Urticarial vasculitis in systemic lupus erythematosus: fair response to prednisolone/dapsone and persistent hypocomplementemia

ARTICLE

Urticarial vasculitis (UV), first described by Gammon & Wheeler in 1979 [1], is a disorder characterized by recurrent, raised, erythematous wheals which persist 24-72 hrs and may resolve with purpura and hyperpigmentation. Histopathologically, these lesions show leucocytoclastic vasculitis. Patients with UV are categorized into the three classes: those without hypocomplementemia or any connective tissue diseases, those with systemic lupus erythematosus (SLE) or another connective tissue disease, and those with hypocomplementemia [2].

UV has been reported as a manifestation of SLE, Sjögren syndrome, viral infection such as hepatitis B and infectious mononucleosis, IgA myeloma, IgM gammopathy, serum sickness and exposure to sunlight or drugs [3]. In 22% of SLE patients with UV, the disease activity of SLE parallels the appearance of UV [4].

Although UV patients with hypocomplementemia are reported to be more likely to have associated systemic involvement, the relationship of UV to both hypocomplementemia and SLE remains unclear.

We herein report two cases of UV in patients with SLE and hypocomplementemia, which persisted even after the improvement of disease activity by oral steroid treatment with dapsone or dapsone plus cyclophosphamide. The cutaneous manifestation of UV preceded the overt manifestation of SLE in one patient.

Case reports

Case 1

A 53-year-old man visited our clinic with a 7-month history of recurrent urticarial rash without pruritus. His ophthalmologist had detected uveitis four months previously. He complained of joint pain and general fatigue and presented with a temperature of over 38° C that had persisted for two weeks.

The skin lesions resolved within 48 to 72 hrs, leaving faint pigmentation. The physical examination at the first visit revealed various sized urticarial lesions, some round and some arch-shaped, all over his body.

The complete blood count (CBC) indicated slight anemia and hypereosinophilia, with a red blood cell count of 4.13 x 10⁴/mm³, hemoglobin of 12.0 g/dl, hematocrit of 36.2 g/dl, and white blood cell count of 3.3 x 10³/mm³ with 56% neutrophils, 8% eosinophils, 31% lymphocytes, 1% basophils, and 4% monocytes. Hypocomplementemia with elevated immunocomplex levels (C3, 23 mg/dl; C4, 6 mg/dl; CH50, 9 mg/dl; C1q IC, 4.3 µg/ml; and C3dIC, 25.1 µg/ml) was found. Serological examination revealed positive antinuclear antibody reaction with a speckled pattern and titer of 40x. Anti-ss-A and ss-B antibodies were both positive, while anti-DNA, anti-RNP and anti-Sm antibodies were negative.

A skin biopsy was obtained from an urticarial lesion on the chest. Hematoxylin-eosin study revealed endothelial cell swelling and a superficial perivascular mixed-cell infiltrate containing numerous neutrophils, nuclear dust and lymphocytes, which were consistent with lymphocytoclastic vasculitis. The direct immunofluorescence study (DIF) of lesional skin revealed deposits of IgG and C1q along the dermoepidermal junction with a granular pattern, and deposits of C3 in the papillary blood vessels.

One week after admission, he presented exudative erythema on his face and chest. The repeated laboratory evaluation also disclosed hypocomplementemia. The titer of antinuclear antibody was elevated to 160x. CBC revealed lymphocytopenia (800/µl). Urinalysis disclosed proteinuria (0.5~0.6 g/day), granular cast, blood casts and hyaline casts. The urinary ß2 microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) levels were both high. All the complement levels were measured and no evidence of congenital hypocomplementemia was found. The C1q inhibitor level was also normal.

Skin biopsies were again obtained from the erythema on his chest and cheek which showed liquefaction degeneration with a perivascular lymphocyte infiltrate. DIF of the lesional skin revealed deposits of IgG and C1q along the dermoepidermal junction with a granular pattern. A renal biopsy revealed mesangial proliferative change.

At this time, his clinical profile fulfilled the American Rheumatism Association (ARA) criteria for the diagnosis of SLE. Treatment with oral steroid (prednisolone at 30 mg daily) was begun, which relieved all of his symptoms (including the exudative erythema) except for the urticarial lesions. The indurated urticarial lesions developed a "target-shape", resolving with purpura and pigmentation (Fig. 1). Although systemic dapsone or corticosteroid pulse therapy did not completely abolish the UV lesions, the dapsone was considered to be effective because interruptions of dapsone resulted in the recurrence of the UV lesions. Finally, the combination of 35 mg of prednisolone, 75 mg of dapsone and 100 mg of cyclophosphamide relieved all the cutaneous symptoms.

The patient remained essentially free of symptoms for nine months, although he remained chronically hypocomplementemic in spite of the multi-drug therapy.

Case 2

A 47-year-old woman visited our clinic with a 5-month history of erythema which left pigmentation on her face, and a recurrent urticarial rash with pruritus on the neck and forearms. She complained of joint pain, general fatigue and had pyrexia. She also had a 10-year history of Raynaud's phenomenon.

Physical examination revealed several urticarial lesions and faint pigmentations on the trunk and extremities. Erythema and pigmentation were found on her face except for the nose. Scars and pigmentation were found on the upper part of her back.

CBC was within the normal range. Hypocomplementemia with elevated immunocomplex levels (C3, 13 mg/dl; C4, 5 mg/dl; CH50, 12 mg/dl; C1qIC, 3.3 µg/ml; and C3dIC, 13.1 µg/ml) was found. She tested positive for antinuclear antibody with a homogeneous/speckled pattern and a titer of 2,560x, and for anti-DNA, anti-Sm, and anti-RNP antibodies.

Skin biopsies were obtained from an erythematous lesion on her face and an urticarial lesion on the left upper extremity. Hematoxylin-eosin study of the former specimen disclosed lymphocytoclastic vasculitis. Hemorrhagic changes were seen in some vessels. In the latter specimen, liquefaction degeneration and perivascular lymphocytic infiltrates were found (Fig. 2).

Urinalysis revealed proteinuria (0.5 g/day) and granular casts. The urinary ß2 microglobulin and NAG levels were both high. A renal biopsy revealed pure mesangial proliferative change. Her profile met the ARA criteria for the diagnosis of SLE.

Although treatment with oral steroid (prednisolone at 40 mg daily) was begun, the urticarial lesions remained in spite of the improvement of other symptoms and laboratory data. Then systemic dapsone was started at 50 mg daily in addition to the oral steroid. This produced a resolution of the skin lesions. The patient has remained essentially free of symptoms for seven months except for the persistent hypocomplementemia. Testing of all the complement levels failed to disclose any evidence of congenital hypocomplementemia.

Discussion

UV is defined as a syndrome of urtical lesion with cutaneous necrotizing vasculitis which may vary in severity from a multisystem disorder closely resembling SLE, to a mainly cutaneous disorder closely resembling chronic idiopathic urticaria [5]. Gammon & Wheeler [1] reported that UV could be differentiated from SLE itself by failure to meet the ARA criteria for SLE, by the absence of antibodies to double-strand DNA, and by the absence of severe renal disease. However, several authors have pointed out that urticaria-like lesions are present in 7 to 22% of patients with SLE [4, 6]. Recently, Davis et al. examined 132 patients with UV. He compared hypocomplementemic and normocomplementemic UV, and concluded that those patients with hypocomplementemia also showed a high incidence of SLE. He pointed out that the patients with hypocomplementemic UV should be investigated and observed for the onset of SLE [7]. In one of our patients, the UV lesions preceded the overt manifestation of SLE fulfilling the criteria for SLE, for about 7 months. Bisaccica et al. reported a patient with the target-shaped UV lesions who developed SLE and autoimmune thyroiditis and SLE after 20 years of follow up [8].

Zeiss et al. [9] described the profile of four patients with angioedema and urticaria showing low levels of C1q as a hypocomplementemic urticarial vasculitis syndrome. Although these authors considered that C1q precipitin was an essential and distinct marker for this syndrome, similar antibodies to C1q have also been described in SLE patients without UV [10]. Therefore hypocomplementemic urticarial vasculitis syndrome and SLE are considered to be related conditions. Recently, D'Cruz et al. [11] studied the autoantibodies in SLE and UV and suggested that the autoantibodies to vascular endothelial cells play a role in the pathogenesis of UV in both patients with hypocomplementemic urticarial vasculitis and with SLE with UV.

Hypocomplementemia is a frequent finding in SLE. In UV patients, it is more likely to manifest systemic symptoms such as a urticaria that resolves with purpura, arthralgia, abdominal pain, and chronic obstructive pulmonary disease. Although the levels of complements are a useful marker of the disease activity in the majority of patients with SLE, hypocomplementemia often persists during periods of clinical remission in many patients with UV [12, 13].

Approximately half of the patients with UV respond to nonsteroidal antiinflammatory drugs or antihistamines [3], but the response to treatment is variable and generally unsatisfactory. Multi-drug therapy is often necessary. One of our patients responded to a combination of systemic corticosteroid, dapsone and cyclophosphamide, and the other patient responded to systemic corticosteroid and dapsone. In both patients, we found dapsone useful for the urticarial lesions, while corticosteroid relieves all the systemic inflammatory changes. Dapsone alone or a combination of dapsone and other drugs is reported to be useful in the treatment of UV [14-16]. Although a recent study has suggested suppression of neutrophil adherence to antibodies as a mechanism involved in the clinical efficacy of dapsone [17], the exact mechanism is still unclear.

We believe that some patients with idiopathic UV have a latent immunological deficiency which contributes to SLE, even if they do not meet the ARA criteria for SLE. Careful observation of these patients may be needed, especially those with UV with hypocomplementemia.

REFERENCES

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