Polyarteritis nodosa systemic M30.0

Authors: Prof. Dr. med. Peter Altmeyer, Alexandros Zarotis

All authors of this article

Last updated on: 29.10.2020

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Synonym(s)

Classical panarteritis nodosa; Classic panarteritis nodosa; cPAN; Kussmaul-Maier syndrome; Kussmaul-Meier syndrome; Necrotizing polyarteritis; PAN; panarteritis nodosa; periarteritis nodosa; polyarteritis nodosa

History
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Rokitanski, 1852; Kussmaul and Maier, 1866

Definition
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Older name for non-granulomatous microscopic polyangiitis. For historical reasons the older name is discussed here again.

Definition: Rare, potentially life-threatening, multi-organ systemic disease with necrotizing vasculitis of medium-sized vessels (no small vessels), rheumatoid general symptoms, abdominal pain, various skin symptoms and signs of arterial occlusive disease (PAD).

Note: In childhood the microscopic polyangiitis cannot be distinguished from the Kawasaki syndrome.

Occurrence/Epidemiology
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Incidence: Incidences have been decreasing for 20 years. In earlier decades, there were proven associations (about 1/3 of cases) with hepatitis B virus infection. Such associations are found in newer study collectives in only about 5% of patients. The current incidence is 0.1-1.0/100,000 inhabitants/year. The prevalence is 0.2-3.0/100,000 inhabitants. It is significantly higher in HBsAg (hepatitis B surface antigen) positivity.

Etiopathogenesis
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Idiopathic (90%). In 5% of cases, HbS antigen is detectable in the sense of the term, partly also in the affected vessel sections in the form of immune complexes.

PAN as a consequence of minocycline ingestion is a very rare event. This constellation can occur if the preparation is taken over a longer period of time.

It is further assumed that in a smaller proportion of patients ANCA plays an inducing role in triggering the disease. However, ANCA is mostly negative.

A genetic variant of systemic polyarteritis nodosa is caused by an autosomal recessive mutation in the CECR1 gene and is associated with a deficiency of adenosine deaminase 2(ADA2).

Manifestation
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Mostly occurring in middle age, the majority of patients are > 50 years old at onset. Disease peak: 65th-74th LJ. Men are affected 3 times more frequently than women (these figures refer to a Caucasian population; in other ethnic groups e.g. Persia no gender emphasis).

Clinical features
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Systemic manifestations:

  • Severe disorder of the AZ with fever, weight loss and/or night sweats.
  • Renal involvement (70%): Partly glomerular nephritis (proteinuria), risk of uremia. Myalgia (50%), arthralgia (50%).
  • Gastrointestinal symptoms (50%): gastrointestinal ulcerations with colic (infestation of the mesenteric vessels).
  • Neurological symptoms (80%): polyneuropathy, convulsions, apoplexy (juvenile stroke).
  • Cardiac symptoms (70%): angina pectoris, pericarditis, myocardial infarction. CNS symptoms (50%):
  • Opthalmological symptoms: hypertonic fundus, vasculitis.
  • Orchitis with testicular pain.
  • Remark: PAN affects viscerally only medium and small arteries. Capillaries, arterioles and venules are not affected. There is no glomerulonephritis nor involvement of the small pulmonary vessels.

Skin symptoms (50% of cases):

  • skin manifestation occurring in the context of (primary) systemic PAN with subcutaneous papules or nodules palpable along the course of the arteries.
  • Livedo racemosa (leading symptom!)
  • Atrophy blanche
  • Purpura (laminar or petechial: no leukocytoclastic vasculitis!)
  • Ischemic fingertip necrosis due to digital artery occlusion.
  • therapy-resistant ulcers

Laboratory
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  • Increase in inflammatory parameters with high SPA and increased CRP, leukocytosis (neutrophilia); possibly thrombocytosis;
  • hepatitis B surface antigens, complement consumption (complement reduced) and antineutrophil antibodies (pANCA).
  • Notice! pANCA are only positive in a small percentage of patients.
  • Therefore the immunopathogenesis of PAN is heterogeneous.

Histology
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  • Degenerative stage: Fibrinoid necrosis of all wall layers of the affected middle artery.
  • Inflammatory stage: Infiltration with neutrophils, eosinophils, round cells, possibly thrombosis.
  • Granulomatous stage: granulation tissue.
  • Fibrotic stage: scarring.
Histopathological algorithm of (systemic) polyarteritis nodosa (lowest common denominator:italics, leading symptoms:bold) varies according to Ratzinger et al. 2105
Accentuates around post-capillary venules and larger vessels in the skin and subcutis
Concerns arterioles and arteries in the subcutis or at the border between cutis and subcutis.
perivascular, intramural and intraluminal leukocytoclasia
Damage to endothelial cells
Fibrin in/around vessel walls
Perivascular extravasation of erythrocytes
No edema in the papillary dermis
Pathologist. Changes limited to vessel position, no extravascular, interstitial or soft tissue granulomas
Variable (rather low) eosinophilia
plasma cells or fibrosclerosis to a lesser extent

Reorganization due to lymphocytic vasculitis

Diagnosis
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Criteria of the American College of Rheumatology (ARA) for the diagnosis of PAN.

PAN is diagnosed if at least 3 of the criteria are met. The sensitivity of the method is approx. 82%, the specificity approx. 86%.

  1. Weight loss > 4 kg bw since the beginning of the disease.
  2. Livedo "racemosa" on the extremities or the trunk.
  3. Pain in the testicles which is not due to infection, trauma or other tangible causes.
  4. Diffuse myalgia or muscle weakness outside the shoulder or pelvis or atrophy of the leg muscles.
  5. Hypertension with diastole > 90 mm Hg.
  6. Mononeuropathy, multiple mononeuropathies or polyneuropathy.
  7. Increase in blood urea > 40 mg/dl or creatinine > 1.5 mg/dl.
  8. Detectability of HBsAg or antibodies.
  9. Aneurysms or occlusions of abdominal arteries not due to arteriosclerosis, fibromuscular dysplasia or non-inflammatory causes.
  10. Biopsy: granulocytic or mononuclear infiltrate in the arterial walls of small or medium-sized arteries.

Therapy
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  • Generally valid therapy schemes cannot be given for this (certainly very heterogeneous) disease. The therapy is adapted to the organs and activities (see Table 3).
  • The continuous glucocorticoid(100-150 mg prednisone equivalent) and cyclophosphamide(endoxane) therapy(Fauci scheme) is only used in cases of severe systemic vasculitis until a stable partial remission has occurred. Subsequently cyclophosphamide saving interval therapy. Alternative: Low-dose therapy with 25-30 mg methotrexate (MTX), once/week i.v.

    Cave!

    The dose of cyclophosphamide must always be adjusted to the kidney function; leukocytes: > 3000-3500/μl!
  • If there is a chronic hepatitis B virus infection (HBsAd pos., HBeAg pos., HBV neg., PCR pos.), treatment with interferon alfa and/or lamivudine is also possible.

Progression/forecast
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Intermittent course in phases. Fulminant course with exitus lethalis possible within 1-2 years in 20-30% of cases. Possible healing under glucocorticoid therapy. 5-year survival time without therapy approx. 10-15%, with therapy 80%.

Tables
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Therapy scheme1

Clinic/progress

Substance

Dosage

Induction

Fauci scheme

active

CP

2 mg/kg bw/day p.o.

(NIH-Standard2 intensified3)

rapid-progressive

CP

3-4 mg/kg bw/day p.o.

Interval therapy

Austin scheme (bolus procedure4)

active

CP

15-20 mg/kg bw i.v. over 21 days

Maintenance

MTX bolus

T-R emission

MTX

30 mg/week i.v.

Azathioprine

T-R emission

Azathioprine

2-3 mg/kg bw/day p.o.

Ciclosporin A

T-R emission

CyA

3-4 mg/kg bw/day p.o.

1 always in combination with systemic glucocorticoid administration;

2 cyclophosphamide dose is maintained until 1 year after achieving remission, then reduced by 25 mg/day at 6-8 weekly intervals (= NIH protocol);

3 Cyclophosphamide dose is based on the total leukocyte value (usually only a few days!);

4 Cyclophosphamide dose is based on the leukocyte count (8th-12th day after bolus: > 3000/μl;

CP = Cyclophosphamide; MTX = Methotrexate; CyA = Ciclosporin A

Note(s)
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There is currently no firm evidence that cutaneous PAN (cutaneous polyarteritis nodosa) transforms into systemic PAN. Cutaneous polyarteritis nodosa is thus defined as an independent clinical picture with a fundamentally better prognosis.

Recently, a mutation in the CECR1 gene in PAN has been described. This mutation is associated with a significantly reduced activity of adenosine deaminase 2 (ADA 2) and is phenotypically related to the clinical picture of PAN. Pathogenetically it is assumed that the increased adenosine levels are responsible for macrophage activation, consecutive immunodeficiency and thrombotic occlusion of medium-sized vessels (see CECR1 gene below).

Literature
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  1. Brody M et al (1994) Successful treatment of panarteritis nodosa with methotrexate low-dose therapy. dermatologist 45: 476-479
  2. Crowson AN et al (2003) Cutaneous vasculitis: a review. J Cutan catheter 30: 161-173
  3. Gross WL (1995) Vasculitis. News on classification, pathogenesis and therapy. Dt Ärztebl 92: 1019-1026
  4. Gupta S et al (2001) Lamivudine in the treatment of polyarteritis nodosa associated with acute hepatitis B. N Engl J Med 344: 1645-1646
  5. Heron E et al (2003) Polyarteritis nodosa presenting as acute leg ischemia. J Rheumatol 30: 1344-1346
  6. Kart-Koseoglu H et al (2003) Polyarteritis nodosa complicated by intrahepatic-perihepatic hemorrhage and acute appendicitis: successful treatment with cyclophosphamide and corticosteroids. Clin Rheumatol 22: 251-253
  7. Kratzsch J et al (2015) Therapy-resistant chronic leg ulcers crurum. JDDG 13: 825-827
  8. Kussmaul A, Maier R (1866) On a hitherto undescribed peculiar arterial disease (periarteritis nodosa) associated with Morbus Brightii and rapidly progressing general muscle paralysis. German Archive for Clinical Medicin (Leipzig) 1: 484-518
  9. Magro CM et al (2003) The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients. J Cutan catheter 30: 1-10
  10. Navon Elkan P et al (2014) Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 370:921-931.
  11. Pagnoux C et al (2010) 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 62:616-626.
  12. Ratzinger G et al (2015) The Vasculitis Wheel-an algorithmic approach to cutaneous vasculitis. JDDG 1092-1118
  13. by Rokitansky K (1852) On some of the most important diseases of the arteries. Memoirs of the Imperial Academy of Sciences in Vienna 4: 1-72

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Last updated on: 29.10.2020