Ilya Smitienko

Rituximab as induction therapy in relapsing eosinophilic granulomatosis with polyangiitis: A report of 6 cases.

OBJECTIVE Recently few reports have suggested a potential benefit of rituximab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). However, the current evidence is limited. We describe the efficacy and safety of rituximab in six patients with relapsing EGPA. METHODS Candidates for rituximab therapy were selected from a cohort of 118 patients with EGPA. The main indication for B-cells depletion was moderately severe or severe relapsing disease that was refractory to conventional immunosuppression. A primary end-point was a complete or partial remission within 3 to 6 months after rituximab administration. RESULTS All six patients (four ANCA-positive and two ANCA-negative) had active EGPA manifesting by severe lung disease and/or deteriorating peripheral neuropathy. The median duration of follow-up after the first rituximab dose administration was 10 months. All patients rapidly responded to rituximab treatment, e.g. disappearance of lung infiltrates, improvement of asthmatic symptoms, at least partial recovery of motor and sensory function. Within 3 to 6 months, complete (4/6) or partial (2/6) remission was achieved in all patients. After switching to rituximab all patients except one discontinued cyclophosphamide or other immunomodulators. Four patients continued maintenance treatment with rituximab. One patient developed severe bronchospasm during infusion and two patients presented with moderately severe purulent bronchitis that was successfully treated with intravenous antibiotics. CONCLUSION Our retrospective case series suggest that rituximab may be effective for induction of remission in selected EGPA patients. These data warrant further studies to evaluate safety and efficacy of rituximab in EGPA.

Biological agents for giant cell arteritis: treat to target

In a case series published in the Annals of the Rheumatic Diseases , Conway et al 1 reported a significant steroid-sparing effect of ustekinumab (monoclonal antibody to interleukin (IL)-12 and IL-23) in 14 patients with giant cell arteritis (GCA). Recently, Ferfar et al 2 summarised current evidence showing the efficacy of tocilizumab and abatacept in patients with GCA. In the ongoing multicentre, randomised GiACTA trial (NCT01791153), the efficacy and safety of tocilizumab will be evaluated in approximately 250 patients with active GCA. Another randomised, placebo-controlled trial (NCT02531633) aims to study sirukumab (a fully human anti-IL-6 immunoglobulin G1κ) in approximately 204 subjects with a diagnosis of GCA. Therefore, in the nearest future we will probably face a wider use of biological agents as a second-line treatment for relapsing GCA and maybe as a first line in patients with more unfavourable prognosis. Should we welcome biologics in the current framework of treatment? On the one hand, the steroid-sparing effect of these medications is particularly valuable for the elderly patients with GCA who usually develop adverse events related to glucocorticoids and frequently relapse during tapering the dose of prednisone. Furthermore, it is expected that certain biological agents may have antiatherosclerotic effect that is currently under investigation in the randomised controlled trials (eg, the Canakinumab Antiinflammatory Thrombosis Outcomes Study (NCT01327846) that will evaluate canakinumab in 17 200 patients with coronary artery disease and persistently elevated C reactive protein). On the other hand, glucocorticoids are cheap and effective in a significant proportion of patients while the safety of …

Certolizumab pegol in the treatment of Takayasu arteritis

Objectives Certolizumab pegol (CZP) is a PEGylated antigen-binding fragment-fragment of a humanized mAb neutralizing TNF. It lacks Fc-fragment and has a very low potential to cross the placenta. We aimed to report the efficacy and safety of CZP in a case series of patients with refractory Takayasu arteritis (TA). Methods Ten females of reproductive age (18-35 years) with TA were treated with CZP (at a dose of 400 mg at weeks 0, 2 and 4 and at 200 mg every 2 weeks thereafter) for a median of 10 months (range 3-28). Prior to CZP administration all patients received glucocorticoids and ± MTX, CYC, AZA, HCQ, LEF or MMF. Six patients were previously treated with other biological anti-cytokine drugs. The National Institutes of Health criteria and the Indian Takayasu Clinical Activity Score 2010 were used to define disease activity. Results All patients rapidly responded to treatment with CZP and were able to taper prednisone and MTX doses. Treatment with CZP resulted in a significant decrease in median serum CRP levels and normalization of Indian Takayasu Clinical Activity Score 2010 score in 9 of 10 patients. Remission of systemic vasculitis was achieved in all patients. Seven patients maintained remission for at least 4 months, while one patient developed relapse after 2 years of CZP treatment. Side effects included mild infections (n = 5). Conclusion Our case series suggests that CZP may be an effective and steroid-sparing treatment option in patients with active TA even if they did not previously respond to other TNF inhibitors or tocilizumab.

Eosinophilic granulomatosis with polyangiitis – new definition, new treatment? – comment of the article by Puéchal et al

The recently published CHUSPAN 2 study addresses an important issue of the optimum treatment for nonsevere systemic necrotising vasculitis (SNV) that poses no immediate threat to life or essential organs function (1). This study was conducted by the French Vasculitis Study Group that contributed a lot to our understanding of systemic vasculitis. All SNVs have serious prognosis and require prompt immunosuppressive therapy. Nevertheless, it is clear today that less aggressive and less toxic immunosuppressive regimens (i.e. intravenous instead of oral cyclophosphamide for induction of remission, azathioprine with glucocorticoids in a lower dose for maintenance therapy, rituximab both for remission induction and maintenance) are appropriate for the majority of patients with SNVs. Current guidelines encompass mainly patients with more severe forms of granulomatosis with polyangiitis and microscopic polyangiitis leaving behind the scene patients with milder SNVs [2]. This article is protected by copyright. All rights reserved.

Giant cell arteritis, infections and biologics

To the editor, Numerous infectious agents have been implicated in the aetiology and/or pathogenesis of systemic vasculitides through direct damage of the vessel wall or autoimmune disorders. Mechanisms by which pathogens cause autoimmunity may include molecular mimicry (cross-reactivity between pathogen-derived and self-derived epitopes), epitope spreading (the immune response to a persisting pathogen), bystander activation (non-specific activation of autoimmune cells by the inflammatory environment during infection) or immune response to cryptic antigens (subdominant epitopes which are normally hidden from T-cell recognition).1 The causative role of infectious agents is clearly established in polyarteritis nodosa and cryoglobulinemic vasculitis that are commonly associated with hepatitis B virus and hepatitis C virus (HCV), respectively. Microbial pathogens may probably contribute to the development of other systemic vasculitides as well. However, the evidence for a definitive link between infection and induced autoimmunity in many vasculitides is less strong or lacking. Epidemiological studies showing an increased incidence of systemic vasculitis in people infected with a particular agent, while not wholly definitive, may strengthen the infection-induced autoimmunity concept.1 In the impressive nested case–control study recently published in the Annals of the Rheumatic Diseases, 2 Rhee et al examined the relationship between any infection or herpes zoster infection and the development of giant cell arteritis (GCA) in a large cohort of patients (n=4559) and controls …

SAT0546 Clinical Manifestations and Features of Cryofibrinogenemia: Russian Experience

Background Cryofibrinogen is a cryoprotein that was first identified in 1955 by Korst and Kratochvil. Unlike cryoglobulin, cryofibrinogen precipitate forms only in plasma and not in the serum. Objectives A few series have described the clinical manifestations and epidemiological data of cryofibrinogenemia (CF). But sometimes CF is crucial in clinical manifestation of different diseases. Moreover in cases with no verified diagnosis CF may be a reason of severe skin lesions and thrombotic events. Methods Between 2005 and 2012, 512 patients were tested for CF in hospital. A total of 294 patients had positive test results. Cryofibrinogen were analised in plasma with standard method – the sera and plasma were chilled at 4°C for 7 days and finally analyzed after precipitate or gel formation. Results All cryofibrinogen-positive patient were divided into 2 groups: with essential (eCF) and secondary (sCF) CF. In group with essential CF differential diagnoses include cryoglobulinemia, peripheral vascular disease, thrombotic thrombocytopenia purpura, disseminated intravascular coagulation, coumarin necrosis, hereditary hypercoagulable states, antiphospholipid syndrome, infective endocarditis and other infections, primary systemic vasculitides, and purpura fulminans. There are 223 patients with essential CF and 71 with secondary CF. The mean age of patients in the group of essential CF was 42±13 years, in the group of secondary CF – 47±10 years old. The most common reasons for secondary CF were: SLE (42,6%) and cryoglobulinemia (30,8%); CF was revealed in ANCA-associated vasculitis (9.8%), rheumatoid arthritis (4,2%), Takayasu arteritis (2,8%), thromboangigitis obliterans (2,8%), dermatomyositis, sarcoidosis, Caroli disease, Sjogren syndrome, ulcerative colitis, Crohns disease all 1,4%. In both groups skin manifestations are inaugural and suggestive in more than 72% of cases: skin ulcers (50% in essential, 41,7% in secondary), purpura (58,3% eCF, 29,2% sCF), livedo reticularis (8,3% in eCF, 12,5% sCF) and Raynaud phenomenon (20,8% in eCF, 33,3% in sCF). In 2% cases because of gangrenes amputations were perfomed (all of them had secondary CF). Less frequent manifestations included venous thrombosis (3,5%), arterial thrombosis (2,1%), arthralgia, myalgia, neurological symptoms. We identified 5 cases of lymphoprolifirating disoders and 2 cases of solid cancers cancer (lung, colon) during follow up (3-7 years). Most of patients with essential CF treated with warfarin (35%), danasol (17%). glucocorticosteroid (9%), combination of anticoagulants and steroids (34%). All patients with secondary CF received the treatment of the main disease, but in some cases it was not enough, and therapy were enhanced by anticoagulants (warfarin). Conclusions CF is more common, than its expected. A defect in the fibrinolysis process clotting small and medium arteries might be a reason for dangerous complications. CF can be a predictor of lymphoprolifirative diseases or solid cancer. Effective treatment is still unknown. Disclosure of Interest None declared

Personalized Biologic Therapy for Large Vessel Vasculitis: Comment on the Articles by Langford et al: LETTERS

To the Editor: Langford and colleagues recently reported results from an interesting multicenter, randomized, double-blind study of treatment of giant cell arteritis (GCA) with abatacept together with glucocorticoids as adjunctive treatment. The authors concluded that the addition of abatacept to a regimen of treatment with prednisone results in a longer duration of relapse-free survival compared with treatment with prednisone alone, and that abatacept possibly has a steroid-sparing effect (1). Some points deserve to be discussed. First, published studies in GCA usually refer to the dosage of glucocorticoids in mg/kg of body weight, which allows for a more homogeneous comparison of cumulative glucocorticoid dosages between patients. Second, the tapering schedule used in the study by Langford and colleagues is different from that in other trials and current recommendations (2–4). These investigators used a tapering schedule that was very slow during the first 12 weeks (dosage 20 mg/day at week 12, which would correspond to a dose of 0.2 mg/kg and a dose of 0.4 mg/kg [for patients with a body weight of 100 kg and 50 kg, respectively], versus 0.1 mg/kg in other trials [2,3]) and accelerated rapidly during the subsequent 16 weeks. Consequently, as shown in Figure 3 of the Langford article, most relapses in both treatment arms occurred between the fourth and seventh months, which is earlier than in other published cohorts in which relapses occurred after 6 months (2–4). Besides abatacept effect, the fast tapering schedule increases the risk of relapse, especially in the placebo arm, therefore potentially overestimating the effectiveness of abatacept in controlling disease in the experimental arm. The analysis of adverse events, the number of which typically increases with increasing cumulative glucocorticoid doses, may also be biased by the design of this study, with patients exposed to glucocorticoids for a short period of 28 weeks, but at high doses during the first 3 months. It is not clearly established that cumulative glucocorticoid doses per kg of body weight are lower in this study than in previous studies using classic tapering schedules lasting longer than 28 weeks (which is the actual standard of care). Consequently, this study does not answer the question of whether abatacept acts as a glucocorticoid-sparing agent. Finally, because of the nonstandard design, especially regarding glucocorticoid management, this study cannot be compared with the standard of care, which is a probable significant bias. Therefore, the place of abatacept as adjunctive treatment to obtain superior effectiveness against relapses or as a glucocorticoid-sparing agent remains to be firmly proven by comparison with standard management.

Duration of maintenance therapy for ANCA-associated vasculitis: more questions than answers

Over the last decades, numerous randomised clinical trials and long-term observational studies were conducted in dozens or hundreds patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) and provided a basis for an evidence-based treatment. With immunosuppressive therapy, up to 85%–90% of patients will achieve remission, though the disease can follow a relapsing course in a significant proportion of patients, and prolonged exposure to glucocorticoids and immunosuppressive agents may have devastating consequences. However, the attempts to shorten maintenance therapy can lead to recurrent exacerbations of AAV and an accumulation of irreversible organ damage. In the recent randomised, prospective REMAIN (prolonged REmission-MAINtenance therapy in systemic vasculitis) study, conducted in 117 patients with AAV in stable remission after cyclophosphamide/prednisolone-based induction, Karras et al showed that prolonged maintenance therapy with azathioprine/prednisolone (up to 48 months from diagnosis) was relatively safe and more effective than withdrawal of azathioprine/prednisolone by 24 months1. Extension of immunosuppression was associated with a significantly lower risk both of any and major relapses (22% vs 63%, p<0.0001, and 14% vs 35%, p<0.007, respectively) and resulted in a better renal survival. Notably, almost all patients completed the prolonged follow-up. The results of the REMAIN study were satisfying to us since prolonged immunosuppression with low dose cyclophosphamide and currently azathioprine or metothrexate in combination with corticosteroids for many years remains a preferred treatment option for patients with AAV in our clinic. However, there is the other side of the coin. A paradigm for treating patients with AAV has changed significantly over recent years. Currently, it is apparent that …

THU0293 Safety and Efficacy of Short-Term Treatment with Tocilizumab in Patients with Refractory Takayasu Arteritis

Background Takayasu arteritis (TAK) is a granulomatous vasculitis that involves aorta and/or its main branches and usually affects young or middle-aged women (before 50 years of age). Tocilizumab (TOCI) (monoclonal antibodies to IL-6 receptor) is a promising agent for treatment of refractory TAK, also clinical experience is very limited. Objectives To evaluate the efficacy and safety of short-term treatment with TOCI in patients with TAK refractory to standard immunosuppressive treatment. Methods We enrolled in our case series all patients with TAK who were treated with TOCI. Diagnosis of TAK was established according to the ACR criteria and CHCC2012. TOCI was administered intravenously at a dosage of 8 mg/kg every 4 weeks. Criteria of efficacy included complete and incomplete remission and relapse of arteritis. Activity of disease was evaluated using the NIH criteria. In all patients, we calculated the Indian Takayasu Clinical Activity Score (ITAS2010). Results Ten patients with TAK (all females, median age 23.5 years (19-56), type 5 (generalized) in nine patients) were included in retrospective study. Median duration of disease was 48.5 months (29-146). High activity of disease was confirmed by standard laboratory tests (median ESR 56 mm/h, CRP 15.4 mg/L) and MRA/PET/US. Median ITAS score was 5 (3-12), median Kerr index was 2 (1-4). Prior to tocilizumab administration all patients were treated with combination of immunosuppressive drugs (PRED + MTX or MMF or TNF inhibitors (n=3)) for 41 months (16-140). Average duration of TOCI treatment was 6 months (3-15). Complete and partial remission was achieved in 4 (40%) and 3 (30%) patients, respectively. Median PRED dose was reduced from 30 mg (10-60) to 9.5 mg daily (≤10 mg daily in 5 patients). In 3 patients we observed carotodynias and PRED dose was increased to 10-20 mg. After treatment average ESR and CRP were 12 mm/h and 0.8 mg/L, respectively. Repeated MRA and US confirmed low activity of disease in 5 (71.4%) of 7 patients while in 2 patients (28.6%) MRA showed persistent active vascular inflammation. Median ITAS score declined to 1 (1-5) and median Kerr index to 0 (0-2). TOCI infusions were well-tolerated; we observed 3 cases of carotodynia in few days after infusions; 2 patients developed community-acquired pneumonia and 1 – Herpes zoster infection and purulent bronchitis, with subsequent TOCI dose reduction to 4 mg/kg. In 2 patients surgical vascular intervention was performed (before treatment it was impossible due to active vasculitis). Two patients developed relapse of arteritis when we attempted to increase the dosing interval of TOCI to 6–8 weeks. Conclusions TOCI is effective in case of active systemic inflammation in patients with refractory TAK. The risk of infections should be taken into account. We observed high rate of carotodynias after TOCI infusions, that requires further confirmation. Long-term results with clinically important end-points (vascular interventions, risk of stenosis progression, long-term outcomes etc.) are awaited. Disclosure of Interest None declared