EARP questionnaire is simple and fast to administer and proved robust for the identification of PsA in the dermatological setting. Dermatologists should consider the EARP for patients attending clinics, as it correlates well with early PsA diagnosis.

Biomarkers of good EULAR response to the B cell depletion therapy in all seropositive rheumatoid arthritis patients: clues for the pathogenesis.

OBJECTIVE: To find out whether a high number of auto-antibodies can increase the probability of a "good-EULAR response" and to identify the possible biomarkers of response in seropositive rheumatoid arthritis (RA) patients undergoing the B cell depletion therapy (BCDT). PATIENTS AND METHODS: One hundred and thirty-eight patients with long standing RA (LSRA), 75% non or poorly responsive to one or more TNFα blockers, all seropositive for at least one autoantibody (AAB) (RF-IgM, RF-IgA, RF-IgG, anti-MCV, ACPA-IgG, ACPA-IgA, ACPA-IgM) received one full course of BCDT. The major outcomes (moderate or good-EULAR response) were assessed after 6 months of therapy. The IL6 and BAFF levels were also determined. RESULTS: At a 6-month follow-up, 33 (23.9%) of the RA patients achieved a good EULAR response. Having up to 5-AABs positivity increased the chances for treatment response. After a logistic regression analysis, however, only 4 baseline factors arose as associated with a good-EULAR response: no steroid therapy (OR = 6.25), a lymphocyte count <1875/uL (OR = 10.74), a RF-IgG level >52.1 IU/ml (OR = 8.37) and BAFF levels <1011 pg/ml (OR = 7.38). When all the AABs, except for RF-IgM and ACPA-IgG, were left in the analysis, the two final predictors were no-steroid therapy and low lymphocyte count. DISCUSSION: The number of AABs increased the chances of being a "good-EULAR" responder. The only predictors, however, at the baseline of a good response in this seropositive cohort of RA patients were 2 simple variables--no steroids and lymphocyte count--and two laboratory assays--IgG-RF and BAFF.

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.

Digital amputation in systemic sclerosis: prevalence and clinical associations. A retrospective longitudinal study.

OBJECTIVE: To evaluate the prevalence of digital necrosis requiring surgical amputation in a single-center group of patients with systemic sclerosis (SSc) and to compare the characteristics of patients with and those without this severe complication. METHODS: We reviewed the medical records of 188 patients with SSc [162 women, 26 men, mean age 59.2 yrs, mean disease duration 8.0 yrs, mean time from onset of Raynaud's phenomenon (RP) 11.7 yrs, median followup duration 92 mo] enrolled in the Rheumatology Unit since 2004. Demographic and clinical features were collected, as well as the presence of the typical risk factors for atherosclerosis. RESULTS: Nine patients (4.8%) underwent partial or total surgical digital amputation because of necrotic process; all these patients except 1 had a long history of multiple and persisting digital ulcers. All 9 patients had concomitant large-vessel involvement. Comparison of cases with and without digital amputation showed that this complication was associated with older age, long history of RP, long disease duration, presence of anticentromere antibody, and coexistence of peripheral artery disease and hypercholesterolemia. Discussion. We noted that 4.8% of patients with SSc underwent digital amputation. Our retrospective analysis suggests that peripheral artery disease is strongly associated with digital amputation. The preventive strategy for digital ulcers and amputation associated with SSc should include an extensive diagnostic and preventive investigation for peripheral atherosclerosis.