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Polyarteritis nodosa – Challenges and options in management
indian journal of rheumatology 10 (2015) s64–s71
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Review Article
Polyarteritis nodosa – Challenges and options in management Christian Pagnoux a,*, Nader A. Khalidi b a
Division of Rheumatology, Vasculitis Clinic, Mount Sinai Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada b Division of Rheumatology, Vasculitis Clinic, McMaster University, St. Joseph's Healthcare, Hamilton, Ontario, Canada
article info
abstract
Article history:
Polyarteritis nodosa (PAN) was one of the first systemic necrotizing vasculitides to be
Received 15 July 2015
described, in the late 19th century. Hepatitis B virus (HBV) was the major cause of the
Accepted 3 August 2015
observed PAN cases between 1970 and the early 2000s. However, in the revised 2012 Chapel
Available online 24 August 2015
Hill Consensus Conference nomenclature, HBV-related PAN is now included with vasculitides associated with probable etiologies (and named HBV-associated vasculitis). PAN should
Keywords:
thus now refer exclusively to primary cases, without an identified or probable cause. Besides
Vasculitis
systemic forms of the primary and ‘‘classical’’ PAN, which have become more rare over the
Polyarteritis nodosa
past decade, isolated and/or single organs can be affected, including the skin. In this article,
Cyclophosphamide
we review the main clinical, biological, and radiological characteristics of ‘‘classical’’
Glucocorticoids
primary PAN and its different forms, their treatment options, and outcomes. We also discuss other possible etiologies (other than HBV) of PAN-like medium-sized vessel vasculitis and newly described PAN-like vasculopathies, such as recessive loss-of-function mutations in adenosine deaminase 2, as well as the treatment options for isolated or refractory cases and the current place of biologic agents for the treatment of PAN. # 2015 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Polyarteritis nodosa (PAN) was one of the first systemic vasculitides to be described, in the late 19th century.1 It is a necrotizing arteritis that involves predominantly mediumsized vessels.1–4 In the late 1970s, hepatitis B virus (HBV) was shown to be and remained as, during the next 2 decades, the major cause of observed PAN cases.5,6 However, in the nomenclature of the 1994 Chapel Hill Consensus Conference
(CHCC; Table 1), HBV-related PAN was not clearly individualized.3 Therefore, until recently, PAN series often included both HBV-related and non-HBV-related PAN.5,7–9 The 2 diseases have some differences; in addition, some cases of PAN are probably due to associated conditions other than HBV infection. Since the development of a vaccine for HBV in the mid1990s and changes in blood donor policies, the incidence of HBV-related PAN has decreased markedly but also, in parallel, has that of non-HBV-related PAN, for reasons that remain
* Corresponding author. E-mail address: [email protected] (C. Pagnoux). http://dx.doi.org/10.1016/j.injr.2015.08.002 0973-3698/# 2015 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.
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Table 1 – American College of Rheumatology (1990) classification criteria for polyarteritis nodosa, and places and definitions of polyarteritis nodosa in the 1994 and 2012 revised Chapel Hill nomenclatures.2–4 American College of Rheumatology (1990) classification criteria for PAN (adapted2) For classification purposes, a patient shall be said to have polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%. 1. Weight loss ≥4 kg 2. Livedo reticularis 3. Testicular pain or tenderness 4. Myalgias, weakness or leg tenderness 5. Mononeuropathy or polyneuropathy 6. Diastolic blood pressure >90 mmHg 7. Elevated blood urea nitrogen >40 mg/dl or creatinine >1.5 mg/dl 8. Hepatitis B virus 9. Arteriographic abnormality (aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory causes) 10. Biopsy of small or medium-sized artery showing the presence of granulocytes or granulocytes and mononuclear leukocytes in the artery wall Place and definition of PAN according to the 1994 Chapel Hill nomenclature (adapted3) Large-vessel vasculitis Medium-sized vessel vasculitis Polyarteritis nodosa (classic polyarteritis nodosa): Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Small-vessel vasculitis Place and definition of PAN according to the 2012 revised Chapel Hill nomenclature (adapted4) Large vessel vasculitis Medium vessel vasculitis Polyarteritis nodosa (PAN): Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with antineutrophil cytoplasmic antibodies (ANCAs) Small vessel vasculitis Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) Immune complex small vessel vasculitis Variable vessel vasculitis Single-organ vasculitis (SOV): Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ. Some patients originally diagnosed as having SOV will develop additional disease manifestations that warrant redefining the case as one of the systemic vasculitides (e.g., cutaneous arteritis later becoming systemic polyarteritis nodosa, etc.). Cutaneous leukocytoclastic angiitis Cutaneous arteritis Others Vasculitis associated with systemic disease Vasculitis associated with probable etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis
unknown.5,10 In the revised 2012 CHCC nomenclature (Table 1), HBV-related vasculitis is now included with the vasculitides associated with probable etiologies.3,4 PAN should now refer exclusively to primary cases without an identified or probable cause. In addition, cases of medium-sized vessel vasculitis isolated to the skin should be considered cutaneous arteritis and no longer cutaneous PAN and should, whenever possible, be differentiated from cutaneous (small-sized vessel) leukocytoclastic vasculitis (LCV). Similarly, several case reports or series of PAN affecting a single organ have been published, which should now be called single-organ vasculitis rather than PAN.4,11 In this article, we review the main clinical, biological, and radiological characteristics of primary ‘‘classical’’ PAN, and its treatment options. We briefly highlight the main differences between ‘‘classical’’ PAN and HBV-associated vasculitis because diagnosing the latter is paramount especially for its management. Because systemic primary PAN has become even rarer, new challenges have arisen that include (1) the diagnosis of new possible etiologies (other than HBV) and ruling out newly described mimickers such as recessive loss-
of-function mutations in adenosine deaminase 2, which can cause a very similar vasculopathy; (2) the treatment of refractory cases; and (3) the current place of biologic agents.12,13 The diagnostic work-up and management of medium-sized-vessel cutaneous arteritis or single-organ vasculitis are, in theory, beyond the scope of this review but are briefly mentioned because they largely overlap with those of systemic primary PAN.
2.
Common clinical presentations
The 1990 classification criteria from the American College of Rheumatology highlight the main and, when combined, most characteristic features of PAN or HBV-related (PAN-type) vasculitis (Table 1).2 Several series and cohorts have helped to further describe the possible manifestations of PAN and their frequencies. PAN can occur in patients of every age, from children to older adults, but the median age at diagnosis is typically 40–60 years.5
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Constitutional symptoms (fever, weight loss, fatigue), arthralgias (arthritis sometimes), and/or myalgias are present in two-third of patients and can remain isolated before other more suggestive manifestations.5,8,9 Cutaneous or subcutaneous nodules and/or necrotic purpura occur in one-third to one half of patients. Ulcerations and livedo reticularis are less frequent. Peripheral nerve involvement is the other most frequent finding (50–75%), usually in the form of sensory or sensori-motor mononeuritis multiplex. The onset is usually acute but may be more progressive, particularly in older adults. The superficial peroneal nerves, sural, radial, ulnar, and/or median nerves are the most commonly affected nerves, in order of decreasing frequency. Electromyography typically shows axonal (ischemic-type) neuropathy. Cranial nerve palsies and central nervous system (CNS) involvement (ischemic, or more rarely hemorrhagic, stroke, seizure, confusion) are more rare, with the latter carrying poor prognostic value. Orchitis is an often-cited characteristic manifestation. The eyes can be affected, with uni- or bilateral choroiditis, iritis, iridocyclitis, retinal detachment, and/or retinal vasculitis.14 Other manifestations are slightly less common and are more directly the consequence of the medium-sized artery disease, with stenoses, occlusions, dilations, and/or microaneurysms. Renal artery stenosis can be responsible for mild to severe and malignant arterial hypertension and/or vascular ischemic nephropathy with renal insufficiency. Microaneurysms can rupture, spontaneously or after renal biopsy, which is therefore strongly contraindicated in the presence of microaneurysms and can cause perirenal hematoma or intraperitoneal hemorrhage. Dissections of the aorta or other large arteries such as carotid, hepatic, renal, or splenic arteries have been reported.15–18 Cardiac involvement is reported in 10–40% of patients in clinical series and up to 78% in some histological studies. Angiography can show coronary involvement in 85% of the patients with clinical signs of myocardial infarction.19 Gastrointestinal (GI) tract involvement is reported with a frequency of 40– 60% of patients, more often in HBV-related PAN, and includes hemorrhage and small-intestine perforations due to ischemic vasculitis of the GI tract. Acute necrotizing pancreatitis, malabsorption, and exudative enteropathy, liver and spleen involvement (infarct[s] and/or hematoma [s]) are more rare.20 Importantly, the lungs are spared and PAN features no glomerular disease, in contrast to small-sized-vessel vasculitides, such as microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) or granulomatosis with polyangiitis (GPA). Most patients show elevated values of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, white blood cell count). Patients with PAN are ‘‘normally’’ negative for antineutrophil cytoplasm antibodies (ANCAs), which, if present, should really challenge the diagnosis.5 Hepatitis B serology must be ordered systematically. Radiologically, medium-sized arterial stenoses and microaneurysms can be observed on celio-mesenteric and renal angiography or high-resolution MRI/CT angiography. Arterial microaneurysms range from 1 to 5 mm and are predominantly seen in the kidneys, mesentery, and liver.
PAN can be formally confirmed on biopsy of an affected organ or tissue, when timely and safely feasible. In patients complaining of myalgia with or without concomitant mononeuritis multiplex, muscle and nerve biopsy has good sensitivity (60%) when performed at the myalgia site or in the gastrocnemius or peroneal muscles. However, nerve biopsy does not always allow for distinguishing between PAN and another small-sized-vessel vasculitis. Renal biopsy is not relevant because renal involvement results from ischemia and not glomerular involvement (and it can be hazardous in patients with renal artery microaneurysms and should be strongly cautioned). The histological lesion defining PAN is focal segmental necrotizing vasculitis of medium-sized arteries, which can coexist with healed, fibrotic, and/or aneurysmal lesions or normal arteries in the same tissues.
3.
Diagnostic challenges
3.1.
Diagnosis with imaging studies and/or histology
The diagnosis of PAN relies on the combination of clinical and biological findings, and is ideally confirmed by vessel imaging with angiography (microaneurysms on medium-sized vessels) and histology. In practice, conventional angiography remains invasive and exposes patients to substantial doses of radiation. As mentioned previously, new MRI/MRA and CT scanners have sufficient resolution to reveal microaneurysms. However, microaneurysms are not that pathognomonic of PAN because they can be seen in endocarditis or fibrodysplasia of the artery and, rarely, ANCA-associated vasculitides.21 Biopsy of an affected organ may not be easily feasible. The easiest biopsies to perform are of skin and muscle-nerve and in patients with cutaneous lesions or peripheral neuropathy. However, the sensitivity is not absolute and because of the segmental distribution of the lesions (and issues of sampling), small vessels may appear as predominantly involved. PAN is classified as a medium-sized vessel disease, but small vessels are also often affected, as perfectly exemplified in the CHCC definition. In some historical series, such patients with primarily small-vessel involvement were considered to have ‘‘micro-PAN’’. With the discovery of ANCA in the late 1980s, some of these patients would have been reclassified as having MPA, but the final diagnosis in the ANCA-negative cases would still be challenging and can still be debated (ANCA-negative MPA vs ‘‘micro-PAN’’).5,8,9
3.2.
Isolated forms
Isolated cutaneous vasculitis is relatively common. Historically, an artificial and debatable distinction was made between small- and medium-sized-vessel cutaneous vasculitis, with the latter often referred to as cutaneous PAN. However, we lack consensus on the threshold for the size, vessel type, or location on deep-skin biopsy to separate these subsets. Skin-isolated LCV is considered a different form of cutaneous vasculitis and affects mostly small-sized-vessel vasculitis.22–24 Clinically, subcutaneous nodules would be more characteristic of cutaneous PAN. Purpuric lesions are less distinctive and can be observed in both LCV and cutaneous PAN, and in several
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other vasculitides (including GPA, MPA, EGPA, IgA vasculitis, and cryoglobulinemic vasculitis). On histology, deep dermis and hypodermis arterial involvement is more suggestive of medium-sized-vessel vasculitis. Importantly, cutaneous PAN has often been considered a specific entity with ‘‘isolated’’ skin disease, but it is tacitly accepted that the disease can be associated with peripheral neuropathy within the same parts of the skin lesions. In these cases, the line between ‘‘cutaneous PAN’’ and the more classical and ‘‘systemic’’ PAN, though in a more limited form, is indistinct and overlaps. In practice, we lack clear consensus on how to treat this ‘‘cutaneous’’ PAN and peripheral neuropathy with no other organ involvement (cf. section on treatment, patients with FFS = 0). Other types of localized PAN are more rare.11,25 Isolated involvement of one skeletal muscle or a muscle group and isolated neuropathy (mononeuritis multiplex or simplex) without systemic or any other symptoms have been described, as have occasional cases involving only one organ, appendix, colon or stomach, gallbladder, testis, breast, or uterus. In some cases, the vasculitic etiology might be considered an unexpected finding and pathological curiosity after surgical removal of the inflamed organ, and systemic medical therapy may be unnecessary. Possibly more striking presentations are spontaneous ruptures of an artery (renal, hepatic or splenic arteries mainly, in the free peritoneal cavity or as subcapsular hematomas), which may require urgent surgical or endovascular procedures.26–29 Spontaneous arterial dissections are rare presenting features of PAN but have been reported in different arteries such as the internal carotid, coronary, renal, and/or ilio-femoral arteries as well as the aorta.15–18 In all these latter cases, the main differential vasculopathies include acute segmental arterial mediolysis and fibromuscular dysplasia. These localized forms of PAN usually carry good overall prognoses, but for PAN limited to the skin or muscle, relapse is frequent. Evolution to a systemic form of PAN is possible but rare.
3.3.
Forms with (probable) etiologies
Besides HBV-associated vasculitis, a few other PAN-like conditions have identified etiology(ies), including rare (and controversial) forms of PAN due to hepatitis C virus infection and PAN secondary to hairy cell leukemia.30,31 Multiple drugs have been incriminated as causing LCV or ANCA-associated vasculitis, but only a few cases of drug-induced PAN have been reported, including minocycline-induced PAN.32 More recently, recessive loss-of-function mutations in adenosine deaminase 2 have been shown to cause a PAN-like vasculopathy with necrotic cutaneous manifestations, early-onset stroke, renal, and/or gastro-intestinal ischemia and infarct.12,13
4. Principles of treatment and therapeutic challenges 4.1.
Treatment of (non-HBV-related) PAN
The initial treatment of PAN relies on glucocorticoids (GCs), combined with an immunosuppressive agent, mainly cyclophosphamide (CYC), in severe forms, followed by maintenance
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(e.g., with azathioprine or methotrexate), although relapse is not that common in PAN, at least as compared with GPA.5 The initial treatment can be adapted to the type, extent, and severity of the disease (Fig. 1). In 1996, the French Study Group established the five-factor score (FFS), which has significant prognostic value in PAN (as well as in MPA and EGPA) in terms of survival.33 The FFS parameters responsible for increased mortality are proteinuria >1 g/day, renal insufficiency (serum creatinine level >140 mmol/l), vasculitis-related cardiomyopathy, GI manifestations, and/or CNS involvement. In a subsequent study of 278 patients with PAN, MPA, or EGPA, the combination of CYC and GCs was beneficial for patients with FFS ≥ 2.34 Therefore, the 1996 FFS can be used to guide the initial therapeutic decisions. The revised 2009 FFS, detailed in Table 2, also has good prognostic value for PAN, MPA, EGPA, and GPA but has not been (and thus must not be) used to similarly guide therapeutic choices.35 The Birmingham vasculitis activity score, the standard assessment tool in most prospective trials of vasculitis, can also be used to determine disease severity and help determine the intensity of treatment.36 Patients with PAN and FFS = 0 do not require the addition of CYC, unless the disease is rapidly progressive and not controlled with GCs.37 However, the disease relapse rate is >50% after 2 years of follow-up in these patients, especially those with initial peripheral nerve involvement.38 CHUSPAN2 (ClinicalTrials.gov Identifier: NCT00400075) is an ongoing randomized trial of patients with PAN (or EGPA or MPA) and FFS = 0. It aims to compare treatment with GC alone versus GCs and azathioprine, especially in terms of relapse. Results should be available in late 2015. Historically, few patients with FFS = 0 have also achieved remission with dapsone (without GCs), but this option is no longer advised, except for limited cutaneous PAN (cf. section on the treatment of isolated forms). Patients with PAN with FFS = 0 but not responding promptly to GC alone or those with FFS ≥ 1 must receive GCs and CYC as induction regimens. CYC induction regimens in the oral route (2 mg/kg/d) and intravenous route (15 mg/kg per pulse, on days 1, 15, 29 then every 3–4 weeks) were prospectively compared only in GPA and MPA; they achieved similar rates of remission (but with more frequent neutropenia with the oral route).39 In PAN, either route can be used; the most important point is to adjust the CYC doses to age and renal function and to stop CYC after a maximum of 6 months and switch to a less toxic maintenance agent. The CHUSPAN trial showed 12 CYC pulses associated with a lower relapse rate than only 6 pulses, but no maintenance was given after the 6 pulses.40 Although no randomized controlled study has been conducted to evaluate the best maintenance treatment following CYC induction in PAN, the staged inductionmaintenance strategies used for GPA or MPA have been routinely used with PAN. Possible maintenance agents include methotrexate (0.3 mg/kg/week, with folic acid) or azathioprine (2 mg/kg/day). Fewer data are available for mycophenolate mofetil (2 g/day) or leflunomide (10–20 mg/day). Rituximab has been used with some interesting results in a few patients with refractory PAN, but the experience remains limited and the pathogeny of primary PAN, although not totally understood, does not overly call for B-cell depletion therapy.41–43 Plasma
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[(Fig._1)TD$IG]
Fig. 1 – Suggested management algorithm for polyarteritis nodosa (PAN). *see text for more information on vasculitis with a probable etiology or limited to a single organ. FFS, five-factor score; GCs, glucocorticoids; HBV, hepatitis B virus.
exchange has a central place in HBV-associated vasculitis, but does not appear to provide additional benefit in PAN.44
4.2.
Treatment of HBV (and other virus-related) vasculitis
The treatment of HBV-related PAN relies on the combination of antiviral agents to eradicate the virus (currently mostly entecavir or tenofovir), plasma exchange to remove circulating immune complexes, and a short course of GCs (about 2 weeks) to rapidly control the most severe life-threatening vasculitic manifestations without increasing viral replication.5,7,45
Plasma exchange aims to clear circulating immune-complexes induced by HBV and are usually prescribed until seroconversion of HBe antigen to anti-HBe antibody is achieved. Because of the rarity of HBV-associated vasculitis, no study is and will be able to determine which new antiviral drugs or combinations are the most efficient, but therapeutic advances in chronic HBV infection can probably be transposed to HBVassociated vasculitis. Treatment for other virus-related PAN-like vasculitis cases should also rely on the combination of short GC therapy and antiviral agents, along with plasma exchange when manifes-
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Table 2 – The original 1996 and 2009 revised prognostic five-factor score (FFS) for prognosis of systemic necrotizing vasculitides.33–35 1996 FFS33 Applies to No. of patients analyzed to develop the score Usability to guide therapy FFS parameters
2009 revised FFS35
PAN and EGPA, with subsequent extension to MPA 342 (260 PAN, 82 EGPA) plus 58 MPA in the 2001 extension study33,34
PAN, MPA, GPA, EGPA 1108 (349 PAN, including 122 HBV-infected, 311 GPA, 230 EGPA, 218 MPA)
Yes (patients with FFS = 0 can initially receive GCs alone; patients with FFS ≥ 1 must receive a combination of GCs and an immunosuppressant such as cyclophosphamide) Proteinuria > 1 g/24 h Serum creatinine level > 140 mmol/L Specific gastrointestinal involvement Specific cardiomyopathy Specific CNS involvement
No (the revised FFS is only a tool for survival prognostication)
Prognostic value
For survival only (alveolar hemorrhage and severe peripheral nervous system involvement did not significantly predict poor survival in this analysis, but they may still require a combination of GCs and an immunosuppressant; therapeutic decisions are first based on physician's impression of the disease severity, which must prevail over any score)
5-year mortality rate by FFS
FFS = 0 ! 12% FFS = 1 ! 18% FFS ≥ 2 ! 29%
Age > 65 years Renal insufficiency (peak serum creatinine level ≥ 150 mmol/L) Cardiac symptoms Gastrointestinal involvement Absence of ENT involvement (for GPA and EGPA only) For survival only (alveolar hemorrhage, CNS and/or severe peripheral nervous system involvement[s] did not significantly predict poor survival in this revised analysis but may still represent severe manifestations and/or affect different outcomes) FFS = 0 ! 9% FFS = 1 ! 21% FFS ≥ 2 ! 40% (for GPA or EGPA with ENT involvement ! 23% GPA, 8% EGPA; without ENT involvement ! 43% GPA, 16% EGPA)
CNS, central nervous system; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose and throat; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; HBV, hepatitis B virus; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa.
tations are severe. For HCV-related vasculitis, rituximab (contraindicated in HBV-infected patients) should be considered, as suggested for treating HCV-associated cryoglobulinemic vasculitis.46,47
4.3.
Treatment of isolated PAN and variant forms
As mentioned previously, localized forms of PAN usually carry good overall prognoses, and progression to a systemic form is rare. However, isolated cutaneous PAN, especially if associated with peripheral nerve involvement, may require some treatment to limit the disease extent or severity and/or limit the frequency of flares. We lack randomized controlled studies to determine the best drug in cutaneous PAN. The only available prospective study in skin vasculitis (not only PAN) was small-sized and showed no major difference between placebo and colchicine.48 Short courses of GCs can be used to treat severe flares. Background therapy for cutaneous PAN, when needed, can consist of colchicine, dapsone, hydroxychloroquine, or azathioprine.22–24 More uncertainties remain as to the need to use systemic medications for isolated testis, gallbladder or appendix PAN, after surgical removal of the affected organ. Most of these cases will not develop any other organ involvement and will not progress to systemic PAN.11,25 Therefore, an initial and close monitoring of these patients, without any systemic
treatment, is most often sufficient and can be stopped after a couple of years. Similarly, whether systemic therapy is indicated for patients with spontaneous and isolated renal artery rupture or subcapsular hematoma with localized aneurysms ‘‘suggestive of PAN’’ on imaging is unclear. The diagnosis of PAN in these latter cases is challenging, in the absence of histological confirmation of PAN. Hence, systemic treatment should not be initiated in all patients, especially those without inflammatory syndrome (normal erythrocyte sedimentation rate and C-reactive protein level), or continued uselessly for months, if it had been started during the acute phase, for fear of an ongoing and possibly progressive systemic PAN. Loss-of-function mutations in adenosine deaminase 2 causing a PAN-like vasculopathy tends to respond better to anti-tumor necrosis factor alpha agents, such as infliximab, rather than other immunosuppressive agents, including CYC.12,13
4.4.
Outcomes and long-term management
In its systemic form, PAN is most often an acute disease, which can be severe and responsible for death, unless timely adequate treatment is prescribed. From the most recent series of PAN, overall survival rates are 76–89% for PAN and 64–70% for HBV-associated vasculitis.5 After 5 years of follow-up, 28%
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of patients with primary PAN and 11% with HBV-associated vasculitis show relapse, with a mean time to first relapse of 43 and 26 months, respectively.5,7 Older age at diagnosis (>65 years), hypertension, and surgical GI manifestations are independent predictors of death. Early death in the first few months of disease usually results from multi-visceral involvement and/or the inability of treatment to control disease. Death during the following years more often results from treatment side effects.
5.
Conclusion and perspectives
PAN has become more rare in its systemic and primary form, in parallel with the decreased frequency of HBV-associated vasculitis, formerly called HBV-related PAN. The exact reason for the decreasing incidence of PAN is unknown. However, the disease has not totally disappeared and physicians must remain alert to this condition, one of the first systemic necrotizing vasculitis ever described, and how to diagnose and manage it. In contrast, cutaneous PAN remains relatively common, although the distinction between cutaneous medium- and small-sized-vessel vasculitis lacks consensus. Studies are now needed to determine the optimal treatment approach for this non-severe but still-diffuse, visible, often relapsing and annoying skin condition. Other single-organ PAN-type vasculitis has always been and remains another challenging situation, for both diagnosis and therapeutic decisions. Finally, new genetic diseases (such as mutations in adenosine deaminase 2) that can mimic PAN have been discovered and others will likely be identified, and we may have to revisit some of our concepts about unusual cases of PAN and/or cases refractory to conventional GC- and CYCbased treatment.
Conflicts of interest Dr. Pagnoux has declared having received consultancies, speaking fees, and/or honoraria from Hoffman-La Roche, BMS, GSK, and Sanofi (<$10,000) over the last 5 years. Dr. Khalidi has declared having received consultancies, speaking fees, and/or honoraria from Roche, UCB, and Abbott (<$10,000) over the last 5 years.
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4. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1–11. 5. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010;62:616–626. 6. Trepo C, Thivolet J. Hepatitis associated antigen and periarteritis nodosa (PAN). Vox Sang. 1970;19:410–411. 7. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virusassociated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine. 2005;84:313–322 [Baltimore]. 8. Frohnert PP, Sheps SG. Long-term follow-up study of periarteritis nodosa. Am J Med. 1967;43:8–14. 9. Leib ES, Restivo C, Paulus HE. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med. 1979;67:941–947. 10. Mohammad AJ, Jacobsson LT, Westman KW, Sturfelt G, Segelmark M. Incidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa. Rheumatology. 2009;48:1560–1565 [Oxford]. 11. Mahr A, Battistella M, Bouaziz JD, Chaigne-Delalande S. L47. Single-organ vasculitis: conceptual and practical considerations. Presse Med. 2013;42:628–634. 12. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370:921–931. 13. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911–920. 14. Rothschild PR, Pagnoux C, Seror R, Brezin AP, Delair E, Guillevin L. Ophthalmologic manifestations of systemic necrotizing vasculitides at diagnosis: a retrospective study of 1286 patients and review of the literature. Semin Arthritis Rheum. 2013;42:507–514. 15. Chu KH, Menapace FJ, Blankenship JC, Hausch R, Harrington T. Polyarteritis nodosa presenting as acute myocardial infarction with coronary dissection. Cathet Cardiovasc Diagn. 1998;44:320–324. 16. Hekali PE, Pajari RI, Kivisaari ML, Haapanen EJ, Leirisalo M. Bilateral renal artery dissections: unusual complication of polyarteritis nodosa. Eur J Radiol. 1984;4:6–8. 17. Iino T, Eguchi K, Sakai M, Nagataki S, Ishijima M, Toriyama K. Polyarteritis nodosa with aortic dissection: necrotizing vasculitis of the vasa vasorum. J Rheumatol. 1992;19:1632–1636. 18. Lomeo RM, Silver RM, Brothers M. Spontaneous dissection of the internal carotid artery in a patient with polyarteritis nodosa. Arthritis Rheum. 1989;32:1625–1626. 19. Pagnoux C, Guillevin L. Cardiac involvement in small and medium-sized vessel vasculitides. Lupus. 2005;14:718–722. 20. Pagnoux C, Mahr A, Cohen P, Guillevin L. Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine. 2005;84:115–128 [Baltimore]. 21. Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndrome. Lupus. 1998;7:238–258. 22. Calabrese LH. Sorting out cutaneous vasculitis – a rheumatologist's perspective. Clin Exp Rheumatol. 2000;18:661–663.
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23. Gibson LE. Cutaneous vasculitis update. Dermatol Clin. 2001;19:603–615. vii. 24. Kluger N, Pagnoux C, Guillevin L, Frances C. Comparison of cutaneous manifestations in systemic polyarteritis nodosa and microscopic polyangiitis. Br J Dermatol. 2008;159:615–620. 25. Hernandez-Rodriguez J, Hoffman GS. Updating single-organ vasculitis. Curr Opin Rheumatol. 2012;24:38–45. 26. Jongsma TE, Wallis JW. Ruptured aneurysm of a renal artery in a patient with polyarteritis nodosa. JBR-BTR. 2008;91:104–105. 27. Nakashima M, Suzuki K, Okada M, Takada K, Kobayashi H, Hama Y. Successful coil embolization of a ruptured hepatic aneurysm in a patient with polyarteritis nodosa accompanied by angioimmunoblastic T cell lymphoma. Clin Rheumatol. 2007;26:1362–1364. 28. Sautter T, Trinkler FB, Sulser T, Schopke W, Hauri D. Spontaneous perirenal hemorrhage after rupture of an aneurysm in case of polyarteritis nodosa along with anuric renal failure. Case report and review of the literature. Urol Int. 1997;59:188–190. 29. Choy CW, Smith PA, Frazer C, Jeffrey GP. Ruptured hepatic artery aneurysm in polyarteritis nodosa: a case report and literature review. Aust N Z J Surg. 1997;67:904–906. 30. Saadoun D, Terrier B, Semoun O, et al. Hepatitis C virusassociated polyarteritis nodosa. Arthritis Care Res. 2011;63:427–435 [Hoboken]. 31. Carpenter MT, West SG. Polyarteritis nodosa in hairy cell leukemia: treatment with interferon-alpha. J Rheumatol. 1994;21:1150–1152. 32. Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum. 2012;42:213–221. 33. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine. 1996;75:17–28 [Baltimore]. 34. Gayraud M, Guillevin L, Le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum. 2001;44: 666–675. 35. Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P. The five-factor score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine. 2011;90:19–27 [Baltimore]. 36. Flossmann O, Bacon P, de Groot K, et al. Development of comprehensive disease assessment in systemic vasculitis. Ann Rheum Dis. 2007;66:283–292.
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37. Ribi C, Cohen P, Pagnoux C, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis without poorprognosis factors: a prospective randomized study of one hundred twenty-four patients. Arthritis Rheum. 2010;62:1186–1197. 38. Samson M, Puechal X, Devilliers H, et al. Long-term followup of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors. Autoimmun Rev. 2014;13:197–205. 39. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150:670–680. 40. Guillevin L, Cohen P, Mahr A, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: a prospective trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in sixty-five patients. Arthritis Rheum. 2003;49:93–100. 41. Sonomoto K, Miyamura T, Watanabe H, et al. A case of polyarteritis nodosa successfully treated by rituximab. Nihon Rinsho Meneki Gakkai Kaishi. 2008;31:119–123. 42. Ribeiro E, Cressend T, Duffau P, et al. Rituximab efficacy during a refractory polyarteritis nodosa flare. Case Rep Med. 2009;2009:738293. 43. Seri Y, Shoda H, Hanata N, et al. A case of refractory polyarteritis nodosa successfully treated with rituximab. Mod Rheumatol. 2015;1–3. 44. Guillevin L. Treatment of polyarteritis nodosa and ChurgStrauss angiitis: indications of plasma exchange. Results of three prospective trials in 162 patients. The Cooperative Study Group for the Study of Polyarteritis Nodosa. Prog Clin Biol Res. 1990;337:309–317. 45. Vallet-Pichard A, Hepatitis Pol SlS. B virus treatment beyond the guidelines: special populations and consideration of treatment withdrawal. Therap Adv Gastroenterol. 2014;7:148–155. 46. Pagnoux C, Cohen P, Guillevin L. Vasculitides secondary to infections. Clin Exp Rheumatol. 2006;24:S71–S81. 47. Terrier B, Saadoun D, Sene D, et al. Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus-related vasculitis: a long-term followup study of thirty-two patients. Arthritis Rheum. 2009;60:2531–2540. 48. Sais G, Vidaller A, Jucgla A, Gallardo F, Peyri J. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399–1402.
Available online at www.sciencedirect.com
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Review Article
Polyarteritis nodosa – Challenges and options in management Christian Pagnoux a,*, Nader A. Khalidi b a
Division of Rheumatology, Vasculitis Clinic, Mount Sinai Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada b Division of Rheumatology, Vasculitis Clinic, McMaster University, St. Joseph's Healthcare, Hamilton, Ontario, Canada
article info
abstract
Article history:
Polyarteritis nodosa (PAN) was one of the first systemic necrotizing vasculitides to be
Received 15 July 2015
described, in the late 19th century. Hepatitis B virus (HBV) was the major cause of the
Accepted 3 August 2015
observed PAN cases between 1970 and the early 2000s. However, in the revised 2012 Chapel
Available online 24 August 2015
Hill Consensus Conference nomenclature, HBV-related PAN is now included with vasculitides associated with probable etiologies (and named HBV-associated vasculitis). PAN should
Keywords:
thus now refer exclusively to primary cases, without an identified or probable cause. Besides
Vasculitis
systemic forms of the primary and ‘‘classical’’ PAN, which have become more rare over the
Polyarteritis nodosa
past decade, isolated and/or single organs can be affected, including the skin. In this article,
Cyclophosphamide
we review the main clinical, biological, and radiological characteristics of ‘‘classical’’
Glucocorticoids
primary PAN and its different forms, their treatment options, and outcomes. We also discuss other possible etiologies (other than HBV) of PAN-like medium-sized vessel vasculitis and newly described PAN-like vasculopathies, such as recessive loss-of-function mutations in adenosine deaminase 2, as well as the treatment options for isolated or refractory cases and the current place of biologic agents for the treatment of PAN. # 2015 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Polyarteritis nodosa (PAN) was one of the first systemic vasculitides to be described, in the late 19th century.1 It is a necrotizing arteritis that involves predominantly mediumsized vessels.1–4 In the late 1970s, hepatitis B virus (HBV) was shown to be and remained as, during the next 2 decades, the major cause of observed PAN cases.5,6 However, in the nomenclature of the 1994 Chapel Hill Consensus Conference
(CHCC; Table 1), HBV-related PAN was not clearly individualized.3 Therefore, until recently, PAN series often included both HBV-related and non-HBV-related PAN.5,7–9 The 2 diseases have some differences; in addition, some cases of PAN are probably due to associated conditions other than HBV infection. Since the development of a vaccine for HBV in the mid1990s and changes in blood donor policies, the incidence of HBV-related PAN has decreased markedly but also, in parallel, has that of non-HBV-related PAN, for reasons that remain
* Corresponding author. E-mail address: [email protected] (C. Pagnoux). http://dx.doi.org/10.1016/j.injr.2015.08.002 0973-3698/# 2015 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.
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Table 1 – American College of Rheumatology (1990) classification criteria for polyarteritis nodosa, and places and definitions of polyarteritis nodosa in the 1994 and 2012 revised Chapel Hill nomenclatures.2–4 American College of Rheumatology (1990) classification criteria for PAN (adapted2) For classification purposes, a patient shall be said to have polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%. 1. Weight loss ≥4 kg 2. Livedo reticularis 3. Testicular pain or tenderness 4. Myalgias, weakness or leg tenderness 5. Mononeuropathy or polyneuropathy 6. Diastolic blood pressure >90 mmHg 7. Elevated blood urea nitrogen >40 mg/dl or creatinine >1.5 mg/dl 8. Hepatitis B virus 9. Arteriographic abnormality (aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory causes) 10. Biopsy of small or medium-sized artery showing the presence of granulocytes or granulocytes and mononuclear leukocytes in the artery wall Place and definition of PAN according to the 1994 Chapel Hill nomenclature (adapted3) Large-vessel vasculitis Medium-sized vessel vasculitis Polyarteritis nodosa (classic polyarteritis nodosa): Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Small-vessel vasculitis Place and definition of PAN according to the 2012 revised Chapel Hill nomenclature (adapted4) Large vessel vasculitis Medium vessel vasculitis Polyarteritis nodosa (PAN): Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with antineutrophil cytoplasmic antibodies (ANCAs) Small vessel vasculitis Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) Immune complex small vessel vasculitis Variable vessel vasculitis Single-organ vasculitis (SOV): Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ. Some patients originally diagnosed as having SOV will develop additional disease manifestations that warrant redefining the case as one of the systemic vasculitides (e.g., cutaneous arteritis later becoming systemic polyarteritis nodosa, etc.). Cutaneous leukocytoclastic angiitis Cutaneous arteritis Others Vasculitis associated with systemic disease Vasculitis associated with probable etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis
unknown.5,10 In the revised 2012 CHCC nomenclature (Table 1), HBV-related vasculitis is now included with the vasculitides associated with probable etiologies.3,4 PAN should now refer exclusively to primary cases without an identified or probable cause. In addition, cases of medium-sized vessel vasculitis isolated to the skin should be considered cutaneous arteritis and no longer cutaneous PAN and should, whenever possible, be differentiated from cutaneous (small-sized vessel) leukocytoclastic vasculitis (LCV). Similarly, several case reports or series of PAN affecting a single organ have been published, which should now be called single-organ vasculitis rather than PAN.4,11 In this article, we review the main clinical, biological, and radiological characteristics of primary ‘‘classical’’ PAN, and its treatment options. We briefly highlight the main differences between ‘‘classical’’ PAN and HBV-associated vasculitis because diagnosing the latter is paramount especially for its management. Because systemic primary PAN has become even rarer, new challenges have arisen that include (1) the diagnosis of new possible etiologies (other than HBV) and ruling out newly described mimickers such as recessive loss-
of-function mutations in adenosine deaminase 2, which can cause a very similar vasculopathy; (2) the treatment of refractory cases; and (3) the current place of biologic agents.12,13 The diagnostic work-up and management of medium-sized-vessel cutaneous arteritis or single-organ vasculitis are, in theory, beyond the scope of this review but are briefly mentioned because they largely overlap with those of systemic primary PAN.
2.
Common clinical presentations
The 1990 classification criteria from the American College of Rheumatology highlight the main and, when combined, most characteristic features of PAN or HBV-related (PAN-type) vasculitis (Table 1).2 Several series and cohorts have helped to further describe the possible manifestations of PAN and their frequencies. PAN can occur in patients of every age, from children to older adults, but the median age at diagnosis is typically 40–60 years.5
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Constitutional symptoms (fever, weight loss, fatigue), arthralgias (arthritis sometimes), and/or myalgias are present in two-third of patients and can remain isolated before other more suggestive manifestations.5,8,9 Cutaneous or subcutaneous nodules and/or necrotic purpura occur in one-third to one half of patients. Ulcerations and livedo reticularis are less frequent. Peripheral nerve involvement is the other most frequent finding (50–75%), usually in the form of sensory or sensori-motor mononeuritis multiplex. The onset is usually acute but may be more progressive, particularly in older adults. The superficial peroneal nerves, sural, radial, ulnar, and/or median nerves are the most commonly affected nerves, in order of decreasing frequency. Electromyography typically shows axonal (ischemic-type) neuropathy. Cranial nerve palsies and central nervous system (CNS) involvement (ischemic, or more rarely hemorrhagic, stroke, seizure, confusion) are more rare, with the latter carrying poor prognostic value. Orchitis is an often-cited characteristic manifestation. The eyes can be affected, with uni- or bilateral choroiditis, iritis, iridocyclitis, retinal detachment, and/or retinal vasculitis.14 Other manifestations are slightly less common and are more directly the consequence of the medium-sized artery disease, with stenoses, occlusions, dilations, and/or microaneurysms. Renal artery stenosis can be responsible for mild to severe and malignant arterial hypertension and/or vascular ischemic nephropathy with renal insufficiency. Microaneurysms can rupture, spontaneously or after renal biopsy, which is therefore strongly contraindicated in the presence of microaneurysms and can cause perirenal hematoma or intraperitoneal hemorrhage. Dissections of the aorta or other large arteries such as carotid, hepatic, renal, or splenic arteries have been reported.15–18 Cardiac involvement is reported in 10–40% of patients in clinical series and up to 78% in some histological studies. Angiography can show coronary involvement in 85% of the patients with clinical signs of myocardial infarction.19 Gastrointestinal (GI) tract involvement is reported with a frequency of 40– 60% of patients, more often in HBV-related PAN, and includes hemorrhage and small-intestine perforations due to ischemic vasculitis of the GI tract. Acute necrotizing pancreatitis, malabsorption, and exudative enteropathy, liver and spleen involvement (infarct[s] and/or hematoma [s]) are more rare.20 Importantly, the lungs are spared and PAN features no glomerular disease, in contrast to small-sized-vessel vasculitides, such as microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) or granulomatosis with polyangiitis (GPA). Most patients show elevated values of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, white blood cell count). Patients with PAN are ‘‘normally’’ negative for antineutrophil cytoplasm antibodies (ANCAs), which, if present, should really challenge the diagnosis.5 Hepatitis B serology must be ordered systematically. Radiologically, medium-sized arterial stenoses and microaneurysms can be observed on celio-mesenteric and renal angiography or high-resolution MRI/CT angiography. Arterial microaneurysms range from 1 to 5 mm and are predominantly seen in the kidneys, mesentery, and liver.
PAN can be formally confirmed on biopsy of an affected organ or tissue, when timely and safely feasible. In patients complaining of myalgia with or without concomitant mononeuritis multiplex, muscle and nerve biopsy has good sensitivity (60%) when performed at the myalgia site or in the gastrocnemius or peroneal muscles. However, nerve biopsy does not always allow for distinguishing between PAN and another small-sized-vessel vasculitis. Renal biopsy is not relevant because renal involvement results from ischemia and not glomerular involvement (and it can be hazardous in patients with renal artery microaneurysms and should be strongly cautioned). The histological lesion defining PAN is focal segmental necrotizing vasculitis of medium-sized arteries, which can coexist with healed, fibrotic, and/or aneurysmal lesions or normal arteries in the same tissues.
3.
Diagnostic challenges
3.1.
Diagnosis with imaging studies and/or histology
The diagnosis of PAN relies on the combination of clinical and biological findings, and is ideally confirmed by vessel imaging with angiography (microaneurysms on medium-sized vessels) and histology. In practice, conventional angiography remains invasive and exposes patients to substantial doses of radiation. As mentioned previously, new MRI/MRA and CT scanners have sufficient resolution to reveal microaneurysms. However, microaneurysms are not that pathognomonic of PAN because they can be seen in endocarditis or fibrodysplasia of the artery and, rarely, ANCA-associated vasculitides.21 Biopsy of an affected organ may not be easily feasible. The easiest biopsies to perform are of skin and muscle-nerve and in patients with cutaneous lesions or peripheral neuropathy. However, the sensitivity is not absolute and because of the segmental distribution of the lesions (and issues of sampling), small vessels may appear as predominantly involved. PAN is classified as a medium-sized vessel disease, but small vessels are also often affected, as perfectly exemplified in the CHCC definition. In some historical series, such patients with primarily small-vessel involvement were considered to have ‘‘micro-PAN’’. With the discovery of ANCA in the late 1980s, some of these patients would have been reclassified as having MPA, but the final diagnosis in the ANCA-negative cases would still be challenging and can still be debated (ANCA-negative MPA vs ‘‘micro-PAN’’).5,8,9
3.2.
Isolated forms
Isolated cutaneous vasculitis is relatively common. Historically, an artificial and debatable distinction was made between small- and medium-sized-vessel cutaneous vasculitis, with the latter often referred to as cutaneous PAN. However, we lack consensus on the threshold for the size, vessel type, or location on deep-skin biopsy to separate these subsets. Skin-isolated LCV is considered a different form of cutaneous vasculitis and affects mostly small-sized-vessel vasculitis.22–24 Clinically, subcutaneous nodules would be more characteristic of cutaneous PAN. Purpuric lesions are less distinctive and can be observed in both LCV and cutaneous PAN, and in several
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other vasculitides (including GPA, MPA, EGPA, IgA vasculitis, and cryoglobulinemic vasculitis). On histology, deep dermis and hypodermis arterial involvement is more suggestive of medium-sized-vessel vasculitis. Importantly, cutaneous PAN has often been considered a specific entity with ‘‘isolated’’ skin disease, but it is tacitly accepted that the disease can be associated with peripheral neuropathy within the same parts of the skin lesions. In these cases, the line between ‘‘cutaneous PAN’’ and the more classical and ‘‘systemic’’ PAN, though in a more limited form, is indistinct and overlaps. In practice, we lack clear consensus on how to treat this ‘‘cutaneous’’ PAN and peripheral neuropathy with no other organ involvement (cf. section on treatment, patients with FFS = 0). Other types of localized PAN are more rare.11,25 Isolated involvement of one skeletal muscle or a muscle group and isolated neuropathy (mononeuritis multiplex or simplex) without systemic or any other symptoms have been described, as have occasional cases involving only one organ, appendix, colon or stomach, gallbladder, testis, breast, or uterus. In some cases, the vasculitic etiology might be considered an unexpected finding and pathological curiosity after surgical removal of the inflamed organ, and systemic medical therapy may be unnecessary. Possibly more striking presentations are spontaneous ruptures of an artery (renal, hepatic or splenic arteries mainly, in the free peritoneal cavity or as subcapsular hematomas), which may require urgent surgical or endovascular procedures.26–29 Spontaneous arterial dissections are rare presenting features of PAN but have been reported in different arteries such as the internal carotid, coronary, renal, and/or ilio-femoral arteries as well as the aorta.15–18 In all these latter cases, the main differential vasculopathies include acute segmental arterial mediolysis and fibromuscular dysplasia. These localized forms of PAN usually carry good overall prognoses, but for PAN limited to the skin or muscle, relapse is frequent. Evolution to a systemic form of PAN is possible but rare.
3.3.
Forms with (probable) etiologies
Besides HBV-associated vasculitis, a few other PAN-like conditions have identified etiology(ies), including rare (and controversial) forms of PAN due to hepatitis C virus infection and PAN secondary to hairy cell leukemia.30,31 Multiple drugs have been incriminated as causing LCV or ANCA-associated vasculitis, but only a few cases of drug-induced PAN have been reported, including minocycline-induced PAN.32 More recently, recessive loss-of-function mutations in adenosine deaminase 2 have been shown to cause a PAN-like vasculopathy with necrotic cutaneous manifestations, early-onset stroke, renal, and/or gastro-intestinal ischemia and infarct.12,13
4. Principles of treatment and therapeutic challenges 4.1.
Treatment of (non-HBV-related) PAN
The initial treatment of PAN relies on glucocorticoids (GCs), combined with an immunosuppressive agent, mainly cyclophosphamide (CYC), in severe forms, followed by maintenance
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(e.g., with azathioprine or methotrexate), although relapse is not that common in PAN, at least as compared with GPA.5 The initial treatment can be adapted to the type, extent, and severity of the disease (Fig. 1). In 1996, the French Study Group established the five-factor score (FFS), which has significant prognostic value in PAN (as well as in MPA and EGPA) in terms of survival.33 The FFS parameters responsible for increased mortality are proteinuria >1 g/day, renal insufficiency (serum creatinine level >140 mmol/l), vasculitis-related cardiomyopathy, GI manifestations, and/or CNS involvement. In a subsequent study of 278 patients with PAN, MPA, or EGPA, the combination of CYC and GCs was beneficial for patients with FFS ≥ 2.34 Therefore, the 1996 FFS can be used to guide the initial therapeutic decisions. The revised 2009 FFS, detailed in Table 2, also has good prognostic value for PAN, MPA, EGPA, and GPA but has not been (and thus must not be) used to similarly guide therapeutic choices.35 The Birmingham vasculitis activity score, the standard assessment tool in most prospective trials of vasculitis, can also be used to determine disease severity and help determine the intensity of treatment.36 Patients with PAN and FFS = 0 do not require the addition of CYC, unless the disease is rapidly progressive and not controlled with GCs.37 However, the disease relapse rate is >50% after 2 years of follow-up in these patients, especially those with initial peripheral nerve involvement.38 CHUSPAN2 (ClinicalTrials.gov Identifier: NCT00400075) is an ongoing randomized trial of patients with PAN (or EGPA or MPA) and FFS = 0. It aims to compare treatment with GC alone versus GCs and azathioprine, especially in terms of relapse. Results should be available in late 2015. Historically, few patients with FFS = 0 have also achieved remission with dapsone (without GCs), but this option is no longer advised, except for limited cutaneous PAN (cf. section on the treatment of isolated forms). Patients with PAN with FFS = 0 but not responding promptly to GC alone or those with FFS ≥ 1 must receive GCs and CYC as induction regimens. CYC induction regimens in the oral route (2 mg/kg/d) and intravenous route (15 mg/kg per pulse, on days 1, 15, 29 then every 3–4 weeks) were prospectively compared only in GPA and MPA; they achieved similar rates of remission (but with more frequent neutropenia with the oral route).39 In PAN, either route can be used; the most important point is to adjust the CYC doses to age and renal function and to stop CYC after a maximum of 6 months and switch to a less toxic maintenance agent. The CHUSPAN trial showed 12 CYC pulses associated with a lower relapse rate than only 6 pulses, but no maintenance was given after the 6 pulses.40 Although no randomized controlled study has been conducted to evaluate the best maintenance treatment following CYC induction in PAN, the staged inductionmaintenance strategies used for GPA or MPA have been routinely used with PAN. Possible maintenance agents include methotrexate (0.3 mg/kg/week, with folic acid) or azathioprine (2 mg/kg/day). Fewer data are available for mycophenolate mofetil (2 g/day) or leflunomide (10–20 mg/day). Rituximab has been used with some interesting results in a few patients with refractory PAN, but the experience remains limited and the pathogeny of primary PAN, although not totally understood, does not overly call for B-cell depletion therapy.41–43 Plasma
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[(Fig._1)TD$IG]
Fig. 1 – Suggested management algorithm for polyarteritis nodosa (PAN). *see text for more information on vasculitis with a probable etiology or limited to a single organ. FFS, five-factor score; GCs, glucocorticoids; HBV, hepatitis B virus.
exchange has a central place in HBV-associated vasculitis, but does not appear to provide additional benefit in PAN.44
4.2.
Treatment of HBV (and other virus-related) vasculitis
The treatment of HBV-related PAN relies on the combination of antiviral agents to eradicate the virus (currently mostly entecavir or tenofovir), plasma exchange to remove circulating immune complexes, and a short course of GCs (about 2 weeks) to rapidly control the most severe life-threatening vasculitic manifestations without increasing viral replication.5,7,45
Plasma exchange aims to clear circulating immune-complexes induced by HBV and are usually prescribed until seroconversion of HBe antigen to anti-HBe antibody is achieved. Because of the rarity of HBV-associated vasculitis, no study is and will be able to determine which new antiviral drugs or combinations are the most efficient, but therapeutic advances in chronic HBV infection can probably be transposed to HBVassociated vasculitis. Treatment for other virus-related PAN-like vasculitis cases should also rely on the combination of short GC therapy and antiviral agents, along with plasma exchange when manifes-
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Table 2 – The original 1996 and 2009 revised prognostic five-factor score (FFS) for prognosis of systemic necrotizing vasculitides.33–35 1996 FFS33 Applies to No. of patients analyzed to develop the score Usability to guide therapy FFS parameters
2009 revised FFS35
PAN and EGPA, with subsequent extension to MPA 342 (260 PAN, 82 EGPA) plus 58 MPA in the 2001 extension study33,34
PAN, MPA, GPA, EGPA 1108 (349 PAN, including 122 HBV-infected, 311 GPA, 230 EGPA, 218 MPA)
Yes (patients with FFS = 0 can initially receive GCs alone; patients with FFS ≥ 1 must receive a combination of GCs and an immunosuppressant such as cyclophosphamide) Proteinuria > 1 g/24 h Serum creatinine level > 140 mmol/L Specific gastrointestinal involvement Specific cardiomyopathy Specific CNS involvement
No (the revised FFS is only a tool for survival prognostication)
Prognostic value
For survival only (alveolar hemorrhage and severe peripheral nervous system involvement did not significantly predict poor survival in this analysis, but they may still require a combination of GCs and an immunosuppressant; therapeutic decisions are first based on physician's impression of the disease severity, which must prevail over any score)
5-year mortality rate by FFS
FFS = 0 ! 12% FFS = 1 ! 18% FFS ≥ 2 ! 29%
Age > 65 years Renal insufficiency (peak serum creatinine level ≥ 150 mmol/L) Cardiac symptoms Gastrointestinal involvement Absence of ENT involvement (for GPA and EGPA only) For survival only (alveolar hemorrhage, CNS and/or severe peripheral nervous system involvement[s] did not significantly predict poor survival in this revised analysis but may still represent severe manifestations and/or affect different outcomes) FFS = 0 ! 9% FFS = 1 ! 21% FFS ≥ 2 ! 40% (for GPA or EGPA with ENT involvement ! 23% GPA, 8% EGPA; without ENT involvement ! 43% GPA, 16% EGPA)
CNS, central nervous system; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose and throat; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; HBV, hepatitis B virus; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa.
tations are severe. For HCV-related vasculitis, rituximab (contraindicated in HBV-infected patients) should be considered, as suggested for treating HCV-associated cryoglobulinemic vasculitis.46,47
4.3.
Treatment of isolated PAN and variant forms
As mentioned previously, localized forms of PAN usually carry good overall prognoses, and progression to a systemic form is rare. However, isolated cutaneous PAN, especially if associated with peripheral nerve involvement, may require some treatment to limit the disease extent or severity and/or limit the frequency of flares. We lack randomized controlled studies to determine the best drug in cutaneous PAN. The only available prospective study in skin vasculitis (not only PAN) was small-sized and showed no major difference between placebo and colchicine.48 Short courses of GCs can be used to treat severe flares. Background therapy for cutaneous PAN, when needed, can consist of colchicine, dapsone, hydroxychloroquine, or azathioprine.22–24 More uncertainties remain as to the need to use systemic medications for isolated testis, gallbladder or appendix PAN, after surgical removal of the affected organ. Most of these cases will not develop any other organ involvement and will not progress to systemic PAN.11,25 Therefore, an initial and close monitoring of these patients, without any systemic
treatment, is most often sufficient and can be stopped after a couple of years. Similarly, whether systemic therapy is indicated for patients with spontaneous and isolated renal artery rupture or subcapsular hematoma with localized aneurysms ‘‘suggestive of PAN’’ on imaging is unclear. The diagnosis of PAN in these latter cases is challenging, in the absence of histological confirmation of PAN. Hence, systemic treatment should not be initiated in all patients, especially those without inflammatory syndrome (normal erythrocyte sedimentation rate and C-reactive protein level), or continued uselessly for months, if it had been started during the acute phase, for fear of an ongoing and possibly progressive systemic PAN. Loss-of-function mutations in adenosine deaminase 2 causing a PAN-like vasculopathy tends to respond better to anti-tumor necrosis factor alpha agents, such as infliximab, rather than other immunosuppressive agents, including CYC.12,13
4.4.
Outcomes and long-term management
In its systemic form, PAN is most often an acute disease, which can be severe and responsible for death, unless timely adequate treatment is prescribed. From the most recent series of PAN, overall survival rates are 76–89% for PAN and 64–70% for HBV-associated vasculitis.5 After 5 years of follow-up, 28%
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of patients with primary PAN and 11% with HBV-associated vasculitis show relapse, with a mean time to first relapse of 43 and 26 months, respectively.5,7 Older age at diagnosis (>65 years), hypertension, and surgical GI manifestations are independent predictors of death. Early death in the first few months of disease usually results from multi-visceral involvement and/or the inability of treatment to control disease. Death during the following years more often results from treatment side effects.
5.
Conclusion and perspectives
PAN has become more rare in its systemic and primary form, in parallel with the decreased frequency of HBV-associated vasculitis, formerly called HBV-related PAN. The exact reason for the decreasing incidence of PAN is unknown. However, the disease has not totally disappeared and physicians must remain alert to this condition, one of the first systemic necrotizing vasculitis ever described, and how to diagnose and manage it. In contrast, cutaneous PAN remains relatively common, although the distinction between cutaneous medium- and small-sized-vessel vasculitis lacks consensus. Studies are now needed to determine the optimal treatment approach for this non-severe but still-diffuse, visible, often relapsing and annoying skin condition. Other single-organ PAN-type vasculitis has always been and remains another challenging situation, for both diagnosis and therapeutic decisions. Finally, new genetic diseases (such as mutations in adenosine deaminase 2) that can mimic PAN have been discovered and others will likely be identified, and we may have to revisit some of our concepts about unusual cases of PAN and/or cases refractory to conventional GC- and CYCbased treatment.
Conflicts of interest Dr. Pagnoux has declared having received consultancies, speaking fees, and/or honoraria from Hoffman-La Roche, BMS, GSK, and Sanofi (<$10,000) over the last 5 years. Dr. Khalidi has declared having received consultancies, speaking fees, and/or honoraria from Roche, UCB, and Abbott (<$10,000) over the last 5 years.
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