Moving towards new treatments for vasculitis

KEYWORDS:

• Treatment
• systemic vasculitis
• biotherapies
• immunosuppressants
• rituximab
• tocilizumab

1. Introduction

Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with systemic vasculitis. Interleukin-6 inhibitors appear efficacious in treatment of refractory large vessel vasculitis (LVV). Blocking tumor necrosis factor (TNF) may also provide benefit to difficult-to-treat patients with Takayasu’s arteritis (TA), relapsing polychondritis, and Behçet’s disease (BD) associated LVV. Apremilast, an orally effective small molecule that specifically inhibits phosphodiesterase-4 proved very effective in Behçet’s patients with refractory mucocutaneous lesions. In small vessel vasculitides such as anti-neutrophil cytoplasmic antibody (ANCA) and cryoglobulinemia, vasculitis-specific targeting of B lymphocytes with rituximab has been shown to be an effective treatment strategy. An inherent problem with studying vasculitis and its management is the variable definition of disease remission. Several studies defined LVV remission as the absence of symptoms and normalization of inflammatory markers. However, inflammatory markers are not completely reliable (in particular with tocilizumab [TCZ]). One important issue in assessing the potential value of biological agents in the treatment of vasculitis (especially in LVV) is the lack of studies adequately comparing these agents with conventional disease-modifying antirheumatic drugs such as MTX. Relapse is common in vasculitis, especially after discontinuation of immunosuppression; the risk of prolonged immunosuppression must be balanced with the risk of relapse and varies from patient to patient.

2. Giant cell arteritis

Glucocorticosteroids (GCs) are the treatment of choice for giant cell arteritis (GCA). Adequate doses quickly suppress clinical manifestations of this disorder and prevent further ischemic complications. Even with gradual reduction of doses of GC, clinical flares have been reported to occur in more than 50% of patients, particularly during the first 12–16 months, when the prednisone dose is reduced to about 5–10 mg/day [1]. Adverse events related to GC are common and are related to the age of patients and the cumulative dose of GC. In a population-based study [1], 86% of patients with giant-cell arteritis had adverse events. Interleukin-6 is a pleiotropic cytokine that has been linked to giant-cell arteritis activity. TCZ blockade of interleukin-6 receptor quickly lowers the serum C-reactive protein concentration, independent of its potential effect on vasculitis. Evaluation of disease activity should be based on clinical symptoms and not biological parameters. Fourteen articles [2,3] reported 59 GCA patients (32 with polymyalgia rheumatica and 32 with aortitis) receiving TCZ. These patients received TCZ because 32 of them were GC dependent, 2 had GC side effects, 1 was GC resistant. Fifty-three of the 59 GCA patients experienced improvement of clinical manifestations. The GC dose has been decreased in 40 patients and stopped in 13 patients. The median follow-up period was 7 months (range 3–45). Two relapses and three deaths were reported (infectious endocarditis [n = 1], septicemia [n = 1], myocardial infarction [n = 1]). Villiger et al. [4] recently reported the first randomized trial showing efficacy of TCZ in patients with GCA. Thirty patients were randomly assigned (2:1) to receive TCZ or placebo for 1 year combined with glucocorticoid tapering. At week 12, a significantly higher percentage of patients in the TCZ group were in clinical remission without any inflammatory syndrome and with glucocorticoids at 0.1 mg/kg/day, compared with patients in the placebo group (p = 0.03). Moreover, at week 52, 85% of patients given TCZ achieved relapse-free survival compared with 20% of the placebo group (p = 0.001). Furthermore, the cumulative weight-adapted prednisolone dose was significantly lower in patients in the TCZ group than in the placebo group (43 vs. 110 mg/kg, respectively; p = 0.0005). Side effects were recorded in 75% of patients in the TCZ group and 70% in the placebo group. Gastrointestinal complications were more frequent in the TCZ group and nine neutropenic episodes were reported in the TCZ group. Biotherapy recipients had fewer metabolic complications. The study was not sufficiently powered to identify and describe all potential side effects. Because of uncertainties regarding long-term efficacy and potential side effects, its place as first-line treatment replacing or sparing glucocorticoids, relapse therapy, and long-term administration remains a matter of debate. A multicentric, not yet published, study using abatacept in 49 GCA patients was presented in the San Francisco ACR meeting in 2015. All the patients had the same corticosteroid regimen (stop by week 28) plus abatacept from baseline to week 12 (open label, phase 1). Forty-one (84%) patients who were responders at week 12 were randomized in a phase 2, randomized, double-blinded, placebo-controlled trial. The relapse-free survival at 12 months was 48% in the abatacept group versus 31% in the placebo group (p = 0.049). The median duration of remission was 9.9 months in the abatacept group versus 3.9 months in the placebo group. The tolerance was similar in the two groups.

3. Takayasu arteritis

As in GCA, GC is still the mainstay of treatment for TA. However, although most patients initially achieve disease remission, relapses and GC dependence are seen in more than two-thirds of patients: between 46% and 84% of patients will need a second agent to achieve sustained remission with acceptable GC dosages [5,6]. Thirteen articles [2] reported 96 TA patients receiving anti-TNF-α (infliximab [n = 77] 3–10 mg/kg every 4–8 weeks, etanercept [n = 17] 50 mg/week, adalimumab [n = 5] at the dose of 40 mg every 2 weeks). These patients received anti-TNF because 44 of them had a relapsing disease despite GC and other immunosuppressive treatments, 39 of them were GC dependent, 10 of them had a refractory TA, and one patient had an adverse effect of mycophenolate mofetil. In two patients, anti-TNF was used as first line of treatment. Fifty-nine (61.4%) of the 96 patients experienced improvement of clinical manifestations. The GC dose has been decreased in 45 patients (38.5%) and stopped in 38 patients (39.6%). In three patients, an improvement of vascular lesions has been reported (MRA showed a reduction of the wall thickening and a dilatation of an aortic stenosis immediately above the iliac bifurcation, a carotid ultrasound showed bilateral increase in blood flow compared to baseline). The median follow-up period was 24 months (range 2–95). Twenty-eight relapses were reported (24 during anti-TNF treatment and 4 after anti-TNF treatment). No death was reported. A recent multicenter study from the French Takayasu network [7] reported 49 TA patients treated by anti-TNF (80%) or TCZ (20%). Eighty-eight percent of patients with TA were inadequately controlled with or were intolerant to conventional immunosuppressive therapy. Overall response (i.e. complete and partial) to biologically targeted treatments at 6 and 12 months was 75% and 83%, respectively. The median follow-up period was 24 months (2–95months). The 3-year relapse-free survival was 90.9% (83.5–99%) over the biological treatment period. No difference in efficacy was found between anti-TNF and TCZ. No death was reported.

4. Behçet’s disease

Recurrent oral ulcers can be disabling and have a substantial effect on quality of life in BD. The current first-line therapy for the mucocutaneous lesions of BD includes colchicine and topical agents (e.g. glucocorticoids). The efficacy of colchicine has been debated. For lesions that are resistant to these treatments, azathioprine, interferon-α, thalidomide, and TNF-α antagonists are prescribed. Apremilast is an orally effective small molecule that specifically inhibits phosphodiesterase-4 and thereby increases levels of intracellular cyclic adenosine monophosphate, particularly in immune cells, with consequent effects on several inflammatory pathways. With apremilast treatment, levels of proinflammatory cytokines, such as TNF-α, interleukin-23, and interferon-γ, are decreased, and levels of anti-inflammatory cytokines, such as interleukin-10, are increased. A recent phase 2, multicenter, placebo-controlled study in which 111 patients with BD who had ≥2 oral ulcers were randomly assigned to receive 30 mg apremilast twice daily or placebo for 12 weeks [8]. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day posttreatment observational follow-up phase. The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5 ± 1.0 vs. 2.1 ± 2.6) (p < 0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (−44.7 ± 24.3 vs. −16.0 ± 32.5 mm) (p < 0.001). There were two serious adverse events in patients receiving apremilast [8]. A phase 3 is ongoing and should better define the place of apremilast in BD.

5. ANCA vasculitis

B lymphocytes are implicated in the pathogenesis of ANCA vasculitis by giving rise to autoantibody-producing plasma cells, contributing to local cytokine production, acting as antigen-presenting cells, and enabling T-cell costimulation. Cyclophosphamide has profound suppressive effects on B lymphocytes. Specific targeting of B lymphocytes with rituximab has been shown to be an effective treatment strategy in severe ANCA vasculitis.

5.1. Induction therapy

In the 18-month follow-up data of the RAVE trial [9–11], durable complete remission was defined as a score of 0 on a disease activity index, no use of corticosteroids, and absence of relapse or any other reason for treatment failure. Using these strict criteria, complete remission was present at 6, 12, and 18 months in 64%, 48%, and 39%, respectively, of patients in the rituximab arm (without any maintenance treatment) and in 53%, 39%, and 33%, respectively, of patients in the cyclophosphamide (CYC) (induction) – azathioprine (maintenance) arm. There were similar rates of flares and serious adverse events in both groups. Data from the RAVE study [9] show that the absence of both B cells and ANCA following treatment was associated with a very low risk for relapse. In the subset of patients with relapsing disease at trial enrollment, rituximab appeared to be superior to cyclophosphamide in inducing remission at 6 months, but that was not the case by longer follow-up at 18 months. Rituximab as compared to cyclophosphamide did not significantly reduce the number of serious infections during early and long-term follow-up. The rituximab versus cyclophosphamide in ANCA associated renal vasculitis (RITUXIVAS) 76% of patients in the RTX-CYC group and 82% of the CYC-only patients had achieved sustained remission at 12 months [12].

5.2. Maintenance therapy

A recent prospective, multicenter, randomized controlled study have shown that fixed-interval rituximab retreatment (0.5 g every 6 months) performs better than azathioprine for preventing relapses [13]. Other investigators have shown that 2-year, fixed-interval rituximab retreatment (1 g every 6 months) reduced relapse rate from 73% to 11% [14]. The optimal duration of maintenance therapy is unknown. Ideally, duration of maintenance therapy should be individualized and balance the patient’s risk of relapse with treatment morbidity. Several factors associated with relapsing disease, including presence of PR3, prior relapse, and lung or upper-airway involvement, have been identified [15].

6. Cryoglobulinemia vasculitis

Two randomized controlled trial (57 and 24 patients, respectively) in cryoglobulinemia vasculitis (including mainly HCV-positive patients), comparing conventional treatment (i.e. one of the followings: glucocorticoids, azathioprine or cyclophosphamide, or plasmapheresis) and rituximab have been reported [16,17]. De Vita et al. [17] reported survival of treatment at 12 months (i.e. the proportion of patients who continued taking their initial therapy) was higher in the rituximab group (64.3% vs. 3.5%, p < 0.0001), and the Birmingham Vasculitis Activity Score decreased only after treatment with rituximab, indicating the absence of efficacy of conventional treatment. Sneller et al. reported statistically higher remission rate at month 6 in the rituximab group (83% vs. 8%, p < 0.0001). The median duration of remission for rituximab-treated patients was 7 months, and the safety profile was good [16]. New antiviral combination, IFN-free regimens have recently proved very high virological response rate and with a very good safety profile and now need to be evaluated in hepatitis C virus (HCV)-cryoglobulinemia vasculitis patients. Recently, we reported the results from the VASCUVALDIC study on the safety and efficacy of sofosbuvir (400 mg/day) plus ribavirin (200–1400 mg/day) for 24 weeks in 24 consecutive HCV-cryoglobulinemia vasculitis patients [18]. Twenty-one patients (87.5%) were complete clinical responders at week 24. Complete clinical response was achieved in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16, and one (4.2%) at week 20. The cryoglobulin level decreased from 0.35 (0.16–0.83) at baseline to 0.15 (0.05–0.45) g/l at week 24. Seventy-four percent of patients had a sustained virological response at week 12 post treatment. The most common side effects were fatigue, insomnia, and anemia. Two serious adverse events were observed. Taken together, rituximab is still indicated in severe forms (rapidly progressive glomerulonephritis, skin necrosis, severe multinevritis, and/or life-threatening symptoms) of mixed cryoglobulinemia (associated or not with HCV) vasculitis. In type 1, rituximab is indicated for patients with clonal IgM (lymphoplasmocytic proliferation), but in those with clonal IgG plasmocytes, targeted therapies are recommended. Further investigations should answer whether immunosuppressive therapy always has a place in HCV-cryoglobulinemia vasculitis.

7. Expert opinion

Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with systemic vasculitis. Specific targeting of B lymphocytes with rituximab has been shown to be an effective treatment strategy in small vessel vasculitis including ANCA and cryoglobulinemia vasculitis. Emerging reports on the use of TCZ suggest an important role of IL-6 in the pathogenesis of large-vessel vasculitides and deserve further investigation. Relapse is common in vasculitis, especially after discontinuation of immunosuppression; the risk of prolonged immunosuppression must be balanced with the risk of relapse and varies from patient to patient. Emerging therapeutic options are expected in next years with the appearance of biological agent combinations.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.