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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