Are You Confident of the Diagnosis?

Microscopic polyangiitis (MPA) is a systemic small vessel vasculitis, which, although primarily associated with necrotizing and crescentic glomerulonephritis and pulmonary capillaritis, often has cutaneous and musculoskeletal features. MPA is a member of the family of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides and is strongly associated with antimyeloperoxidase (MPO)-ANCA.

Characteristic findings on physical examination

The cutaneous involvement is present at an early stage of MPA with other nonspecific symptoms, such as arthralgias and myalgias. The skin lesions in MPA demonstrate mainly palpable purpura, erythematous macules, livedo reticularis, nodules, and cutaneous ulcerations, scattered over the lower extremities (Figure 1).

Figure 1.
Examination of a 78-year-old woman revealed palpable purpuric lesions, erythematous macules, livedo racemosa, and nodules scattered over her edematous legs.

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Figure 2.
Histopathologic examination of the lower extremity eruption revealed fibrinoid degeneration, nuclear dust, neutrophilic infiltration, and erythrocyte extravasation in the dermis (H&E, X400).

Expected results of diagnostic studies

Detection of ANCA by indirect immunofluorescence (IIF) of ethanol-fixed neutrophils reveals two relevant ANCA patterns; a cytoplasmic pattern (C-ANCA) and a perinuclear pattern (P-ANCA). The C-ANCA and P-ANCA patterns found in vasculitis patients are mostly directed against proteinase 3 (PR3) and myeloperoxidase (MPO), respectively. Both enzymes are located in azurophilic granules in the cytoplasm of neutrophilic granulocytes.

In patients with primary vasculitis, more than 90% of C-ANCA are directed against proteinase 3 (PR3-ANCA) whereas approximately 80-90% of P-ANCA recognize myeloperoxidase (MPO-ANCA). C-ANCA (PR3-ANCA) is preferentially associated with Wegener’s granulomatosis (WG), while P-ANCA (MPO-ANCA) is associated with microscopic polyangiitis (MPA) and Churg-Strauss syndrome (3). PR3-ANCA and MPO-ANCA are typically determined by an antigen-specific direct enzyme-linked immunosorbent assay (ELISA).

Diagnosis confirmation

Watts et al., in the 2007 European League Against Rheumatism (EULAR), published a classification of systemic vasculitides with a total of four diseases; including three ANCA-related diseases, namely, MPA, WG, and CSS; and polyarteritis nodosa (PAN). I adopted the Watts Algorithm in the advanced KAWAKAMI Algorithm because it is popular among specialists in vasculitis (Algorithm).

Algorithm for vasculitis (advanced KAWAKAMI algorithm).

The first stage is to classify CSS. A few patients with CSS may only be classified using the Lanham criteria, and therefore this is included in the first stage. The second stage is to classify WG. The Chapel Hill Consensus Conference (CHCC) definitions are applied using the strict histological definitions only, not surrogate markers or ANCA. For a classification of WG in CHCC there has to be evidence of granulomatous change in the biopsy. Small-vessel vasculitis alone is classified as MPA in CHCC. A patient is classified as WG if there are surrogate markers for WG and the histology is compatible with MPA. The third and fourth stages are to distinguish between MPA and PAN using the CHCC definitions for MPA and PAN and surrogate markers for renal vasculitis and ANCA.

Who is at Risk for Developing this Disease?

Most of the data come from white populations of European descent, and the overall annual incidence is estimated at approximately 10-20/million with a peak age of onset in those aged 65 to 74 years.

Poor prognostic markers that are consistently associated with ANCA-associated vasculitis include older age and renal impairment, especially if severe. A kidney biopsy gives further information regarding outcome. Chronic lesions, particularly interstitial fibrosis, are associated with poor outcome and correlate with renal function.

What is the Cause of the Disease?

If ANCA can be implicated in the development of vasculitis, it would likely involve the autoantibodies interacting with neutrophils in the circulation, resulting in activation, microvascular adherence of leukocytes, and subsequent vascular inflammation and necrosis (the ANCA-cytokine-sequence-theory). Neutrophils play an important role in the pathogenesis and predominate at the site of tissue injury and they are the main target cell of the ANCA antigens.


ANCA interacts with primary granule constituents (ie, PR3, MPO) on the surface of apoptotic neutrophils. Subsequent inflammatory mediators and adhesion molecules activate around the vascular conditions, which is indicative of vasculitis. The potential pathogenic role of ANCA is that ANCA in combination with exogenous factors aggravate a clinical inflammatory process and may result in systemic vasculitis.

Systemic Implications and Complications

MPA is the most common cause of pulmonary-renal vasculitic syndrome. Renal and pulmonary symptoms are characteristic in MPA, and interstitial pneumonitis and pulmonary hemorrhage are common. The kidney is an organ that contains a maze of vessels, and the incidence of nephropathy in systemic vasculitis is high. Biopsy of the involved organs reveals necrotizing crescentic glomerulonephritis and necrotizing vasculitis of arterioles, capillaries, and venules with few immune deposits.

Treatment Options

The standard regimen for MPA is based on a combination of corticosteroids and cyclophosphamide. Corticosteroids were the first applied treatment and were found to improve 5-year survival rates. Glucocorticoid dosing has not been examined in randomized trials with most protocols commencing prednisolone 0.5-1mg/kg/day and reducing to 10-20mg/day by 12 weeks.

Intravenous methylprednisolone (500-3000mg) is widely used for more severe presentations but has not been formally evaluated and is likely to contribute to adverse events. In addition, cyclophosphamide has risks of myelosuppression, infection, infertility and malignancy. Some investigators recommended that an intermittent pulse-therapy with cyclophosphamide (15mg/kg/day) was as efficacious as oral cyclophosphamide (2mg/kg/day) at inducing remission while generating fewer side effects.

Optimal Therapeutic Approach for this Disease

The Birmingham Vasculitis Activity Score (BVAS) is the most commonly used instrument to record disease activity in vasculitis. First, intravenous methylprednisolone pulse-therapy (1000mg/day × 3 days) is received and an intermittent pulse-therapy of cyclophosphamide (15mg/kg/day × 1 day) is added. The intermittent pulse-therapy of cyclophosphamide is then continued once a month and oral prednisolone (0.5-1mg/kg/day) is given. Oral prednisolone should be reduced to 5-20mg/day by 12 weeks while disease activity score including BVAS falls. After the 12 weeks, the prednisolone is maintained at the same dose (5-20mg/day). For milder cases, I start with oral prednisolone (0.5-1 g/kg/day) without cyclophosphamide.

C-reactive protein (CRP) or erythrocyte sedimentation rate can provide useful information markers for monitoring of disease activity. Serial monitoring of MPO-ANCA and PR3-ANCA in serum using enzyme-linked immunosorbent assay to identify patients who might be at risk of relapse is useful. The complete blood count in patients with active phase often shows features consistent with inflammation, including leucocytosis, anaemia and thrombocytosis. Measurement of serum creatinine and urinalysis should be performed in any patient.

The presence of hematuria should prompt evaluation of the urine sediment for red blood cell casts, which are a direct indicator of glomerulonephritis. On a plain chest radiograph, abnormalities that can be attributed to a vasculitic process include: patchy consolidation, nodules (often multiple), infiltrates, pleural effusion, bronchial wall thickening, cardiomegaly and lymphadenopathy. Computed tomography (CT) scanning of the chest is of value in the monitoring in patients with pulmonary involvement.

Patient Management

The Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) study evaluated the efficacy and safety of rituximab for remission induction in severe ANCA-associated vasculitis in comparison to cyclophosphamide. The Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis (RITUXVAS) study adopted standard high-dose glucocorticosteroids regimen plus either rituximab (375 mg/m2 intravenous weekly × 4) with two intravenous cyclophosphamide pulses given concomitantly with the first and third rituximab infusion, or intravenous cyclophosphamide for 3-6 months followed by azathioprine.

The results of RITUXVAS and RAVE demonstrated that rituximab combined with high-dose glucocorticosteroids or with high-dose glucocorticosteroids and cyclophosphamide was not inferior to the standard therapy for the induction of remissions in patients with severe MPA, and was better than cyclophosphamide for patients with relapsing disease.

For less aggressive presentations, methotrexate, azathioprine, mycophenolate mofetil, or mizoribine have been demonstrated to be as good as cyclophosphamide for remission induction and are probably safer. Mizoribine is manufactured in Japan and is a newly developed immunosuppressive agent that has low toxicity. The pharmacological effects of mizoribine are similar to those of another purine biosynthesis inhibitor, mycophenolate mofetil.

As older patients have more aggressive disease, worse outcomes, and tolerate therapies less well, they have attracted regimens with reduced cyclophosphamide and glucocorticoid dosing or alternative approaches. Intravenous immunoglobulin (IVIg) can be included in a therapeutic strategy with other drugs used to treat relapses of MPA. The utility of IVIg in MPA will be clearly established with randomized controlled trials. Plasma exchange is indicated for severe nephritis or other severe organ manifestations of MPA.

I recommend follow-up at least once at the end of the first month of therapy with laboratory test including CRP, complete blood count, serum creatinine and blood urea nitrogen (BUN) along with electrolyte, urinalysis, and PR3-ANCA and MPO-ANCA. Once in remission, blood tests (complete blood count [CBC], ESR, CRP, liver function and renal functions tests with electrolytes), urinalysis, and chest X-ray should be performed regularly.

All patients on long-term prednisalone/prednisone should be assessed for infectious complications and bone loss. The use of a bisphosphonate with vitamin D and calcium supplementation should be strongly considered. Evaluation by an endocrinologist for guidance is very beneficial.

Unusual Clinical Scenarios to Consider in Patient Management

Heightened awareness of the early manifestations of MPA can facilitate expeditious institution of therapy, minimizing irreversible tissue destruction. We believe that the incidence and variety of cutaneous manifestations in MPA have been underestimated. Until recently, MPA has been recognized and described primarily by nephrologists, and therefore the results of studies may have been biased toward one part of the disease spectrum.

A study has found that skin involvement, consisting of purpura in MPA, to be the first sign in 13% of patients, compared to another series where this occurred in 4% of patients. In dermatological journals, cutaneous manifestations are frequently reported, with palpable purpura occurring in 30% to 40% of cases. We suggest that a full awareness of the cutaneous manifestations, together with the histopathological features, can facilitate early diagnosis and the initiation of appropriate treatment. It is essential for dermatologists to detect cutaneous signs associated with MPA in order to establish a timely and accurate diagnosis.

What is the Evidence?

Kawakami, T, Soma, Y, Kawasaki, K. “Initial cutaneous manifestations consistent with mononeuropathy multiplex in Churg-Strauss syndrome”. Arch Dermatol. vol. 141. 2005. pp. 873-8. (Review of Churg-Strauss syndrome.)

Kawakami, T, Kawanabe, T, Saito, C. “Clinical and histopathologic features of 8 patients with microscopic polyangiitis including two with a slowly progressive clinical course”. J Am Acad Dermatol. vol. 57. 2007. pp. 840-8. (Case reviews of eight patients with microscopic polyangiitis.)

Kawakami, T, Obara, W, Soma, Y, Mizoguchi, M. “Palisading neutrophilic granulomatous dermatitis in a Japanese patient with Wegener’s granulomatosis”. J Dermatol. vol. 32. 2005. pp. 487-92. (Wegener’s granulomatosis and palisading neutrophilic granulomatous dermatitis described.)

Watts, R, Lane, S, Hanslik, T. “Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies”. Ann Rheum Dis. vol. 66. 2007. pp. 222-7. (Review paper on classification of vasculitis.)

Kawakami, T. “New Algorithm (KAWAKAMI Algorithm) to diagnose primary cutaneous vasculitis”. J Dermatol. vol. 37. 2010. pp. 113-24. (Discusses the new proposed KAWAKAMI Algorithm for vasculitis.)

Lanham, JG, Elkon, KB, Pusey, CD, Hughes, GR. “Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome”. Medicine (Baltimore). vol. 63. 1984. pp. 65-81. (Review of Churg-Strauss syndrome.)

Ntatsaki, E, Watts, RA, Scott, DG. “Epidemiology of ANCA-associated vasculitis”. Rheum Dis Clin North Am. vol. 36. 2010. pp. 447-61. (Overview of the ANCA-associated vasculitides.)

Xiao, H, Schreiber, A, Heeringa, P. “Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies”. Am J Pathol. vol. 170. 2007. pp. 52-64. (Another review of the ANCA vasculitides.)

Martinez, V, Cohen, P, Pagnoux, C, Vinzio, S, Mahr, A, Mouthon, L. “Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients”. Arthritis Rheum. vol. 58. 2008. pp. 308-17. (Therapeutic options presented for ANCA + vasculitis.)