Massimo Radin

Infliximab Biosimilars in the Treatment of Inflammatory Bowel Diseases: A Systematic Review

BackgroundBiological therapies represent a fundamental innovation for the management of inflammatory bowel diseases (IBD). However, many biological originators have reached, or are about to reach, patent expiry and long-term therapy costs have become progressively unsustainable. CT-P13, a biosimilar of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody infliximab, might represent a significant alternative to its originator, with the potential to decrease medical care costs and, therefore, become available to a large number of patients.ObjectivesIn this systematic review, we analyzed the data from available clinical trials that recently investigated the validity of indication extrapolation of CT-P13 for the treatment of IBD in naïve patients and in patients who switched from its originator infliximab, focusing on clinical efficacy, safety and immunogenicity.MethodsA detailed literature search was developed a priori to identify articles that investigated the validity of indication extrapolation of CT-P13 for the treatment of IBD in TNF inhibitor treatment-naïve patients and in patients who switched from the originator infliximab. This was applied to Ovid MEDLINE, In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus for content from 2012 to September 2016.ResultsWe based our review on the available data from 11 studies that included a total of 1007 IBD patients: 570 patients suffering from Crohn’s disease (294 switched and 276 naïve), 435 patients suffering from ulcerative colitis (127 switched and 308 naïve), and two IBD unclassified patients (switched). Overall, no significant difference in efficacy and safety between the originator infliximab and its biosimilar CT-P13 was observed. When assessing the safety of CT-P13, we found that 9.2% of patients experienced adverse effects (4.1% infusion-related reactions and 4.3% infections).ConclusionThe analyzed studies did not report a significant difference in terms of efficacy, safety and immunogenicity when comparing the clinical experience with CT-P13 with the available literature data on the originator treatment in IBD. However, some debate is ongoing regarding interchangeability and immunogenicity.

Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence.

In this study, we aimed to systematically review available literature on the efficacy of eculizumab for the treatment of renal involvement in patients with systemic lupus erythematosus (SLE). We conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement. The search strategy was applied to Ovid MEDLINE, EMBASE, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present. Abstracts from EULAR and ACR congresses were also screened. We included six publications describing the renal outcome in SLE patients receiving eculizumab. Five out of six cases described the occurrence of thrombotic microangiopathy (TMA) in renal biopsies of patients with known SLE; three cases with biopsy-proven lupus nephritis (LN) and two patients with SLE-related antiphospholipid syndrome without histologic evidence of LN. One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab. All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment. All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab[median follow-up 9 months (1–17)]. Despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

Thrombotic risk assessment in antiphospholipid syndrome: the role of new antibody specificities and thrombin generation assay.

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by the presence of antiphospholipid antibodies (aPL) in subjects presenting with thrombosis and/or pregnancy loss. The currently used classification criteria were updated in the international consensus held in Sidney in 2005. Vascular events seem to result of local procoagulative alterations upon triggers influence (the so called “second-hit theory”), while placental thrombosis and complement activation seem to lead to pregnancy morbidity. The laboratory tests suggested by the current classification criteria include lupus anticoagulant, a functional coagulation assay, and anticardiolipin and anti-β2-glycoprotein-I antibodies, generally detected by solid phase enzyme-linked immunosorbent assay. The real challenge for treating physicians is understanding what is the actual weight of aPL in provoking clinical manifestations in each case. As thrombosis has a multi-factorial cause, each patient needs a risk-stratified approach. In this review we discuss the role of thrombotic risk assessment in primary and secondary prevention of venous and arterial thromboembolic disease in patients with APS, focusing on new antibody specificities, available risk scoring models and new coagulation assays.

Prevalence and Thrombotic Risk Assessment of Anti-β2 Glycoprotein I Domain I Antibodies: A Systematic Review

Background To date, the exact prevalence of anti‐&bgr;2 glycoprotein I domain I (anti‐&bgr;2 GPI‐DI) antibodies in patients with antiphospholipid syndrome (APS) and their role when assessing thrombosis risk is uncertain. Objectives To estimate the prevalence of anti‐&bgr;2 GPI‐DI in patients with APS and to determine whether anti‐&bgr;2 GPI‐DI‐positive individuals are at greater risk of thrombosis, as compared with individuals without anti‐&bgr;2 GPI‐DI, by systematically reviewing the literature. Methods A detailed literature search was applied a priori to Ovid MEDLINE In‐Process and Other Non‐Indexed Citation 1986 to present and to abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR)/Association for Rheumatology Health Professionals (ARHP) Annual Meetings (2011–2015). Results A total of 11 studies, including 1,585 patients, were analyzed. Patients were distributed as follow: 1,218 patients APS (45.4% anti‐&bgr;2 GPI‐DI‐positive; in more detail: 504 primary APS [55.4% anti‐&bgr;2 GPI‐DI‐positive], 192 secondary APS [43.2% anti‐&bgr;2 GPI‐DI‐positive], and 522 not specified), 318 with systemic lupus erythematosus (SLE; 26.7% anti‐&bgr;2 GPI‐DI‐positive), 49 asymptomatic carriers of antiphospholipid antibodies (aPL) (30.6% anti‐&bgr;2 GPI‐DI‐positive), and 1,859 healthy controls. When considering the five studies eligible for thrombotic risk assessment, four studies found a significant association of anti‐&bgr;2 GPI‐DI‐positivity with thrombotic events, whereas one study found no predictive correlation with thrombosis (overall odds ratio [OR] for pooled data: 1.99; 95% confidence interval [CI]: 1.52–2.6; p < 0.0001). Conclusion We report an overall estimated median prevalence of anti‐&bgr;2 GPI‐DI antibodies of 44.3% in patients with APS and/or SLE and a significantly higher prevalence among patients with APS compared with SLE alone. Anti‐&bgr;2 GPI‐DI antibodies might represent a promising tool when assessing thrombotic risk in patients with APS.

Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: A systematic review.

Both BLISS-52 and BLISS-76 international phase III trials in Systemic Lupus Erythematosus (SLE) met their primary outcomes; however, they were not designed to assess the efficacy of belimumab for the treatment of lupus nephritis (LN). LN is a frequent cause of SLE-associated morbidity and mortality, and emerging evidence suggests a potential therapeutic role for agents that target B lymphocyte stimulator (BLyS). We conducted a systematic review to identify data on the effect of belimumab on LN. A total of 2004 patients with SLE were identified from 11 studies. Three hundred and twenty-six patients had LN at baseline and 234 (71.8%) of those received belimumab. Thirteen patients out of 234 (5.5%) received belimumab for active LN. Due to the heterogeneous definitions of treatment response, clinical presentation and renal involvement, it was not possible to compare results using a single outcome parameter. However, the majority of these studies defined clinical response in terms of rates of renal flare, renal remission, and/or renal organ disease improvement. One hundred twenty-nine (55.1%) of the 234 patients with LN at baseline showed an improvement in renal parameters after treatment with belimumab. In patients with baseline proteinuria>0.2g/24h, (n=687), those receiving belimumab had a median reduction in proteinuria during follow-up as high as 38%. When focusing on patients with proteinuria≥1g/24h (n=228), 70.7% of those treated with belimumab (n=157) achieved a renal response. In the pooled population of patients receiving belimumab, we found an overall annual renal flare rate of 1.7% [24/1448, mean observation time 1,1years (0,5-3)]. Despite the limitations of the studies included in this analysis, available data are promising and provide preliminary support for targeting BlyS to induce or maintain a renal response. Further trials should examine whether belimumab (alone or following rituximab) represents an additional therapeutic option in the treatment of LN.

Autologous Hematopoietic Stem Cell Transplantation in Systemic Lupus Erythematosus and Antiphospholipid Syndrome: A systematic review

BACKGROUND Hematopoietic stem cell transplantation (HSCT) has been proposed as a therapeutic option for patients with Systemic Lupus Erythematosus (SLE) refractory to standard therapy. This therapeutic approach has been applied to other severe autoimmune diseases refractory to standard therapy with promising results. AIM To systematically review the literature and analyze the available evidence on HSCT therapy in patients with SLE and antiphospholipid syndrome (APS), with a focus on therapy efficacy and occurrence of adverse events. METHODS A detailed literature search, applied to Ovid MEDLINE, In-Process and Other Non-Indexed Citation and Ovid Medline 1986 to 2014, has been developed a priori to identify articles that reported findings from clinical and laboratory studies that investigated the effect of HCT in patients with SLE. RESULTS Twenty-five studies met all inclusion criteria, including a total of 279 SLE patients; of those, 54 patients also fulfilled the classification criteria of APS. The majority of the studies reported an improvement after HSCT in terms of diseases activity control (assessed with SLEDAI, or time-free from diseases) or overall survival. However, one study reported no net benefit of HSCT when compared to immunosuppression alone. One retrospective study reported an overall survival at 5years of 81% in 28 SLE patients. Of note, 5 cases (9.3%) of aPL negativization were reported after HSCT in the APS patients. When combining these studies and analyzing these patients with APS, 32 out of 44 (73%) were able to discontinue anticoagulation after HSCT. Our findings also demonstrate a total of 86 infections in the pool of patients (30.8%), 3 of which resulted in the death of the patient (1.3%). We observed an annual incidence of infection of 11.9% with a mean follow up of 36.2months. CONCLUSION Preliminary results of HSCT as a therapeutic option for SLE appear promising. Further studies are warranted in order to assess the safety of the procedure for both the occurrence of secondary autoimmune disease and the rate of infection. However, the rate of adverse effects confines this option to very selected cases of SLE patients resistant or refractory to standard approaches.

The adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for risk stratification in young APS patients with acute myocardial infarction

BACKGROUND Young adults with acute myocardial infarction are a critical group to examine for the purpose of risk factor stratification and modification. In this study we aimed to assess the clinical utility of the adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for the risk stratification of acute myocardial infarction in a cohort of young patients with antiphospholipid syndrome (APS). METHODS The analysis included 83 consecutive APS patients (≤50years old) who presented with arterial or venous thromboembolic events. Data on cardiovascular risk factors and antiphospholipid antibodies (aPL) positivity were retrospectively collected. The aGAPSS was calculated by adding the points corresponding to the risk factors, based on a linear transformation derived from the ß-regression coefficient as follows: 3 for hyperlipidaemia, 1 for arterial hypertension, 5 for aCL IgG/IgM, 4 for anti-b2 glycoprotein I IgG/IgM and 4 for LA. RESULTS Higher aGAPSS values were observed in patients with acute myocardial infarction when compared to the others [mean aGAPSS 11.9 (S.D. 4.15, range 4-18) Vs. mean aGAPSS 9.2 (S.D. 5.1, range 1-17); T test: p<0.05]. Significantly higher aGAPSS values were also seen in patients with acute coronary syndrome compared to patients with a history of peripheral or cerebrovascular arterial thrombotic events [mean aGAPSS 11.9 (S.D. 4.15, range 4-18) Vs. mean aGAPSS 6.7 (S.D. 5.7, range 1-17); T test: P<0.005]. CONCLUSIONS The aGAPSS is based upon a quantitative score and could aid risk stratifying APS patients younger than 50years for the likelihood of developing coronary thrombotic events and may guide pharmacological treatment for high-risk patients.

Novel diagnostic and therapeutic frontiers in thrombotic anti-phospholipid syndrome

The anti-phospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity, associated with a persistent positivity for anti-phospholipid antibodies (aPL). The current classification criteria for APS include three laboratory tests: lupus anti-coagulant (LA), anti-cardiolipin (aCL), and anti-β2 glycoprotein-I (β2GPI). To date, the therapeutic approach for thrombotic APS mainly centers on long-term anti-coagulation with a vitamin K antagonist (VKA). APS management may represent a challenge for the treating physicians. Patients with different aPL profiles need a tailored risk-stratified approach. Moreover, in patients with recurrent thrombotic events despite therapy with VKA, or in those with microvascular involvement, new therapeutic options are highly needed. In this review, we aim to elucidate recent findings about new aPL specifities, available risk scoring models, and novel therapeutic approaches in APS management.

Can we withdraw anticoagulation in patients with antiphospholipid syndrome after seroconvertion

The current mainstay of treatment in patients with thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation, mainly with Vitamin K antagonist agents. Some recently available studies have created new ground for discussion about the possible discontinuation of anticoagulation therapy in patients with a history of thrombotic APS in whom antiphospholipid antibodies (aPL) are not detected any longer (i.e. aPL seroconversion). We report the main points discussed at the last CORA Meeting regarding the issue whether or not anticoagulation can be stopped after aPL seroconversion. In particular, we systematically reviewed the available evidence investigating the clinical outcome of APS patients with aPL seroconversion in whom anticoagulation was stopped when compared to those in whom therapy was continued regardless the aPL profile. Furthermore, the molecular basis for the aPL pathogenicity, the available evidence of non-criteria aPL and their association with thrombosis are addressed. To date, available evidence is still limited to support the indication to stop oral anticoagulation therapy in patients with a previous diagnosis of thrombotic APS who subsequently developed a negative aPL profile. The identification of the whole risk profile for cardiovascular manifestations and possibly of a second level aPL testing in selected patients with aPL might support the eventual clinical decision but further investigation is warranted.

Clinical utility of the global anti-phospholipid syndrome score for risk stratification: A pooled analysis

Objective Recently, our group conceived a risk score for clinical manifestations of APS (the global APS score, or GAPSS) that takes into account the combination of independent cardiovascular risk factors and the aPL positivity profile. These include hyperlipidaemia, arterial hypertension, aCL, anti-β2 glycoprotein-I, aPS-PT and the LA. A complementary version, the adjusted GAPSS (aGAPSS), which excludes aPS-PT, was also designed. The aim of our study was to systematically review the literature to assess the clinical utility of the GAPSS and aGAPSS for risk stratification of any APS clinical manifestation. Methods We pooled data from available cohort studies, including a total of 10 studies, comprising 2273 patients, in which the GAPSS has been applied. A search strategy was developed a priori to identify an available cohort that reported findings which investigated the clinical utility of GAPSS or aGAPSS. Results Seven studies used the GAPSS in their cohort, whereas three studies used the aGAPSS. In brief, we found a statistically significant difference in the cumulative GAPSS and aGAPSS between patients that experienced an arterial and/or venous thrombotic event [cumulative mean GAPSS (s.d.) 10.6 (4.74) and aGAPSS 7.6 (3.95)], patients without any thrombotic manifestation [cumulative GAPSS 7.01 (5.46) and aGAPSS 4.9 (4.33)] and patients with pregnancy morbidity [cumulative GAPSS 8.79 (2.59) and aGAPSS 6.7 (2.8)]. The highest levels of GAPSS were found in patients that experienced arterial thrombosis [mean GAPSS 12.2 (5.2)] and patients that experienced any recurrences of clinical manifestations of APS [mean GAPSS 13.7 (3.1)]. Conclusion GAPSS may represent a useful tool to assess the thrombosis or pregnancy loss risk in aPL-positive patients, switching from the concept of aPL as a sole diagnostic antibody to aPL as risk factors for clinical events.