BAFF Levels and Lupus Nephritis (LN)

B-cell activating factor (BAFF), serves as a vital survival and differentiation factor for normal B-cell development. BAFF levels have been associated with the clinical activity of SLE in humans. BAFF plays a pathogenic role in SLE in part through T cell-dependent B cell autoantibody production. BAFF, has a role in the maintenance of memory B cells and promotes plasma cell survival. Treatment strategies involving BAFF blockade haven been studied in patients with SLE inducing overall improvement in disease activity, mainly in musculoskeletal and mucocutaneous domains leading to the approval of Belimumab for the treatment of patients with SLE without severe renal or neurological involvement.

Antibodies against CD20 molecule, (Rituximab), cyclophosphamide (CYC), and mycophenolate (MMF) have all been used for the treatment of different manifestations of SLE and both moderate and severe activity. Baseline C4 level, early normalization of complement, and reduction in proteinuria have been shown to predict renal response to therapy with MMF or CYC in lupus nephritis. With Rituximab (RTX), B cell depletion has been associated with response to treatment and relapse prediction. The elevation of serum BAFF levels after B cell depletion with RTX in SLE are associated with anti-double-stranded DNA antibody levels and disease flare. The rise of BAFF is probably due to the decrease in its receptors leading to a release of BAFF and a delayed regulation of BAFF mRNA transcription, both of which could favor the re-emergence of autoreactive B cells. It has been suggested that the rise in BAFF levels after anti-CD20 therapy might be related to flares of the disease. Additionally, the combination of anti-CD20 with anti-BAFF or antibodies against CD4, reduces the number of splenic plasma cells in mouse models and has been proven to have a lasting benefit both in lupus-prone mice and in mice with established disease. Currently, there is a lack of information regarding MMF or CYC and BAFF levels. We consider that it is fundamental to know the behavior of BAFF in patients with SLE after treatment with MMF or CYC bearing in mind the proposal of multiple experts of the possible use of sequential therapy of BAFF inhibition after B-cell depletion. Knowledge of the behavior of BAFF will allow me to better understand its implications in SLE and its therapy and postulate the use of sequence therapy with Belimumab after CYC o MF induction with the proposal to reduce the flares

1.3. Research question Flares of lupus nephritis are related to the behavior of BAFF levels before, during, and after induction therapy.

2. Theoretical framework B-cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS) serves as a vital survival and differentiation factor for normal B-cell development. There is an inverse relationship between BAFF circulating levels and the percentage and number of circulating B cells. APRIL (a proliferation-inducing ligand) shares substantial homology with BAFF and binds to two of the three BAFF receptors (BCMA and TACI) but not to BR3. Like BAFF, APRIL has little role in the maintenance of memory B cells but does promote plasma cell survival better than does BAFF. Both BAFF and APRIL levels behave differently after B cell depletion in SLE and rheumatoid arthritis. BAFF levels have been associated with the development of systemic lupus erythematosus (SLE) in murine models and with clinical activity of SLE in humans. BAFF plays a pathogenic role in SLE in part through T cell-dependent B cell autoantibody production. Treatment strategies involving BAFF blockade haven been studied in patients with SLE inducing overall improvement in disease activity, mainly in musculoskeletal and mucocutaneous domains leading to the approval of Belimumab for the treatment of patients with systemic lupus erythematosus without severe renal or neurological involvement.

Anti-CD20 antibodies (Rituximab), cyclophosphamide (CYC), and mycophenolate (MMF) have all been used for the treatment of systemic lupus erythematosus, and both moderate and severe activity. Both MMF and CYC show a significant effect on disease activity and circulating B, T, Natural Killer cells (NK), and Natural Killer T cells (NKT) cell subsets. Baseline C4 level, early normalization of complement, and reduction in proteinuria have been shown to predict renal response to therapy with MMF or CYC in lupus nephritis. With Rituximab (RTX), B cell depletion has been associated with response to treatment and relapses. The elevation of serum BAFF levels after B cell depletion with RTX in SLE are associated with anti-double-stranded DNA antibody levels and disease flare. The rise of BAFF is probably due to the decrease in its receptors leading to a release of BAFF and a delayed regulation of BAFF messenger-RNA (mRNA) transcription, both of which could favor the re-emergence of autoreactive B cells.

It has been suggested that the rise in BAFF levels after anti-CD20 therapy might be related to flares of the disease and that repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of the disease. Additionally, the combination of antiCD20 with anti-BAFF or anti-CD4 antibody greatly reduces the number of splenic plasma cells in mouse models and anti-CD20 plus anti-BAFF has been proven to have a lasting benefit both in lupus-prone mice and in mice with established disease.

B-cell depletion therapy (BCDT) has been used in patients with refractory disease with failure to standard therapy through a combination of RTX and CYC, which showed an improvement in clinical and serological disease activity. Serological findings suggest that B cell clones committed to producing antinucleosome antibodies and anti-dsDNA have a relatively rapid turnover compared with cell clones producing other autoantibodies(30). BAFF levels rose in most patients at 3 months post BCDT. Those patients with an expanded autoantibody profile and raised BAFF levels at baseline had shorter responses to BCDT. Retreatment with BCDT may produce a more sustained clinical response.

Currently, there is a lack of information regarding MMF or CYC and BAFF levels without the use of concomitant RTX (for CYC) and in monotherapy (for MMF). We consider that it is fundamental to know the behavior of BAFF in patients with SLE after treatment with MMF or CYC bearing in mind the proposal of multiple experts of the possible use of sequential therapy of BAFF inhibition after B-cell depletion. Knowledge of the behavior of BAFF will allow to better understand its implications in SLE and its therapy.

3. Hypothesis Elevated BAFF levels after induction therapy with MMF or CYC is associated with disease relapse.

4. Objectives 4.1. Main objective Analyze the relationship between BAFF levels and relapses after treatment with CYC and MMF

4.2. Specific objectives

* Describe the clinical and immuno-serological characteristics of patients with lupus nephritis at weeks 0, 12, and 24 of induction therapy.
* Compare the effects of CYC and MMF on BAFF levels in patients with lupus nephritis in induction therapy
* Evaluate the association between BAFF levels and remission of lupus nephritis treated with CYC and MMF.

Eligibility Criteria:
Inclusion Criteria:

1. Patients are older than 18 years
2. Patients that fulfill any of the available classification criteria for systemic lupus erythematosus
3. Patients with new-onset lupus nephritis or with lupus nephritis relapse after successful remission.
4. Patients with a diagnosis of lupus nephritis according to Wallace and Dubois criteria
5. Patients with class III and IV lupus nephritis with or without Class V lupus nephritis.

Exclusion Criteria:

1. Women with a positive pregnancy test
2. Class I, II, V lupus nephritis without Class III or IV lupus nephritis
3. Patients with an active malignancy or active treatment for malignancy.
4. Patients with kidney disease with GFR \<30ml / min
5. Patients with severe leukopenia
6. Patients with active infection