Reversal of osteomyelosclerosis-associated systemic lupus nephritis

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osteosclerosis (Figure 2). In addition, she had relapse. Myelofibrosis is a rare but well-recognized complica- of scleritis and persistent severe pancytopenia. She.
Nephrol Dial Transplant (1998) 13: 1559–1561

Nephrology Dialysis Transplantation

Case Report

Reversal of osteomyelosclerosis-associated systemic lupus nephritis Bhavesh J. Vora1, Richard J. Byers2, Guy S. Lucas3 and Ram Gokal1 Departments of 1Renal medicine, and 3Haematology, Manchester Royal Infirmary, and 2Department of Pathological Sciences, University of Manchester, Manchester, UK

Key words: systemic lupus erythematosus; osteomyelosclerosis; nephrotic syndrome; pancytopenia

Introduction Myelofibrosis is a rare but well-recognized complication of systemic lupus erythematosus [1–6 ]. We describe a young woman with lupus nephritis who developed severe osteomyelosclerosis which responded to treatment with steroids, with normalization of the blood counts, regression of splenomegaly, and reversal of osteomyelosclerosis.

Case Report A 22-year-old female was referred to the renal unit in November 1993 with nephrotic syndrome following a first-trimester spontaneous abortion. She had a history of pre-eclampsia during her two previous pregnancies at the age of 19 and 20 years. Laboratory evaluation revealed proteinuria of 10.2 g/day and normal biochemistry. ANA titre was significantly elevated to 1000. Anti-ds-DNA, anti-Sm and anticardiolipin were negative. Kidney biopsy revealed membranous nephropathy with mesangeal proliferation and positive immunofluorescence for IgG, IgA, and IgM, all 3+. A diagnosis of membranous lupus nephropathy was made and she was treated with 40 mg of prednisolone a day and captopril. Her subsequent course was complicated by generalized tonic–clonic seizures due to lupus and severe recurrent posterior scleritis resulting in restrictive ophthalmoplegia. All these flare-ups were steroid responsive. By November 1995 the patient had proteinuria of 0.6 g/day, and was then started on 100 mg of azathioprine daily as a steroid-sparing agent. Unfortunately, 2 weeks later she developed pancytopenia and hence azathioprine was stopped (Figure 1). She also had splenomegaly on clinical examination. As there was no Correspondence and offprint requests to: Dr R. J. Byers, Department of Pathological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.

improvment in her blood counts 4 weeks after stopping azathioprine, a bone marrow aspirate and trephine biopsy were performed. No aspirate was obtained and the trephine biopsy showed marked osteomyelosclerosis, with severe myelofibrosis of the marrow spaces and near total effacement of normal haematopoiesis, together with irregular thickened trabeculae showing osteosclerosis (Figure 2). In addition, she had relapse of scleritis and persistent severe pancytopenia. She received six plasma exchanges during March 1996 without any benefit. Her haemoglobin was 6.4 g/dl, her platelet count 7×109/l and her WBC 4.7×109/l. In addition repeat bone-marrow biopsy showed no improvement. Hence, she received three 1-g pulses of methylprednisolone in May 1996, which resulted in a remarkable increase in all three cell counts. Her haemoglobin increased to 13.1 g/dl, her platelet count to 145×109/l, and her WBC to 5.3×109/l by 4 weeks, and have remained at these levels to the present time, July 1997. A repeat bone marrow examination in May 1997 showed remarkable improvement, with marked reduction in reticulin and little residual fibrosis, together with a less marked, but definite reduction in osteosclerosis, with widespread evidence of active bone remodelling. Trilineage haematopoiesis was restored, with normal numbers and maturation of precursor cells ( Figure 3). The patient’s spleen has returned to normal size and she currently has normal renal function with mild (0.9 g/day) proteinuria.

Discussion We report a female with aggressive systemic lupus erythematosus with involvement of renal, cerebral, haematological, and ocular systems together with spontaneous abortion. Such patients demand higher dosage of steroids and can have higher long-term complications due to steroid therapy than those with less aggressive disease. Immunosuppressive agents have been increasingly used as steroid-sparing agents in such patients. The National Institute of Health study showed best outcome with cyclophosphamide pulse therapy in patients with aggressive disease [7].

© 1998 European Renal Association–European Dialysis and Transplant Association

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Fig. 1. Blood counts during the clinical course. Bold circles indicate time of bone marrow evaluation.

(a)

(b) Fig. 2. (a) Pre-treatment trephine biopsy showing reticulin fibrosis (grade 4) and osteosclerosis (reticulin ×40), (b) Marked osteosclerosis, with irregular, thickened trabeculae, and paucity of haematopoietic elements (H&E ×200).

However, long-term complications with cyclophosphamide limit its routine use. Azathioprine is a suitable alternative. Marrow suppression is a common sideeffect of azathioprine; however, it is dose dependent and most recover after discontinuation of therapy. Our patient failed to recover, possibly because of underlying myelofibrosis. Azathioprine is not known to cause

(a)

(b) Fig. 3. (a) Post-treatment trephine biopsy showing reduced reticulin and increase in haematopoietic elements. (b) Marked increase in haematopoietic elements and bone remodelling, with fragments of osteiod and new bone (both H&E ×200).

myelofibrosis, and in any case the patient only received a 2-week course, which would have been too short to have caused the changes present. In view of the aggressive disease in the past and lifethreatening pancytopenia, plasmapheretic therapy was tried, but without success. This was consistent with reports in the past [8]. Myelofibrosis is an uncommon

Osteosclerosis in systemic lupus nephritis

disorder and is particularly rare in the setting of collagen disease [9]. It has been reported in association with systemic lupus erythematosus. These cases either present with de novo cytopenia [1,2] or develop it in the setting of known systemic lupus [3–6 ]. In most of the cases reported there has been improvement with high-dose steroid therapy [1,2,4,5]. However, improvement in the peripheral blood count need not be consistent with complete marrow recovery. In fact most have reported only partial resolution of marrow fibrosis. The improvement in the cell count in our patient after steroid therapy supports our view that she developed pancytopenia due to immune-mediated myelofibrosis and not to azathioprine-induced myelosuppression. Paquette et al. reported a series of eight patients and a review of nine other patients having myelofibrosis with systemic lupus erythematosus [1]. Twelve of 17 were steroid responsive. A single previous case report, in which myelofibrosis was accompanied by osteosclerosis due to lupus, failed to show resolution of osteosclerosis [1]. This is the first case report of osteomyelosclerosis in which both the myelofibrosis and osteosclerosis responded to steroid therapy. The cause of osteomyelosclerosis is unknown in this case, but the parallels between the case and those reported with myelofibrosis suggest that a immunological mechanism is probably operating.

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Received for publication: 5.12.97 Accepted: 28.1.98