Abstract
Autoimmune rheumatic disorders have complex etiopathogenetic mechanisms in which B cells play a central role. The importance of factors stimulating B cells, notably the B-cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) axis is now recognized. BAFF and APRIL are cytokines essential for B-cell proliferation and survival from the immature stages to the development of plasma cells. Their levels are increased in some subsets of patients with autoimmune disorders. Several recent biologic drugs have been developed to block this axis, namely belimumab [already licensed for systemic lupus erythematosus (SLE) treatment], tabalumab, atacicept and blisibimod. Many clinical trials to evaluate the safety and efficacy of these drugs in several autoimmune disorders are ongoing, or have been completed recently. This review updates the information on the use of biologic agents blocking BAFF/APRIL for patients with SLE, rheumatoid arthritis, Sjögren’s syndrome and myositis.
Keywords
Introduction
B cells have a key role in the pathogenesis of autoimmune rheumatic disorders. The early stages of B-cell development occur in the bone marrow, where they develop initially in the absence of antigen recognition, leading to the development of a high percentage of self-reactive cells [Nemazee, 1995; Townsend et al. 2010; Von Boehmer and Melchers, 2010]. Subsequently, during B-cell proliferation and maturation in the germinal centres present in the peripheral lymphoid organs, the interaction with antigens and processes including somatic hypermutation leads to the development of further self-reactive cells [Hartley et al. 1991; Townsend et al. 2010]. During B-cell development there are several checkpoints, both in the bone marrow and the periphery, that lead to deletion or anergy of these autoreactive cells [Townsend et al. 2010; Von Boehmer and Melchers, 2010]. However, cells that escape these diverse selection mechanisms may drive autoimmune disorders through various pathways including the generation of autoantibody-secreting plasma cells, formation of immune complexes, presentation of autoantigens to T cells, production of pro-inflammatory cytokines, and formation of ectopic lymphoid structures [Yanaba et al. 2008; Townsend et al. 2010; Dorner and Lipsky, 2014].
Several therapeutic strategies have focused on B cells, either by depleting their number (anti-CD20 drugs such as rituximab and ocrelizumab) or by modulating their functions [anti-CD22 and blocking several pro-inflammatory cytokines including interleukin (IL) 6 and tumour necrosis factor (TNF) α] [Mok, 2010; Townsend et al. 2010; Dorner and Lipsky, 2014; Faurschou and Jayne, 2014].
Since its discovery in 1999, much attention has focused on the B-cell activating factor (BAFF) pathways. BAFF, also known as B lymphocyte stimulator (BLyS) or TNF superfamily member 13B (TNFSF13B), and a proliferation inducing ligand (APRIL), also known as TNFSF13A, are TNF superfamily ligands that have an important role on B-cell proliferation and survival [Schneider et al. 1999; Batten et al. 2000]. BAFF is a cytokine promoting B-cell survival and maturation. APRIL was identified as a cell growth stimulator and a promoter of immunoglobulin class switching [Batten et al. 2000; Mackay et al. 2003]. The levels of BAFF might set a threshold for B-cell competition determining the stringency of naïve B-cell selection because of the higher dependence of autoreactive B cells on BAFF relative to naïve mature B cells [Mackay et al. 2003].
BAFF and APRIL are produced as transmembrane proteins, like many of the TNF family ligands, cleaved at a furin protease site and then released in a soluble form [Lahiri et al. 2012; Morel and Hahne, 2013; Vincent et al. 2013]. BAFF also remains active as a membrane-bound form, although the soluble form is required for B-cell homeostasis, so its role is not completely understood [Batten et al. 2000; Mackay et al. 2003; Vincent et al. 2014]. APRIL is cleaved in the Golgi apparatus prior to release and functions mainly in its soluble form. A membrane-bound variation of APRIL, TWE-PRIL, has also been identified. This is a hybrid protein of APRIL and TWEAK (TNF-related weak inducer of apoptosis or TNFSF12) that results from trans-splicing between their adjacent genes. Little is known about the physiological functions of this fusion protein [Batten et al. 2000; Lahiri et al. 2012; Vincent et al. 2014]. Processed soluble BAFF and APRIL become active ligands as homotrimers, which are the main forms found in the circulation.
Three receptors have been identified for the BAFF/APRIL pathways. Both BAFF and APRIL bind to TACI (transmembrane activator and cyclophilin ligand interactor or TNFRSF13B) and BCMA (B-cell maturation antigen or TNFESF17). BAFF has an additional receptor: BAFF-R or TNFRSF13C to which it binds strongly. Furthermore, BAFF binds strongly to TACI and weakly to BCMA [Batten et al. 2000; Mackay et al. 2003; Vincent et al. 2014].
APRIL binds strongly to BCMA and weakly to TACI, although this can be optimized by the interaction of APRIL with heparin sulphate proteoglycans (HSPGs) that increase the signalling at a local site and concentrates APRIL on the cell surface. The APRIL/HSPG complex interacts only with TACI (Figure 1) [Townsend et al. 2010; Vincent et al. 2014].
BAFF and APRIL signalling.
BAFF and APRIL are predominantly produced and release by myeloid cells, notably monocytes, neutrophils, macrophages, dendritic cells and T cells. The receptors for these cytokines have distinct expression patterns based on B-cell development stages [Vincent et al. 2014]. BAFF-R is absent on B cell precursors in the bone marrow and their expression increases as B-lineage cells develop in the periphery and is critical for immature B-cell survival [O’Connor et al. 2004; Townsend et al. 2010]. BAFF-R expression is diminished, but still detectable, on germinal centre B cells, whereas it is greatly reduced or absent on plasma cells [O’Connor et al. 2004; Townsend et al. 2010]. TACI is expressed on mature innate-like B cells (such as marginal zone B cells), but reaches its highest levels on plasma cells, as do BCMA that are restricted to plasmablasts and plasma cells, and promotes long-lived plasma cell survival [Benson et al. 2008; Townsend et al. 2010].
All three types of receptors are expressed on memory B cells [Benson et al. 2008; Townsend et al. 2010].
Recent studies have demonstrated the expression of these cytokines and their receptors on a wide variety of hematopoietic (astrocytes and microglia, immature and mature B cells) and nonhematopoietic cell lineages (adipocytes, human skin keratinocytes, several lines of cancer cells) [Vincent et al. 2014].
Even though the exact role of BAFF/APRIL in autoimmune disorders is not completely understood, animal studies demonstrated that BAFF transgenic mice develop a systemic lupus erythematosus (SLE)/ Sjögren’s syndrome (SS) like syndrome [enlarged B-cell compartment and lymphoid organs, high titres of anti-double stranded DNA (anti-dsDNA) antibodies and rheumatoid factor, hypergammaglobulinemima, circulating immune complexes and glomerulonephritis with immunoglobulin deposits] [Mackay et al. 1999]. Furthermore SLE-prone mice tend to have increased serum BAFF levels and BAFF blockade reduces disease manifestations [Kamal and Khamashta, 2014]. Analysis of an experimental model for rheumatoid arthritis (RA) revealed elevated BAFF levels, but normal or low APRIL levels.
Some human studies have demonstrated elevated serum levels of BAFF and APRIL in a proportion of patients suffering from SLE, RA, SS and other disorders of the immune system. Some studies on lupus patients suggest there is a positive correlation between BAFF and anti-dsDNA levels [Vaux, 2002]. This evidence supports the idea that some patients might benefit from BAFF-blocking therapies. In fact, several recent biologic drugs have been developed in an attempt to block this pathway, namely belimumab, tabalumab, atacicept and blisibimod. Of these drugs belimumab is already licensed by the US Food and Drug Administration (FDA) for SLE treatment. Belimumab (GSK1550188 or HGS1006) is a human monoclonal antibody that antagonizes the effect of BAFF by binding to the free form of the cytokine [Baker et al. 2003].
Atacicept (K3D9A0ICQ3) is a TACI-Fc fusion protein that binds to and blocks the receptor for both BAFF and APRIL [Nestorov et al. 2008]. It acts both in homotrimers and heterotrimers, and results in diminished plasma cell survival and antibody production in mice and humans [Nestorov et al. 2008; Faurschou and Jayne, 2014].
Tabalumab (LY2127399) and blisibimod (AMG623) both block the two biologically active forms of BAFF, but whereas tabalumab is a human monoclonal antibody, blisimibod is a fusion polypeptide protein [Hsu et al. 2012; Genovese et al. 2013b; Manetta et al. 2014].
All of these drugs are being/have been tested for rheumatic disease with varying results. In the next sections the role of these drugs on SLE, RA, SS and myositis are further reviewed.
SLE
SLE is an autoimmune rheumatic disease characterized by autoantibody production, immune complex deposition and end organ damage. It principally affects women of childbearing age (20–45 years) [Lisnevskaia et al. 2014; Rahman and Isenberg, 2008]. The clinical course is characterized by spontaneous or treatment-induced remissions and relapses [Lisnevskaia et al. 2014], with patients liable to develop diverse symptoms, ranging from fatigue, arthralgias, fever or oral ulcerations to more severe musculoskeletal, cutaneous, pulmonary, renal, hematopoietic, cardiac and nervous system manifestations [Rahman and Isenberg, 2008].
Disease activity in SLE can be assessed using several validated tools recognized amongst others by the Task Force on SLE of the European League Against Rheumatism (EULAR) [Bertsias et al. 2008]. The 2008 EULAR recommendations advised that at least one of the following indices should be used to monitor disease activity in SLE, namely, the SLE Disease Activity Index (SLEDAI), the Safety of Oestrogens in Lupus Erythematosus National Assessment (SELENA)–SLEDAI, the British Isles Lupus Assessment Group (BILAG) index, the European Consensus Lupus Activity Measurement (ECLAM) or the Systemic Lupus Activity Measure (SLAM). These scores are valid, reliable and sensitive to change. In general, more active disease leads to permanent change (or damage) and that in turn to mortality [Bertsias et al. 2008]. In addition, the assessment of patients’ health status can be performed with health-related quality of life measures, such as the 36-item short form health survey (SF-36®) [Ware and Sherbourne, 1992] or the more lupus specific, LupusQoL [Devilliers et al. 2015].
Many factors, including genetic, environmental, hormonal, hereditary and immunoregulatory defects have been shown to play a role in the etiology of SLE [Tsokos, 2011].
Although the precise mechanisms leading to SLE remain incompletely understood, extensive evidence suggests that B cells play an important role in its pathogenesis [Kamal and Khamashtra, 2014]. It is believed that following environmental triggers, inherent abnormalities in the innate and adaptive immune systems result in apoptotic nuclear fragments, including double- and single-stranded DNAs (dsDNA, ssDNA), RNA binding nuclear antigens (Ro, La and Smith antigens) and non-nuclear fragments, being inadequately cleared. These fragments are then processed by antigen presenting cells (APCs) such as B cells or plasmacytoid dendritic cells (pDCs). Thereafter, these self-antigens are presented on the cell surface to autoreactive T cells, which subsequently trigger auto B cells to stimulate self-antibody production and propagate their APC function. In addition, cytokines, such as BAFF, APRIL, IL-6 and IL-10, interferon α (IFN-α) and TNF-α are thought to be released by APCs and positively enhance auto B-cell and subsequent auto T-cell activation [Chan et al. 2013; Kamal and Kharmashtra, 2014].
It was soon realized that BAFF-deficient mice had considerable reductions in mature B cells, leading to a marked drop in baseline total serum immunoglobulins (IgM, IgG and IgA levels) and attenuation of antigen-specific humoral responses to T-cell dependent and T-cell independent antigens [Gross et al. 2001; Schiemann et al. 2001]. Conversely, overexpression of BAFF in transgenic mice resulted in significant increases in all serum immunoglobulin isotypes (IgM, IgG, IgA, IgE), with notable increases in IgA levels [Khare et al. 2000]. SLE-like features, including high titres of circulating anti-dsDNA autoantibodies, immune-complex glomerulonephritis and proteinuria, developed in these otherwise nonautoimmune-prone mice that constitutively overexpressed BAFF [Mackay et al. 1999; Gross et al. 2000; Khare et al. 2000].
In parallel, treatment of either of two genetically disparate, widely studied and well-established strains of SLE-prone mice (MRL/lpr; and NZBW F1) with atacicept ameliorated disease expression [Gross et al. 2000].
Previous humans studies also showed that BAFF was elevated in the serum of 50–67% lupus patients, and APRIL was increased in 38% [Stohl et al. 2003; Dillon et al. 2010]. Interestingly, the levels of these cytokines seem to be positively correlated with disease activity as assessed by SLEDAI and the titres of serological markers, such as anti-dsDNA autoantibodies [Petri et al. 2008; Chu et al. 2009; McCarthy et al. 2013; Boghdadi and Elewa, 2014]. BAFF was also related to cumulative organ damage over time [McCarthy et al. 2013]. These data suggest that BAFF and APRIL play a significant role in disease pathogenesis and thus become logical candidate targets for disease therapies [Stohl et al. 2012; Stohl, 2014].
Curiously, increased BAFF levels were also observed in SLE patients during an absence of circulating B cells after B-cell depletion therapy (BCDT) with an anti-CD20 drug [Vallerskog et al. 2006; Cambridge et al. 2008; Carter et al. 2013]. However, the levels are of course measured in the serum and we do not know how effective B-cell depletion is within human tissues.
Cambridge and colleagues showed that SLE patients with increased BAFF baseline levels and expanded autoantibodies profile (anti-Ro/SSA or anti-RNP/Sm) had a shorter clinical response to BCDT [Cambridge et al. 2008]. This observation suggests that BAFF levels might have a predictive value for the length of clinical response in this group of SLE-treated patients. In BCDT and subsequent B-cell repopulation, serum BAFF levels were significantly higher during relapse and may help to distinguished relapse from ongoing disease remission [Carter et al. 2013]. In addition, there was an inverse correlation between serum BAFF levels and B cell numbers. Ultimately, all these results suggest a significant role of BAFF in promoting a disease flare after the B-cell repopulation following BCDT [Carter et al. 2013].
Studies with belimumab
Belimumab is currently the only approved biologic for the treatment of SLE [Gottenberg et al. 2014], its efficacy being demonstrated by two large phase III randomized studies, the BLISS-52 and BLISS-76 trials (Table 1) [Furie et al. 2011; Navarra et al. 2011].
Published clinical trials in SLE.
↓, decrease; =, similar; ≠, different; AE, adverse event; Atb(+), autoantibody-positive; BCDT, B-cell depletion therapy; CNS, central nervous system; CS, corticosteroids; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HR, hazard ratio; Ig, immunoglobulin; IV, intravenous; LN, lupus nephritis; MMF, mycophenolate mofetil; OR, odds ratio; PE, primary endpoint; Rx, treatment; SC, subcutaneous; SELENA, Safety of Oestrogens in Lupus Erythematosus National Assessment; SFI, time to flare; SLEDAI, SLE Disease Activity Index; SRI, Systemic Lupus Erythematosus responder index; UPCr, urine protein to creatinine ratio.
The initial promising results were shown in a phase I randomized trial of belimumab in SLE patients with mild-to-moderate disease affecting the skin and joints. Belimumab was well tolerated and reduced peripheral B cell levels (CD20+ B cells) [Furie et al. 2008].
In a subsequent 52-week, phase II trial, 449 SLE patients were randomized to receive placebo or 1, 4 or 10 mg/kg of belimumab. The drug was well tolerated and biologically active, with 63–71% of patients depleted in their naïve, activated and plasmacytoid CD20+ B cells, and a decrease in anti-dsDNA titres was noted (p ⩽ 0.0017). Primary endpoints were not met in this study, quite possibly because approximately 30% of the patients were antinuclear antibody (ANA) negative, as no difference was seen in SELENA-SLEDAI score at week 24 or in the median time to first SLE flare over the 52 weeks (as compared with placebo group). However, post hoc subgroup analyses revealed that patients who were serologically positive (low C3 and high anti-dsDNA antibody level) at baseline, when treated with belimumab, did have a significant improvement in SELENA-SLEDAI and SF-36 scores at week 52 [Wallace et al. 2009].
Based on the data from the seropositive SLE patient subgroup, a novel responder index [Furie et al. 2009], the SLE Responder Index (SRI) has been used in the subsequent belimumab trials. It has three components: the SLEDAI documenting the improvement of overall disease activity; the BILAG ascertaining individual organ/system change; and a physician’s global assessment (PGA) that provides confirmation by clinicians [Furie et al. 2009].
The BLISS-52 trial [ClinicalTrials.gov identifier: NCT00424476] included 865 SLE patients from Latin America, Asia-Pacific and eastern Europe, with moderate-to-severe disease (⩾6 on SELENA-SLEDAI score) and positive ANA and/or anti-dsDNA who were randomized to receive intravenous (IV) belimumab 1 (n = 289) or 10 mg/kg (n = 290) or placebo (n = 288) with standard of care (SOC). The primary efficacy endpoint was improvement in the SRI at week 52 versus baseline; 58% of the autoantibody-positive SLE patients in the 10 mg/kg belimumab group met the SRI response criteria at week 52 versus 44% in the placebo group [odds ratio (OR) 1·83 (1·30–2·59); p = 0·0006]. In the patients treated with belimumab 1 mg/kg, 51% met the primary endpoint, also a significantly better response than placebo group [OR 1·55 (1·10–2·19); p = 0.0129]. Generally, a higher response rate was observed in belimumab-treated patients. In addition, belimumab was shown to be well tolerated, reduced disease activity and improved serologic activity, prevented flares and reduced corticosteroid (CS) use [Navarra et al. 2011].
A second trial, BLISS-76 [ClinicalTrials.gov identifier: NCT00410384], of very similar design was conducted in 819 patients from North/Central America and Europe who were randomized to receive IV belimumab 1 (n = 271) or 10 mg/kg (n = 273) or placebo (n = 275) with SOC. It had the same primary efficacy endpoint and treatment continued through week 76, although the main evaluation took place at week 52. The results revealed that 43.2% of SLE patients in the 10 mg/kg belimumab group were SRI responders versus 33.5% in the placebo group (p = 0.017) at 52 weeks, although at 76 weeks there was no significant difference between the treatment arms [Furie et al. 2011].
The pooled data from the two phase III trials (BLISS-52 and 76) added new information about changes in autoantibodies, immunoglobulins, complement levels, B and T cell populations [Stohl et al. 2012], effects on prior vaccine-induced antibody levels [Chatham et al. 2012; Stohl et al. 2012] and on disease activity across multiple organ domains [Manzi et al. 2012].
Belimumab-treated patients had showed a modest fall in their IgG levels (median reduction 13.8% and 15.3% for 1 mg/kg and 10 mg/kg belimumab, respectively, versus 2.5% for placebo; p < 0.001). In addition, C3 and C4 levels increased (p < 0.001) and several autoantibody levels fell with significantly more patients converting from seropositive to seronegative for anti-dsDNA (p < 0.001), anti-Smith (Sm) (p < 0.01), anti-ribosomal P protein (p < 0.01) and IgG anticardiolipin (aCL) autoantibodies (p < 0.05). In the BLISS-76 cohort, the effect of belimumab on lymphocytes revealed a significant reduction on median levels of CD19+ and CD20+ B cells (55–58%; p < 0.001) and preservation of B and T cell populations. In addition, a significantly greater reduction in naïve (CD20+CD27-) and activated (CD20+CD69+) B cells was observed in belimumab-treated patients, a common effect also seen in plasmacytoid cells (CD20+CD138+). Memory cells transiently increased and gradually returned to baseline levels over 76 weeks. The effects on pre-existing vaccine antigen-specific antibody levels in patients who had received pneumococcal or tetanus vaccine within 5 years [Chatham et al. 2012; Stohl et al. 2012] or influenza vaccine [Chatham et al. 2012] within 1 year of the start of treatment were also assessed in BLISS-76. The results revealed no significant differences across treatment groups, showing that belimumab did not affect the ability of patients with SLE to maintain antibody titres to previous pneumococcal, tetanus and influenza immunizations [Chatham et al. 2012; Stohl et al. 2012].
Improvements in disease activity were significantly more frequent in the 10 mg/kg belimumab treated group [Manzi et al. 2012]. Post hoc analysis of SLE patients with renal involvement on mycophenolate mofetil (MMF) or with serologic activity at baseline showed a higher improvement after belimumab treatment, better results with renal flare rates, renal remission, proteinuria reduction and renal organ disease improvement [Dooley et al. 2013], although few of those improvements were statistically significant. However, the trial excluded patients with really active renal disease. A study of these patients is ongoing (Table 3) [ClinicalTrials.gov identifier: NCT01639339].
A better response to belimumab treatment was associated with patients with higher disease activity (SELENA-SLEDAI ⩾10), anti-dsDNA positivity, low complement or CS treatment at baseline. In addition, the results showed that early normalization of C3 or anti-dsDNA values were predictors of a reduced risk of severe flares [Stohl et al. 2012; van Vollenhoven et al. 2012]. Interestingly, the baseline serum BAFF was not a predictor of clinical response.
Of note, in the uncontrolled part of phase II randomized controlled trials (RCTs), the rate of serious infections and cancers was similar between belimumab and placebo [Ginzler et al. 2014]. The 7-year open-label study showed a stable rate of adverse events and infections among belimumab-treated patients and, in some cases, they may have decreased over time [Ginzler et al. 2014]. However, the implication from the earlier trials that the more serologically active patients would have a better response was not confirmed in this study.
Based on the favourable results of the two RCT studies, IV belimumab was licensed and approved by the FDA in March 2011 and the European Medicines Evaluation Agency (EMEA) as an addon therapy in adults with active disease in the skin and/or joints despite optimized standard immunosuppression who are ANA or anti-dsDNA-positive SLE. In the approved regimen, belimumab is administered at 10 mg/kg at 2 week intervals for the first 3 doses and then given every 4 weeks [Human Genome Sciences, 2010].
However, patients with severe lupus kidney disease or active central nervous system (CNS) lupus are excluded from belimumab treatment, as those conditions were not evaluated in the BLISS-52 and BLISS-76 studies [Furie et al. 2011; Navarra et al. 2011]. However, the real determinant of whether belimumab becomes more widely accepted will be the cost. The current price per patient per year ($30,000) in the USA is too high for many countries to bear, especially considering that the efficacy of the drug is only evident after some months of treatment. Nonetheless, cost-effectiveness analysis must take into account the results from a post hoc analysis of BLISS-52 and BLISS-76 trials that suggested a significant improvement in health-related quality of life in patients treated with belimumab compared with placebo at week 52, in SF-36 and a fatigue assessment questionnaire (p < 0.001 in both analysis) [Furie et al. 2014b].
Based on favourable results of previous RCT in belimumab, several trial programmes in SLE are ongoing (Table 3).
Of note, the follow-up open extension phases of BLISS-52 and BLISS-76 studies did not show any increase risk for serious infections or development of cancer. Nevertheless, it is important to considerer that, so far, a relatively small number of patients have been evaluated and the duration of follow up is limited (Table 1) [Wallace et al. 2009; Furie et al. 2011; Navarra et al. 2011; Ginzler et al. 2014].
Belimumab did not seem to be effective among Black American SLE patients, which raises a concern about the responsiveness of the drug across racial groups. The results of an ongoing study in this group of patients is addressing this issue directly (Table 3) [ClinicalTrials.gov identifier: NCT01632241].
It will also be useful to evaluate belimumab efficacy and safety in specific patient subpopulations that were not included in the phase III trials (see Table 3), including paediatric patients (the PLUTO study is currently recruiting [ClinicalTrials.gov identifier: NCT01649765]), lupus nephritis (patients with severe kidney involvement were not evaluated on previous studies, the BLISS-LN study will provide some information on that area) [ClinicalTrials.gov identifier: NCT01639339] and CNS lupus (the only subgroup of patients where no human study has been started or proposed so far).
There are other questions yet to be answered. For example, is belimumab better used to induce disease remission or to maintain it? This question arises following recent findings by Carter and colleagues that suggest that, although baseline BAFF levels do not predict treatment outcome, after BCDT with rituximab it does predict further flares [Carter et al. 2013]. Thus, it might be interesting to treat patients with belimumab after depleting B cells whose BAFF levels are rising.
Studies with atacicept
Atacicept inhibits both BAFF and APRIL, and previous in vivo studies showed that NZBWF1 mice (lupus-prone mice) treated with soluble TACI-Ig fusion protein inhibited the development of proteinuria and prolonged animal survival [Gross et al. 2000]. This BAFF/APRIL antagonist has shown promise in the treatment of some autoimmune diseases.
The first human study was published in 2007, with a phase I study of healthy male volunteers who received a single subcutaneous (SC) dose of atacicept (2.1, 70, 210 or 630 mg) or placebo (and monitored over 7 weeks). The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of atacicept were assessed. Results revealed that single SC doses of the drug were well tolerated and demonstrated biological activity (with the 70, 210 and 630 mg doses inducing a reduction in IgM serum concentrations, persistent up to 210 days post dose) [Munafo et al. 2007].
In the same year a phase Ib dose-escalating trial was performed in patients with mild-to-moderate SLE to evaluate its safety and tolerability, and its biologic effect on B lymphocyte and immunoglobulin levels. Atacicept decreased levels of IgG, IgM and IgA, naïve B cells and plasma cells in a dose-dependent manner [Dall’era et al. 2007].
However, some doubts were raised when in 2012 a clinical trial was stopped prematurely, although this turned out to be inappropriate, due to safety concerns (Table 1) [Ginzler et al. 2012]. This trial was designed to be a 52-week phase II/III, randomized study to evaluate the efficacy and safety of atacicept in patients with active lupus nephritis (LN), receiving newly initiated CS and MMF. Patients were initiated treatment with high-dose CS and MMF for 2 weeks prior to starting atacicept or placebo (150 mg, SC, twice weekly for 4 weeks, then weekly). Three out of four atacicept treated patients developed serious infections in association with low IgG levels. However, a closer look at the data revealed that the sharp drop in the IgG levels occurred when MMF was given for 2 weeks before the atacicept was started and that, by chance, patients in the atacicept group had higher levels of proteinuria [urine protein to creatinine ratio (UPCr) ⩾ 3.0 versus ⩽ 2.3 mg/dl] and this protein loss might account for hypergammaglobulinemia [Ginzler et al. 2012; Isenberg, 2012].
The results of a 52-week phase II/III, randomized trial of atacicept in patients who originally had moderate-to-severe SLE brought to remission by steroids, with the purpose of determining the efficacy and safety of atacicept in the prevention of flares in SLE [Isenberg et al. 2014a] was published recently and reported more promising results (Table 1). In order to understand further the impact of atacicept on the onset of new flares, patients were started on high doses of CS for two weeks and then tapered down to 7.5 mg daily gradually from week 3 to week 10. At week 12, patients with a BILAG C or D (mild, improving or inactive disease) were randomized (n = 461) to receive atacicept 75 mg (n = 159) or 150 mg (n = 145), or placebo (n = 157) twice-weekly for 4 weeks, then weekly for 48 weeks. Flares were defined as having an adjudicated BILAG A (severely active) or B (moderately active) score. Patients were followed up for 24 weeks after the last dose of trial medication. The primary outcome measure was the proportion of patients experiencing at least one flare of BILAG A or B severity [Isenberg and Gordon, 2000] during the 52-week trial period. Of note, enrolment and follow up in the atacicept 150 mg arm was discontinued prematurely due to 2 deaths, 1 from leptospirosis. However, this decision was most unfortunate as the mortality rate in this study was identical to that in the Benlysta trials [Furie et al. 2011; Navarra et al. 2011]. The results revealed that the primary endpoint of reducing the numbers of new flares was not met in the atacicept 75 mg arm compared with placebo. Nevertheless, post hoc analysis of patients treated with atacicept 150 mg showed a beneficial effect versus placebo in flare rates (OR: 0.48, p = 0.002) and time to first flare [hazard ratio (HR): 0.56, p = 0.009]. Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels [Isenberg et al. 2014a]. In spite of the potential safety concerns, atacicept still seems an attractive drug to treat SLE and needs further investigation.
Studies with other BAFF inhibitors
Other BAFF inhibitors currently being evaluated for SLE are blisibimod and tabalumab (Table 3) [Gottenberg et al. 2014].
The results of 2 phase III, 52-week randomized trials where the efficacy and safety of SC tabalumab in SLE patients were recently presented in the annual meeting of the American College of Rheumatology (ACR) [Isenberg et al. 2014b]. A total of 2288 SLE patients were randomized (n = 1164 in ILLUMINATE-1 and n = 1124 in ILLUMINATE-2) to receive SC tabalumab every 2 or 4 weeks or placebo. Patients with severe, active renal and/or CNS manifestations were excluded. Tabalumab showed a good safety profile in both RCTs. The primary endpoint of SRI-5 was met in trial 2 for a 120 mg every 2 weeks dose of tabalumab (p < 0.002). Biologic activity, as observed, was consistent with the inhibition of the BAFF pathway as demonstrated by changes in anti-dsDNA (normalization at week 52 – trial 1: 14–16% versus 9% in placebo group; trial 2: 12% versus 7% in placebo group), complement (normalization at week 52 – trial 1: 29–36% versus 22% in placebo group; trial 2: 31–37% versus 22% in placebo group), B cells and immunoglobulins. Of note, secondary efficacy endpoints, namely, time to first severe flare or CS sparing effect, did not achieve statistical significance.
Despite these promising results, Eli Lilly decided, unfortunately, to stop all further clinical trials with tabalumab in SLE [Eli Lilly & Co, 2014] due to their perception of insufficient efficacy in the phase III trials (Table 3) [ClinicalTrials.gov identifier: NCT01196091, NCT01205438, NCT01488708, NCT02041091].
Blisibimod resembles tabalumab as both have the ability to inhibit soluble and membrane-bound BAFF. In vivo studies on blisibimod have showed promising results in several murine models of autoimmune diseases. In the NZBW F1 lupus model, blisibimod induced a reduction in B cell numbers, leading to improvement of disease activity and survival [Hsu et al. 2012]. In addition, in a phase I study repeated administration of blisibimod resulted in a significant decrease in B cell counts in SLE patients [Furie et al. 2014a].
The PEARL-SC study is a 24-week, phase IIb randomized trial that evaluated the efficacy and safety of blisibimod in SLE patients with moderate-to-severe disease [Furie et al. 2014a]. The primary endpoint was a SLE Responder Index (SRI-5) [Furie et al. 2009] in which were all the following criteria where present: ⩾5 point improvement in SELENA-SLEDAI; no new BILAG A organ domain scores (or no more than one new BILAG B score); and no worsening in PGA. A total of 547 patients were randomized to receive placebo or one of 3 dose levels of SC blisibimod (100 or 200 mg weekly, or 200 mg every 4 weeks). Blisibimod only met SRI-5 response rates with the 200 mg weekly blisibimod group (reaching statistical significance at week 20, p = 0.02). It induced a significant reduction in proteinuria, as well as a reduction in anti-dsDNA and B cells, and increase of complement (C3 and C4) from baseline. The study established a patient population likely to benefit from blisibimod treatment, notably those with severe disease (SELENA-SLEDAI ⩾10) and receiving CS [Furie et al. 2014a]. The data supported further evaluation of 200 mg weekly blisibimod and therefore a phase III clinical study was started in 2013 (see Table 3) [ClinicalTrials.gov identifier: NCT01395745, NCT02074020] and its results are awaited with great interest.
Apart from belimumab, no BAFF/APRIL antagonist agents are being prescribed in routine clinical practice and some will never become available, as they have missed primary endpoints on RCTs. The challenging diversity of SLE pathogenic mechanisms makes it unrealistic that a single drug or combination of drugs will be sufficient for every patient. Many questions remain to be addressed on anti-BAFF/APRIL treatment for SLE. Do these drugs have different efficacy when combined with different disease-modifying antirheumatic drugs (DMARDs)? Or is it more feasible to treat a particular end organ lesion or a specific ethnic group? These are questions that will, we hope, be answered with future trials. Furthermore, clinical trial design is also a major issue. Adding a biological drug to partially effective SOC can make it very challenging to demonstrate the efficacy of the drug in a trial and may increase the risk of side effects. Likewise setting unrealistic goals for biologic (or other) drugs in clinical trials also renders the possibility of a successful outcome less likely.
RA
RA is an autoimmune disease, characterized by chronic inflammation predominantly affecting synovial joints and a high risk of inflammation induced irreversible joint damage [McInnes and Schett, 2011]. It is a common disease that affects approximately 0.5–1% of the adult population in northern Europe and North America [Alamanos and Drosos, 2005].
The predominant autoantibodies in RA are against the Fc part of IgG (rheumatoid factors, RFs) present in approximately 80% of patients and to protein sequences which have undergone citrullination (anticitrullinated protein autoantibodies, ACPA). Seropositive RA patients have a more aggressive disease [Bukhari et al. 2002].
Although, the aetiology of RA is incompletely understood, B cells contribute to the disease process by playing a combination of roles from T-cell activation (that leads to production of proinflammatory chemokines and cytokines, such as IFN-γ, IL-6 or IL-10), being precursors of plasmablasts and inducing plasma cells to secrete autoantibodies [Boumans et al. 2011; Cambridge et al. 2014] and having a direct deleterious action on chromatin [Martin and Chan, 2006].
As previously described, BAFF and APRIL play important roles in B-cell survival on the periphery by triggering B-cell survival, differentiation, proliferation and antibody production which may influence RA autoimmunity [Avery et al. 2003; Mackay et al. 2003].
Fibroblast-like synoviocytes isolated from RA patients, which are characterized by an aggressive phenotype in these inflammatory conditions, can produce large amounts of cytokines including BAFF, enabling these cells to collaborate with autoimmune B cells [Alsaleh et al. 2011].
In patients with RA, elevated serum and tissue levels of BAFF have been described [Cheema et al. 2001; Nakajima et al. 2007] and further studies have showed an association with autoantibody production (anti-dsDNA and RF in particular) and synovitis [Bosello et al. 2008] and, ultimately, higher disease activity [Cheema et al. 2001; Hong et al. 2009; Gheita et al. 2012].
In RA patients treated with BCDT, similar to SLE, studies have showed that serum BAFF levels went up after treatment and started to decrease when B cells returned and relapsed [Cambridge et al. 2006, 2014]. Nevertheless, after multiple courses of treatment, the patients developed persistently raised serum BAFF levels that did not always return to initial baseline values prior to retreatment. These failures may cause downregulation of BAFF-binding receptors, decreasing the ability of B cells to bind excess BAFF and ultimately inducing a paradoxical reduction in naïve B-cell survival [De La Torre et al. 2010; Cambridge et al. 2014].
BAFF receptor expression on B cells is inversely proportional to serum BAFF [Kreuzaler et al. 2012]. In vitro studies have also shown that exogenous BAFF decreased the ability of memory B cells (CD38+ and -) to secrete immunoglobulins [De La Torre et al. 2012]. In treated patients the hypothesis is that persistently raised serum BAFF levels may reduce the ability for B cells to differentiate, resulting in a delay in Ig production. This may conversely contribute to longer clinical responses to treatment as described previously [De La Torre et al. 2010, 2012; Cambridge et al. 2014]. Unlike the situation in SLE, in B cell depleted RA patients, raised serum BAFF levels were not related to disease activity [Cambridge et al. 2014].
As increased BAFF expression in the sera and synovial fluid may increase the likelihood of B-cell survival in patients with RA, neutralizing BAFF and/or APRIL is an alternative therapeutic approach to targeting B cells [Ohata et al. 2005; Bosello et al. 2008; Faurschou and Jayne, 2014].
Belimumab was the first anti-BAFF drug to be evaluated in RA patients (Table 2). In a phase II study, patients fulfilling the ACR20 criteria for RA [Arnett et al. 1988] for ⩾ 1 year who had at least moderate disease activity while receiving stable DMARD therapy and failed ⩾ 1 DMARD were randomly assigned to placebo or belimumab 1, 4 or 10 mg/kg, administered intravenously (IV) on days 1, 14 and 28, and then every 4 weeks for 24 weeks (n = 283) [McKay et al. 2005; Stohl et al. 2013]. This was followed by an optional 24-week extension (n = 237) in which all patients received belimumab. ACR20 responder rates after 24 weeks of treatment with placebo and belimumab 1, 4 and 10 mg/kg, defined as the primary endpoint, were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168) and 28.2% (p = 0.080), respectively, indicating relatively low efficacy of belimumab in this RA cohort [McKay et al. 2005; Stohl et al. 2013].
Published clinical trials in RA.
↓, decrease; =, similar; ACR20, 50, 70, American College of Rheumatology criteria for RA; AE, adverse event; BAFF, B-cell activating factor; BCDT, B-cell depletion therapy; CCP+, anticitrullinated protein antibody positive; CRP, C-reactive protein; CS, corticosteroids; DAS28, Disease Activity Score for RA; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; EULAR28, EULAR Response Criteria for RA; HAQ-DI, Health Assessment Questionnaire for RA; Ig, immunoglobulin; IL, interleukin; IV, intravenous; MTX, methotrexate; PE, primary endpoint; RA, rheumatoid arthritis; RF, rheumatoid factor; RF+, rheumatoid factor positive; Rx, treatment; ; SC, subcutaneous; TNF, tumour necrosis factor.
Nonetheless, patients on any belimumab dose who continued with the drug in the open-label extension had an ACR20 response of 41% at 48 weeks, similar to the ACR20 response (42%) of patients taking placebo who switched in the extension to belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were RF+, ACPA+ or TNF-α inhibitor-naïve, or had elevated C-reactive protein (CRP) levels, DAS28 > 5.1, or low BAFF levels (<0.858 ng/ml) [Ding, 2008; Stohl et al. 2013].
Belimumab efficacy and safety were also studied in a subgroup of TNF inhibitor-experienced patients with no differences being detected in ACR20 response rate between belimumab and placebo [Genovese et al. 2013b].
Resembling the outcome with belimumab, an exploratory phase Ib study involving 73 RA patients treated with 6 escalating doses of atacicept demonstrated good local and systemic tolerability to the drug. Treatment-related decreases in immunoglobulin (particularly IgM), RF levels and B-cell response were noted [Tak et al. 2008]. However, further studies with atacicept did not demonstrate significant efficacy in RA patients with inadequate response to methotrexate (MTX) [van Vollenhoven et al. 2011] or TNF inhibitors [Genovese et al. 2011] (Table 2).
Tabalumab had favorable results in the first clinical trials (Table 2) [Genovese et al. 2009]. Genovese and colleagues reported the results from a 24-week double-blind, placebo-controlled, dose-ranging (1–120 mg SC tabalumab) trial of 158 patients with active RA receiving MTX. Tabalumab met the primary endpoint, at week 12, and patients in the 120 mg tabalumab dose group had significantly higher ACR20 and 50 response rates as compared with placebo (66.7% and 33.3% versus 33.3% and 11.1%, respectively), but by week 24, only the ACR50 response rate on 120 mg tabalumab group was significantly different from placebo [Genovese et al. 2013c].
After this study, a 16-week, phase II randomized study was undertaken to evaluate the efficacy and safety of tabalumab in 100 patients with active RA and inadequate response to TNF inhibitors (Table 2) [Genovese et al. 2013b]. Patients on stable MTX and with inadequate response to ⩾1 TNF inhibitors were randomized to placebo (n = 35), 30 mg tabalumab (n = 35) or 80 mg tabalumab (n = 30) given IV at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an ACR50 response at week 16 (all tabalumab-treated patients versus placebo). No significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% versus 2.9%, p = 0.101) or ACR20 response rates (27.0% versus 17.1%, p = 0.198). Although the primary endpoint was not met, clinical responses were observed early in the study (peaking at week 9) as measured by ACR50 and ACR20 responses, and decreases in Disease Activity Score 28 (DAS28) CRP. Tabalumab-treated patients had a significantly lower swollen joint count (combined tabalumab, 12.1; placebo, 14.5; p < 0.05) and a statistically significant reduction of IgM and IgA from baseline at week 16 (p < 0.05).
Recently, an open-label study evaluated the safety and efficacy of tabalumab in RA (Table 2) [Genovese et al. 2013c; Greenwald et al. 2014]. The trial was designed to evaluate the safety and efficacy of SC 60 mg tabalumab in RA patients who had completed ⩾24 weeks of participation in 2 prior phase II tabalumab studies [Genovese et al. 2013a]. Patients enrolled in the first RCT (RCT1) were TNF antagonist inadequate responders (TNF-IR) who received placebo, 30 mg tabalumab or 80 mg tabalumab IV [Genovese et al. 2013b]. Patients enrolled in the second RCT (RCT2) were MTX inadequate responders (MTX-IR) who received placebo or 1, 3, 10, 30, 60 or 120 mg SC tabalumab [Genovese et al. 2013c]. During the open-label study, all patients received 60 mg SC tabalumab regardless of prior treatment [Greenwald et al. 2014].
Of the 186 eligible patients who completed RCT1 or RCT2, 98% (n = 182) were enrolled in the open-label study; 80% of patients (n = 146) completed 52 weeks of treatment. On the whole, over the treatment course, the results obtained for RA patients in both tabalumab groups demonstrated efficacy by various measures of disease activity including ACR20, ACR50, ACR70, EULAR28, DAS28-CRP and HAQ-DI. In addition, long-term tabalumab treatment resulted in gradual declines in total B cells without total depletion. Declines in immature and mature naïve B-cell subsets were also observed, whereas switched memory B cells initially increased from baseline and then declined by week 52 [Greenwald et al. 2014].
Based on these phase II trials [Genovese et al. 2013a], a phase III trial programme was initiated to evaluate the efficacy and safety of tabalumab in RA patients (Table 4) [ClinicalTrials.gov identifier: NCT01198002]. In February 2013, however, Eli Lilly announced the discontinuation of the phase III RA programme after interim analyses produced results that did not meet efficacy expectations. The decision was not based on safety concerns [Eli Lilly & Co, 2012, 2013].
Ongoing studies in SLE.
ab, antibody; AE, adverse event; ANA(+), positive antinuclear antibodies; AUC 0-14, area under the concentration time curve from time 0 to 14 days; Autoantibody (+), Autoantibody-positive; BCDT, B cell depletion therapy; Cmax, maximum serum concentration; CNS, central nervous system; CS, corticosteroids; DMARD, disease-modifying antirheumatic drug; Ig, immunoglobulin; IV, intravenous; LN, lupus nephritis; LTE, long-term extension; PK, pharmacokinetics; POR, Prospective Observational Registry; Rx, treatment; SC, subcutaneous; SELENA, Safety of Oestrogens in Lupus Erythematosus National Assessment; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index; SOC, standard of care; SRI, Systemic Lupus Erythematosus responder index; UPCr, urine protein to creatinine ratio.
Ongoing studies in RA.
ACR20, American College of Rheumatology criteria for RA; AUC, area under curve; BCDT, B cell depletion therapy; CCP+, anticitrullinated protein antibody positive; Cmax, maximum serum concentration; CRP, C-reactive protein; CS, corticosteroids; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; HCQ, hydroxychloroquine; Ig, immunoglobulin; mTSS, van der Heijde modified Total Sharp Score; MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug; PK, pharmacokinetic; PO, by mouth; Pred., prednisolone; RA, rheumatoid arthritis; RF+, rheumatoid factor positive; Rx, treatment; SC, subcutaneous; ULN, upper limit of normal.
Other studies with tabalumab were performed in RA patients (Table 4). A phase III study was performed with the purpose of evaluating tabalumab pharmacokinetics following SC administration in RA patients who had an inadequate response to MTX [ClinicalTrials.gov identifier: NCT01676701]. A phase II exploratory open-label biomarker study investigated how tabalumab works in patients with moderate-to-severe RA who had not adequately responded to MTX [ClinicalTrials.gov identifier: NCT01576549]. Key study procedures include biopsies of the lining of an inflamed joint to measure RA activity. The studies were completed in 2013, but no data have been published until now.
In addition, two phase III clinical trials have been performed with the purpose of evaluating the safety and efficacy of tabalumab in RA patients with or without background DMARD therapy [ClinicalTrials.gov identifier: NCT01202760], the FLEX O study, or who had and inadequate response to one or more TNF-α inhibitors [ClinicalTrials.gov identifier: NCT01202773], the FLEX V study. The results are awaited.
Further investigation of BAFF genetics and pathways should be considered as a guide to therapeutic targets. Progress may come from developing better strategies to identify subgroups of patients more likely to benefit from specific biological therapies. In this context, recent studies on BAFF genetics showed a significant association between a -871C>T promoter polymorphism in the BAFF gene (TTTT BAFF haplotype) and a good response to rituximab treatment in seropositive RA patients in whom anti-TNF therapy had previously failed [Fabris et al. 2013; Ruyssen-Witrand et al. 2013].
SS
SS is a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to their progressive destruction [Fox, 2005]. It mainly affects middle-aged women, with an estimated prevalence of between 0.5% and 1% of the general population [Fox, 2005; Mavragani and Moutsopoulos, 2014]. The disease can be primary (pSS) or secondary to other systemic autoimmune diseases such as SLE or RA [Fox, 2005; Mavragani and Moutsopoulos,. 2014].
The main clinical features are xerostomia and keratoconjuntivitis sicca, but patients with SS may have a broad range of clinical manifestations related to periepithelial infiltrates in parenchymal organs (including the kidney, lung and liver) or to immune complex deposition (purpura, peripheral neuropathy, glomerulonephritis) [Fox, 2005; Voulgarelis and Tzioufas, 2010a; Mavragani and Moutsopoulos, 2014].
This immune complex deposition results from one of the hallmarks of pSS–B-cell hyperactivity that also manifests by the presence of hypergammaglobulinemia found in about a third of the patients, various autoantibodies, mainly ANA (about 75% of patients), anti-Ro/SSA (up to 75% approximately), -La/SSB (up to 50%) or RF (60%) [Abrol et al. 2014] and pro-inflammatory cytokines [Mariette et al. 2003; Voulgarelis and Tzioufas, 2010b; Nocturne and Mariette, 2013]. The main complication of the disease is the occurrence of lymphoma, which is estimated to occur in 5–10% of patients with a higher mortality risk than general population [Voulgarelis et al. 1999; Ioannidis et al. 2002].
Exocrine glands of patients with SS have increased inflammatory infiltrates, composed of T and B cells, dendritic cells, macrophages, and increased levels of pro-inflammatory cytokines, including BAFF and APRIL [Mariette et al. 2003; Lavie et al. 2008]. BAFF seems to have a particularly relevant role on pSS pathogenesis. Mice transgenic for BAFF develop clinical features resembling SS with lymphocytic infiltration of the salivary glands [Groom et al. 2002]. Furthermore, salivary and serum BAFF levels are increased in patients with pSS and those serum levels correlate with anti-Ro and -La antibody titres [Mariette et al. 2003; Pers et al. 2005]. BAFF levels are also believed to increase the risk of progression to lymphoma [Quartuccio et al. 2013; Nezos et al. 2014]. Studies in a mouse model of SS suggest that blocking BAFF/APRIL might lead to decreased local inflammation and immunoglobulin levels [Vossenkamper et al. 2012; Vosters et al. 2012].
In addition, in patients treated with rituximab for pSS, serum baseline BAFF levels seem to determine B-cell repopulation in the peripheral blood and salivary glands [Pers et al. 2007; Pollard et al. 2013]. APRIL levels remain altered during rituximab treatments in pSS [Pollard et al. 2013], perhaps reflecting a higher expression of its receptor in activated B cells and plasma cells that are little affected by rituximab [Vallerskog et al. 2006; Pollard et al. 2013].
These data suggest an important role for BAFF in pSS. Recently two phase II open-label clinical trials of belimumab in pSS have been completed. These trials were performed in France [ClinicalTrials.gov identifier: NCT01160666] and in Italy [ClinicalTrials.gov identifier: NCT01008982], and although the final data are still to be published, preliminary results of these studies were presented during the 2012 ACR congress [ClinicalTrials.gov identifier: NCT01008982, NCT01160666; Cornec et al. 2013]. A total of 30 pSS patients were involved in this study and were treated with 10 mg/kg belimumab in weeks 0, 2 and 4, and every 4 weeks until week 24. Patients were considered to reach the primary endpoint if they improved in 2 of the 5 following items: ⩾30% reduction of patient’s dryness in visual analogue scale (VAS); ⩾30% reduction of fatigue VAS; ⩾30% reduction of musculoskeletal pain VAS; ⩾30% reduction of physician’s systemic activity VAS; ⩾25% reduction of different B-cell activation biomarkers (serum IgG, IgA, kappa and lambda-free light chains and RF levels) [ClinicalTrials.gov identifier: NCT01008982, NCT01160666; Cornec et al. 2013]. At week 28, 19 out of the 30 patients (63%) reached the primary endpoint. The percentage of responders was higher in patients with early disease and lower in patients with systemic involvement. However, there was no significant change in the salivary flow or the Schirmer’s test score [ClinicalTrials.gov identifier: NCT01008982, NCT01160666; Cornec et al. 2013].
Although these studies involved a relatively few patients, given the importance of B-cell abnormalities seen in pSS, BAFF blockade seems to be a promising therapy, justifying the realization of RCTs of belimumab and other anti-BAFF drugs in patients with pSS.
Myositis
Idiopathic inflammatory myopathies (IIM) are a group of rare heterogeneous muscle disorders, characterized by inflammation of skeletal muscle, with elevated muscle enzymes (including creatine kinase, CK). Common clinical features are chronic and progressive symmetrical proximal muscle weakness, which may lead to an impaired endurance and significant disability [Dalakas and Hohlfeld, 2003; Mahil et al. 2012]. These disorders can be subclassified into polymyositis (PM), dermatomyositis (DM), cancer associated myositis, inclusion body myositis or immune mediated necrotizing myopathy [Dalakas and Hohlfeld,. 2003; Troyanov et al. 2005]. The pathogenesis of IIM is complex, with adaptive and innate pathways playing a role in the mechanisms of disease [Nagaraju and Lundberg, 2011]. Importantly, the frequent identification of serum autoantibodies (up to 80%) [Hengstman et al. 2002] and cellular infiltrates of both adaptive and innate immune system cells in muscle biopsies suggest an immune-mediated process in myositis.
Among the autoantibodies found in the sera of these patients, up to 60% may have myositis-specific autoantibodies, such as aminoacyl-tRNA synthetases (ARS) (a group that includes the anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies), Mi-2 helicase/histone deacetylase protein complex and the signal recognition particle (SNP) ribonucleoprotein. Recent studies suggest that autoantigens in inflammatory myopathies may drive a B-cell antigen-specific immune response in muscles [Ghirardello et al. 2013]. This statement is supported by previous studies showing an increased number of B cells in the sera and muscle tissue of both PM and DM patients [Greenberg et al. 2005a; Ishii et al. 2008].
In addition, the presence of Ig, type I IFN (α and β) and dendritic cells transcripts were demonstrated by microarrays studies in the muscle fibers of myositis patients [Greenberg, 2007]. As previously described, pDCs – the cellular source of type I IFNs – are major components of the inflamed muscle tissue [Greenberg et al. 2005b; Eloranta et al. 2007], which suggests that dendritic and plasma cells are involved in the development of muscle inflammation.
It has been shown that type I IFN induced the production of BAFF [Ittah et al. 2006] and differentiation of exposed B cells into plasmablasts [Jego et al. 2003]. Furthermore, patients with anti-Jo-1 autoantibodies and DM were found to have high levels of serum BAFF correlating with serum CK (rs = 0.365, p = 0.0005) and negative correlation with glucocorticoid treatment [Krystufkova et al. 2009]. In addition, patients with anti-Jo-1 and anti-Ro52/anti-Ro60 autoantibodies had a significantly higher number of cells expressing BAFF-R, BCMA or TACI [Krystufkova et al. 2014], showing a positive correlation with the number of plasma cells and markers of pDCs, as well as, disease activity [Lopez de Padilla et al. 2013].
Taken together, in the subset of inflammatory myopathies where patients’ present high production of autoantibodies, targeting B cells and BAFF in particular, seems a reasonable approach [Venalis and Lundberg, 2014]. However, we are unaware of any human studies that have been undertaken to evaluate the efficacy and safety of anti-BAFF drugs in myositis.
Conclusion
The BAFF/APRIL axis appears to play a key role in the development of autoimmune disorders, making it an appealing target for biologic drugs. The results of the trials with belimumab in SLE treatment are quite promising and its approval as the first targeted therapy for SLE is a major advance. However, there are still patients who do not respond to this therapy and a significant group of severely ill patients (with renal or neurologic involvement) in whom the effect of belimumab is unknown. Moreover, in the other autoimmune rheumatic disorders the role for blocking BAFFs remains uncertain or unknown (for example, in myositis).
The diversity and complexity of these disorders makes it essential to understand the role of BAFF/APRIL axis in autoimmune rheumatic disorders. This knowledge will help clinicians to optimize the selection of these patients who are more likely to benefit from these expensive biologic treatments.
Further studies are needed to understand the long-term safety and efficacy of these drugs better, as well as to compare the efficacy of these drugs with those already available for the treatment of these challenging conditions.
Footnotes
Acknowledgements
Sandra A. Morais and Andreia Vilas-Boas are regarded as equal first authors.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.