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2nd Congress of the European Group – International Society for Apheresis

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03/24/2018 - Pirouette | 11:00am - 12:30pm 
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Ig-apheresis in vasculitis and autoimmune disease

Chairs: W. Szpirt (Copenhagen, Denmark), G. Stummvoll (Vienna, Austria)

11:00am
IL-29
Plasma Exchange in ANCA Associated Vasculitis (AAV)
*Wladimir M. Szpirt1
1 University of Copenhagen, Rigshospitalet, Dept. of Nephrology, Copenhagen, Denmark
Abstract text :

The rationale for therapeutic plasma exchange (TPE) is the removal of ANCA-antibodies and other circulating factors involved in the pathology of AAV.  5-10% of AAV patients are ANCA-negative, so the removal of other plasma constituents, such as cytokines, complement components and neutrophil microparticles may be therapeutically beneficial. For many years the indication was limited to severe nephritis where creatinine was above 500 micromoles/L or in dialysis dependent patients. The conjunctive standard immunosuppressive drug therapy consists of cyclophosphamide and prednisolone. Rituximab has been introduced as an alternative but is not validated in patients with eGFR lower than 30 ml/min.
The accepted indications for use are severe renal disease and pulmonary hemorrhage, as described in the KDIGO guidelines (7 treatments over 14 days, 60 mL/kg replaced with 5% albumin). However, the controversy refers to the definition of renal severity. In 2009, Walsh et al.  found a reduction in dialysis dependency associated with TPE but no reduction in mortality at 12 months was observed. Short term AAV patient survival is mostly related to treatment complications, mostly infections and not active vasculitis. The sparing effect of TPE on oral CYC dose has been reported by Szpirt et al., where mortality during this lower oral CYC induction treatment was less than 5% compared to 20-30 % in other series.
TPE for AAV patients with both ANCA and anti-GBM disease has been a standard therapy, and a schedule similar to anti-GBM disease has been accepted. TPE has been used in patients with pulmonary hemorrhage which is based on a small uncontrolled retrospective study by Klemmer et al. Since 2010 a new RCT Pexivas recruited 700 AAV patients in more than 100 centres. The first preliminary results will be ready in May 2018 at EDTA/ERA in Copenhagen.
In summary non-randomized, controlled studies, and other case series have indicated a renal recovery rate of 75% in TPE treated AAV patients, when presenting with renal failure and creatinine > 500 μmol/l (5.8mg/dl). These results appear superior to that reported in series not using PLEX, where renal function recovery rates of 40-50% have been observed.  The PLEX effect on milder renal disease in AAV is still not sufficiently investigated. PLEX appears to be of potential importance in moderation and sparing of immune-suppressive induction regimen in AAV.



11:30am
IL-30
Long-term lg-apheresis in lupus nephritis
*Georg Stummvoll1
1 Medizinische Universität Wien, Klinische Abteilung für Rheumatologie, Vienna, Austria
Abstract text :

Autoantibodies are the hallmark of systemic lupus erythematosus (SLE). They are important for diagnosis and also have pathogenetic relevance. Auto-antibodies (such as anti-dsDNA-abs) bind, directly or via the formation of immune complexes (IC), to cells and tissues, inducing complement activation and severe inflammation in the affected organ, such as the kidneys (1). Ig-Apheresis or Immunoadsorption (IAS) provides a method for effectively reducing IC and autoantibodies. The advantage lies in the speed of action, the flexibility to adjust the frequency of therapeutic sessions and in the option to pause them temporarily in situations of infections, when optimal B-cell function is needed (2).


At the Apheresis Unit at the Medical University of Vienna, Dept. of Nephrology, IAS is used as a last-resort procedure since 1993 and SLE patients have been among the first to profit from these new therapeutic approach. We retrospectively analyzed all patients with lupus nephritis (LN, n=16) and followed them for up to ten years of therapy.  


Since proteinuria was found to predict good long-term renal outcome when reduced below 0.8 g/day it is not only a major treatment goal, but also a valuable surrogate marker in lupus nephritis (3). In our group of 16 refractory SLE patients with LN, proteinuria decreased under IAS from 6.7±4.5 to 2.9±2.4 g/day (p<0.001) after one year of therapy, with 38% of patients reaching levels under 0.8 g/day (4).


In addition, also pre-treatment values of anti-dsDNA-abs and scoring in the SLE Disease Activity Index (SLEDAI) significantly decreased during therapy. While the effects on antibodies and disease activity occurred rapidly, the effects on proteinuria took some time and have not become significant before three full months of IAS. In an additional observation, 13 patients under prolonged IAS (mean 6.7±3.5 yrs.) were analyzed: They were included after successful short- and mid-term IAS (i.e. one year of therapy), showing mild to moderate disease activity at start of observation. In patients without renal remission after 1 year (n = 5), prolonged IAS decreased proteinuria from 4.3±2.4 to 0.5±0.4 g/day, p=0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels (5). In all observations, patients under IAS had safety data comparable to similarly active SLE patients without IAS therapy.


At our center, IAS was performed following a standardized protocoll and three different IAS-adsobers were used upon availability (Ig-Therasorb®, Immunosorba®, Globaffin®, respectively). In a retrospective analysis, all 3 of them were similarly effective in maintenance therapy in SLE with moderate disease activity (6).


Thus, thinking of a possible future multicenter RCT, we think that is not the type of the ligand/adsorber, but rather the achievement in the main outcome, i.e. the successful removal of Ig, IC, and (auto-) abs that is required for controlling SLE activity.


 


References


  (1)    Wener MH. Immune complexes in systemic lupus erythematosus. In: Tsokos GC, Gordon C, Smolen JS, editors. Systemic lupus erythematosus. 1 ed. Philadelphia: Mosby; 2007. 214-24.


  (2)    Stummvoll G, Aringer M, Handisurya A, Derfler K. Immunoadsorption in Autoimmune Diseases Affecting the Kidney. Semin Nephrol 2017; 37(5):478-87.


  (3)    Dall'Era M, Cisternas MG, Smilek DE, Straub L, Houssiau FA, Cervera R et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol 2015; 67(5):1305-13.


  (4)    Stummvoll GH, Aringer M, Smolen JS, Schmaldienst S, Jimenez-Boj E, Horl WH et al. IgG immunoadsorption reduces systemic lupus erythematosus activity and proteinuria: a long term observational study. Ann Rheum Dis 2005; 64(7):1015-21.


  (5)    Stummvoll GH, Schmaldienst S, Smolen JS, Derfler K, Biesenbach P. Lupus nephritis: prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity. Nephrol Dial Transplant 2012; 27(2):618-26.


  (6)    Biesenbach P, Schmaldienst S, Smolen JS, Horl W, Stummvoll GH. Immunoadsorption in SLE: Three different high affinity columns are adequately effective in removing autoantibodies and controlling disease activity. Artherosclerosos Supp 2009; 10:114-21.


 



11:55am
IL-31
Trimethoprim-Sulfamethoxazole Prophylaxis Prevents Severe/Life-threatening Infections Following Rituximab in Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis
*Andreas Kronbichler1, Julia Kerschbaum2, Seerapani Gopaluni1, Federico Alberici1, Rachel Jones1, Rona Smith1, David Jayne1
1 Addenbrooke’s Hospital, Vasculitis and Lupus Clinic, Cambridge, United Kingdom
2 Medical University Innsbruck, Nephrology and Hypertension, Innsbruck, Austria
Abstract text :

Objective. We aimed to assess risk factors for the development of severe infection in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) receiving rituximab.


Methods. 192 patients with AAV, either having granulomatosis with polyangiitis (GPA, formerly Wegener"s granulomatosis), microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss) were identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥ 3 as proposed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.


Results. 78 severe infections were recorded in 45 (23.4%) patients, corresponding to an event rate of 23.3 per 100 person-years. Lower respiratory tract infections were the most frequent (n=41). Positive cultures reflected opportunistic pathogens. The prophylactic use of trimethoprim-sulfamethoxazole was associated with a lower frequency of severe infections (OR 0.17, 95% CI 0.04-0.72, p=0.016). When analysis was restricted to lower respiratory tract infections, MPA (compared to GPA and EGPA) conferred a higher risk (OR 3.44, 95% CI 1.19-9.98, p=0.023).


Conclusions. We found severe infection in one quarter of AAV patients receiving rituximab. Trimethoprim-sulfamethoxazole prophylaxis reduced the risk, while a diagnosis of MPA conferred an increased risk, especially of lower respiratory tract infection.



12:20pm
L-16
Affinity sorbents based on peptides containing aromatic amino acids: Properties and medical application perspectives
Ekaterina Ovchinnikova1, Irina Adamova2, Marina Afanasieva2, Pavel Levashov3, *Sergei Pokrovsky2
1 National Medical Research Center of Cardiology, Ministry of Health of Russian Federation, Moscow, Russia, Institute of Experimental Cardiology, Moscow, Russian Federation
2 National Medical Research Center of Cardiology, Ministry of Health of Russian Federation, Moscow, Russia, Institute of Experimental Cardiology, Moscow, Russian Federation
3 Moscow State University, , Moscow , Russian Federation
Abstract text :

Therapy of different autoimmune diseases is an important problem of modern medicine. An effective method of treatment of these pathologies is extracorporeal removal of autoantibodies. At present clinical practice widely uses sorbents based on polyclonal antibodies to human IgG and bacterial proteins. Last years, many attempts have been made to create sorbents based on synthetic compounds such as aromatic amino acids, synthetic peptides, triazine derivatives, but such sorbents have low efficiency or a large contribution to nonspecific sorption. We have proposed a number of sorbents based on short di- and tripeptides, which contain aromatic amino acids like are present in IgG-binding sites of bacterial proteins A or G.


Dipeptide named «A» and two tripeptides - «B» and «C» were synthesized and immobilized to agarose macro beads. It was shown that all new sorbents efficiently bind IgG from the human plasma. Sorption capacities of sorbents with peptides «A», «B» and «C» and sorbent with polyclonal antibodies against human IgG were: 20±2; 23±3; 21±2; 14±3 (mg IgG per mL of gel) respectively. Sorbents with tripeptide «B» binds IgG3 three times better than sorbents with «A» and «C» peptides as a ligands. IgG3 plays an important role in some autoimmune diseases like DCM. It has been shown that damage of the blood cells is not observed during perfusion of whole human blood through the columns with obtained sorbents. The sorbent with «С» can be used for Ig apheresis procedure with plasma and whole blood perfusion. Such sorbent is non-toxic, pyrogen-free, and also do not have a local irritant effect. In limited clinical testing we have proved that columns with sorbents with «С» can safely and actively bind immunoglobulins from plasma as well as from whole blood of patients with autoimmune diseases in the Ig apheresis procedures.