Rheumatoid vasculitis in a patient with seronegative rheumatoid arthritis

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.

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