Successful treatment with belimumab in a patient with refractory systemic lupus erythematosus after initiation of hemodialysis: Considering the synergistic effect of belimumab and immunological burn-out phenomenon in end stage renal disease patients on hemodialysis

Background: In patients with systemic lupus erythematosus (SLE), disease activity can persist even after initiating dialysis. However, guidelines for the treatment of patients with SLE after dialysis is initiated have not yet been established. Case presentation: We describe the case of a 62-year-old Japanese woman who was diagnosed with SLE at age 12, progressed to end-stage renal disease (ESRD), and initiated hemodialysis for lupus nephritis. However, SLE activity persisted after hemodialysis. Cyclophosphamide and mycophenolate mofetil were administered in addition to prednisolone and immunoadsorption, but this treatment strategy was limited by side effects. The patient was subsequently treated with belimumab, and the activity of SLE decreased rapidly. Conclusions: ESRD patients with SLE show no significant decrease in transitional B cells, and have elevated levels of B-cell activating factor (BAFF). Both transitional B cells and BAFF are important therapeutic targets for belimumab, indicating that patients with ESRD may benefit from belimumab therapy. However, the effects of belimumab may be potentiated in patients with uremia, who may be more susceptible to adverse events such as infections. Patients with SLE who receive belimumab after initiation of hemodialysis therefore require careful follow-up. Here we report the first case of belimumab administration in a patient with SLE after initiation of hemodialysis.

Successful treatment with belimumab in a patient with refractory systemic lupus erythematosus after initiation of hemodialysis: Considering the synergistic effect of belimumab and immunological burn-out phenomenon in end stage renal disease patients on hemodialysis

Case Presentation
A 54-year-old woman was diagnosed with SLE and lupus nephritis 42 years previously. She had no family history.
At diagnosis (X-42 years), she experienced butterfly rash and arthralgia. Laboratory studies revealed high antinuclear antibody (ANA) and anti-DNA double-stranded antibody (anti-dsDNA) titer, and hypocomplementemia. Following a renal biopsy, the patient was diagnosed with SLE and lupus nephritis in International Society of Nephrology/ Renal Pathology Society class IV. Oral prednisolone (PSL) was initiated at a dose of 70 mg/day. At X-35 years, PSL was tapered to 10 mg/day, but at X-34 years, lupus nephritis flared and she was treated with a pulse dose of intravenous methylprednisolone (mPSL) 500 mg/day for 3 days. At X-30 years, PSL was tapered to 10 mg/day and maintained at this dose. The patient's hospital visits paused between X-25 and X-22 because of pregnancy and childbirth. After restarting PSL 10 mg/day, her serum creatinine level increased to 1.7 mg/dl and she again discontinued her hospital visits between X-15 and X-13 years. At X-13 years, conventional hemodialysis was initiated three times a week because of pulmonary congestion, and the serum creatinine level increased to 8.0 mg/dl. Despite maintenance hemodialysis, of the patient's complement level was low and anti-dsDNA antibody titer remained high, but PSL was tapered to 5 mg/day because of an expected decrease in disease activity. However, the anti-dsDNA antibody did not decrease and the patient was referred to our hospital. PSL 5 mg/day was continued. At X-4 years, the anti-dsDNA antibody titer increased to 7980 IU/ml and the patient experienced phlegmon of the lower limbs and central nervous system lupus. Intravenous mPSL pulse was administered for 3 days followed by PSL 50 mg/day, plasma exchange once, and immunoadsorption seven times. The anti-dsDNA antibody titer subsequently decreased to 600 IU/ml. Intravenous Cyclophosphamide (IVCY) as started as maintenance therapy, but cytopenia developed as a side effect. After additional intravenous mPSL pulses were given, the anti-dsDNA antibody titer decreased to 400-600 IU/ml and PSL was continued at 10 mg/dl. IVCY was subsequently administered three times, but the patient's cytopenia worsened and the anti-dsDNA antibody titer did not improve. At X-2 years, SLE flared with fatigue, loss of appetite, diarrhea, and an increase in anti-dsDNA antibody titer to 2260 IU/ml. The patient was again admitted to our hospital where she received intravenous mPSL pulses and immunoadsorption followed by mycophenolate mofetil (MMF) 250 mg/day as maintenance therapy.
The anti-dsDNA antibody titer decreased to 100 IU/ml, but the patient experienced diarrhea and nausea as a side effect of MMF treatment so this treatment was discontinued. At X-1 years, in April, the patient received immunoadsorption because of an anti-dsDNA antibody titer, which subsequently decreased gradually. PSL was tapered to 6 mg/dl, but the anti-dsDNA antibody titer remained above 200 IU/ml. Figure 1A shows the duration of treatment up to this point. From the following December, amoxicillin and carbocysteine were administered because the patient experienced right exudative otitis media. However, in January at X years, the patient experienced a rash on her entire body, followed by fever the next day.  Figure 1B shows the duration of treatment from X years.

Discussion
The evaluation of disease activity prior to initiating therapy can be challenging in patients with SLE who have started hemodialysis. [8] In our previous report, the most frequent symptoms reported by these patients after initiation of hemodialysis were arthritis, fever, pericarditis, and pleuritis. [9] Regarding serological evaluation, hematological BILAG activity can be evaluated even after starting hemodialysis. [10] 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. [11] 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. [13] 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. [12] 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. 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. [22] 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. [25] 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. [27] 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. [ Consent for publicationThe authors obtained written consent from patient for the publication of the data.

Currently, belimumab is covered by health insurance in
Availability of data and materials: All data concerning the case is presented in the manuscript.
Competing Interests: All authors have no conflicts of interest to declare.

Not applicable
Authors' contribution: KK was the corresponding author responsible for the writing of the article.   Figure 1 A) The results of laboratory examinations and the course of treatment from X-9 years to X-1. B) The results of laboratory examinations and the course of treatment from X years.

Figure 1
A) The results of laboratory examinations and the course of treatment from X-9 years to X-1. B) The results of laboratory examinations and the course of treatment from X years. This is a list of supplementary files associated with this preprint. Click to download. Table.pptx Table.pptx