The strategy for the choice of the second biologic agent after the failure of the first TNF inhibitor (TNFi) is still an unclear aspect in the treatment of both rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Switching between structurally different TNFis (from etanercept [ETN] to monoclonal antibody [mAb] or vice versa) has been proposed as a more effective procedure than switching among different mAbs, but to date no study has been specifically focused on exploring this topic.
Objectives
To evaluate the comparative 2-year retention rate and the 12-month efficacy of adalimumab (ADA) as second biologic agent in etanercept (ETN) non-responder RA and PsA patients in a multicentre retrospective study.
Methods
All RA and PsA patients from 11 Italian Rheumatology Units treated with ADA after a first-course ETN failure and with at least 12-month follow-up were retrospectively collected in a multicentre registry. Data analysis was limited to the period from January 2002 to May 2016. Two-year ADA retention rate was calculated by Kaplan-Meier method. 12-month ADA response was defined as achievement of disease activity score 28 calculated by using erythrosedimentation (DAS28-ESR) <2.6 (remission) or >2.6 and <3.2 (low disease activity, LDA). Sub-analyses according to reason for ETN discontinuation and concomitant methotrexate in RA and PsA patients have been performed.
Results
The study population (219 patients) included 117 RA (female 85.5%, mean [± standard deviation, SD] age 53.2±13.5 years, mean [±SD] disease duration 10.1±7.7; positive rheumatoid factor 70.2%; positive anti-citrullinated peptide antibodies [ACPA] 59.6%; mean [±SD] baseline DAS28-ESR 4.97±1.3; MTX users 64.9%) and 102 PsA (female 63.7%; mean [±SD] age 51.7±10.6; mean [±SD] disease duration 7.1±5.1; mean [±SD] baseline DAS28-ESR 4.4±1.1; MTX users 50%). The 2-year retention rate was 48.2% in RA and 56.5% in PsA patients, irrespective of reason for ETN discontinuation. Similarly, concomitant MTX was not associated with an increased drug survival in both RA (p=0.09) and PsA (p=0.969) subgroup. 12-month clinical remission and LDA were achieved respectively in 27.3% and 23.9% RA patients, and 27.4% and 23.5% PsA patients.
Conclusions
In our large real-life cohort, the use of ADA in primary and secondary ETN failures was highly effective in both RA and PsA patients, with more than 50% of ADA treated patients achieving remission or LDA. Reasons for ETN discontinuation were not associated with different ADA clinical response, as well as concomitant MTX.
Objective. Rituximab, an anti-CD20 monoclonal antibody, has been used in lupus nephritis and membranous idiopathic nephropathy and has proved effective in non-renal manifestations of type II mixed cryoglobulinaemia (MC) syndrome. We investigated the possible efficacy and safety of rituximab in the treatment of cryoglobulinaemic nephritis.
The remarkable deformability of red blood cells (RBCs) depends on the viscoelasticity of the plasma membrane and cell contents and the surface area to volume (SA:V) ratio; however, it remains unclear which of these factors is the key determinant for passage through small capillaries. We used a microfluidic device to examine the traversal of normal, stiffened, swollen, parasitised and immature RBCs. We show that dramatic stiffening of RBCs had no measurable effect on their ability to traverse small channels. By contrast, a moderate decrease in the SA:V ratio had a marked effect on the equivalent cylinder diameter that is traversable by RBCs of similar stiffness. We developed a finite element model that provides a coherent rationale for the experimental observations, based on the nonlinear mechanical behaviour of the RBC membrane skeleton. We conclude that the SA:V ratio should be given more prominence in studies of RBC pathologies.
Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value < 0.05, q-value < 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41–0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26–1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40–0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16–0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa.
Background: ANCA-associated vasculitides (AAV) are a group of systemic vasculitis carrying a high risk of hospitalization because the multiorgan involvement, the acute nature of some clinical manifestations, the chronic but very disabling course of some other manifestations and finally the risk of severe infections due to chronic glucocorticoid and immunosuppressor administration. However, data on hospitalization due to ANCA-associated vasculitis are still scarce. Objectives: to estimate the rate of the first hospitalization or the death in patients suffering from AAV in the Italian region of Friuli Venezia Giulia (about 1,200,000 inhabitants) from year 2013 to 2017. Methods: integration of the information coming from many administrative databases were used to this end. The Regional Health Information System of Friuli Venezia Giulia was used as the source of information for this retrospective cohort study. The system covers the entire regional population and includes various electronic health administrative databases that can be linked with one another on an individual basis through a unique encrypted identifier. In particular, the following databases were matched: the database of the regional potential health care beneficiaries (including demographic information and the residential history of all of the subjects living in the region), the hospital discharge database, the database of exemptions from medical charges were used for this study, the database of the different regional laboratories. The population under study was selected based on the following inclusion criteria: patients were residents in Friuli Venezia Giulia and they had to carry the exemption code for AAV, including Granulomatosis with Polyangiitis (GPA), or Eosinophilic Granulomatosis with Polyangiitis (EGPA), or Microscopic Polyangiitis (MPA). This population was observed from 2013 to 2017. The coded event was the occurrence of the first hospitalization or the death. Also, all the hospitalization and their main discharge diagnoses were registered. Results: 103 patient with AAV were identified. The number of patients with at least one hospitalization/death was 74/103 (71,8%). Seven patients died during the observation period (6,6%). The whole number of hospitalizations was 285 in 74 patients. 55/74 (74,3%) patients experienced more than one hospitalization. In the majority of the hospitalizations (119/285, 41,7%), the cause of hospitalization was directly attributable to the disease itself, while the second cause of hospitalization was the infections (26/285, 9,1%). In 10/103 patients (9,7%), an end stage renal disease was recorded as event. The presence of at least one positivity for ANCA antibodies was documented in 76/103 patients (73,8%), mainly in patients carrying GPA. Globally, the presence of ANCA antibody seems to be associated with greater likelihood of an event (p=0,07, log-rank test). The first event occurred in 50% of ANCA-positive patients within 180 days from diagnosis, while in 50% of ANCA negative patients in 859 days. 6 out of the 7 deaths occurred in ANCA positive patients. Conclusion: the rate of hospitalization in AAV is very high confirming the high health care burden of illness. The disease itself is often the cause of the hospitalization, as well as the infectious complication, highlighting the need for more effective treatments, and glucocorticoid sparing therapies. ANCA antibody may represent a biomarker of a more serious disease. Disclosure of Interests: Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer, Elena Treppo: None declared, Salvatore De Vita Consultant of: Roche, GSK, Speakers bureau: Roche, GSK, Novartis, Francesca Valent: None declared
Cryoglobulinemic vasculitis in primary Sjögren's syndrome (pSS-CryoVasc) is a specific phenotype marked by B-cell lymphoproliferation and immunocomplex-mediated vasculitis affecting skin, nerves, joints and kidneys. With a prevalence of 3-10% among pSS, pSS-CryoVasc is linked to high clinical and biological disease activity, increased morbidity, and mortality. The link between CryoVasc and pSS involves pronounced B-cell activation, leading to salivary MALT lymphoproliferation and a significantly elevated risk of non-Hodgkin lymphoma (NHL) development. In the context of CryoVasc, Rituximab (RTX) has shown efficacy in controlling lymphoproliferation and associated manifestations. However, its safety, effectiveness, and optimal therapeutic regimen in the specific pSS-CryoVasc subset remain unclear.
Objectives:
To compare safety and efficacy of two different Rituximab (RTX)-based therapeutic approaches on vasculitic and lymphoproliferative-related disease activity and on Non-Hodgkin Lymphoma (NHL) development in a cohort of patients affected by pSS-CryoVasc.
Methods:
pSS-CryoVasc patients followed from January 1999 with an active follow-up in August 2023 were selected. 3 groups were identified: 1) Early RTX induction followed by maintenance; 2) Late RTX induction with possible on-demand retreatment; 3) No RTX treatment. For each group it was evaluated from pSS-CryoVasc diagnosis to last assessment: a) changes in disease activity according to the overall ESSDAI score related to vasculitis and lymphoproliferation and to each ESSDAI domain related to the same manifestations; b) the development of NHL; c) the occurrence of persistent hypogammaglobulinemia and serious infections.
Results:
13 pSS-CryoVasc patients were identified: 1) 5/13 treated earlier with RTX with subsequent maintenance; 2) 5/13 treated late with RTX with possible on-demand retreatment; 3) 3/13 not treated with RTX. A significant decrease in total ESSDAI considering domains related to vasculitic and lymphoproliferative manifestations was highlighted in the two RTX groups, with group 1 showing the most substantial reduction (median -17 vs -4 vs 7; H=6.55; p=0.03). Regarding CV-related ESSDAI domains (cutaneous, PNS, articular) a significant improvement was observed among patients receiving RTX vs patients not receiving RTX (p=0.007; p=0.006; p=0.03; respectively) while no difference was noted between patients receiving the two distinct RTX-based regimens. Considering lymphoproliferative-related ESSDAI domains no improvement was observed between those undergoing RTX and those not undergoing RTX, however, when evaluating the two RTX schemes an improvement in the glandular and nodal ESSDAI was noted in patients of group 1 (p=0.03; p=0.03, respectively). No significant differences among NHL occurrence (p=0.42) or safety concerns (p=1) were observed among the groups.
Conclusion:
RTX is an effective and safe treatment to control pSS-CryoVasc disease activity with a greater impact when administered early with a subsequent maintenance regimen (Figure 1); whilst an on-demand RTX strategy is sufficient to control vasculitic manifestations, a more aggressive approach is required to control lymphoproliferative disease activity. However, RTX alone cannot affect the possible development of an overt NHL in pSS-CryoVasc (Figure 2). These preliminary findings support the use of RTX in pSS-CryoVasc emphasizing the importance of precise stratification of these patients to ensure them a tailored and effective treatment.
REFERENCES:
[1] Quartuccio L et al. Cryoglobulinemia in Sjögren Syndrome: A Disease Subset that Links Higher Systemic Disease Activity, Autoimmunity, and Local B Cell Proliferation in Mucosa-associated Lymphoid Tissue. J Rheumatol. 2017;44(8):1179-1183. [2] Quartuccio L, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023;42(2):359-370.
Preliminary data provided encouraging results on efficacy and safety of B cell depletion with rituximab in active glomerulonephritis in the course of mixed cryoglobulinemia (MC).1 2
B cell oligomonoclonal expansion in peripheral blood and in bone marrow (BM) seems to be a key pathological and molecular feature in MC.3 4 Recently, renal involvement in MC has been associated with B cell clonal expansion in the BM.5 We report new data on the possible relationship between clinical efficacy of rituximab in MC nephritis and the disappearance of BM B cell clonal expansion after (month +6) rituximab administration demonstrated by molecular studies (fig 1).4
Figure 1 Bone marrow (BM) B cell expansion before and after rituximab. Bone marrow B cell expansion was evaluated in BM needle aspiration samples by semi-nested PCR using an upstream primer directed to the third framework variable (V) region of the IgH genes and downstream primers directed to the joining (J) region, as described previously.5 Samples were tested in duplicate, and the results were confirmed in repeated experiments. PCR products were analysed on 10% polyacrylamide gels stained with ethidium bromide. A clonal B cell expansion was defined by the presence of discrete, reproducible narrow band(s) within the predicted size range, while a polyclonal pattern by a ladder of bands with similar intensities or by the presence of weakly dominant bands, not become reproducible in repeated amplification. A monoclonal pattern of B cell expansion is shown at baseline in patients 1 and 2, and an oligoclonal pattern in patient 3. At 6 months after rituximab therapy the molecular pattern of B cell expansion had changed in all the three cases from clonal to polyclonal.
Three patients, two females and one male, aged 58, 62 …
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='translate(0 -400)'/%3e%3cuse xlink:href='%23a' transform='translate(0 -600)'/%3e%3cuse xlink:href='%23a' transform='translate(0 -800)'/%3e%3cuse xlink:href='%23a' transform='translate(0 -1000)'/%3e%3cuse xlink:href='%23a' transform='translate(0 -1200)'/%3e%3cpath d='M0 0h1400v800H0z' style='fill:%23010066'/%3e%3cpath d='M576 100c-166.146 0-301 134.406-301 300s134.854 300 301 300c60.027 0 115.955-17.564 162.927-47.783-27.353 9.44-56.71 14.602-87.271 14.602-147.327 0-266.897-119.172-266.897-266.01 0-146.837 119.57-266.01 266.897-266.01 32.558 0 63.746 5.815 92.602 16.468C696.217 118.91 638.305 100 576 100z' style='fill:%23fc0'/%3e%3cpath d='m914.286 471.429-99.538-53.25 29.43 108.982-66.575-91.165-20.77 110.96-20.428-111.024-66.857 90.96L699.314 418l-99.701 52.943 74.065-85.192-112.8 4.441 103.694-44.62-103.555-44.94L673.8 305.42 600 220l99.538 53.25-29.43-108.982 66.575 91.165 20.77-110.96 20.428 111.023 66.857-90.959L814.97 273.43l99.702-52.944-74.065 85.193 112.8-4.441-103.694 44.62 103.555 44.94-112.785-4.79z' style='fill:%23fc0' transform='matrix(1.2738 0 0 1.2423 -89.443 -29.478)'/%3e%3c/svg%3e)
