ARTICLE
Rheumatoid vasculitis (RV) is a serious complication of rheumatoid arthritis
(RA). It is characterized by necrotizing arthritis or smaller vessel vasculitis,
and is associated with high mortality due to various cutaneous and systemic
manifestations [1-3]. Cutaneous vasculitis is usually benign [4], but
when other organs are involved, the prognosis is poor. The characteristic
laboratory findings are high titers of rheumatoid factors, antinuclear
antibodies, cryoglobulins and immune complexes, and low levels of complement.
The proportion of RV patients positive for rheumatoid factors is reportedly
more than 94% [1, 5]. In the present case, immunofluorescence staining
and examination revealed immunoglobulin and complement deposits around
the vessels. These findings suggest that an immune mechanism may play
an important role in the development of RV despite the absence of circulating
rheumatoid factors and immune complexes.
Case report
A 47-year-old woman had been diagnosed in 1987 as having RA based on
American Rheumatism Association criteria [6]. Examination revealed systemic
synovitis involving the proximal interphalangeal (PIP) joints, wrists,
elbows and knees, and the patient had experienced more than an hour of
morning stiffness for several years. X-ray examination of the hands and
elbows revealed evidence of widespread symmetrical cartilage destruction
and subchondral bone erosion. She was treated with low doses of prednisolone
(from 5 to 10 mg/day), anti-inflammatory drugs, intramuscular gold, and
methotrexate. When she had complained in 1995 of exacerbation of the systemic
synovitis, elevated levels of CRP (14.3 mg/dl), ESR (81 mm/h), and WBC
(13,000/µl) were found, and bilateral aseptic and non-tuberculous
exudative pleuritis was diagnosed. On administration of a medium dose
of prednisolone (20 mg/day), the pleural effusion disappeared rapidly
and the laboratory data showed improved levels of CRP (0.9 mg/dl) and
ESR (14 mm/h) (Fig. 1).
Two years later, after the dosage of prednisolone had been tapered off
to 7.5 mg/day, livedo reticularis developed on both lower extremities,
and then ulcers appeared one month later in the infiltrated portion of
the erythematous lesion. She was admitted to our department because of
slow healing of the ulcers, which were deep, had sharp margins, and measured
from 2 to 11 cm in diameter (Fig.
2).
Histologic examination of the infiltration in the livedo reticularis
showed perivascular infiltration of lymphocytes, neutrophils, and histiocytes
within the upper dermis and subcutaneous fat. Necrosis and swelling not
only of arteriolar and venular walls but also of the walls of capillary
vessels were present (Fig. 3).
Direct immunofluorescence staining showed IgG and C3d deposition around
the capillary vascular walls and the basement membrane zone of the epidermis
(Fig. 4). Electron-microscopic
findings showed destruction of the endothelial cells of the capillary
vessels, intercellular dissociation, thickening of the basement membrane,
and deposition of electron-dense matter around the vessels (Fig.
5).
The routine laboratory investigations yielded
unremarkable results: ESR, 56 mm/h; CRP, 8.7 mg/dl; WBC, 14,300/µl,
including lymphocytes 13.5%, neutrophils 79%, eosinophils 2.5%. There
were no circulating immune complexes, complement activity was normal,
the antinuclear and DNA antibody titers were not significantly elevated,
and neither cryoglobulin, nor perinuclear or cytoplasmic anti-neutrophil
cytoplasmic antibodies (P,C-ANCA) were detected. IgG and IgM rheumatoid
factors were negative whenever tested. The serologic tests for hepatitis
B virus, hepatitis C virus, human immunodeficiency virus, and syphilis
were negative. Bacterial cultures of the ulcer floor were negative. Physical
examination revealed no splenomegaly. The extremities showed swelling
due to arthritis. The patient had no noteworthy past history, such as
bronchial asthma, weight loss, renal disease, otorhinological disease
or diabetes mellitus.
Three months after admission, the ulcers were considerably smaller and
had almost healed, while her RA activity improved as a result of increased
doses of prednisolone (30 mg/day), bed rest, administration of prostaglandin
E1 (lipo-PGE1; Alpostadil 10 µg/day) by intravenous injection for
2 months, followed by oral PGE1 analogue (Limaprost 30 µg/day), surgical
debridement, and topical application of bucladesine sodium ointment, cadexomer
iodine, and other anti-ulcer agents.
Discussion
The causes of leg ulcers in patients with RA are reported to be pyoderma
gangrenosum, Felty's syndrome, rheumatoid vasculitis, venous stasis and
pressure sores. Pyoderma gangrenosum is characterized by acute, necrotizing,
and rapidly expanding ulceration of the skin with a typical undermined
border. Leg ulcers in Felty's syndrome, characterized by granulocytopenia
and splenomegaly with RA, are extremely refractory and often occur at
sites of previous trauma with recurrent bacterial infection. Our patient's
leg ulcers had characteristic deep and sharp margins in the infiltrated
portion of livedo reticularis without trauma, granulocytopenia or splenomegaly.
From these clinical findings, her leg ulcers were suspected to be due
to RV.
Characteristics of the laboratory findings in RV are high titers of
IgG, IgM, or both rheumatoid factors, antinuclear antibodies, cryoglobulins,
and immune complexes, and low levels of complement. Reports regarding
rheumatoid factors indicated that more than 94% of patients with RV were
seropositive for these factors [1, 5], and histologic examination showed
that the number of perivascular infiltrated cells was related significantly
to the titer of circulating rheumatoid factors [7]. In our RA patient,
however, there were no such laboratory findings, and she was seronegative
whenever examined. On the other hand, light-microscopic examination revealed
inflammation and degeneration of small blood vessels, and direct immunofluorescence
examination disclosed deposits of IgG and C3d in the same location. These
results suggest the operation of an immune mechanism in the pathogenesis
of the lesion despite the absence of circulating immune complexes [8].
Electron microscopy showed that the endothelial cells were destroyed,
that vessels were obstructed and that an amorphous dense substance was
deposited around the vessels. This substance was suspected to consist
of immune complexes. These pathological findings supported the suggestion
that the leg ulcers were caused by RV.
Cutaneous vasculitis, such as allergic granulomatous angiitis, Wegener's
granulomatosus, polyarteritis nodosa, hypersensitivity angiitis, the vasculitis
of systemic lupus erythematosus, and viral and bacterial infections, were
not seriously entertained as explanations for our patient's distinctive
clinicopathologic picture.
Seronegative RA with RV is rare. This RA patient
was seronegative, but our awareness of the immune mechanism involved in
the pathogenesis of the patient's condition was alerted by observing the
results of histological examination.
Treatment of RV is generally initiated with corticosteroids and cytotoxic
drugs. In severe and systemic RV, high doses of corticosteroid, combined
corticosteroid and cytotoxic drug therapy, especially including the use
of cyclophosphamide, and plasmapheresis have been reported to be effective.
Although effective, treatment of RV with cyclophosphamide appears to be
fraught with the usual systemic toxicity generally associated with its
use. Thus, the cutaneous vasculitis is usually treated only with corticosteroid
[3].
It has been reported that the overall mortality of patients with RV
was 30%. For 2 years after the onset of vasculitis, especially in the
first 6 months, mortality is high. Rheumatoid vasculitis is considered
to be a recurrent disease [1]. In our case, before the leg ulcers developed,
bilateral exudative pleuritis was already present. The diagnosis of vasculitis
can be confirmed because of the aseptic effusion, exacerbation of the
activity of RA, and the good response to prednisolone. Reflecting upon
the mortality and recurrence of RV, it is necessary to examine and follow
up carefully the condition of both the leg ulcers and the internal organs
of RA patients with RV.
REFERENCES
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