MATERIALES Y MÉTODOS

Since the introduction of corticosteroids as a therapy in the 1950s and the advent of modern immunosuppression with combinations using cyclophosphamide (CYC), there have been significant advances in the treatment of the vasculitides. Newer biologic therapies have emerged over the last three decades and were first introduced into vasculitis therapy in the late 1980s [4]. Their clinical development in vasculitis has been slow, but as with systemic lupus erythematosus (SLE), is now beginning to gain ground. Biologics are now increasingly used as rescue therapy and will probably have a more substantive role as part of induction and maintenance therapy in the future. The specificity of some biological agents enables both pathogenic and therapeutic studies to advance simultaneously.

A summary of the type of biologic drug, explaining the mechanism of action/target molecule discussed in this chapter and their main clinical use in vasculitis is presented in Table 3.

Table 3. Summary of Biologic Drug Use in Medium and Small Vessel Vasculitis

Biologic Mechanism of action Main clinical use in vasculitis

B Cell depleting agent

Rituximab IgG1 chimeric, murine/human

monoclonal antibody against CD20 GPA and MPA Case reports in PAN, KD, UV, IgAV and CV

Anti B cell activating factor

Belimumab human monoclonal IgG1 antibody against B lymphocyte stimulator (BLyS)

Under investigation as a potential therapeutic option in GPA

Interleukin inhibitors

Tocilizumab humanised monoclonal antibody

against interleukin 6 receptor (IL6R) Randomised controlled trial in GCA is currently underway Mepolizumab humanised monoclonal antibody

against interleukin 5 (IL5) Resistant cases of EGPA Anakinra interleukin1 (IL1) receptor antagonist Successful case report in UV Canakinumab humanised monoclonal against IL1β

antibody Open label study of 10 patients with severe UV some success

IgE antibody

Omalizumab humanised monoclonal antibody

against IgE Severe refractory EGPA-related asthma Case reports of beneficial effects in UV

Tumour necrosis factor (TNF) inhibitions

Etanercept p75 Fc fusion protein which acts as a

receptor blocker for TNF GPA Prospective study open label trial using etanercept as adjunctive therapy for IVIG in acute KD was safe and effective Infliximab chimeric murine/human monoclonal

antibody against TNFα GPA and MPA Multicenter RCT showed infliximab effective and safe in refractory KD Adalimumab humanised monoclonal antibody

against TNFα AAV with renal involvement

Anti-T cell therapy

Alemtuzumab humanised anti-CD52 monoclonal antibody (CAMPATH-1H) selectively depletes the peripheral circulation of T lymphocytes, monocytes and macrophages

Ongoing trial for AAV No widespread use yet

Abatacept fusion protein composed of the Fc region of IgG1 fused to the

extracellular domain of CTLA4 which inhibits T cell co-stimulation

Open-label study of AAV patients with mild relapsing GPA reported remission induction in the majority of patients (80%) and overall good tolerance

Legend: AAV - ANCA associated vasculitis; BLyS - B lymphocytes stimulator; CTLA4 - cytotoxic T lymphocyte- associated protein 4; CV - cryoglobulinaemic vasculitis; EGPA - eosinophilic granulomatosis with polyangiitis; Fc - fragment crystallisable region of the antibody; GCA - giant cell arteritis; GPA - granulomatosis with polyangiitis, IgAV – Ig A vasculitis; IgG1 - immunoglobulin G1; IVIG - intravenous immunoglobulins; KD - Kawasaki disease; MPA - microscopic polyangiitis, PAN - polyarteritis nodosa, RCT - randomised controlled trial; UV - urticarial vasculitis.

ANCA-A

V

(AAV)

The ANCA-associated vasculitides (AAVs) are a group of rare autoimmune conditions comprising of three separate syndromes (GPA, MPA and EGPA). They are characterised by the development of necrotising vasculitis and share a number of clinical features, and are therefore treated using similar treatment protocols. Their definitions as per the Chapel Hill Consensus definitions (2012) for primary systemic vasculitis are seen in Table 4.

Table 4. Definitions for ANCA-Associated Vasculitis

Definitions for ANCA-associated vasculitis ANCA-Associated

Vasculitis (AAV) Necrotising vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles and small arteries), associated with MPO-ANCA or PR3- ANCA. Not all patients have ANCA.

A prefix is frequently added indicating ANCA reactivity, e.g., PR3-ANCA, MPO-ANCA, ANCA-negative (not to be confused with non-ANCA associated vasculitis).

Granulomatosis with Polyangiitis

(Wegener’s) (GPA)

Necrotising granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotising vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries and veins). Necrotising

glomerulonephritis is common. Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) (EGPA)

Eosinophil-rich and necrotising granulomatous inflammation often involving the respiratory tract, and necrotising vasculitis

predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.

Microscopic polyangiitis (MPA)

Necrotising vasculitis, with few or no immune deposits,

predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotising arteritis involving small and medium arteries may be present. Necrotising glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent.

Legend: ANCA - anti - neutrophil cytoplasmic antibodies; MPO-ANCA - ANCA antibodies directed to myeloperoxidase; PR3-ANCA - ANCA antibodies directed to proteinase 3.

Epidemiology

A considerable body of data on the epidemiology of the AAV has been built in the past 25 years with interesting age, geographic, and ethnic variations. Most of the data come from white European populations and the overall annual incidence is estimated at approximately 10-20/million with a peak age of onset in those aged 65 to 74 years, with GPA generally being the most common and CSS the least frequent. In other regions of the world, such as the far-east, MPA is more common than GPA [5]. The aetiopathogenesis is unknown but like

most autoimmune diseases these conditions are thought to arise from an interaction between an environmental factor and a genetically predisposed host.

The introduction of CYC combined with prednisolone resulted in a significant improvement in mortality for AAV over the last 30 years. In 2010, the European Vasculitis Study (EUVAS) Group trials reported 11.1% mortality at 1 year, with an overall better long- term prognosis of survivors and late deaths, mainly due to cardiovascular disease or infection [6]. Although the mortality has indeed improved from a mean survival of 5 months and a 1 year mortality rate of 82% for GPA in the 1960’s [7], there is still considerable morbidity associated with both treatment as well as the disease leading to a reported 5 year survival rate of only 81% for MPA and 87% for GPA in the new millennium [8].