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Cutaneous manifestations and histological features of microscopic polyangiitis

European Journal of Dermatology. Volume 19, Number 1, 57-60, January-February 2009, Clinical report

DOI : 10.1684/ejd.2008.0566

Summary

Author(s) : Yayoi Nagai, Michiko Hasegawa, Naoya Igarashi, Setsuko Tanaka, Masayoshi Yamanaka, Osamu Ishikawa , Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashishi, Gunma 371-8511, Japan.

Summary : Purpura and livedo are common cutaneous manifestations of microscopic polyangiitis (MPA)\; however, only a few clinical analyses focusing on the relationship between clinical symptoms and the affected vessels in the skin have been reported. We herein report the cutaneous manifestations and histological features of four patients with MPA. In two patients, a Henoch-Shönlein purpura-like eruption developed with necrotizing vasculitis localized in the upper dermis. The other two patients presented with livedo racemosa\; with histological findings of necrotizing vasculitis of the small vessels around the muscle fibers or from the deep dermis to subcutaneous tissue. Two patients’ cases were complicated by systemic sclerosis and had poor prognoses. MPA can present with various cutaneous manifestations. Additional research is required to ascertain the relationship between the prognosis and the affected vessels.

Keywords : microscopic polyangiitis, livedo racemosa, purpura, systemic sclerosis, MPO-ANCA

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ARTICLE

Auteur(s) : Yayoi Nagai, Michiko Hasegawa, Naoya Igarashi, Setsuko Tanaka, Masayoshi Yamanaka, Osamu Ishikawa

Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashishi, Gunma 371-8511, Japan

accepté le 12 Septembre 2008

In the 1994 Chapel Hill Conference, microscopic polyangiitis (MPA) was defined as vasculitis of microvessels including capillaries, micro-arteries and veins without immune complex deposition [1]. In addition, the presence of antineutrophil cytoplasmic autoantibody (ANCA) differentiates MPA from polyarteritis nodosa (PN), which involves medium and small muscular arteries. MPA usually affects the kidneys and lungs, and occasionally the skin, peripheral nerves, gastrointestinal tract, brain, heart, muscles and joints. In the kidney, MPA may cause marked renal dysfunction even in the early stages and lead to rapidly progressing crescentic glomerulonephritis or mild chronic nephritis. In the lung, diffuse capillary hemorrhages or interstitial pneumonia may develop.

Although MPA may present with various cutaneous manifestations, the only skin manifestations included in the Japanese diagnostic criteria are purpura and subcutaneous bleeding [2]. The reason is that most cases have been reported from the field of internal medicine, and histological findings of the skin have not been described in detail. Since cutaneous manifestations reflect the size of the affected vessels, close histological examination of the skin may enable physicians to predict the prognosis more accurately.

We herein report four patients with MPA and refer to the relationship between the cutaneous manifestations and the histological features of the affected vessels.

Case reports

Case 1 [3]

A 72-year-old man first noticed purpura on his lower legs in 1990, at the age of 67. Leg edema developed gradually in the lower legs. He was admitted to the nephrology department due to hematuria and proteinuria in 1995, and referred to our department. Physical examination revealed multiple palpable purpura on the lower legs (figure 1A). Elevated levels of C-reactive protein (CRP), 3.5 mg/dL, and serum creatinine 3.2 mg/dL, were noted. The levels of myeloperoxidase (MPO)-ANCA were elevated at 140 EU.

Histological examination of the purpura revealed fibrinoid degeneration, neutrophil infiltration and nuclear dust around the capillary and small vessels in the upper dermis (figure 1B). A direct immunofluorescent study showed no immunoglobulin deposition. The result of a renal biopsy indicated crescentic glomerulonephritis. Methylprednisolone pulse therapy gradually improved renal function and rapidly alleviated the purpura.

Case 2

A 51-year-old woman noticed Raynaud’s phenomenon in 1977, and was diagnosed as having limited cutaneous-type systemic sclerosis (SSc) in 1987. Microscopic hematuria had been noted since 1998, at the age of 72. In August 2000, mildly elevated titers of MPO-ANCA were first noted; however, renal function was normal. In April 2003, she was admitted to our department because of purpura on her lower legs. Physical examination revealed edema and palpable purpura on her lower legs (figure 2A). Abnormal laboratory findings included BUN 48 mg/dL, creatinine 2.2 mg/dL, and markedly elevated titers of MPO-ANCA, 3,100 EU. Proteinuria, hematuria and low creatinine clearance, 8.8 mL/min (normal range: 70-130 mL/min) were also noted. Chest computed tomography (CT) revealed interstitial shadows in her lower lungs; however, there were no marked changes compared to previous studies.

Histological examination of the purpura showed fibrinoid degeneration of the vessels in the upper to middle dermis, along with neutrophil infiltration and nuclear dust (figure 2B). A direct immunofluorescent study showed no immunoglobulin deposition. A renal biopsy was not performed. After methylprednisolone pulse therapy, prednisolone (PSL) 50 mg/day, cyclophosphamide (CPA) 50 mg/day and heparin (9,000 units/day) were administered. The treatment alleviated the pupura and gradually improved her renal function, with decreased levels of MPO-ANCA. The dose of PSL was gradually tapered to 10 mg/day. However, the patient suddenly died in September 2004. The cause of death was unclear as an autopsy was not performed.

Case 3

A 48-year-old woman noticed Raynaud’s phenomenon in 1993, and was diagnosed as having a limited cutaneous form of SSc in 1996. In December 2001, she suffered from numbness and weakness of her legs, and she was diagnosed with multiple mononeuritis. In January 2002, at the age of 57, reticular erythema appeared on her legs. Physical examination revealed purple-reddish livedo racemosa accompanied by mild infiltration on her lower legs and the dorsa of the feet (figure 3A). Urinalysis and renal function were normal; however, CRP levels were high at 11.6 mg/dL and the titer of MPO-ANCA was mildly elevated at 54 EU. Chest CT showed reticular and honeycomb shadows in the lower lung fields. A skin biopsy specimen taken from the livedo racemosa revealed no remarkable changes; however, a gastrocnemius muscle biopsy revealed necrotizing vasculitis of the small vessels adjacent to the muscle fibers (figure 3)B. A direct immunofluorescent study showed no immunoglobulin deposition. Methylprednisolone pulse therapy and CPA administration improved the skin rash. Thereafter, an intractable headache developed with elevated levels of CRP in 2005. After intensive examination, we could find no organic abnormalities. An empiric treatment with increased doses of corticosteroids and methylprednisolone pulse therapy was started on suspicion of exacerbated MPA and brought about symptomatic improvement. However, in June 2006, respiratory distress developed and her condition rapidly deteriorated. Despite various treatments such as antibiotics, antifungal agents and steroid pulse therapy, she died of respiratory failure. Whether the patient died of infection or acute exacerbation of interstitial pneumonia was not ascertained since an autopsy was not performed.

Case 4

A 72-year-old woman presented with a one-month history of a skin rash on her lower legs in July 2006. Pale purplish livedo racemosa was seen on her lower legs and the dorsa of the feet. Mild infiltration was palpated in some areas (figure 4A). Pale purplish erythemas as large as rice grains were also scattered on her legs. A skin biopsy specimen taken from livedo showed occluded small vessels from the dermal-fat junction to the fat tissue. The vascular wall was thickened and the vascular lumen was organized accompanied by fibrinoid degeneration. Cellular infiltration of lymphocytes and neutrophils was seen around the affected vessels (figure 4B). A direct immunefluorescent study showed no immunoglobulin deposition.

Proteinuria and hematuria were noted and creatinine clearance was low, at 38.7 mL/min. The titer of MPO-ANCA was elevated at 239 EU. Chest CT showed reticular lesions in the lower lung fields, and multiple mononeuritis was also confirmed. A renal biopsy was not performed. Oral administration of PSL, 40 mg/day, promptly improved clinical symptoms and alleviated the proteinuria. The titer of MPO-ANCA decreased to 34 EU one month after the treatments.

Discussion

Cutaneous symptoms and histological features of MPA

Lung and renal involvement, which may profoundly affect the patient’s prognosis, have been extensively described. In contrast, cutaneous manifestations have rarely been investigated in detail. Agard et al. reported that cutaneous manifestations developed as the initial symptoms of MPA in 13% of their cases [4]. In other studies, purpura were most frequently noted as the initial symptom of MPA, in 30-40% of patients [5-7]. However, Cupps et al. claimed that purpura were the initial symptom in only 4% of patients [8]. The caliber and size of the vessels predominantly involved strongly influence the clinical features of the different forms of vasculitis and therefore are one major criterion for classification.

In 2007, Kawakami et al. closely examined cutaneous manifestations of MPA in 8 patients. They reported that erythematous macules were seen in the extremities of all patients, livedo in 5 patients, and various other symptoms such as papules, ulcers and purpura [9]. They pointed out that livedo accompanied by erythematous macules and purpura are the characteristic skin symptoms. In these lesions, small vessels from the papillary layer to the subcutaneous fat were affected. Seishima et al. [10] reported that purpura and petechiae were the most common skin manifestations and patients who showed vasculitis in the upper dermis histologically had purpura and erythema as skin symptoms.

In our four patients (table 1), case 1 developed purpura as the initial symptom, then renal function rapidly worsened along with exacerbated purpura. Case 2 was a patient with SSc accompanied by elevated MPO-ANCA. Mild hematuria persisted, and nephropathy rapidly progressed when the purpura appeared. In these two patients, palpable purpura was clinically indistinguishable from Henoch-Schönlein purpura (HSP). On the other hand, cases 3 and 4 revealed livedo racemosa as the initial symptom. Livedo was palpable and accompanied by pale purplish macules. Livedo racemosa in two patients was similar to that reported as the most common clinical presentation of MPA [9]. It is of note that in cases 3 and 4 multiple mononeuritis developed when the skin symptoms appeared.

Necrotizing vasculitis was histologically confirmed in the gastrocnemius muscle in case 3 and in the deep subcutaneous tissue in case 4. On the other hand, the two patients with HSP-like lesions had vascular lesions in the upper dermis. Since MPA affects capillaries, micro-arteries and veins, we should keep in mind that the cutaneous manifestations reflect the degree to which vessels are affected. Chen reported that cutaneous vasculitis manifests most frequently as palpable purpura or infiltrated erythema, indicating dermal superficial small-vessel vasculitis, and less commonly as nodular erythema, livedo racemosa, deep ulcers, or digital gangrene, implicating deep dermal or subcutaneous, muscular-vessel vasculitis [11]. The caliber and size of the vessels predominantly involved strongly influence the clinical features of the different forms of vasculitis and therefore are one major criterion for classification [12]. As livedo indicates arterial and venous lesions in the deep dermal layers or underlying tissue, in some cases muscle or nerve biopsies are useful to reveal the affected vessels when necrotizing vasculitis is not found in the skin.

Kawakami et al. also described two patients with slowly progressing MPA [9] which is considered to be a subtype of smoldering MPA [13-15]. In this subtype, the titer of MPO-ANCA was mildly elevated and laboratory results of the inflammatory findings were unremarkable. They reported that both patients presented with purpura and erythema, and necrotizing vasculitis was found from the papillary to middle dermis. In our patients with mild initial symptoms, purpura (case 1) and hematuria (case 2) were present for five years before other symptoms rapidly exacerbated. Both patients had HSP-like lesions as the main symptom, and necrotizing vasculitis was localized in the upper dermis and partially in the middle dermis. Previous reports suggest the length of time from the appearance of the initial symptoms to diagnosis was long when patients only showed purpura with vasculitis in the upper dermis [16, 17]. MPA in which affected vessels are localized to capillaries may thus progress slowly and respond well to corticosteroids and immunosuppressive therapy; however, confirmation of this hypothesis requires further investigation in more patients.
Table 1 Cutaneous manifestations and histological features of 4 patients with microscopic polyangiitis

	Age and sex at the onset of the initial symptoms of MPA	Skin manifestation	Location of the skin eruption	Location of the histological findings of necrotizing vasculitis	Skin lesion of the biopsy	Initial symptoms	Duration from the onset	Complication	Outcome
Case 1	72M	Purpura	Lower legs	Upper dermis	Purpura	Skin eruption	5 years
Case 2	77F	Purpura	Lower legs	Upper and middle dermis	Purpura	Hematuria	5 years	SSc	Death
Case 3	57F	Livedo racemosa	Lower legs	Muscle layer	Gastrocnemius muscle	Skin eruption	1 month	SSc	Death
Case 4	72F	Livedo racemosa purplish macules	Lower legs	Subcutaneous	Livedo	Skin eruption	1 month

Systemic sclerosis (SSc) and MPA

Two patients in the present study (cases 2 and 3) were complicated with SSc. The incidence of elevated MPO-ANCA in SSc is 0-15% [18-22]. Although drugs such as D-penicillamine, propyothiouracil and minocycline have been shown to induce ANCA-related angiitis [23, 24], none of our patients had taken these drugs. It is well recognized that not all SSc patients with elevated MPO-ANCA develop vasculitis [19]. Of 125 SSc patients in whom MPO-ANCA was examined in our department, eight patients, including the two patients presented had elevated titers of MPO-ANCA. Besides the two patients in the present study, we have reported two additional patients with elevated MPO-ANCA complicated by either progressive nephritis or interstitial pneumonia who developed purpura and toe gangrene [25]. In these two patients, necrotizing vasculitis could not be histologically confirmed in the skin. Widespread ulcers and gangrene were considered to indicate the involvement of larger arteries due to SSc per se. The remaining four patients with SSc and elevated MPO-ANCA levels have been asymptomatic for 2-6 years. However, once vasculitis occurs in MPO-ANCA positive SSc patients, it can affect the prognosis. Close attention should be paid to the titers of MPO-ANCA, as well as nonspecific symptoms such as fever and laboratory data such as CRP.

Conclusion

In MPA, HSP-like lesions develop when only the capillaries are affected, and various cutaneous manifestations can appear when the vessels in the dermis and underlying tissues are affected. Livedo is a common symptom that reflects vascular involvement from the deep dermis to the fat tissue, muscule tissue or nerve tissue. Close physical examination can reveal erythematous patches and purpura with mild infiltration in which the affected vessels are deeper than one would expect based on the clinical findings. Muscle or nerve biopsies could be useful in finding the lesions. It is important for physicians to keep in mind the relationship between cutaneous manifestations and the degree of involvement of the affected vessels in order to recognize the importance of skin symptoms in the diagnosis and treatment of MPA.

Acknowledgements

Financial support: none. Conflict of interest: none.

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