ARTICLE
Recently, rheumatoid papules, which are often located in the fingers
and show both necrobiotic change and leukocytoclastic vasculitis, have
been described as a skin manifestation of RA [1].
Our patient had multiple rheumatoid papules, showing both necrobiotic
changes and leukocytoclastic vasculitis, on the bilateral extensor forearms.
They appeared as the initial cutaneous lesion and increased in number
at the same time as the level of RA activity became elevated and other
cutaneous manifestations showing rheumatoid vasculitis pathologically
appeared. It was suggested that rheumatoid papules represent the early
stage of rheumatoid vasculitis and that they are a reliable clinical marker
of rheumatoid vasculitis.
Case report
A 59-year-old Japanese woman presented with a one month history of papules
on her bilateral extensor forearms, near the elbows, in 1994. She had
been diagnosed as having rheumatoid arthritis based on the American Rheumatism
Association Criteria in 1989 and treated with prednisolone at 5 mg/day,
methotrexate at 5 mg/week, and nonsteroidal anti-inflamatory drugs. Topical
application of corticosteroid ointment resulted in the disappearance of
these papules, leaving pigmentation. The same course was repeated in 1996.
In March 1997, she presented for the third time with the same complaints.
Cutaneous examination revealed marked multiple papules on the bilateral
extensor forearms and a dome-shaped subcutaneous nodule on each side near
the elbow. The right nodule, measuring 13 x 16 mm (Fig. 1A),
was excised and the papules were treated by topical application of corticosteroid
ointment. The papules improved and became pigmented lesions.
In July 1997, she presented for the fourth time with an ulcer on her
left leg and multiple papules on the bilateral extensor forearms. Her
systemic synovitis was becoming worse and her laboratory data were elevated:
IgG rheumatoid factor (RF) 3.1 from 1.1Unit/ml, RF positive in the sheep-cell
agglutination test (RAHA) at a titer of 1:1,280 from 1:40 for 3 years
(Table). Multiple erythematous
papules were present on the bilateral extensor forearms (Fig.
2A). The ulcer on the left lower leg was deep, had a sharp margin,
and measured 8 mm to 11 mm in diameter (Fig.
3A).
Histological examinations were performed on
the nodule on the right forearm in March 1997, and on an erythematous
papule on the right forearm and on the left leg ulcer in July 1997. Hematoxylin-eosin
(H-E) staining of the nodule showed a typical subcutaneous rheumatoid
nodule in the form of a palisading granuloma. In this case, leukocytoclasis
and vessel wall damage were observed adjacent to the granuloma (Fig.
1B). In the papule, inflammatory cells with polymorphonuclear
cells undergoing leukocytoclasis and swelling of the vessel walls in the
superficial and deep vascular plexus, and liquefactive degeneration of
the epidermal basement zone were observed. In the dermis, collagen alteration,
which was homogenized and basophilic, was associated with leucocytoclasis,
vessel wall swelling, and lymphohistiocytic infiltration around the focus.
Neither mucin deposition nor a palisade arrangement was detected (Fig.
2B). In the left leg ulcer, fibrinoid degeneration of the vascular
walls and leukocytoclasis in the dermis and subcutaneous fat were observed
(Fig. 3B). In immunofluorescence
studies, C3d was found to be deposited around the vascular walls in the
dermis and the basement membrane of the epidermis in the papule, rheumatoid
nodule, and leg ulcer.
The laboratory findings included the following: WBC 7,300/ml, ESR 20
mm/hour, CRP 1.8 ng/ml, RAHA positive at a titer of 1:1,280, IgG RF 3.1
Units/ml (normal, less than 2.1), IC (C1Q) 3.6 µg/ml( normal, less
than 3.0), CH50 33.8 U/ml, C3 82.8 mg/ml, C4 33.6mg/ml, anti-nuclear antibody
(ANF) at 1:40, perinuclear and cytoplasmic anti-neutrophil cytoplasmic
antibody (P and C ANCA) less than 10 EU. Hepatitis B and C virus, HIV,
and the syphilis serological tests were all negative.
Objective joint findings included synovial thickening deformity or reduction
in the range of motion bilaterally in the metacarphalangeal joints, proximal
interphalangeal joints, wrists, knees, and several joints of the feet.
Other physical examinations revealed no remarkable findings. The patient
had no noteworthy past history, such as diabetes mellitus.
She was admitted to the Division of Rheumatology of the Sasaki Institute
Kyoundo Hospital in July 1997 because of the leg ulcer and high level
of RA activity. She was administrated prednisolone with the dose increased
to 20 mg/day. The systemic arthritis and the papules on the forearms improved
rapidly with gradual healing of the leg ulcer. Three months later, the
leg ulcer was almost healed. The prednisolone dose has been tapered gradually.
Laboratory data improved as follows: RAHA at 1:160, IgG RF 0.7 Unit/ml,
ANF not detected, CH50 43.6 U/ml, and IC less than 1.5. Although the prednisolone
dose has been reduced to 10 mg/day, she has had no relapses of the papules
or the leg ulcer (Table).
Discussion
In 1989, Smith et al. described papular lesions in a patient
with RA showing leukocytoclastic vasculitis and necrobiotic changes histopathologically
and proposed that these lesions be called rheumatoid papules [1]. Immunofluorescence
studies of rheumatoid papules revealed deposits of immunoglobulins and
complement in vessel walls and in the area of altered collagen [2]. These
papules were found in patients with RA who had cutaneous vasculitic lesions
and subcutaneous nodules. It was noted that vasculitis might be important
in the pathogenesis of rheumatoid papules [1, 2].
In our case, rheumatoid papules were present on the bilateral extensor
forearms. Histopathology revealed dermal collagen alteration and leukocytoclastic
vasculitis. C3d deposition was found in the dermal vessels around the
focus. Although a palisading arrangement was not found around the altered
collagen, histiocyte infiltration was present. Mucin deposition was not
observed. The patient had no diabetes mellitus. The increasing number
of papules coincided with the elevation of the level of RA activity, such
as the titers of IgG RF, RAHA, and IC, low level of CH50, and systemic
synovitis. These laboratory data and the papular eruptions improved with
medium doses of prednisolone.
It has been reported that rheumatoid papules resolved with low-dose
oral corticosteroid therapy might resolve spontaneously at an early stage
[1]. In our case, the multiple papules disappeared with prednisolone at
20 mg/day and the earlier papules might have improved spontaneously although
we treated them with topical application of corticosteroid ointment.
Patients with not only RA but also Lupus erythematosus
and other diseases that generate immune complexes can develop symmetrical,
papular eruptions on the extremities as one of the clinical features of
cutaneous extravascular necrotizing granuloma (Churg-Strauss granuloma)
[3]. It is said that histopathological examination of papular eruptions
shows a spectrum of changes reflecting the evolution of lesions, i.e.,
leukocytoclastic vasculitis with dense neutrophilic infiltrates and degenerated
collagen in early lesions, palisaded granulomas surrounded by leukocytoclastic
debris, fibrin, and altered collagen in fully developed lesions, and as
the process wanes, palisaded granulomas with dermal fibrosis and scant
neutrophilic debris. These histopathological findings are consistent with
the evolution of an immune complex-mediated disease [4]. The authors propose
that these lesions be called palisaded neutrophilic and granulomatous
dermatitis of immune complex disease. In our case the papules coincided
with those early lesions histopathologically. Our case may also be included
in this entity from the overall viewpoint.
Recently systemic nodulosis with leukocytoclastic vasculitis and palisading
granuloma was described as an adverse reaction to MTX [5]. Our patient
had been treated with MTX for 6 years, at a total dose of 1,200 mg, when
the papules appeared. When nodulosis associated with MTX occurs in patients
with RA, it often does not appear for several months after initiating
MTX and the laboratory findings do not become worse following the appearance
of vasculitis and eruptions. In addition, nodulosis due to MTX does not
disappear spontaneously unless the administration of MTX is stopped. The
course of our patient does not coincide with an adverse reaction to MTX.
Specific cutaneous manifestations such as rheumatoid nodules, leg ulcers,
rheumatoid papules, and rheumatoid neutrophilic dermatitis, which are
detected in 10% of patients with RA, correlate with high titers of rheumatoid
factors and the progression of RA [6]. In rheumatoid vasculitis, more
than 85% of patients have cutaneous manifestations such as those mentioned
above [7, 8]. In our case, histological examination of the leg ulcer revealed
necrotizing vasculitis. C3d deposition in the vessel walls was observed
in both the rheumatoid nodule and the leg ulcer. Rheumatoid vasculitis
might be involved in both events. The papules were recurrent and increased
in number when the leg ulcer appeared following the rheumatoid nodule
and elevation of the level of RA activity. These findings supported a
correlation between rheumatoid papules and the existence of rheumatoid
vasculitis. In addition, rheumatoid papules appeared prior to the other
cutaneous manifestations of rheumatoid vasculitis, and they may be an
early marker of rheumatoid vasculitis.
CONCLUSION
Acknowledgement
The authors thank Dr. K. Yamanaka for providing the laboratory data
for this case and his excellent comments.
REFERENCES
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papules: lesions showing features of vasculitis and palisading granuloma.
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papules: a report on four patients with histopathologic analysis. J
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3. Finan MC, Winkekmann RK. The cutaneous extravascular necrotizing
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with arthritis. J Am Acad Dermatol 1983; 8: 439-45.
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