Barbara Tolusso

Clinical and ultrasonographic remission determines different chances of relapse in early and long standing rheumatoid arthritis

Objectives Treatment of rheumatoid arthritis (RA) should aim at full remission. The aims of this study were to define: (1) how many patients reached ultrasound power Doppler (US-PD) remission in a cohort of patients with early RA (ERA) compared with longstanding RA (LSRA); (2) possible predictors of US-PD remission; and (3) how many patients with and without US-PD remission relapsed after 1 year of follow-up in ERA and LSRA. Methods 48 patients with ERA and 46 with LSRA with disease activity score <1.6 underwent US assessment. Six hand and wrist joints were studied for active synovitis. 56.2% of patients with ERA and 50.0% of those with LSRA fulfilled American College of Rheumatology (ACR) remission criteria. Results 43.7% of patients with ERA and 17.4% of those with LSRA had no evidence of synovitis at US evaluation. Using a stricter clinical definition of remission (ie, ACR criteria), US evaluation confirmed clinical remission in 66.7% of patients with ERA and 26.1% of those with LSRA. Early disease was predictive of clinical US remission. 20.0% of patients with RA who had a negative PD signal at the US evaluation had a flare during the 12-month follow-up period compared with 47.1% of patients who had a positive PD signal. Conclusion US-PD remission occurs in half of patients with ERA and in a minority of patients with LSRA in clinical remission. Early disease seems to be the major determinant of full remission.

B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial

IntroductionAn over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry.MethodsNine patients with SSc with mean age 40.9 ± 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times.ResultsAfter 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline.ConclusionsAnti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion.Trial registrationISRCTN77554566.

Interleukin-1β and Interleukin-6 in Arthritis Animal Models: Roles in the Early Phase of Transition from Acute to Chronic Inflammation and Relevance for Human Rheumatoid Arthritis

Tumor necrosis factor-α (TNF-α) is the major target of the therapeutic approach in rheumatoid arthritis. A key issue in the approach to chronic arthritis is the understanding of the crucial molecules driving the transition from the acute phase to the chronic irreversible phase of the disease. In this review we analyzed five experimental arthritis animal models (antigen-induced arthritis, adjuvant-induced arthritis, streptococcal cell wall arthritis, collagen-induced arthritis and SKG) considered as possible scenarios to facilitate interpretation of the biology of human rheumatoid arthritis. The SKG model is strictly dependent on interleukin (IL)-6. In the other models, IL-1β and IL-6, more than TNF-α, appear to be relevant in driving the transition, which suggests that these should be the targets of an early intervention to stop the course toward the chronic form of the disease.

IL-1B and IL-1RN gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy

OBJECTIVES To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1beta/IL-1Ra plasma levels and response to therapy. PATIENTS AND METHODS We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). RESULTS None of the two IL-1B (-511 and +3953) gene polymorphisms were significantly different in frequency between RA patients and healthy controls. We observed an increased frequency of the rare allele IL1RN*3 in RA patients with active disease, not responding to MTX therapy (MTX-NR) (4.5%) vs MTX-R (3.6%) and healthy controls (0.8%). Interestingly, RA patients whose genotypes included the IL1RN*long allele (haplotype long-C-T) showed the worse response to MTX. HBDs harboring the IL1RN*2/2 genotype showed significantly lower levels of plasma IL1-Ra, but comparable levels of IL-1beta with regard to subjects with the presence of the IL1RN* long allele. Furthermore, the presence of the TT IL-1B +3953 genotype was associated with lower plasma levels of IL1-Ra, both in HBDs and in RA patients. Carriers of the IL1RN*2 allele responded better to infliximab therapy. CONCLUSIONS The results of this study provide evidence of an association between the IL1RN*long allele and RA, the strongest association being observed in RA patients with an aggressive disease resistant to MTX treatment.

Functional, radiological and biological markers of alveolitis and infections of the lower respiratory tract in patients with systemic sclerosis

BackgroundA progressive lung disease and a worse survival have been observed in patients with systemic sclerosis and alveolitis. The objective of this study was to define the functional, radiological and biological markers of alveolitis in SSc patients.Methods100 SSc patients (76 with limited and 24 with diffuse disease) underwent a multistep assessment of cardiopulmonary system: pulmonary function tests (PFTs) every 6–12 months, echocardiography, high resolution computed tomography (HRCT) and bronchoalveolar lavage (BAL), if clinically advisable. Alveolar and interstitial scores on HRCT and IL-6 plasma levels were also assessed as lung disease activity indices.Results90 SSc patients with abnormal PFTs and 3 with signs and/or symptoms of lung involvement and normal PFTs underwent HRCT and echocardiography. HRCT revealed evidence of fibrosis in 87 (93.5%) patients, with 55 (59.1%) showing both ground glass attenuation and fibrosis. In 42 patients who had exhibited ground glass on HRCT and consented to undergo BAL, 16 (38.1%) revealed alveolitis. 12 (75%) of these patients had restrictive lung disease (p < 0.0001) and presented diffuse skin involvement (p = 0.0009). IL-6 plasma levels were higher in patients with alveolitis than in patients without (p = 0.041). On logistic regression model the best independent predictors of alveolitis were diffuse skin involvement (OR(95%CIs):12.80(2.54–64.37)) and skin score > 14 (OR(95%CIs):7.03(1.40–34.33)). The alveolar score showed a significant correlation with IL-6 plasma levels (r = 0.36, p = 0.001) and with the skin score (r = 0.33, p = 0.001). Cultures of BAL fluid resulted positive in 10 (23.8%) of the 42 patients that underwent BAL and after one year a deterioration in PFTs occurred in 8 (80%) of these patients (p = 0.01). Pulmonary artery systolic pressure ≥ 40 mmHg was found in 6 (37.5%) patients with alveolitis.ConclusionWe found alveolitis only in 38.1% of the patients who had exhibited ground glass on HRCT and then underwent BAL, probably because the concomitant fibrosis influenced results. A diffuse skin involvement and a restrictive pattern on PFTs together with ground glass on HRCT were judged possible markers of alveolitis, a BAL examination being indicated as the next step. Nevertheless BAL would be necessary to detect any infections of the lower respiratory tract that may cause further deterioration in lung function.

Very early rheumatoid arthritis is the major predictor of major outcomes: clinical ACR remission and radiographic non-progression

Objectives To identify predictors of clinical remission as well as of no x-ray progression in a cohort of early rheumatoid arthritis (ERA) treated with a tight-control protocol. Methods A total of 121 consecutive patients with ERA were treated to reach European League Against Rheumatism (EULAR) and/or American College of Rheumatology (ACR) clinical remission with methotrexate (MTX) for 3 months, then with a combination with anti-tumour necrosis factor if the patient did not achieve a 44-joint Disease Activity Score (DAS44) ≤2.4. At baseline and after 12 months all the patients had hand and foot joint radiographs. Very early rheumatoid arthritis (VERA) was defined as a disease with symptoms of less than 12 weeks. Results In all, 46.3% of the patients reached DAS remission and 24.8% achieved ACR remission. More than 60% of patients reached remission with MTX. Male sex and an erythrocyte sedimentation rate <35 mm/h at onset arose as significant predictors of EULAR remission, while VERA disease was the only predictor of ACR remission. At baseline, 28.1% of the patients were erosive. Multivariate analysis demonstrated that the only independent predictor of erosiveness was ‘not having VERA disease’. After 12 months, VERA was the only factor predicting a lack of new erosions. Conclusions VERA represents the best therapeutic opportunity in clinical practice to achieve a complete remission and to stop the erosive course of rheumatoid arthritis.

Skin ulcers in systemic sclerosis: Determinants of presence and predictive factors of healing

BACKGROUND Skin ulcers are common vascular complications of systemic sclerosis (SSc). OBJECTIVE The aim of the study was to identify clinical, biologic, and imaging parameters that constitute risk factors for the occurrence and persistence of skin ulcers. METHODS One hundred thirty Italian SSc patients were examined at entry and after 20 months of follow-up. RESULTS The diffuse SSc phenotype with avascular areas on capillaroscopy, thrombophilia, and systemic inflammation as defined by interleukin 6 plasma levels, represented the major risk factors for ulcer development. Infection was associated with a risk of poor or no healing, and cardiopulmonary involvement was a major comorbid factor in patients with ulcers. The presence of infection and avascular areas represented the main determinants for ulcer healing. LIMITATIONS Our data should be confirmed with a longer follow-up period since skin ulcers represent a frequent vascular complication in scleroderma patients. CONCLUSION Aggressive therapies aiming at improving angiogenesis and controlling infection and the course of the disease appear to be crucial to obtain ulcer healing.

B cells in systemic sclerosis: A possible target for therapy

Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive extracellular matrix (ECM) deposition in the skin and other visceral organs and it is associated with immune activation characterized by autoantibody production, release of various cytokines and T-lymphocyte activation. Several recent lines of evidence in animal models and in SSc patients indicate a potential role for B cells in the SSc. B cells have arisen as a possible player in tissue fibrosis in some experimental models and, since IL-6 produced by B cells, along with TGF-β, may induce matrix synthesis and less collagen degradation, targeting B cells could be one way to reduce ECM deposition and reduce the inflammatory background. Both SSc patients and tight-skin mice, a genetic model of SSc, have intrinsic B-cell abnormalities characterized by chronic B-cell activation. SSc patients present an increased number of naïve B cells and an activation of memory B cells, despite a reduction in their number. B cells from SSc patients exhibit increased expression of CD19. Remarkably, CD19 loss or B-cell depletion using antimouse CD20 antibody suppresses the development of skin hyperplasia and autoimmunity in tight-skin mice. Additionally, recent studies revealed a possible beneficial effect of anti-human CD20 antibody (Rituximab) therapy on skin fibrosis and lung involvement in SSc patients. These studies reported also the safety of Rituximab in SSc patients. All these findings suggest a possible role of antiCD20 treatment in SSc patients.

Body weight, gender and response to TNF-α blockers in axial spondyloarthritis

OBJECTIVE The objective of this study was to determine whether BMI and gender could lead to a different response rate to anti-TNF agents in patients affected by axial SpA. METHODS One hundred and seventy patients with active axial SpA (defined as a BASDAI ≥ 4) treated with an anti-TNF agent [adalimumab (ADA), etanercept (ETA), infliximab (IFX)] were retrospectively evaluated. Patients were divided according to the baseline BMI as normal weight (BMI < 25), overweight (BMI 25-30) and obese (BMI ≥ 30). After 12 months of treatment a 50% improvement of the initial BASDAI (BASDAI50) was the primary end point and BASDAI ≤ 1 was the secondary end point. RESULTS After 12 months of anti-TNF treatment, 67.8% of men and 46.2% of women reached the BASDAI50 (P = 0.01). According to BMI categories, the rate of BASDAI50 achievement decreased from 72.8% in normal weight subjects to 54.5% in overweight and 30.4% in obese subjects (P < 0.001). In the logistic regression analysis, the best independent predictors of failure to obtain a BASDAI50 response at the 12th month of therapy in axial SpA patients were female gender [odds ratio (OR) 3.23 (95% CI 1.52, 7.14)] and a BMI ≥ 30 [OR 3.57 (95% CI 1.15, 11.11)]. Analysing outcomes based on IFX therapy (the larger subgroup), the BASDAI50 response rate fell from 79.0% in normal weight subjects to 56.7% in overweight and 16.7% in obese subjects (P < 0.001). No significant differences were observed with ADA and ETA. CONCLUSION Data suggest that being female, overweight and mostly obese is associated with a lower rate of success in obtaining response status in axial SpA patients treated with anti-TNF drugs. Body weight could represent a modifiable factor to reach the best outcome in axial SpA patients treated with TNF blockers.

PTPN22 1858C>T Polymorphism Distribution in Europe and Association with Rheumatoid Arthritis: Case-Control Study and Meta-Analysis

Objective The PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data. Methods A total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies. Results The PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis. Conclusions The PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.