Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore, Milano, Italia
Introduction
Diffuse proliferative (class IV) glomerulonephritis is the most frequent and severe form of renal involvement in systemic lupus erythematosus (SLE). The prognosis of patients with class IV lupus nephritis has dramatically improved over the last 30 years [13] allowing many patients to survive for decades. Although information on the outcome of patients with a very long-term follow-up is still scanty [46], the available data suggest that after 10 years patients have an increased risk of cardiovascular, cerebrovascular, and neoplastic complications [5,7,8] related either to therapy or to the consequences of SLE damage. In contrast, the activity of the disease seems to quench over time [5] and the risk of renal flares becomes increasingly rare in the long-term [6]. In view of the side-effects of prolonged treatment and of the progressive quenching of SLE over the years, slow reduction of therapy until complete discontinuation has been tried in patients with quiescent SLE [9]. Unfortunately, although some patients may maintain asymptomatic and without signs of active disease for years and even decades, the possibility of a late reactivation of SLE cannot be ruled out. We report here the case of a woman with diffuse proliferative lupus nephritis who, after stopping therapy, enjoyed complete clinical remission of SLE for more than 20 years and eventually developed a nephritic flare-up, that could be reversed with appropriate therapy.
Case
A 33-year-old woman was admitted to our Unit in September 1975 for an acute nephritic syndrome. Since 1970 she had complained of arthralgias, asthenia, and psychic irritability. In August 1975, after exposure to sunlight, a malar rash appeared together with fever and oedema. Her body weight increased 12 kg in 2 weeks.
At presentation the patient was in good general condition. The physical examination revealed diffuse and marked oedema. Her temperature was 37.8°C, blood pressure was 165/105 mmHg, and heart rate was 80 beats/min. Laboratory tests showed: haematocrit 30%, white cells count 6700/mm3 with a normal differentiation, platelet count 180000/mm3, plasma creatinine 1.2 mg/dl, plasma urea 58 mg/dl, creatinine clearance 56 ml/min, total serum proteins 6.2 g/dl, albumin 2.3 g/dl, gammaglobulins 2.8 g/dl, C3 10% (normal value >80%), C4 5 mg/dl (normal value 2040], ANA positive (3+) and anti DNA antibodies 84% (normal value <13%). The urinary protein excretion was 1.2 g/24 h. The urinary sediment showed 50 red blood cells and 7 white blood cells/high-power field, together with granular and cellular casts. The patient was submitted to a percutaneous renal biopsy. The specimen contained 20 glomeruli. At light microscopy, all the glomeruli showed diffuse intracapillary proliferation and polymorphonuclear infiltration. Twenty per cent of glomeruli had segmental epithelial crescents with fibrinoid necrosis and karyorrhexis of the adjacent lobules. In two glomeruli haematoxylin bodies were present. With trichrome stain, diffuse and large subendothelial deposits were seen. No relevant abnormalities were observed in interstitial, tubular, and vascular structures (Figure 1). At immunofluorescence, mesangial and parietal deposits of IgA (2+), C3 (2+), C1q (2+), IgG (1+), IgM (1+) and tubular basement membrane deposits of IgM (1+) were found. A diagnosis of diffuse proliferative lupus nephritis was made.
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Since January 1991 decreased levels of serum C3 and positive values of anti dsDNA antibodies were observed without any clinical symptom or sign of SLE. Since that time on, the patient was more closely examined, but renal function and urinalysis remained normal for the following 9 years. In November 1999 she developed skin purpura on her legs, diffuse oedema, dyspnoea, arterial hypertension, and severe myoarthralgias. The patient was admitted to our Unit in December 1999. At presentation she looked pale and ill. The arterial blood pressure was 150/100 mmHg, with a heart rate of 90 beats/min. The physical examination revealed diffuse oedema, with purpuric lesions on legs and hands. Laboratory tests showed plasma creatinine 1.9 mg/dl, blood urea 80 mg/dl, creatinine clearance 32 ml/min, haematocrit 28%, white blood cells 10000 mm3, platelets 217000 mm3, total serum proteins 6.4 g/dl, albumin 2.8 g/dl, C3 complement fraction 48 mg/dl (normal value 90180) and C4 3 mg/dl (normal value: 1040), and positive anti dsDNA antibodies. The urine examination revealed proteinuria 6.7 g/day, severe microscopic haematuria (>100 red blood cells/high power field), leukocyturia, and granular and cellular casts. The patient was submitted to a second renal biopsy. The specimen contained 20 glomeruli, none of which was sclerotic. All the glomeruli showed mild to severe increase of mesangial and endothelial cells together with infiltration of mononuclear and polymorphonuclear leukocytes. Five glomeruli showed a small area of fibrinoid necrosis and karyorrhexis surrounded by segmental epithelial crescents. At trichrome stain mesangial, intramembranous, and subendothelial deposits were seen. Focal areas of mild tubular atrophy and interstitial fibrosis were present (Figure 2). At immunofluorescence a full-house pattern of immune deposits was observed: C1q 3+, IgG 2+, IgA 2+, IgM 1+, C3 1+ in parietal and mesangial distribution, fibrin 3+ in necrotic areas and C1q 2+, IgM 1+ along tubular basement membranes. A diagnosis of diffuse proliferative lupus nephritis with high activity index was made.
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Discussion
Little information is available about the possibility of late flare-up in patients with long-term quiescent lupus nephritis [5]. To the best of our knowledge it is exceptional that a patient who has maintained complete remission of lupus nephritis for an extremely long time can develop a renal flare.
After such a long period of clinical remission we believed that the disease had been definitively beaten in our patient. Nevertheless she continued to be regularly checked in our Unit. After 14 years, serum levels of C3 decreased and anti-dsDNA antibodies became positive, but no other clinical sign of SLE reappeared and renal disease remained silent for the following 9 years. At our surprise, however, a nephritic flare developed without identifiable causes after 23 years of clinical quiescence. As the patient was in good general condition, the therapy was vigorous. Six months later she went again into remission.
The activity of SLE seems to reduce over time. In our previous experience the incidence of renal and extrarenal flares significantly decreased after the 10th year of the disease [6]. Although one cannot exclude that this reduced clinical activity may be induced by previous corticosteroid and immunosuppressive therapy, it is also possible that it reflects a spontaneous remission of the disease. At any rate, it must be pointed out that even patients with prolonged inactive disease may develop flares of activity. Therefore patients with lupus nephritis should undergo regular check-ups after years of complete remission, particularly when previously negative serological markers become positive. This attitude may allow an early diagnosis and an appropriate treatment of renal flares, which is a paramount prerequisite for therapeutic success.
This case demonstrates that there is no such thing as burnt-out lupus, any more than there are extinct volcanoes: the possibility of further eruption is always present.
Notes
Correspondence and offprint requests to: Gabriella Moroni MD, Divisione di Nefrologia e DialisiPadiglione Croff, Ospedale Maggiore IRCCS, Via della Commenda 15, I-20122 Milano, Italy.
1 Present address: Servicio de Nefrología, Hospital Italiano, Buenos Aires, Argentina.
References