Review Vasculitides secondary to

C. Pagnoux, P. Cohen, L. Guillevin

Christian Pagnoux, MD; Pascal Cohen, ABSTRACT Introduction MD; Loïc Guillevin, MD. Many viruses can be responsible for Infectious agents can be the underlying Department of Internal Medicine, Hôpital systemic , the most frequent cause of several vasculitides, usually Cochin, Assistance Publique-Hôpitaux de being hepatitis B virus-related poly- not associated with antineutrophil cyto- Paris, Université Paris 5, Paris, France. nodosa (HBV-PAN), even plasmic antibodies (ANCA), and affect Please address correspondence and though its incidence has decreased vessels of various calibers. There are reprint requests to: Dr Christian Pagnoux, over the past few decades. Mixed cryo- two major virus-associated vasculitides Department of Internal Medicine, Hôpital globulinemia has been shown to be (VAV): polyarteritis nodosa resulting Cochin, Assistance Publique–Hôpitaux de Paris, Université Paris 5, 27, rue du associated with hepatitis C virus from hepatitis B virus (HBV-PAN) Faubourg Saint-Jacques, 75689 Paris (HCV) in more than 80% of infection (1), and cryoglobulinemic Cedex 14, France. the patients, but it remains asymp- vasculitis (CV), occurring in patients E-mail: [email protected] tomatic in most of them with only a infected with hepatitis C virus (HCV) Received and accepted on February 9, minority developing vasculitis. Human (2). Other viruses can be associated, 2006. immunodeficiency virus (HIV), ery- albeit less frequently, with the develop- Clin Exp Rheumatol 2006; 24 (Suppl. 41): throvirus B19, cytomegalovirus, vari- ment of vasculitis (Table I): human S71-S81. cella-zoster virus and human T-cell immunodeficiency virus (HIV) (3), ©Copyright CLINICAL AND EXPERIMENTAL lymphotropic virus (HTLV)-1 have also erythrovirus B19 (formerly parvovirus RHEUMATOLOGY 2006. been reported to be associated with or B19) (4), cytomegalovirus (CMV), implicated in the development of vas- varicella-zoster virus (VZV) and human Key words: Systemic necrotizing culitides. On the other hand, some bac- T-cell lymphotropic virus-1 (HTLV-1). vasculitides, secondary vasculitides, teria, fungi or parasites can also cause To treat these VAV, original therapeutic virus-associated vasculitis, vasculitis, mainly by direct invasion of approaches have been devised that HBV-related polyarteritis nodosa, blood vessels or septic embolization, avoid prolonged administration of cor- cryoglobulinemic vasculitis, leading, e.g., to the well-known feature ticosteroids (CS) and cytotoxic agents. HCV-associated cryoglobulinemia, of ‘mycotic ’. Syphilitic aorti- They are mainly based on the combina- HIV infection. tis and/or cerebrovascular disease and tion of antiviral agents and plasma rickettsial diseases are other, more spe- exchanges (PE). Two prospective trials cific, bacteria-induced vasculitides. organized by the French Vasculitis Recognizing an infectious origin of Study Group (FVSG) validated that vasculitides is of great importance therapeutic strategy for HBV-PAN (5, because treatment strategies differ from 6). A specific antiviral strategy is also those applied to non-infectious forms. recommended for HCV-related CV, Effective antimicrobial drugs are despite less favorable results (7, 8). On mandatory to treat bacterial, parasitic the other hand, syphilitic and/or or fungal infections, while the combi- cerebrovascular disease (9-11) and nation of antiviral agents and plasma rickettsial diseases (12-14) often mimic exchanges has been proven to be effec- primary systemic vasculitides. Other tive against HBV-PAN. This latter strat- bacterial, fungal or parasitic infections egy might also be effective against HIV- may also be responsible for vasculitic associated vasculitis and, unlike cyto- features and are usually easier to diag- toxic agents, does not jeopardize the nose because of their suggestive clini- outcome of HIV-infected patients. In cal manifestations such as ‘mycotic the context of HCV-related cryoglobu- aneurysm’ in endocarditis or necrotiz- linemic vasculitis, antiviral drugs are ing and/or destructive lung vasculitis necessary to achieve recovery, in com- associated with to Pseudomonas aerug- bination with low-dose corticosteroids inosa infection (15, 16). These latter and/or rituximab. In the near future, vasculitides require specific anti- newer antiviral agents will probably microbial therapy, with adjunctive CS also have their place in the therapeutic only in very rare instances, but no imm- armamentarium for these patients. unosuppressant.

S-71 REVIEW Vasculitides secondary to infections / C. Pagnoux et al.

Table I. The main virus-associated vasculitides and their therapeutic management.

Virus Type of vasculitis Standard therapy (see text for details)

HBV PAN Short CS therapy, with PE and lamivudine

HCV Cryobulinemic vasculitis Short CS therapy, with IFNα and ribavirin ± PE (anti-CD20 ?) PAN (controversial)

HIV PAN Short CS therapy, with ARV ± PE Large-, medium- and/or small-sized vessel vasculitides Cerebral vasculitis

Erythrovirus B19 PAN CS Henoch–Schönlein purpura-like CS and/or IVIg

VZV Retinitis Acyclovir Meningoencephalomyelitis Acyclovir ± CS

CMV Retinitis Valganciclovir, ganciclovir or foscarnet Colitis PAN

HTLV-1 Necrotizing retinitis Not established Cerebral vasculitis

ARV: antiretroviral drugs; CS: corticosteroids; IFNα: interferon-alpha; IVIg: intravenous immunoglobulins; PE: plasma exchanges.

I. Virus-associated polyarteritis ly with other viruses, HBV or HIV, and HBV-PAN is certainly the purest form nodosa also with (type II or III) mixed cryo- of PAN and no overlap with other vas- I. 1. HBV and other viruses associated globulinemia (MC). HIV infection has culitides, especially microscopic poly- with PAN: clinical presentation also been associated with PAN in sev- angiitis, has been observed in our expe- Since the first reports on HBV-PAN (1, eral patients (3, 21-23). GB virus-C, rience. Microaneurysms and/or stenos- 17), this causal relationship has been when sought in patients with PAN, was es may be seen on celiomesenteric and largely confirmed based on clinical, occasionally found and could have be- renal of medium-sized epidemiological and therapeutic data en an underlying cause (24). Several in 40–62% of the patients with- (6). During the 1970s, about half of the concomitant erythrovirus B19 infec- out gastrointestinal symptoms, and in patients with classic PAN were infected tions have been described but system- up to 90% with gastrointestinal with HBV. However, over the past few atic testing of PAN patients did not involvement (30-33). HBe antigen years, the frequency of HBV-PAN has show them to have a higher frequency (Ag) to anti-HBe antibody (Ab) sero- declined from 35% in 1984 to less than of erythrovirus B19 infection than the conversion usually parallels recovery. 5% today (18). In France, the HBV- general population (25, 26). The major sequelae are the conse- PAN incidence has decreased dramati- HBV-PAN usually becomes manifest quence of vascular nephropathy and cally since blood testing and donor less than 12 months after viral infec- peripheral neuropathy but, even in selection were reinforced, and large tion, with a mean of 4 months after ex- patients who initially develop renal vaccination campaigns were organized posure (6, 27), and occurs mainly in insufficiency; it is possible to cure PAN for teenagers and subjects at risk. Intra- patients under 40 years old. Hepatitis is with little residual impairment of renal venous drug abuse has now become the rarely diagnosed, as it is usually silent function. predominant cause of HBV-PAN. Since before PAN develops and remains 2002, fewer new cases of HBV-PAN absent or mild (2–3-fold transaminase- I. 2. Outcome but also PAN have been registered in level rise) when PAN symptoms ap- Once remission has been obtained, France, which further, albeit indirectly, pear. Immune-complex deposition on HBV-PAN tends not to recur. In FVSG supports the hypothesis of a viral cause and throughout vessel walls, in an cohorts (28), only 6% of HBV-PAN of PAN [HBV and/or other unidentified excess amount of viral antigens, could patients relapsed, but it is still not pos- virus(es)]. trigger vasculitis and be responsible for sible to identify the subgroup of Some other viruses have been also subsequent organ damage. Clinical patients who will relapse. The clinical incriminated in PAN onset. HCV does manifestations start suddenly and are pattern of relapse does not necessarily not appear to be a major etiological fac- roughly the same as those commonly mimic the original presentation, in that tor for PAN and its responsibility has observed in PAN (28). Orchitis, gas- previously unaffected organs can be only rarely been advanced (19). Less trointestinal and kidney vessel involve- involved at relapse. Due to the low than 5% of our PAN patients were ment, with , are common relapse rate, maintenance treatment is infected with HCV (20). When present, in HBV-PAN, whereas cutaneous and not necessary and short-term treatment HCV was often observed concomitant- pulmonary symptoms are rarer (29). can be envisaged.

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I. 3. Deaths II. HCV-related cryoglobulinemic mononeuritis multiplex, as described in The causes of death can be divided into vasculitis PAN. The neuropathy tends to be three categories: related to vasculitis Type II and, more rarely, type III MC chronic and, although the motor symp- manifestations, attributed to treatment are the consequence of HCV infection toms can regress, the sensory symp- side effects and miscellaneous causes, in more than 80% of the patients (2, toms can remain definitively. Kidney usually independent of the vasculitis. 36). MC can be detected in 30–50% of involvement is glomerulonephritis but, the patients infected with HCV but unlike ANCA-associated vasculitides, I. 3. 1. Vasculitis-related deaths remains asymptomatic in most of them. pauci-immune glomerulonephritis is In all vasculitides, involvement of vital CV is defined as a small-vessel vasculi- not found. Membranoproliferative glom- organs can be lethal. A few patients die tis by the Chapel Hill Nomenclature erulonephritis is the hallmark of CV early from multivisceral involvement, (37). The disease duration, hepatic renal involvement, with some intracap- often gastrointestinal (34), that cannot fibrosis or cirrhosis (19, 38, 39) might illary thrombi containing cryoglobulin be controlled by treatment. In such be factors associated with the presence precipitates (49). Few patients progress cases, the course of the disease is gen- of clinical symptoms in patients with to end-stage renal failure. About 20% erally characterized by fever, rapid MC (19, 40), whereas no clear associa- of the patients have sicca syndrome but weight loss, diffuse pain and involve- tion has been found between the HCV without the characteristic anti-SSA(Ro) ment of one or several vital organs. genotype and MC or CV (41-43). HLA and/or SSB(La) autoAb of Sjögren’s Prognosis can also be evaluated using DR11 (44), DR3 or DR4 (45) and B8 syndrome. Dilated and/or ischemic car- the French five-factor score (FFS), combined with DR3 (46) phenotypes diomyopathy (47), ischemic cerebral validated for PAN, microscopic po- were associated in some populations stroke, cerebral vasculitis (50), isch- lyangiitis and Churg–Strauss syn- with an increased risk for the develop- emic intestinal perforations or hemor- drome (Table II) (35). The FFS empha- ment of type II MC in patients with rhages (51) have also been described. sizes the poor prognosis of specific chronic HCV infection. The outcome of CV is characterized by gastrointestinal, renal, cardiac and/or Type II MC, usually with a monoclonal chronicity and relapses, even under central nervous system (CNS) involve- IgM-kappa component, is more fre- treatment. ment(s). quent and characteristic of CV. Com- plement, especially the C4 component III. HIV-associated vasculitis I. 3. 2. Deaths attributed to treatment is low, and a rheumatoid factor may be Vasculitides occurring during the side effects found, and, because it is sometimes dif- course of HIV infection have been re- Conventional treatment with CS and ficult to detect a cryoprecipitate, this ported (3, 23). According to Calabrese cyclophosphamide jeopardizes the pa- biological context is highly suggestive (23), the frequency is low (1%), with tient’s outcome by allowing the virus to of the diagnosis. AutoAb are absent, most of the reported cases having been persist, stimulating its replication and especially ANCA. identified at autopsy. In our experience thereby facilitating evolution towards The more frequent symptoms of CV (3), HIV-associated vasculitis is an chronic hepatitis and liver cirrhosis. are purpura, painful leg ulcers, periph- extremely rare entity, which has been Thus, cyclophosphamide, like pro- eral neuropathy, glomerulonephritis, encountered in several large centers longed CS administration, is contra- arthritis and sicca syndrome (40, 47). specializing in the management of HIV indicated. In addition to these long- The clinical symptoms (40, 47, 48) infection. term side effects, infectious complica- may develop progressively and are This vasculitis can develop in adults tions are more frequent when immuno- often of moderate intensity initially. and children at any HIV-infection suppressants are prescribed. PE can Neuropathy can be symmetrical and stage, as defined by the Centers for also favor the susceptibility to infec- limited to sensory signs, including Disease Control classification. Its clini- tions when central venous access is hypoesthesia and pain, is usually distal, cal spectrum and histological findings necessary, while CS are responsible for and occurs more frequently in the legs vary widely. Most of them involved well-known side effects (34). than arms. It can also take the form of skin (often with digital or ery-

Table II. The five-factor score, as established based on 342 patients with PAN or Churg-Strauss syndrome (35).

Proteinuria > 1 g/24 h FFS 5-year survival Relative rate (%) risk of death Creatininemia > 140 µmol/l Specific gastrointestinal involvement 0 88.1 0.62 Specific cardiomyopathy 1 74.1* 1.35

Specific central nervous system involvement ≥ 2 54.1** 2.40

1 point accorded for each of these 5 items when present. *p < 0.005 and **p < 0.0001 vs patients with FFS = 0.

S-73 REVIEW Vasculitides secondary to infections / C. Pagnoux et al. throcyanosis; Figure 1), peripheral neu- ropathy (mononeuritis multiplex (52)) or the CNS (ischemic stroke, focal neu- rological deficits or cerebral vasculi- tis). Cerebral lymphomas or granulo- matous vasculitis have also been reported anecdotally (53). Large-, medium- and small-sized arteries can be affected. Necrotizing arteritis, non- necrotizing arteritis, giant-cell arteritis and eosinophilic arteritis have been observed (23). Indeed, some cases seem to be caused by opportunistic infections, such as Pneumocystis jiroveci (formerly, P. carinii), CMV, VZV or Toxoplasma gondii, non-opportunistic infectious Fig. 1. Digital ischemia and necrosis in a patient with HIV-associated PAN. agents or drug-induced hypersensitivi- ty. However, for most HIV patients who develop vasculitis, the exact cause helpful in distinguishing between the leptomeningeal biopsies and cere- remains unknown. two diseases, when IgM directed brospinal fluid is usual in this setting. HIV was thought to be the etiological against erythrovirus B19 are detected agent in a few patients because of the during the symptomatic acute phase. IV. 3. Cytomegalovirus localization of the virus in the tissue Some authors used polymerase-chain CMV-associated vasculitides can lesions and the absence of evidence reaction (PCR) to detect erythrovirus occur along with the virus direct suggesting other mechanisms (52). The B19 in endothelial cells and suggested pathogenic effects, mainly seen in pathogenesis of these HIV-associated a possible association with giant-cell immunocompromised patients, i.e. vasculitides is heterogeneous, but at arteritis (57), but this role remains con- HIV-infected subjects or in bone-mar- least two general mechanisms have troversial (58). Erythrovirus B19 infec- row recipients. Leading target organs been hypothesized: virus replication tion, based on serology, has also been are the gastrointestinal tract, mainly might induce direct injury of the vessel reported in some PAN (4), Kawasaki the large bowel, the CNS and skin wall or vascular damage might be the disease (59) and Wegener’s granulo- (64). Characteristic cytological fea- result of an immune mechanism. These matosis (60) patients, but these cases tures of CMV infection in endothelial mechanisms may be cellular and/or were most probably anecdotal. cells may be seen, arguing for a poten- humoral and include deposition of tially direct vasculitis-inducing effect immune complexes and/or their in situ IV. 2. Varicella-zoster virus of the virus on small vessels (65). Pos- formation (52). Indeed, immune com- VZV vasculitis can develop in infected sible gastrointestinal manifestations plexes are frequently detected in HIV- adults or children, during the acute pri- range from abdominal pain and febrile infected patients and their frequency mary infection, zoster recurrence or diarrhea to more severe bowel increases with advancing stages of several weeks or months thereafter, and ischemia with perforations and/or infection (3). Some authors have ana- affects the CNS (61), retinal and/or hemorrhage (66). CNS involvement lyzed their composition and found choroidal small-vessels, and some- may be non-specific encephalopathy, them to contain both HIV Ag and Ab times skin or kidney (62). cranial nerve palsies, meningitis, specific to HIV. However, their role in Encephalitis and/or myelitis can be meningoencephalitis or radiculomyeli- the vasculitic process remains to be seen in immunocompromised patients, tis. Vasculitis may be retained based on demonstrated. during acute infection, characterized by cerebral MR angiographic images, diffuse small-vessel vasculitis. CNS occasionally showing vessel irregulari- IV. Other virus-associated involvement may also occur several ties or stenoses, or by histological vasculitides weeks after trigeminal zoster, and is examination, which is rarely feasible IV. 1. Erythrovirus B19 manifested by a sudden ischemic cere- in practice (67, 68). Skin might be in- During the viremic phase of ery- bral stroke in middle cerebral - volved, especially when the viral throvirus B19 infection, cutaneous supplied areas. Cerebral infection is widely disseminated. Non- leukocytoclastic vasculitis may devel- or magnetic resonance (MR) angiogra- specific necrotic infiltrated purpuric op, with purpuric lesions, with or with- phy may show ischemic lesions with lesions, subcutaneous nodules, vesi- out arthralgias, fever or abdominal artery irregularities and stenoses sugges- cles or erythematous rash have been cramps, mimicking Henoch–Schönlein tive of medium- and small-sized vessel described (69). Finally, only rare cases purpura (54-56). Serological assays are vasculitis (63). Viral PCR detection in of PAN or microscopic polyangiitis

S-74 Vasculitides secondary to infections / C. Pagnoux et al. REVIEW associated with CMV-infection sero- such as or tropenic patients, and is a 1- to 5-cm logical markers have been reported. in the lungs, macular indurated lesion with a central or Fusobacterium necrophorum in the necrotic ulceration. Disseminated in- IV. 4. HTLV-1 internal jugular after to pharyngi- fections with Nocardia, Aspergillus or HTLV-1 is a human retrovirus highly tis. Mycobacterium tuberculosis, Myco- Mucor spp. may result in ecthyma-like endemic in the Caribbean islands, bacterium spp., Aspergillus or Mucor lesions, mostly in immunocompromis- Africa, and southwestern Japan. It is (necrotizing sinusal, orbital or intracra- ed patients. Neisseria meningitides almost always asymptomatic but may nial vasculitis, with frequent arterial bacteremia is often associated with a led to adult T-cell leukemia/lymphoma thromboses) (75), Coccidioides immitis diffuse macular and purpuric rash, with (ATL) or myelopathy/tropical spastic (basilar granulomatous meningitis) evidence of necrotic vasculitis and paraparesis (TSP). Retinal vasculitis, (76), and Wuchereria spp. or Dirofilar- presence of the germ in endothelial with or without granulomatous and ia immitis (pulmonary vasculitis) (77) cells and surrounding mononuclear necrotizing features in microdissected infections may also be involved in cells in skin biopsies, when taken. retinal biopsies, has been described in necrotizing vasculitis, sometimes gran- Syphilitic aortitis and cerebrovascular some patients carrying HTLV-1, in ass- ulomatous and usually localized. Rarer disease have become rare since the ociation or not with ATL, TSP or cases of such localized vasculitides advent of , which still consti- HTLV-1-associated uveitis, which is a have been reported in patients infected tutes their reference treatment, but have more common ophthalmic manifesta- with Histoplasma capsulatum (cerebral not disappeared, primarily due to the tion of this viral infection (70, 71). vasculitis), Cryptococcus neoformans HIV epidemic. These lesions are clas- HTLV-1–related cutaneous or CNS (cerebral or skin vasculitis), Candida sic vascular lesions of tertiary , vasculitis is extremely rare (72). albicans (exceptional cases of cerebral and usually develop, respectively, vasculitis) or Malassezia furfur (pul- 10–30 and 6–10 years after the first V. Vasculitides secondary to monary vasculitis) (78, 79). Toxocara, stage of the infection. TPHA testing of bacterial, fungal or parasitic Schistosoma spp., Angylostrongylus sera and cerebrospinal fluid from these infections and Filariae infections have been asso- patients for Treponema pallidum is Vasculitis onset following bacterial, ciated with more diffuse forms of vas- usually positive. The non-treponemal fungal or parasitic infection results pre- culitic diseases. VDRL test is often negative for serum, dominantly from direct invasion of Septic embolizations result in the so- but can be positive for cerebrospinal endothelial cells, extension of a local- called ‘mycotic ’ (80-82), fluid from 30–70% of the patients with ized focus of infection involving blood even though they do not usually lead to cerebrovascular syphilis and has high vessels or septic hematogenous embol- true aneurysm formation. These sec- specificity in these cases. Conversely, ization. Blood cultures yield positive ondary vasculitic lesions are most fre- TPHA-positive cerebrospinal fluid is results and the germ can be identified quently located in the , followed not diagnostic of , be- in more than 50% of these episodes. by the intracranial, superior mesenteric cause it has been seen in patients with Cutaneous biopsies, when skin is af- or femoral arteries, and may be a con- no signs, but it has a strong negative- fected, may also contain microorgan- sequence of infective endocarditis, predictive value, ruling out the diagno- isms. Prompt antimicrobial therapy, especially when caused by Staphylo- sis when negative (88). T. pallidum is combined with surgery when neces- coccus aureus or streptococci. Howev- only rarely detected in artery wall sary, is mandatory in these cases. er, they can also occur, albeit much lesions. Autoimmune T- and/or B-cell reactions more rarely, in some other settings, like The microorganisms responsible for triggered by microbial antigens may infections with S. aureus, Streptococ- rickettsial diseases are obligate intracel- play a role in some cases, perhaps cus spp. or Salmonella spp. in intra- lular bacteria that can cause vasculitis, because of epitope mimicry or super- venous drug abusers, patients with especially with skin manifestations antigen induced T-cell activation. osteomyelitis or in the elderly. Many (maculopapular extensive rash) in Antimicrobial therapy is also recom- other infective agents have been report- Rocky Mountain spotted fever, which mended, but regression of the lesions is ed to cause mycotic aneurysms, at can, if it goes unrecognized and untreat- more unpredictable. Putative infectious diverse arterial locations, including ed, involve kidney (renal impairment), origins of primary systemic vasculi- Clostridium septicum (83), Burkholde- lung (pulmonary edema) or even brain tides, like, the potential responsibility ria pseudomallei (84), Aspergillus (85) small vessels in up to 25% of the in giant-cell arteritis of Chlamydia or after intravesical BCG therapy for patients, but also in pneumoniae, whose DNA was detected bladder cancer (86, 87). Smaller ves- or epidemic . The diagnosis is in artery specimens from patients in sels may also be affected, with periph- mainly based upon clinical findings, 2001, but was subsequently questioned eral septic embolizations, particularly since serological testing can confirm it (58, 73, 74), are beyond the scope of in the skin, resulting, e.g., in ecthyma only later, whereas antibiotics are indi- this article. gangrenosum, which is usually associ- cated as soon as possible. Borrelia Direct necrotizing vessel-wall destruc- ated with Pseudomonas aeruginosa or burgdorferi has infrequently been re- tion can be induced by some bacteria, Gram-negative bacteremia in neu- ported to cause CNS vasculitis (89).

S-75 REVIEW Vasculitides secondary to infections / C. Pagnoux et al.

Erythema nodosum leprosum is char- The rationale for combining PE and of them. The dose of 3 million units, acterized by painful cutaneous nodules, antiviral drug(s) was to obtain the fol- injected subcutaneously 3 times a week evolving towards ulcerations, that lowing effects: initial CS to rapidly is recommended. In the case of failure, develop in half of the patients with lep- control the most severe life-threatening the dose could theoretically be in- romatous leprosy after the initiation of manifestations of PAN which are com- creased to 6 millions units, injected antimicrobial therapy and are often mon during the first weeks of the dis- subcutaneously, 3 times a week. associated with general symptoms, ease, and abrupt stoppage of CS to Pegylated IFNα, validated for the treat- neuropathy, uveitis and occasionally enhance immunological clearance of ment of hepatitis C, could probably with glomerulonephritis. Biopsy of HBV-infected hepatocytes and favor also be prescribed for HBV-PAN, in skin lesions can reveal features of acute HBeAg to HBeAb seroconversion. PE analogy with what is being done in small-vessel vasculitis, thought to be can almost always control the course of ongoing trials on chronic hepatitis B due to immune-complex vascular de- these PAN without the addition of (94). positions and/or excessive local T- steroids or cyclophosphamide. In HBV-PAN, the combination of helper type 1 (Th-1) lymphocyte acti- An alternative therapy was also needed antiviral agents (vidarabine or IFNα-2a vation, triggered by the release of to lower HBV-PAN mortality and or -2b) gave excellent overall therapeu- mycobacterial debris after starting anti- improve prognosis. In a retrospective tic results (6). The efficacy of this strat- biotic treatment. Adjuvant and short- study, we showed that, when CS and egy was confirmed in a series of 41 term CS may be necessary in some of immunosuppressants were prescribed patients (6); 23 (56%) no longer exhib- these patients and is usually effective. to treat HBV-PAN, the outcome was it serological evidence of replication poorer than for non-viral-PAN (28). and 81% have completely recovered. VI. Treatment Therefore, based on the efficacies of Treatment objectives are two-pronged, antiviral agents against chronic hepati- VI.1.3. Lamivudine to simultaneously treat the infection tis and of PE in PAN, together with Lamivudine is an antiviral agent and the associated vasculitis, with Trépo and Thivolet’s description of specifically designed for the treatment drugs and therapies that do not interfere HBV responsibility in the development of HBV and HIV infections. In a first each other. Indeed, treatment for vas- of PAN (1), we combined the two ther- cohort of 10 HBV-PAN patients (5), we culitides caused by bacteria, fungi or apies to treat HBV-PAN (92, 93). How- prescribed lamivudine (100 mg/d) in parasites primarily relies on antimicro- ever, in our protocol, CS are still pre- combination with PE, after a few days bial agents alone, and only rarely scribed for 1 week to help control as of CS. Because lamivudine is eliminat- require CS. For VAV, strategies have quickly as possible the clinical mani- ed by the kidney, its dose should be now been well defined, using CS festations while waiting for the antivi- adapted to renal function and lowered and/or immunosuppressants principally ral agent’s efficacy to kick in. for patients with renal insufficiency. In for patients in whom antiviral drugs that study, 9/10 patients recovered (1 and/or PE have not achieved recovery VI.1.1. Vidarabine died from catheter-related septicemia) or as an initial adjuvant therapy for the When this therapeutic strategy was first and 6/9 HBe seroconverted. We con- most severe forms (Table I). applied, vidarabine was the only avail- cluded that, because of its oral adminis- able antiviral drug. After a 3-week tration and good safety profile, lamivu- VI. 1. Treatment of HBV-PAN course of intravenous vidarabine (15 dine should henceforth, and to date, be For many years, HBV-PAN was treated mg/kg/d for 1 week then 7.5 mg/kg/d considered the antiviral agent of choice in the same way as non-virus-related for 2 weeks), administered after 1 week to treat HBV-related PAN. For patients PAN, with CS being prescribed some- of CS (prednisone, 1 mg/kg/d) and who do not seroconvert after a well- times in combination with cytotoxic combined with PE, a full clinical conducted 6-month course of therapy agents, mainly cyclophosphamide. This recovery was obtained in three-quarters with lamivudine alone, newer antiviral regimen was often effective in the of the patients and HBe seroconversion agents or a combination of several of short-term but careful analysis of long- was observed in nearly half of the them or lamivudine and IFNα should term results showed that relapses and patients. However, vidarabine’s high probably be proposed. complications (chronic hepatitis or liver neurological and hematological toxici- cirrhosis) occurred because of virus ties finally lead to its replacement by VI.1.4. Newer antiviral drugs, persistence. According to McMahon et less toxic agents, like IFNα and potentially useful in treating HBV-PAN al. (90), who followed Eskimos with lamivudine. Adefovir dipivoxil is a more recent PAN, four (31%) patients died during antiviral drug that has been shown to be the course of PAN. In our first random- VI.1.2. Interferon-alpha as effective and as well-tolerated as ized study (91) in which PAN patients Furthermore, IFNα gave better results lamivudine in the treatment of chronic were not selected according to their than vidarabine. In a series of patients, hepatitis B. Furthermore, oral adefovir viral status, 14/71 were HBV-positive; HBe seroconversion was obtained in dipivoxil (10 mg/d) also led to histo- 84% of them recovered from PAN but two-thirds of the patients and logical improvement in 53% of the two subsequently died of liver cirrhosis. HBsAg–HBsAb seroconversion in half patients with chronic hepatitis B (95,

S-76 Vasculitides secondary to infections / C. Pagnoux et al. REVIEW

96), and can be effective against lami- received the antiviral drug for a few ifestations of PAN appear, the clinician vudine-resistant virus strains (96), weeks or months while PE, which were should consider the possibility of the alone or in combination with other specifically given to control the acute vasculitis occurring coincidentally with newer molecules (entecavir, emtricit- manifestations of the disease, were virus infection but not linked to it. abine, clevudine) (97-99). These drugs stopped after 2 months. Signs of vas- could probably be effective against culitis were sometimes eliminated VI. 2. Treatment of HCV-associated HBV-PAN, but trials will be difficult to more quickly, with some of our patients cryoglobulinemic vasculitis set up, because of the decreasing inci- recovering within 3 weeks. Treatment of chronic hepatitis C and dence of HBV-PAN over the past few In the days following treatment onset, CV must be clearly distinguished. First, decades. transaminase levels increased but they for asymptomatic patients, there is no ar- usually returned to normal within a few gument to treat, and monitoring could be VI.1.5. Plasma exchanges days or weeks. For patients given sufficient. For symptomatic patients, it An antiviral agent was prescribed alone vidarabine, a second increase of transa- should be underlined that no treatment to a few patients (100). In our opinion, minase levels was observed prior to is able to cure the majority of them def- even if it is sometimes possible to seroconversion. This usually mild im- initively and that an optimal therapeutic obtain good clinical results, the severi- munological response was considered strategy has not yet been clearly defined. ty of the vasculitis in most patients normal, as it attested the ability of the requires therapy able to control imme- patients’ hepatocytes to clear the virus. VI.2.1. Medicamentous therapies diately the severe or potentially life- Nevertheless, transaminase levels can According to one study (102), only a threatening manifestations of PAN. rise sharply and fulminant hepatitis can quarter of the patients with chronic Because PE are able to rapidly clear the coincide with HBe seroconversion, as hepatitis C achieved a sustained viro- immune complexes responsible for the for one of our patients (101), who died logical response under treatment, disease, they are the most appropriate of fulminant hepatitis several days after whereas other authors (103) reported means to control the disease. In our seroconversion. The response observed that 69% of their patients had respond- opinion, PE are not indicated because under IFNα or lamivudine is markedly ed to pegylated IFNα at 48 weeks and of their superiority over other medica- different: transaminases normalize pro- achieved clinical recovery. Combining tions but because they are, in combina- gressively and their levels do not rise IFNα and ribavirin may increase the tion with antiviral drugs, able to after stopping the treatment, even when seroconversion rate, with a sustained replace the harmful therapies common- seroconversion has not been obtained. response rate for treatment-naive pa- ly used to treat VAV with equivalent When HBeAb are detected, PE should tients of about 55% (104). efficacy. be stopped to avoid the clearance of the CS and immunosuppressants are com- The optimal schedule is as follows: 4 newly synthesized immunoglobulins. monly used to treat severe symptomat- sessions/week for 3 weeks, then 3 ses- Several patients’ Ab levels fluctuated, ic forms, but they have the same nox- sions/week for 2–3 weeks, followed by sometimes being present or absent. ious effects as discussed above for progressive lengthening of the intervals This Ag-Ab equilibrium can be very HBV-PAN. As for HBV-PAN, we de- between sessions. One plasma volume unstable and treatment should then be vised a strategy (105) combining anti- (60 ml/kg) is usually exchanged using continued. In such cases, it is more reli- viral drugs and PE. For patients with 4% albumin as the replacement fluid. able to monitor virus activity by quan- moderate symptoms of CV (e.g., arth- The circuit can be primed with starch. titative measurements of viral DNA. ralgias, purpura, sensory peripheral During the first weeks of treatment, the After the patient’s recovery from the neuropathy), combining IFNα and rib- high number of PE can decrease the symptoms of the vasculitis, the clini- avirin is indicated. Ribavirin alone is level of clotting factors and thereby cian potentially faces two different not able to completely suppress viral facilitate bleeding. Should bleeding virological situations. First, replication replication but, in conjunction with occur, fresh-frozen plasma can be used continues, as demonstrated by the IFNα, viral replication was no longer instead of albumin. Tolerance of PE is absence of HBeAb and the positivity of detectable in 48% of the patients who usually excellent. viral DNA, and PAN remission has had received the combined regimen for been obtained but relapses may still 12 months (102). We can expect that VI.1.6. Outcome and follow-up occur. In this situation, we recommend virus suppression will also be obtained The previously described short- and focusing on the treatment of viral hep- in cryoglobulinemia. It is worth noting long-term outcomes of the patients atitis and not PAN, which has been that IVIg have been proven ineffective showed the progressive improvement cured, using an adapted and up-to-date against peripheral neuropathy in this of seroconversion rates for patients antiviral strategy. Second, Ab to HBe, setting (106). More recently, therapy receiving antiviral therapy. One of the at least, or to HBs, at best, are present, with pegylated IFNα-2b and ribavirin major advances obtained under our the patient can be considered cured and (for a mean of 13.5 months) was effec- antiviral strategy was the very rapid relapses will, for the majority of the tive in an open study (107) on 9 cure of HBV-PAN, even in its most cases, probably never occur. If, despite patients with CV: 7 of them mounted severe forms. The majority of patients the presence of anti-HBsAb, new man- clinical and virological responses, sus-

S-77 REVIEW Vasculitides secondary to infections / C. Pagnoux et al. tained for 18.6 months after the end of lar ulcers regress quickly and complete cryoglobulin production. We also det- therapy, and serum MC disappeared in healing can be obtained in a few weeks. ected anti-cardiolipin Ab in a patient 5 of them. PE should be tapered progressively to with HIV- and HCV-related vasculitis. Although the majority of the patients avoid a rebound phenomenon due to HIV-associated vasculitides appear to seen for symptomatic MC have virus- the increased synthesis of cryoglobu- be a one-shot disease and do not recur; positive PCR assays, reflecting virus lins as a consequence of the stimulation 1-3 months of therapy are usually suffi- replication, a few of them remain sero- of the B-cell clones responsible for cient to cure them. logically positive but become PCR- their production. Some of our patients negative, reflecting past contamination. remain PE-dependent: clinical symp- VI. 4. Treatment of the other We also observed, in two of our pa- toms recur or worsen during tapering or virus-associated vasculitides tients with very severe CV, the disap- after abrupt discontinuation of the ses- Spontaneous recovery in a few weeks pearance of the virus under combined sions. Maintenance treatment should is the general rule for erythrovirus B19- antiviral therapy and PE but the persis- therefore be prescribed and the clini- related cutaneous vasculitis. However, tence of clinical symptoms, which cian has to try to determine the minimal severe or systemic symptoms may war- necessitated prolonged symptomatic number of sessions able to control the rant CS for several weeks or months. treatment with PE. disease. IVIg have also been used successfully Anti-CD20 monoclonal antibodies (rit- When indicated, the number of ses- in some cases (111). uximab) were used to treat CV, obtain- sions is not clearly established. We rec- Vasculitides caused by VZV or CMV ing some good clinical results on vas- ommend the following schedule: 3 ses- are often severe and life-threatening. culitic manifestations but generating a sions/week for 3 weeks, then 2 ses- Intravenous acyclovir has to be pre- ~2-fold increase of HCV viremia (108, sions/week for 2-3 weeks, then 1 ses- scribed for VZV-CNS vasculitis, even 109). Hence, longer-term results are sion every week or every 10 days until though the diagnosis is often obtained needed to determine the place of this clinical symptoms disappear or the too late for therapy to be effective. biological agent in the therapeutic optimal clinical result is obtained. Prompt antiviral therapy, with oral val- armamentarium for CV. ganciclovir for the milder manifesta- VI. 3. Treatment of HIV-associated tions (retinitis) but mostly intravenous VI.2.2. Plasma exchanges vasculitis ganciclovir and/or foscarnet, is manda- The indications of PE in HCV-related Treatment of HIV-associated vasculitis tory for CMV vasculitis. CS clearly MC and CV are controversial. Based has not yet been well defined, and CS must be avoided in these patients, who on their effectiveness documented in and immunosuppressants should be are usually severely immunocompro- our patients who failed to respond to used cautiously, as they could favor the mised. other treatments, we recommend com- development of opportunistic infec- bining PE and antiviral drugs (5, 110). tions and other clinical manifestations VI. 5. Treatment of vasculitides caused PE should not be prescribed systemati- of HIV infection. Again, the dual by bacteria, fungi or parasites cally for every newly diagnosed case of objective is to cure the vasculitis and to In the case of vasculitis resulting from MC because the majority of patients control HIV infection, and thus to extension of a localized infection or present no or very few symptoms, and avoid CS and cytotoxic agents. septicemia, antimicrobial therapy dir- we still do not know whether or not The first objective is HIV-replication ected against the specific pathogen is treatment is indeed indicated in these suppression, which is more easily mandatory and will not be extensively pauci- or asymptomatic forms. obtained with a combination of antivi- detailed here, with prompt surgical PE are indicated for patients with ral agents. Based on the presence of intervention when needed, e.g., in case symptoms requiring therapeutic inter- immune complexes, we have proposed, of large bacterial abscess(es), destruc- vention. Purpura and sicca syndrome as for other VAV, to treat the patients tive endocarditis or true mycotic an- do not constitute such indications: the with PE, using the same schedule as eurysms that increase in size or fail to former regresses spontaneously and the that for HBV-PAN. PE can clear im- resolve despite adapted medical thera- latter is refractory to them. In the case mune complexes and cytokines in- py. However, no guidelines for the of glomerulonephritis due to CV, PE volved in the vasculitic process. In our indication and timing of surgery in combined with pegylated IFNα and clinical experience, this regimen was these latter conditions have been pub- ribavirin can be effective but random- successful (3), since the patients we lished to date. ized controlled trials are needed to treated improved and recovered from The effect of antibiotics on syphilitic assess their contribution. PE are mainly vasculitis. This strategy was also effec- aortitis and cerebrovascular syphilis is indicated to treat rapidly progressing tive for patients with HIV and HCV or unclear, but they may accelerate recov- peripheral neuropathy and chronic leg HBV coinfections. Some patients with ery and/or limit vascular scar formation ulcers. The latter manifestation is often CV responded very quickly to this ther- and damage. Recommended regimen very severe and accompanied with pain apy. CV symptoms usually recur after consist of 3 doses of 2.4 MU of benza- that can require intensive therapy, stopping PE and, unfortunately, anti- thine penicillin at weekly intervals for including morphine. Under PE, arterio- HIV drugs are not able to suppress syphilitic aortitis; and IV aqueous crys-

S-78 Vasculitides secondary to infections / C. Pagnoux et al. REVIEW talline penicillin G 3-4 MU every 4 h Interferon-alpha and ribavirin treatment in COHEN P, DENY P, GUILLEVIN L: GB virus for 10-14 days for neurosyphilis, or IM patients with hepatitis C virus-related sys- C in systemic medium- and small-vessel temic vasculitis. Arthritis Rheum 2002; 46: necrotizing vasculitides. Br J Rheumatol procaine penicillin 2.4 MU once daily 3317-26. 1998; 37: 1292-4. in combination with probenecid 500 8. VASSILOPOULOS D, CALABRESE LH: Hep- 25. CACOUB P, BOUKLI N, HAUSFATER P et al.: mg orally 4 times a day, both for 10-14 atitis C virus infection and vasculitis: impli- Parvovirus B19 infection, hepatitis C virus days, if compliance can be ensured cations of antiviral and immunosuppressive infection, and mixed cryoglobulinaemia. therapies. Arthritis Rheum 2002; 46: 585-97. Ann Rheum Dis 1998; 57: 422-4. (112). Rickettsial diseases are mainly 9. GAA J, WEIDAUER S, SITZER M, LANFER- 26. LAVORINO C, MANNELLA E, SALVATORI L treated with doxycycline 100 mg orally MANN H, ZANELLA FE: Cerebral vasculitis et al.: Antibodies anti-parvovirus B19 in twice daily for 7-10 days, or until the due to Treponema pallidum infection: MRI chronic hepatitis C virus infection. Am J patient becomes apyretic, with cipro- and MRA findings. Eur Radiol 2004; 14: Gastroenterol 1995; 90: 676-7. 746-7. 27. COHEN P, GUILLEVIN L: Vasculitis associat- floxacin being an alternative for bou- 10. SMITH JL, ISRAEL CW, HARNER RE: ed with viral infections (in French). Presse tonneuse fever. Syphilitic temporal arteritis. Arch Ophthal- Méd 2004; 33: 1371-84. mol 1967; 78: 284-8. 28. GUILLEVIN L, LHOTE F, JARROUSSE B et 11. AIZAWA H, HASEGAWA A, ARAI M et al.: al.: Polyarteritis nodosa related to hepatitis Conclusion Bilateral coronary ostial and aortic B virus. A retrospective study of 66 patients. Vasculitides occurring secondary to regurgitation due to syphilitic aortitis. Intern Ann Méd Interne (Paris) 1992; 143 (Suppl. infections with microorganisms are not Med 1998; 37: 56-9. 1): 63-74. uncommon. A potential microbial 12. DE MICCO C, RAOULT D, BENDERITTER T, 29. GÉNÉREAU T, LORTHOLARY O, ROYER I, GALLAIS H, TOGA M: Immune complex vas- LHOTE F, DARRAS-JOLY C, GUILLEVIN L: cause must be sought because it re- culitis associated with Mediterranean spot- Digestive manifestations of periarteritis quires a specific therapeutic approach. ted fever. J Infect 1987; 14: 163-5. nodosa. (in French). Gastroentérol Clin Biol Adapted antimicrobial agents should 13. SMITH JL, WINWARD KE, NICHOLSON DF, 1997; 21: 503-10. be prescribed to treat vasculitides of ALBERT DW: Retinal vasculitis in Lyme 30. CAMILLERI M, PUSEY CD, CHADWICK VS, borreliosis. J Clin Neuroophthalmol 1991; REES AJ: Gastrointestinal manifestations of bacterial, fungal or parasitic origin. The 11: 7-15. systemic vasculitis. Q J Med 1983; 52: 141-9. combination of antiviral agent(s) and 14. ROMI F, KRAKENES J, AARLI JA, TYSNES 31. DARRAS-JOLY C, LORTHOLARY O, COHEN PE is effective for the majority of OB: Neuroborreliosis with vasculitis caus- P, BRAUNER M, GUILLEVIN L: Regressing patients and, because this strategy is ing stroke-like manifestations. Eur Neurol microaneurysms in 5 cases of hepatitis B 2004; 51: 49-50. virus related polyarteritis nodosa. J adapted to the pathogenesis of the dis- 15. EGAN CA, O’REILLY MA, MEADOWS KP, Rheumatol 1995; 22: 876-80. ease, long-term results are better and ZONE JJ: Relapsing Henoch-Schonlein pur- 32. EWALD EA, GRIFFIN D, MCCUNE WJ: Corre- relapses are rare. The results obtained pura associated with Pseudomonas aerugi- lation of angiographic abnormalities with will surely be further improved with nosa pyelonephritis. J Am Acad Dermatol disease manifestations and disease severity 2000; 42: 381-3. in polyarteritis nodosa. J Rheumatol 1987; the use of new antiviral agents. The 16. HUGHES JR, NEWBOULD M, DU VIVIER AW, 14: 952-6. indications of CS and/or immunosup- GREENOUGH A: Fatal Pseudomonas sep- 33. STANSON AW, FRIESE JL, JOHNSON CM et pressants are very limited, relegated to ticemia and vasculitis in a premature infant. al.: Polyarteritis nodosa: spectrum of angio- short-term and adjuvant therapy only Pediatr Dermatol 1998; 15: 122-4. graphic findings. Radiographics 2001; 21: 17. PRINCE AM, TRÉPO C: Role of immune 151-9. for refractory disease and most severe complexes involving SH antigen in patho- 34. GAYRAUD M, GUILLEVIN L, LE TOUMELIN forms. genesis of chronic active hepatitis and pol- P et al.: Long-term followup of polyarteritis yarteritis nodosa. Lancet 1971; 1: 1309-12. nodosa, microscopic polyangiitis, and 18. MAHR A, GUILLEVIN L, POISSONNET M, Churg-Strauss syndrome: analysis of four References AYMÉ S: Prevalences of polyarteritis prospective trials including 278 patients. 1. TRÉPO C, THIVOLET J: Hepatitis associated nodosa, microscopic polyangiitis, Wegen- Arthritis Rheum 2001; 44: 666-75. antigen and periarteritis nodosa (PAN). Vox er’s granulomatosis, and Churg-Strauss syn- 35. GUILLEVIN L, LHOTE F, GAYRAUD M et al.: Sang 1970; 19: 410-1. drome in a French urban multiethnic popu- Prognostic factors in polyarteritis nodosa 2. AGNELLO V, CHUNG RT, KAPLAN LM: A lation in 2000: a capture-recapture estimate. and Churg-Strauss syndrome. A prospective role for hepatitis C virus infection in type II Arthritis Rheum 2004; 51: 92-9. study in 342 patients. Medicine (Baltimore) cryoglobulinemia. N Engl J Med 1992; 327: 19. CACOUB P, LUNEL-FABIANI F, LÊ THI 1996; 75: 17-28. 1490-5. HUONG D: Polyarteritis nodosa and hepatitis 36. FERRI C, GRECO F, LONGOMBARDO G et 3. GISSELBRECHT M, COHEN P, LORTHOLARY C virus infection. Ann Intern Med 1992; al.: Association between hepatitis C virus O et al.: Human immunodeficiency virus- 116: 605-6. and mixed cryoglobulinemia. Clin Exp related vasculitis. Clinical presentation of 20. QUINT L, DENY P, GUILLEVIN L et al.: Hep- Rheumatol 1991; 9: 621-4. and therapeutic approach to eight cases. Ann atitis C virus in patients with polyarteritis 37. JENNETTE JC, FALK RJ, ANDRASSY K et al.: Méd Interne (Paris) 1998; 149: 398-405. nodosa. Prevalence in 38 patients. Clin Exp Nomenclature of systemic vasculitides. Pro- 4. CORMAN LC, DOLSON DJ: Polyarteritis Rheumatol 1991; 9: 253-7. posal of an international consensus confer- nodosa and parvovirus B19 infection. 21. CALABRESE LH: The rheumatic manifesta- ence. Arthritis Rheum 1994; 37: 187-92. Lancet 1992; 339: 491. tions of infection with the human immunod- 38. LUNEL F, MUSSET L, CACOUB P et al.: 5. GUILLEVIN L, MAHR A, COHEN P et al.: eficiency virus. Semin Arthritis Rheum Cryoglobulinemia in chronic liver diseases: Short-term corticosteroids then lamivudine 1989; 18: 225-39. role of hepatitis C virus and liver damage. and plasma exchanges to treat hepatitis B 22. CALABRESE LH, ESTES M, YEN-LIEBER- Gastroenterology 1994; 106: 1291-300. virus-related polyarteritis nodosa. Arthritis MAN B et al.: Systemic vasculitis in associa- 39. KAYALI Z, BUCKWOLD VE, ZIMMERMAN B, Rheum 2004; 51: 482-7. tion with human immunodeficiency virus SCHMIDT WN: Hepatitis C, cryoglobuline- 6. GUILLEVIN L, LHOTE F, COHEN P et al.: infection. Arthritis Rheum 1989; 32: 569-76. mia, and cirrhosis: a meta-analysis. Hepa- Polyarteritis nodosa related to hepatitis B 23. CALABRESE LH: Vasculitis and infection tology 2002; 36: 978-85. virus. A prospective study with long-term with the human immunodeficiency virus. 40. CACOUB P, HAUSFATER P, MUSSET L, observation of 41 patients. Medicine (Balti- Rheum Dis Clin North Am 1991; 17: 131-47. PIETTE JC: Mixed cryoglobulinemia in hep- more) 1995; 74: 238-53. 24. SERVANT A, BOGARD M, DELAUGERRE C, atitis C patients. GERMIVIC. Ann Méd 7. CACOUB P, LIDOVE O, MAISONOBE T et al.:

S-79 REVIEW Vasculitides secondary to infections / C. Pagnoux et al.

Interne (Paris) 2000; 151: 20-9. vovirus B19 associated adult Henoch- vasculitis in children. Retina 2003; 23: 197- 41. WILLEMS M, SHENG L, ROSKAMS T et al.: Schönlein purpura. J Cutan Pathol 2002; 201. Hepatitis C virus and its genotypes in 29: 602-7. 71. LEVY-CLARKE GA, BUGGAGE RR, SHEN D, patients suffering from chronic hepatitis C 56. FERGUSON PJ, SAULSBURY FT, DOWELL VAUGHN LO, CHAN CC, DAVIS JL: Human with or without a cryoglobulinemia-related SF, TOROK TJ, ERDMAN DD, ANDERSON LJ: T-cell lymphotropic virus type-1 associated syndrome. J Med Virol 1994; 44: 266-71. Prevalence of human parvovirus B19 infec- T-cell leukemia/lymphoma masquerading as 42. FRANGEUL L, MUSSET L, CRESTA P, tion in children with Henoch-Schönlein pur- necrotizing retinal vasculitis. Ophthalmolo- CACOUB P, HURAUX JM, LUNEL F: Hepati- pura. Arthritis Rheum 1996; 39: 880-1. gy 2002; 109: 1717-22. tis C virus genotypes and subtypes in 57. GABRIEL SE, ESPY M, ERDMAN DD, 72. HAYNES BF, MILLER SE, PALKER TJ et al.: patients with hepatitis C, with and without BJORNSSON J, SMITH TF, HUNDER GG: The Identification of human T-cell leukemia cryoglobulinemia. J Hepatol 1996; 25: 427- role of parvovirus B19 in the pathogenesis virus in a Japanese patient with adult T-cell 32. of giant cell arteritis: a preliminary evalua- leukemia and cutaneous lymphomatous vas- 43. HORCAJADA JP, GARCIA-BENGOECHEA M, tion. Arthritis Rheum 1999; 42: 1255-8. culitis. Proc Natl Acad Sci U S A 1983; 80: CILLA G, ETXANIZ P, CUADRADO E, ARE- 58. HELWEG-LARSEN J, TARP B, OBEL N, 2054-8. NAS JI: Mixed cryoglobulinaemia in BASLUND B: No evidence of parvovirus 73. HAUGEBERG G, BIE R, NORDBO SA: Tem- patients with chronic hepatitis C infection: B19, Chlamydia pneumoniae or human her- poral arteritis associated with Chlamydia prevalence, significance and relationship pes virus infection in temporal artery biop- pneumoniae DNA detected in an artery with different viral genotypes. Ann Med sies in patients with giant cell arteritis. specimen. J Rheumatol 2001; 28: 1738-9. 1999; 31: 352-8. Rheumatology (Oxford) 2002; 41: 445-9. 74. REGAN MJ, WOOD BJ, HSIEH YH et al.: 44. CACOUB P, RENOU C, KERR G et al.: Influ- 59. YOTO Y, KUDOH T, HASEYAMA K, SUZUKI Temporal arteritis and Chlamydia pneumo- ence of HLA-DR phenotype on the risk of N, CHIBA S, MATSUNAGA Y: Human par- niae: failure to detect the organism by poly- hepatitis C virus-associated mixed cryo- vovirus B19 infection in Kawasaki disease. merase chain reaction in ninety cases and globulinemia. Arthritis Rheum 2001; 44: Lancet 1994; 344: 58-9. ninety controls. Arthritis Rheum 2002; 46: 2118-24. 60. CORMAN LC, STAUD R: Association of 1056-60. 45. HWANG SJ, CHU CW, HUANG DF, LAN KH, Wegener’s granulomatosis with parvovirus 75. ZELLER V, LORTHOLARY O: Vasculitis sec- CHANG FY, LEE SD: Genetic predispositions B19 infection: comment on the concise ondary to fungal infections (in French). for the presence of cryoglobulinemia and communication by Nikkari et al. Arthritis Presse Méd 2004; 33: 1385-8. serum autoantibodies in Chinese patients Rheum 1995; 38: 1174-5. 76. JOHNSON RH, EINSTEIN HE: Coccidioidal with chronic hepatitis C. Tissue Antigens 61. HAUSLER MG, RAMAEKERS VT, REUL J, meningitis. Clin Infect Dis 2006; 42: 103-7. 2002; 59: 31-7. MEILICKE R, HEIMANN G: Early and late 77. FLIEDER DB, MORAN CA: Pulmonary diro- 46. LENZI M, FRISONI M, MANTOVANI V et al.: onset manifestations of cerebral vasculitis filariasis: a clinicopathologic study of 41 Haplotype HLA B8 DR3 confers suscepti- related to varicella zoster. Neuropediatrics lesions in 39 patients. Hum Pathol 1999; 30: bility to hepatitis C virus-related mixed 1998; 29: 202-7. 251-6. cryoglobulinemia. Blood 1998; 91: 2062-6. 62. CARUSO JM, TUNG GA, BROWN WD: Cen- 78. REDLINE RW, DAHMS BB: Malassezia pul- 47. RIEU V, COHEN P, ANDRÉ MH et al.: Charac- tral nervous system and renal vasculitis monary vasculitis in an infant on long-term teristics and outcome of 49 patients with associated with primary varicella infection Intralipid therapy. N Engl J Med 1981; 305: symptomatic cryoglobulinaemia. Rheuma- in a child. Pediatrics 2001; 107: E9. 1395-8. tology (Oxford) 2002; 41: 290-300. 63. KRAMER LA, VILLAR-CORDOVA C, WHE- 79. SHEK YH, TUCKER MC, VICIANA AL, MANZ 48. CACOUB P, RENOU C, ROSENTHAL E et al.: LESS JW, SLOPIS J, YEAKLEY J: Magnetic HJ, CONNOR DH: Malassezia furfur - dis- Extrahepatic manifestations associated with resonance angiography of primary varicella seminated infection in premature infants. hepatitis C virus infection. A prospective vasculitis: report of two cases. J Magn Am J Clin Pathol 1989; 92: 595-603. multicenter study of 321 patients. The GER- Reson Imaging 1999; 9: 491-6. 80. FEIGL D, FEIGL A, SWEETMAN KM, LOBO MIVIC. Groupe d’Etude et de Recherche en 64. GOLDEN MP, HAMMER SM, WANKE CA, FV, MOLLER JH, EDWARDS JE: Accessory Medecine Interne et Maladies Infectieuses ALBRECHT MA: Cytomegalovirus vasculi- tissue of the tricuspid valve protruding into sur le Virus de l’Hépatite C. Medicine (Bal- tis. Case reports and review of the literature. the left ventricle through a septal defect. timore) 2000; 79: 47-56. Medicine (Baltimore) 1994; 73: 246-55. Arch Pathol Lab Med 1986; 110: 144-7. 49. D’AMICO G, COLASANTI G, FERRARIO F, 65. MEYER MF, HELLMICH B, KOTTERBA S, 81. HSU RB, TSAY YG, WANG SS, CHU SH: Sur- SINICO RA: Renal involvement in essential SCHATZ H: Cytomegalovirus infection in gical treatment for primary infected mixed cryoglobulinemia. Kidney Int 1989; systemic necrotizing vasculitis: causative aneurysm of the descending thoracic aorta, 35: 1004-14. agent or opportunistic infection? Rheumatol abdominal aorta, and iliac arteries. J Vasc 50. PETTY GW, DUFFY J, HOUSTON J: Cerebral Int 2000; 20: 35-8. Surg 2002; 36: 746-50. ischemia in patients with hepatitis C virus 66. FRANK D, RAICHT RF: Intestinal perforation 82. TERVAERT JWC, in “Infection and autoim- infection and mixed cryoglobulinemia. associated with cytomegalovirus infection munity,” Elsevier, B.V. Amsterdam, 2004. Mayo Clin Proc 1996; 71: 671-8. in patients with acquired immune deficiency 83. TAKANO H, TANIGUCHI K, KUKI S, NAKA- 51. LEE MP: Essential mixed cryoglobulinemia syndrome. Am J Gastroenterol 1984; 79: MURA T, MIYAGAWA S, MASAI T: Mycotic as a cause of gastrointestinal hemorrhage. 201-5. aneurysm of the infrarenal abdominal aorta Am J Gastroenterol 1991; 86: 120-1. 67. MORGELLO S, CHO ES, NIELSEN S, DEVIN- infected by Clostridium septicum: a case 52. GHÉRARDI R, LEBARGY F, GAULARD P, SKY O, PETITO CK: Cytomegalovirus report of surgical management and review MHIRI C, BERNAUDIN JF, GRAY F: Necrotiz- encephalitis in patients with acquired of the literature. J Vasc Surg 2003; 38: 847-51. ing vasculitis and HIV replication in periph- immunodeficiency syndrome: an autopsy 84. LOW JG, QUEK AM, SIN YK, ANG BS: eral nerves. N Engl J Med 1989; 321: 685-6. study of 30 cases and a review of the litera- Mycotic aneurysm due to Burkholderia 53. MONTILLA P, DRONDA F, MORENO S, ture. Hum Pathol 1987; 18: 289-97. pseudomallei infection: case reports and lit- EZPELETA C, BELLAS C, BUZON L: Lym- 68. VINTERS HV, KWOK MK, HO HW et al.: erature review. Clin Infect Dis 2005; 40: phomatoid granulomatosis and the acquired Cytomegalovirus in the nervous system of 193-8. immunodeficiency syndrome. Ann Intern patients with the acquired immune deficien- 85. AISENFARB JC, DUPRÉ-MINET M, ASSE- Med 1987; 106: 166-7. cy syndrome. Brain 1989; 112 (Pt 1): 245-68. MAN P, CHAMMAS E, LESENNE M, THERY 54. WATANABE T, ODA Y: Henoch-Schönlein 69. CURTIS JL, EGBERT BM: Cutaneous C: Primary aspergillus endocarditis (in purpura nephritis associated with human cytomegalovirus vasculitis: an unusual clin- French). Arch Mal Coeur Vaiss 1993; 86: parvovirus B19 infection. Pediatr Int 2000; ical presentation of a common opportunistic 259-61. 42: 94-6. pathogen. Hum Pathol 1982; 13: 1138-41. 86. WITJES JA, VRIESEMA JL, BRINKMAN K, 55. CIOC AM, SEDMAK DD, NUOVO GJ, 70. NAKAO K, OHBA N: Human T-cell lym- BOOTSMA G, BARENTSZ JO: Mycotic DAWOOD MR, SMART G, MAGRO CM: Par- photropic virus type 1-associated retinal aneurysm of the popliteal artery as a compli-

S-80 Vasculitides secondary to infections / C. Pagnoux et al. REVIEW

cation of intravesical BCG therapy for 2002; 36: 8. Lancet 1998; 352: 1426-32. superficial bladder cancer. Case report and 95. MARCELLIN P, CHANG TT, LIM SG, SIEVERT 103. ZEUZEM S, FEINMAN SV, RASENACK J et literature review. Urol Int 2003; 71: 430-2. W: Adefovir dipivoxil 10 mg for the treat- al.: Peginterferon alfa-2a in patients with 87. WADA S, WATANABE Y, SHIONO N et al.: ment of patients with HbeAg + chronic hep- chronic hepatitis C. N Engl J Med 2000; Tuberculous abdominal aortic pseudoa- atitis B: continued efficacy beyond 48 343: 1666-72. neurysm penetrating the left psoas muscle weeks. Hepatology 2002; 36: 373A. 104. PEARLMAN BL: Hepatitis C treatment after BCG therapy for bladder cancer. Car- 96. BENHAMOU Y, BOCHET M, THIBAULT V et update. Am J Med 2004; 117: 344-52. diovasc Surg 2003; 11: 231-5. al.: Safety and efficacy of adefovir dipivox- 105. COHEN P, NGUYEN QT, DENY P et al.: Treat- 88. SCHECK DN, HOOK EW: Neurosyphilis. il in patients co-infected with HIV-1 and ment of mixed cryoglobulinemia with Infect Dis Clin North Am 1994; 8: 769-95. lamivudine-resistant hepatitis B virus: an recombinant interferon alpha and adjuvant 89. BROGAN GX, HOMAN CS, VICCELLIO P: open-label pilot study. Lancet 2001; 358: therapies. A prospective study on 20 The enlarging clinical spectrum of Lyme 718-23. patients. Ann Méd Interne (Paris) 1996; disease: Lyme cerebral vasculitis, a new dis- 97. DE MAN RA, WOLTERS LM, NEVENS F et al.: 147: 81-6. ease entity. Ann Emerg Med 1990; 19: 572-6. Safety and efficacy of oral entecavir given 106. LEVY Y, UZIEL Y, ZANDMAN GG et al.: 90. MCMAHON BJ, HEYWARD WL, TEMPLIN for 28 days in patients with chronic hepatitis Intravenous immunoglobulins in peripheral DW, CLEMENT D, LANIER AP: Hepatitis B- B virus infection. Hepatology 2001; 34: neuropathy associated with vasculitis. Ann associated polyarteritis nodosa in Alaskan 578-82. Rheum Dis 2003; 62: 1221-3. Eskimos: clinical and epidemiologic fea- 98. WANG C, LEUNG N, GISH RG, RIGNEY A: 107. CACOUB P, SAADOUN D, LIMAL N, SENE D, tures and long-term follow-up. Hepatology Antiviral activity of 48 weeks of emtric- LIDOVE O, PIETTE JC: PEGylated interferon 1989; 9: 97-101. itabine (FTC) treatment in patients with alfa-2b and ribavirin treatment in patients 91. GUILLEVIN L, JARROUSSE B, LOK C et al.: HBeAg negative / HBV DNA positive with hepatitis C virus-related systemic vas- Longterm followup after treatment of pol- chronic hepatitis B. Hepatology 2001; 34 culitis. Arthritis Rheum 2005; 52: 911-5. yarteritis nodosa and Churg-Strauss angiitis (Suppl.): 323A. 108. ZAJA F, DE VITA S, MAZZARO C et al.: Effi- with comparison of steroids, plasma 99. HUI CK, ZHANG HY, LAU GK: Management cacy and safety of rituximab in type II exchange and cyclophosphamide to steroids of chronic hepatitis B in treatment-experi- mixed cryoglobulinemia. Blood 2003; 101: and plasma exchange. A prospective ran- enced patients. Gastroenterol Clin North 3827-34. domized trial of 71 patients. The Coopera- Am 2004; 33: 601-16. 109. SANSONNO D, DE RE V, LAULETTA G, TUC- tive Study Group for Polyarteritis Nodosa. J 100. AVSAR E, SAVAS B, TOZUN N, ULUSOY NB, CI FA, BOIOCCHI M, DAMMACCO F: Mono- Rheumatol 1991; 18: 567-74. KALAYCI C: Successful treatment of pol- clonal antibody treatment of mixed cryo- 92. GUILLEVIN L, MERROUCHE Y, GAYRAUD yarteritis nodosa related to hepatitis B virus globulinemia resistant to interferon alpha M et al.: Periarteritis nodosa related to hep- with interferon alpha as first-line therapy. J with an anti-CD20. Blood 2003; 101: 3818-26. atitis B virus. Determination of a new thera- Hepatol 1998; 28: 525-6. 110. GUILLEVIN L, LHOTE F, SAUVAGET F et al.: peutic strategy: 13 cases. (in French). Presse 101. GUILLEVIN L, LHOTE F, LÉON A, FAU- Treatment of polyarteritis nodosa related to Méd 1988; 17: 1522-6. VELLE F, VIVITSKI L, TRÉPO C: Treatment hepatitis B virus with interferon-alpha and 93. TRÉPO C, OUZAN D, DELMONT J, TREMISI of polyarteritis nodosa related to hepatitis B plasma exchanges. Ann Rheum Dis 1994; J: Superiority of a new etiopathogenic treat- virus with short-term steroid therapy associ- 53: 334-7. ment curing periarteritis nodosa caused by ated with antiviral agents and plasma 111. VIGUIER M, GUILLEVIN L, LAROCHE L: hepatitis B virus, using a combination of exchanges. A prospective trial in 33 Treatment of parvovirus B19-associated brief corticotherapy, vidarabine and plasma patients. J Rheumatol 1993; 20: 289-98. polyarteritis nodosa with intravenous exchange (in French). Presse Méd 1988; 17: 102. POYNARD T, MARCELLIN P, LEE SS et al.: immune globulin. N Engl J Med 2001; 344: 1527-31. Randomised trial of interferon alpha2b plus 1481-2. 94. COOKSLEY G, PIRATVISUTH T, WANG YJ et ribavirin for 48 weeks or for 24 weeks ver- 112. WORKOWSKI KA, LEVINE WC FOR THE CEN- al.: Evidence for the efficacy of peginterfer- sus interferon alpha2b plus placebo for 48 TERS FOR DISEASE CONTROL AND PREVENTION: on alfa-2a (40 KD) (Pegasys) in the treat- weeks for treatment of chronic infection Sexually transmitted diseases treatment ment of HbeAg positive chronic hepatitis B with hepatitis C virus. International Hepati- guidelines 2002. MMWR Recomm Rep and impact of baseline factors. J Hepatol tis Interventional Therapy Group (IHIT). 2002; 51(RR-6): 1-78.

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