Biologic drugs in the treatment of polyarteritis nodosa and deficit of adenosine deaminase 2: A narrative review

Abstract

Polyarteritis nodosa (PAN) is a medium vessels vasculitis variously involving different organs and systems, sometimes with an aggressive course, leading to death or disability in a significant number of cases. First-line treatment usually relies on steroids and classical immunosuppressants, but a growing number of case reports and small case series shows the potential role of biologic drugs, mostly anti-tumor necrosis factor (TNF)-α agents, in inducing and maintaining remission in patients affected by PAN. Similarly, the recently described autoinflammatory disease named deficit of adenosine deaminase 2 (DADA2), considered by several experts as a more precocious and aggressive variant of PAN, seems to respond to a prompt treatment with TNF-α inhibitors. The aim of this review is to collect all existing evidences about the use of biologic drugs in PAN and DADA2. Fifty-one articles published during the last 15 years were retrieved, including 58 and 76 patients affected by PAN and DADA2, respectively, and treated with biologic drugs. The majority of subjects was treated with TNF-α inhibitors, whose effectiveness was reported in the treatment of such difficult-to-manage diseases, particularly in DADA2. Among the other biologic drugs, Tocilizumab was successfully employed in some subjects affected by PAN who did not respond to TNF-α inhibitors, while Rituximab did not give substantial benefits neither in PAN nor in DADA2. Only few data exist about the role of Janus-kinase inhibitors and anti-IL1 agents.

This study provides the first comprehensive assessment of biologic agents in both PAN and DADA2, with encouraging results especially in the context of TNF-α inhibitors. Nevertheless, due to the lack of prospective, randomized, case control studies, further efforts should be made in order to fully elucidate the role of these drugs in such rare and life-threatening conditions.

Introduction

Polyarteritis nodosa (PAN) is a medium vessel necrotizing vasculitis typically affecting kidney, skin, heart, gastrointestinal and nervous system [1]. PAN is a rare disease with an estimated incidence ranging from 0 to 1.6 cases/millions in Europe [2]. It is more common in adults in their fifth and sixth decades, but pediatric and neonatal cases are reported too. Classically described in association with hepatitis B virus (HBV), nowadays a viral etiology is found in about one third of the patients, being the other ones idiopathic: a larger awareness of the disease, as well as mass vaccination, is increasing the gap between primary and HBV-related, PAN [3]. Nevertheless, PAN has also been reported in association with many other viruses or bacteria, such as hepatitis C virus (HCV), streptococcus, cytomegalovirus, HIV, Epstein-Barr virus, parvovirus B19 [3] and Mycobacterium tuberculosis: the latter is the most common infectious agent associated with cutaneous PAN (cPAN) in countries where tuberculosis is endemic [4]. Almost all organs and systems may be variously and often severely affected: constitutional symptoms are the most common ones, followed by signs and symptoms reflecting skin, kidney, ear, gut, cardiovascular, peripheral and central nervous system and testicular involvement. [3,[5], [6], [7]]. The insidious onset and the overall protean clinical spectrum account, at least partially, for a notable diagnostic delay, which still relies on imaging and biopsy findings, sometimes difficult to obtain. Saccular or fusiform microaneurysms alternating with stenotic lesions are usually evidenced by angio-computed tomography [8] or arteriography in abdominal and lower limbs arteries [9], while biopsy (Fig. 1) displays focal, segmental, full-thickness, necrotizing vasculitis with mixed infiltrate involving medium and small vessels [3,10]. Arteriographic abnormalities and biopsy are required both in 1990 American College of Rheumatology classification criteria [11] and in the recently published, not validated, provisional diagnostic criteria [12]. Childhood PAN may represent a slightly different subset of disease, burdened by a similar severity but higher risk of relapse [13], and is usually diagnosed according to EULAR/PRINTO/PRES criteria [14]. An association with several autoinflammatory diseases is also described [15]: a various percentage of patients affected by Familial Mediterranean Fever (FMF), ranging from 0.9% to 1.4%, suffers from a concomitant PAN [16], usually with a better prognosis than isolated idiopathic PAN [6].

Deficit of adenosine deaminase 2 (DADA2), due to a loss of function mutation in Cat Eye Syndrome Chromosome Region 1 (CECR1), is a recently described disease [17,18], characterized by early onset and aggressive course, with histopathological findings indistinguishable from classic PAN. Whether DADA2 should be considered a variety of PAN or a novel autoinflammatory disease, is still a matter of debate. Despite its extreme rarity, PAN is a potentially life-threatening vasculitis, with an estimated lethality of 10% [13], and a prompt diagnosis, followed by an adequate treatment, is required. If antiviral drugs have a paramount importance in case of HBV-related PAN [19], glucocorticoids (GCs) still represent the cornerstone of the treatment in non-severe cases [20] and skin-limited vasculitis, in which non-steroidal-anti-inflammatory drugs and dapsone should also be considered for first-line treatment [3]. Among non-steroidal synthetic immunosuppressant, Methotrexate (MTX), Cyclophosphamide (CYC), Azathioprine (AZA) [3], Cyclosporine (CsA), Tacrolimus and Mycophenolate Mofetil (MMF) [21] have been extensively proposed and are still commonly used in the clinical practice in nearly half of non-life-threatening forms of PAN [22], while CYC should be employed only in case of life-threatening disease [3]. Nevertheless, their use is burdened by side effects which often do not make them suitable for long-term treatment, particularly in young patients with a remitting-relapsing course. Indeed, sequelae and relapses are common, also in non-severe forms, occurring in more than half of patients without Five-Factors-Score-defined poor prognosis factor [22].

Despite their wide usage in many rheumatic diseases and a growing experience in the field of vasculitis, particularly ANCA-associated vasculitis (AAV) and large vessel vasculitis [23], biologic disease modifying anti-rheumatic drugs (bDMARDs) are rarely employed in the management of PAN patients.