Treatment of classic polyarteritis nodosa in 1999

Loïc Guillevin

Department of Internal Medicine, Hôpital Avicenne, Université Paris-Nord, Bobigny, France

Correspondence and offprint requests to: L. Guillevin, Department of Internal Medicine, Hôpital Avicenne, Université Paris-Nord, 125 rue de Stalingrad, F-93000 Bobigny, France.

Classic polyarteritis nodosa (PAN), so-called Kussmaul–Maier disease [1], was the first systemic vasculitis to be described. For decades, no treatment was available and disease mortality was high. In retrospective series, the 5-year survival rate was no more than 13% [2]. This `old' disease benefited from steroids and cytotoxic agents [3]. More recently, treatment has been optimized by taking into consideration several factors [4] such as aetiology, prognostic scores [5], pathogenesis, age and concomitant or pre-existing underlying disease(s).

In the following, we discuss the main therapeutic principles and analyse their impact on outcome.

General principles

Among vasculitides, PAN is an acute disease. Flares usually occur within a short period after the first clinical manifestations. Relapses are rare and occur in fewer than 10% of cases [5]. This evolution has to be taken into consideration when choosing the duration of treatment and deciding whether maintenance therapy should be prescribed. The aetiology of the disease [6] and prognostic factors [5] determined at the time of the therapeutic decision should also be taken into consideration. The pathogenesis of PAN is also important for the therapeutic decision; nonrelapsing PAN is not, or is only very rarely, associated with antineutrophil cytoplasm antibodies (ANCA) [7]. Conversely, ANCA-positive vasculitides are frequently complicated by relapses.

Steroids and cytotoxic agents

Immunosuppressants were proposed during the mid-1950s and improved the prognosis of patients who had failed to respond to steroids [3,8]. Survival reached 50% in the first studies of the `therapeutic era' [2,8,9]. To improve the prognosis, cytotoxic agents, especially oral cyclophosphamide, were initially given to the most severely affected patients or to those who did not respond to therapy [3,8]. Such combination therapy was progressively extended to all patients. For 20 years, we have now been trying to optimize the indications of cyclophosphamide. We demonstrated in a large population of patients, that cyclophosphamide did not improve the survival rate, although it did facilitate control of PAN [10].

The duration of treatment was established empirically. Treatment is usually given for 1 year [11], but prospective studies are needed to define the optimal duration.

Adaptation of treatment according to prognostic factors

The clinical relevance of prognostic factors has been well established [5,12]. The five-factor score (FFS) [5] can predict the survival rate of patients with PAN. In a prospective study we identified the following items that predict excess mortality: renal insufficiency (S-creatinine concentration >=140 µmol/l); proteinuria (>1 g/day); visceral involvement, e.g. gastrointestinal, central nervous or cardiac. When one factor is present, the expected 5-year mortality is 25%, when two factors are present mortality is 46%. When no factor is found, PAN is considered to have a good prognosis and the expected mortality is no more than 12%. Recently, we showed that the combination of steroids and cyclophosphamide improves prognosis for patients with FFS >=2 compared with treatment with steroids alone (unpublished data). In this prospective study, we assess the indications of cyclophosphamide according to the FFS. We prescribed steroids only for patients with FFS=0. In this trial, cytotoxic agents were be administered only in cases where steroids fail. We also evaluate when necessary, the selection of the optimal immunosuppressant and the duration of its administration.

Because pulse cyclophosphamide is as effective as oral administration [13,14], prescription of cyclophosphamide per os can be recommended only for other vasculitides, e.g. Wegener's granulomatosis [15]. We hope the reasonable goal can be achieved of obtaining recovery from PAN by individualizing therapy according to selective indications, lowering the doses and duration of cytotoxic treatment.

Treatment of PAN associated with hepatitis B virus

Hepatitis B virus (HBV) infection is one of the aetiologies of classic PAN [16]. Among the vasculitides, HBV is only involved in classic PAN. This virus has not been incriminated in other vasculitides. For this reason, HBV-related PAN is the most typical variety of PAN [6]. We learned from this disease that its outcome is good when treatment is appropriate and that it is possible to treat patients for a duration of a few weeks. Based on the efficacy of antiviral agents in chronic hepatitis and of plasma exchange in PAN, we combined both therapies to treat HBV-related PAN. The rationale for the sequential administration of those modalities was as follows: initial administration of corticosteroids to rapidly control the most severe life-threatening manifestations of PAN, which are common during the first weeks of the disease. Steroids are then abruptly stopped to enhance immunological clearance of HBV-infected hepatocytes and to favour seroconversion, i.e. the transition from HBe antigen (Ag) to an anti-HBe antibody (Ab) positive state. Subsequently plasma exchanges are used to control the activity of PAN.

In HBV-related PAN, the combination of antiviral agents, i.e. (vidarabine and interferon-{alpha} 2b, gave excellent overall therapeutic results. This therapy should be preferred to the more risky conventional regimens. Forty-one patients with HBV-related PAN [6] were treated with antiviral therapy (35 with vidarabine and six with interferon-{alpha}). The 10-year survival rate was 83%. HBeAg/HBeAb seroconversion was obtained in 21/41 (51.2%) patients and total virus clearance (HBeAg/HBeAb and HBsAg/HBsAb seroconversions) was documented in 10 (24.4%) cases. Twenty-three (56.1%) no longer exhibit serological evidence of replication. We are now testing new antiviral treatments, such as lamivudine, a promising drug for DNA viruses.

Other viruses (parvovirus B 19, HIV, HCV ...) have been associated with PAN in anecdotal observations [17,18], but it has never been demonstrated that they are more frequently associated with PAN.

Surgery

Involvement of the gastrointestinal tract is one of the most severe manifestations of PAN [19]. Surgery is obligatory in the case of bowel perforation, haemorrhage, digestive tract infarct, pancreatitis, appendicitis or cholecystitis. When surgery is needed, the prognosis is markedly more adverse [5] but, when surgery is performed for cholecystitis or appendicitis only, the outcome is as in patients without PAN. For the other surgical procedures, outcome is often poor; not infrequently multiple perforations sites are found, relapses are frequent, infections and delayed healing are favoured by the adjuvant therapy. Nevertheless, when indicated, surgery cannot be avoided, but intensive medical management and treatment are necessary. One should not lower the steroid dose or postpone the duration of cyclophosphamide administration. Intravenous pulse cyclophosphamide treatment is more indicated than oral treatment for several reasons: more rapid onset of action and nonreliable delivery of the drug to the blood compartment, a consideration that is important in patients with gastrointestinal vasculitis, which can limit drug absorption. We recommend administering the indicated medical treatment at the time of, or immediately after, surgery in order to control the disease at the time of surgery.

Adjuvant medical treatment

Specific treatments are sometimes required. Hypertension is frequent in patients suffering from renal vasculitis. Angiotensin converting enzyme inhibitors or angiotensin II-receptor blockers are effective and able to control severe or malignant hypertension. Chronic renal failure may occur several months or years after recovery from PAN and is attributable to renal scars. In patients with neurological sequelae, no specific treatment is available; physical rehabilitation can prevent deformities and enable functional positioning of the hands or feet, for example. Neurological recovery may occur several months after the onset of the treatment.

References

  1. Kussmaul A, Maier K. Über eine nicht bisher beschriebene eigenthümliche Arterienerkrankung (Periarteritis Nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Dtsch Arch Klin Med 1866; 1: 484–518
  2. Frohnert P, Sheps S. Long-term follow-up study of polyarteritis nodosa. Am J Med 1967; 48: 8–14
  3. Fauci A, Doppman J, Wolff S. Cyclophosphamide-induced remission in advanced polyarteritis nodosa. Am J Med 1978; 64: 890–894[ISI][Medline]
  4. Guillevin L, Lhote F. Treatment of polyarteritis nodosa and microscopic polyangiitis. Arthritis Rheum 1998; 41: 2100–2105[ISI][Medline]
  5. Guillevin L, Lhote F, Gayraud M et al. Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996; 75: 17–28[ISI][Medline]
  6. Guillevin L, Lhote F, Cohen P et al. Polyarteritis nodosa related to hepatitis B virus. A prospective study with long-term observation of 41 patients. Medicine (Baltimore) 1995; 74: 238–253[ISI][Medline]
  7. Kallenberg CG, Mulder AH, Tervaert JW. Antineutrophil cytoplasmic antibodies: a still-growing class of autoantibodies in inflammatory disorders. Am J Med 1992; 93: 675–682[ISI][Medline]
  8. Leib E, Restivo C, Paulus H. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 1979; 67: 941–947[ISI][Medline]
  9. Cohen R, Conn D, Ilstrup D. Clinical features, prognosis and response to treatment in polyarteritis. Mayo Clin Proc 1980; 55: 146–155[ISI][Medline]
  10. Guillevin L, Jarrousse B, Lok C et al. Long-term followup after treatment of polyarteritis nodosa and Churg–Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa. J Rheumatol 1991; 18: 567–574[ISI][Medline]
  11. Guillevin L, Lhote F, Jarrousse B, Fain O. Treatment of polyarteritis nodosa and Churg–Strauss syndrome. A meta-analysis of 3 prospective controlled trials including 182 patients over 12 years. Ann Méd Interne (Paris) 1992; 143: 405–416[ISI][Medline]
  12. Luqmani R, Exley A, Kitas G, Bacon P. Disease assessment and management of the vasculitides. Baillere's Clin Rheumatol 1997; 11: 423–446
  13. Gayraud M, Guillevin L, Cohen P et al. Treatment of good-prognosis polyarteritis nodosa and Churg–Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. Br J Rheumatol 1997; 36: 1290–1297[ISI][Medline]
  14. Guillevin L, Lhote F, Cohen P et al. Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and Churg–Strauss syndrome patients with factors predicting poor prognosis. A prospective, randomized trial in sixty-two patients. Arthritis Rheum 1995; 38: 1638–1645[ISI][Medline]
  15. Hoffman GS, Kerr GS, Leavitt RY et al. Wegener's granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116: 488–498[ISI][Medline]
  16. Trépo C, Thivolet J. Antigen Australia, hépatite à virus et périartérite noueuse. Presse Méd 1970; 78: 1575[ISI][Medline]
  17. Finkel TH, Torok TJ, Ferguson PJ et al. Chronic parvovirus B19 infection and systemic necrotising vasculitis: opportunistic infection or aetiological agent? Lancet 1994; 343: 1255–1258[ISI][Medline]
  18. Gisselbrecht M, Cohen P, Lortholoary O et al. Human immunodeficiency virus-related vasculitis. Clinical presentation of and therapeutic approach to eight cases. Ann Méd Interne (Paris) 1998; 149: 398–405[ISI][Medline]
  19. Guillevin L, Lhote F, Gallais V et al. Gastrointestinal tract involvement in polyarteritis nodosa and Churg–Strauss syndrome. Ann Méd Interne (Paris) 1995; 146: 260–267[ISI][Medline]