The evaluation of disease activity prior to initiating therapy can be challenging in patients with SLE who have started hemodialysis.  In our previous report, the most frequent symptoms reported by these patients after initiation of hemodialysis were arthritis, fever, pericarditis, and pleuritis.  Regarding serological evaluation, hematological BILAG activity can be evaluated even after starting hemodialysis. A previous retrospective, case-controlled study showed that hematologic activity, complement 4, anti-cardiolipin IgM, and age at initiation of renal replacement therapy were independent risk factors for extrarenal SLE flares.  In our case, although low-grade fever and general fatigue was often the only clinical symptom, the patient was in a prolonged serologically active state as shown by persistent neutropenia, lymphocytopenia, anemia, hypocomplementemia, and high anti-dsDNA antibody titer, with a very high possibility of major flare up.
There are few reports on the treatment of patients with SLE who show activity even after initiation of dialysis. [8, 12] Prednisolone represents the mainstay of treatment of SLE, regardless of whether the patient is on dialysis. Side effects such as infections, osteoporosis, and cardiovascular events are managed by immediate tapering of prednisolone tapering to approximately 5 mg/day.  Given that patients on hemodialysis are susceptible to infection, osteoporosis, and cardiovascular events even without prednisolone therapy, we kept the prednisolone dose to a minimum in our case. [14 15] Furthermore, the survival rate in patients with ESRD treated with prednisolone alone is surprisingly similar to that in patients who receive no medication, suggesting that low-dose prednisolone treatment may be inadequate for this patient population, and combined use with an immunosuppressant is recommended.  However, no intradialytic clearance with hemodialysis is observed with the use of immunosuppressive agents, other than azathioprine and cyclophosphamide. [16 17] Given that improvements in non-renal disease were observed in the aspreva lupus management study (ALMS), we used cyclophosphamide and MMF as induction and maintenance therapy combined with immunoadsorption therapy in the present case. [18 19] However, leukopenia and frequent diarrhea are associated with cyclophosphamide and MMF, respectively, despite the use of a dialysis dose, so we decided to administer a biological agent that could be used independently of renal function.
Currently, belimumab is covered by health insurance in Japan for the treatment of SLE as a biological agent targeting B cells. BAFF is an important regulator of B-cell survival and function, and in BAFF-overexpressing mice, SLE-like pathological conditions are induced such as the appearance of anti-dsDNA antibody and the deposition of immune complex to the kidney.  BAFF levels are increased in patients with SLE, and are reported to be correlate positively with anti-dsDNA antibody titer.  Belimumab, as an anti-BAFF antibody, is therefore used to treat active SLE, especially in patients with a high anti-dsDNA antibody titer and low serum complement level.  However, B-cell distribution in patients with ESRD shows a decrease in all B-cell subpopulations except transitional B cells without belimumab administration. In ESRD, BAFF receptor expression on B cells is decreased because of uremia, which causes a reduction in total B cells. [23, 24] These specific findings to ESRD patients led us to following hypothesis. (1) The so-called ‘burnout’ phenomenon of SLE with ESRD was presumed in the case of a patient with autoreactive B cells in the B-cell subpopulations reduced by uremia. (2) Diffuse reduction of B-cell subpopulations results in a high concentration of BAFF via a positive feed-back mechanism in patients with ESRD even if it is not in patients with SLE. In summary, in ESRD patients with SLE, there is no significant decrease in transitional B cells, while BAFF is elevated.  The main target cells of belimumab are transitional B cells, which are antigen-unprimed mature B cells that have recently emerged from bone marrow to a secondary lymphoid organ, and follicles and marginal zone B cells, which is classified as mature B cells. Because Belimumab acts on both insensitive naïve B cells and transitional B cells in uremic patients to attenuate the activity of SLE, and a synergistic immunological effect can be expected in patients with ESRD. (Fig. 2) Moreover, in recent years, belimumab has been reported to act on transitional B cells to induce negative selection of autoreactive B cells.  In the present case, the anti-dsDNA antibody titer decreased and the complement value increased immediately after the administration of belimumab. In contrast, a very small decrease in serum IgG was observed. According to previous reports, a belimumab-induced reduction in anti-dsDNA antibody titer was attributed to loss of naïve B cells and transitional B cells, and secondary loss of memory B cells and plasma cells. Given the secondary effect, anti-dsDNA antibody titer reduction frequently is low in magnitude and takes a considerable amount of time.  However, previous reports have shown that naïve activated B cells from patients with active SLE can directly give rise to plasmablasts. [22, 26] Although plasmablasts are short-lived, they have the ability to produce antibodies, and belimumab may have a role in this process. 
Finally, the side effects of belimumab treatment should be considered. In the BLISS52 and BLISS76 trials, large double-blind studies with belimumab, no significant difference was observed in the incidence of serious infections between a belimumab 10 mg/kg group and a placebo group. [28 29] In the present case, after 4 weeks of administration of belimumab 10 mg/kg, lymphocytes were significantly reduced and Pneumocystis carinii pneumonia occurred. The patient improved immediately after treatment, but increased apoptosis of naïve and central memory CD4 + T cells caused by uremia may have caused the reduction in lymphocytes. [30 31] We subsequently reduced the dose of belimumab to 4 mg/kg to reduce the incidence of side effects in a reference clinical trial to determine the biological activity and safety of belimumab in patients with SLE.  Despite the reduction in belimumab, particular attention should be paid to infection because belimumab and uremia synergistically suppress B-cell lineage via different pathways. Currently, in this case, the treatment can be continued and has a favorable treatment course. However, a major limitation of this study is the short observation period. In conclusion, belimumab may represent a good treatment option for patients with SLE, even after initiation of dialysis. However, in patients with uremia requires careful follow-up also in these patients as it may enhance the side effects of belimumab.