Essay: SLE mortality

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There is a bimodal pattern associated with SLE mortality (1). Early deaths are frequently attributable to inflammation, infections and thromboses whilst later (yet still premature) mortality is more often due to cardiovascular disease and organ damage (2). The standardized mortality rate for SLE has been estimated at 2.4 (3)-5.9 (4). This is significantly higher in those with renal involvement (5), with substantial ethnic and geographic variation (6). Historically, the five-year survival rate in SLE was in the region of 50%, whereas more recently, the 10-year survival exceeds 90% (3, 7). Much of the excess mortality demonstrated in recent cohorts has been attributed to treatment-effects and cardiovascular disease rather than uncontrolled inflammation, highlighting the fact that current therapies are commonly limited by long-term inefficacy and toxicity.

This review outlines the epidemiology and classification criteria for SLE, current treatment regimens including their limitations, the challenges encountered in the development of therapies in SLE and potential future therapeutic agents.

Epidemiology

Estimates of SLE prevalence in the adult US population range from 30-150/100,000 (Table 1.) and incidence from 2.2 to 23.1/100,000 (Table 2.). Despite the wide variation in these estimates, rates are consistently higher in women and amongst non-Caucasian ethnicities. In the USA, the incidence of SLE almost tripled in the latter half of the 20th century (8). This may be in part attributable to the improved detection of mild disease, an increased utilisation of laboratory testing and enhanced physician and patient awareness.

In the USA, the prevalence of SLE is highest among Asians, African-Americans, Afro-Caribbeans, and Hispanic-Americans (9-11). Similarly, in Europe, the prevalence of SLE is more common in those of Asian and African ethnicity (9). Contrarily, SLE appears to occur infrequently in Africa (12). SLE is more common in women. This gender inequality is a universal finding in SLE epidemiologic studies and is contributed to by hormonal factors and by the presence of some SLE susceptibility genes on the X chromosome. At least three predisposing gene variants are located on X chromosomes (IRAK1, MECP2, TLR7)(13) with evidence for a gene dose effect. The prevalence of Klinefelter’s syndrome (genotype XXY) is increased significantly (by a factor of 14) in men with SLE when compared with males in the general population, whereas Turner’s syndrome (genotype X0) is rare in SLE (14). Surprisingly, men with SLE have a more severe phenotype and worse outcomes (15). Supporting hormonal influences in the development of SLE is the fact that gender inequality is much less marked in childhood (16).

SLE Genetics and Pathophysiology

SLE associates with a loss of self-tolerance with the activation of autoreactive T and B cells leading to the development of pathogenic autoantibodies (directed against nucleic acids and their binding proteins), immune complex deposition and subsequent tissue injury. This loss of self-tolerance is a consequence of genetic, environmental and hormonal factors as well as poorly understood random events and exposures with aberrancies in both innate and adaptive immunity, leading ultimately to tissue damage.

SLE has long been recognised to have a heritable component with a high concordance rate in monozygotic twins (24-46%)(17, 18), and an increased incidence in first-degree relatives (19, 20). None the less, the absolute rate of sibling concordance has been reported in the region of 2% and in more than half of monozygotic twin pairs, where one has SLE, the second does not go on to develop disease, suggesting that in most instances genetics alone are not responsible. Numerous genome-wide genetic association studies have identified more than 50 genetic predispositions (21-29). Generally, the associated single nucleotide polymorphisms increase the relative risk of SLE by less than a factor of 2, supporting the notion that environmental factors and epigenetic factors are crucial in most incidences. However, examples exist of rare, monogenic mutations leading to SLE and SLE-like phenotypes. These are important as characterisation of these phenotypes has led to insights into the aberrant physiologic pathways in SLE. Examples include genes known to be involved in DNA damage repair (e.g. TREX 1)(30), nucleic acid sensing and type I interferon overproduction (e.g. STING, TREX 1), apoptosis (FASLG), tolerance (PRKCD), and clearance of self-antigen (DNASE1L3) in addition to complement deficiencies.

An example of monogenic lupus due to aberrant DNA degradation and consequent immunogenicity is illustrated by the phenotypes associated with mutations in TREX 1 (31). Deficiency of TREX 1 allows accumulation of cytosolic single stranded DNA fragments which are capable of directly activating innate immune responses to induce interferon. In SLE, the proportion of patients with TREX 1 mutations has been found to be as high as 2% (32). Inherited complement deficiencies (C1r, C1q, C1s, C2, C4A, and C4B) have been shown to predispose to SLE development (33). In particular, the incidence of SLE in patients with homozygous C1q deficiency is as high as 90%, in multiple ethnic backgrounds with Mendelian inheritance. However, these mutations are rare (34). More frequently, a low gene copy number of C4 is considered a risk factor for the development of SLE, whereas a high copy number appears to be protective (35). In addition to rare monogenic mutations, a large and as of yet poorly understood component of the susceptibility to SLE arises as a result of environmental triggers and epigenetic modifications. Known culpable environmental triggers include ultraviolet exposure, smoking, certain medications and viruses (36-38).

SLE Classification Criteria

Clinical and serological heterogeneity in SLE poses a challenge for diagnosis and classification. The first SLE classification criteria were proposed in 1971 by the American College of Rheumatology (ACR) (39) and subsequently revised in 1982 (40) and 1997 (41)(Table 3.). Criticisms of the 1971 criteria included the observation that there was an over representation of frequently co-existing cutaneous manifestations with too few major organ criteria. In 1982, a set of revised criteria was published (40). This revision excluded Raynaud’s phenomenon and alopecia, and added anti-nuclear antibody positivity. The proteinuria criterion was reduced from >3.5g/day to >0.5g/day and two renal items were consolidated into one. The arthritis criterion was expanded upon to describe a non-erosive arthritis involving two or more joints. The new criteria were found to have a sensitivity of 96% and a specificity of 96%. The 1997 updated classification criteria for SLE added cardiolipin antibodies to the criteria list. Despite revisions, these criteria were limited in a number of ways. Firstly, an over-reliance on dermatologic manifestations persisted with possible duplication of highly correlated cutaneous manifestations such as photosensitivity and malar rash. Secondly, many neurologic manifestations were omitted and thirdly, the importance of other serologic abnormalities such as low complement, and antibodies to beta 2 glycoprotein was not addressed in the ACR criteria. Of further concern was the fact that, despite SLE being an antibody mediated disease the ACR criteria allowed for patients without any immunologic abnormality to be diagnosed with SLE.

The Systemic Lupus International Collaborating Clinics (SLICC) group formulated an evidence-based approach to address the various concerns regarding the ACR criteria (42). The SLICC classification criteria improved upon the ACR criteria in a number of critical ways. The cutaneous criteria, including both acute and subacute cutaneous lupus were used, closer to the Gilliam and Sontheimer classification for cutaneous lupus erythematosus (43). Non-scarring alopecia was included as it performed well in statistical modelling. Photosensiti
vity, which is a common phenomenon in the general population, and overlaps greatly with the presence of photosensitive rashes, was not included in the SLICC criteria. As a minority of patients with SLE develop erosions, the criterion of ‘non-erosive’ arthritis was revised to describe synovitis, joint line tenderness and morning stiffness. To reflect the development of more specific serologic testing and an increasing recognition of the importance of complement activation and antiphospholipid antibodies in SLE, the immunologic components were expanded upon to include low complement, anti-beta 2 glycoprotein 1 and Coomb’s positivity. Recognising that this is an antibody mediated, clinical disease, the SLICC criteria stipulated a requirement that at least one immunologic abnormality be present (out of 4 required criteria) to meet these classification criteria for SLE. Addressing another limitation in the ACR criteria, the SLICC criteria also allowed those with biopsy confirmed lupus nephritis and ANA or anti dsDNA to be classified as SLE. To reflect changes in clinical practice, the spot urine protein to creatinine ratio was incorporated as a means of quantitatively evaluating proteinuria. The neurologic criteria were expanded but due to a lack of specificity all of the ACR neuropsychiatric definitions were not included (44).

At present, in clinical practice, both the 1997 revision and the SLICC criteria are in use and are valid tools. However, the SLICC criteria out-performs the revised ACR criteria in terms of sensitivity, but not specificity, with improvements in both face and content validity. The requirement for both serological abnormalities and clinical manifestations is a particular strength of the SLICC criteria which reflects an enhanced understanding of the pathogenesis of SLE.

SLE Prognosis

As recently as the mid 20th century, the mortality of SLE approached 50% (9) with significant improvements since then. However, despite advances in therapy, including corticosteroids, immunosuppressives, angiotensin converting enzyme inhibitors, antibiotics, earlier recognition of disease and identification of milder forms of disease with improved serological testing, the mortality associated with SLE remains considerable (1). In a large prospective SLE cohort the overall probability of survival at 5, 10, 15, and 20 years after diagnosis was 95%, 91%, 85%, and 78%, respectively (7). Deaths early in the disease course are frequently attributed to active disease and infection, whilst later mortality is attributable to damage, such as in end-stage renal disease, corticosteroid mediated injury, and cardiovascular disease (2, 3, 45-47). Factors associated with adverse outcomes include, poor adherence to therapy and attendance at clinic appointments (48, 49), male gender, low family income and the presence of haemolytic anaemia, renal disease, hypertension, antiphospholipid syndrome and low complement (7, 50-52).

Current Management Strategies.

Non-pharmacologic Interventions

Ultraviolet exposure associates with the development of SLE and can incite flares in disease activity (53). It is recommended that patients avoid ultraviolet exposure and use sunscreen blocking ultraviolet A and B wavelengths with a sun protection factor of at least 50. Maintenance of a healthy body mass index is crucial given the enhanced cardiovascular risks associated with SLE. In those who are obese or overweight with SLE, weight loss through healthy diet and exercise should be recommended. Exercise is a crucial tool in maintaining vascular, bone and muscular health and does not have a deleterious effect on disease activity (54). Patients with SLE should be encouraged to exercise and aim at a minimum to reach the recommendations for cardiovascular fitness as outlined by the American Heart Foundation (55, 56). Again, with particular focus on cardiovascular events as a major cause of mortality in SLE, patients should be strongly counselled against smoking. Smokers also have higher SLE disease activity (57), in addition to the innumerable other adverse health outcomes associated with smoking. Given the accelerated cardiovascular risk it is recommended that patients are screened for other cardiovascular risk factors with modification where possible.

In keeping with the guidelines, vaccination status should be evaluated at diagnosis (58, 59) and patients should ideally have their vaccines updated before commencing immunosuppression. The influenza (inactivated) vaccine should be administered on an annual basis and patients should also receive pneumococcal vaccinations at the recommended intervals. The general guidance on vaccinations in rheumatic diseases is that live vaccines should be avoided, notable exceptions to this rule appear to be the MMR and varicella vaccines, although in SLE there is little guidance on this and the risks and benefits need to be assessed individually. Certainly, patients on immunosuppression or corticosteroids, with daily dose equivalent to 20mg prednisone or more, might need to avoid live vaccines. The quadrivalent human papilloma virus (HPV) vaccine has good safety data in SLE and has been shown to be reasonably effective. It should be considered in those within the 11-26 age bracket (60). The use of glucocorticoids, or other immunosuppressive agents may contribute to a blunted antibody response in SLE.

Hydroxychloroquine

Hydroxychloroquine, originally an antimalarial, is crucial in the management of SLE (61-68). It appears to work via numerous mechanisms, (69-76) and mediates subtle immunomodulation without causing immunosuppression. In numerous diverse SLE populations hydroxychloroquine has been shown to offer a survival advantage (66, 77-79). It is an effective agent in the management of cutaneous disease (36) and is useful in arthritis (80). Hydroxychloroquine has been shown to have a bolstering effect on mycophenolate therapy in lupus nephritis (66). It has antithrombotic properties in those with anti-phospholipid antibodies (64, 81) and has been shown to improve pregnancy outcomes (82-85). For those with undifferentiated connective tissue disease, it is the only agent to date which has been shown to have some effect in hindering the progression to fulfilment of classification criteria for SLE (86). In pregnant patients with the Ro (SSa) antibody, hydroxychloroquine lessens the odds of neonatal congenital heart block (87, 88). Additional to these disease specific effects in SLE, hydroxychloroquine has been shown to improve lipid profiles (89, 90) and has some anti-diabetic effects (91, 92).

Hydroxychloroquine works on many molecular pathways (69-76). T cell responses have been shown to be modified and several cytokines are inhibited, including IL-1, Il-2, Il-6, IL-17, IL-22, interferon- and tumour necrosis factor- (69-73, 75). Hydroxychloroquine is a weak base, working in part by increasing the lysosomal pH in antigen presenting cells, which in turn interferes with phagocytosis and disrupts the presentation of self-antigens (74, 93). This therapy also decreases signalling of toll-like receptors (3,7,8,9) (94) leading to decreased activation of dendritic cells and reduced interferon production (75), in addition to other mechanisms (76).

The clinical trials and longitudinal studies evaluating hydroxychloroquine therapy in SLE have been summarised in a previous review (95). Hydroxychloroquine is well-tolerated with few side-effects. However, questions exist regarding hydroxychloroquine-related retinopathy, in light of new screening methods such as optical coherence tomography, which are thought to have increased sensitivity (96, 97), with significant discrepancies between visual field testing and optical coherence tomography. Current American Academy of Ophthalmology guidelines advise routine monitoring using the newer screening methods in an attempt to identify toxicity early (96). Other reported adverse effects, cardiac and neuromyoapthic, are very rare (93).

Controversy exists regarding the optimum dosing regimen for hydroxyc
hloroquine. Many ophthalmologists advocate a regimen based on ideal body weight, whilst rheumatologists advocate dosing based on actual body weight. Based on our work evaluating hydroxychloroquine blood levels, using ideal and actual body weight, we recommend using actual body weight (98). There are also controversies regarding whether the dose should be 5mg/kg with a cap at 400 mg per day, or 6.5mg/kg, again with a cap at 400 mg per day. We use 6.5mg/kg with a maximum daily dose of 400 mg per day. From a practical perspective, this means that patients under 62 kg or 136lbs should be dose reduced. For those over this weight, a daily dose of 400 mg is appropriate. Chloroquine is an alternative. However, the rate of ocular toxicity is thought to be higher with chloroquine. Quinacrine, also an antimalarial, can be added to hydroxychloroquine, in particular for cutaneous disease (99).

Vitamin D

The steroid hormone, 1,25-dihydroxyvitamin D (vitamin D) is increasingly being recognised for its role as an immune-modulator. Vitamin D, has two major forms (ergocalciferol, D2 and cholecalciferol, D3), and is mainly synthesized in the skin following ultraviolet exposure with less than 10% coming from dietary intake (100) . Vitamin D insufficiency and deficiency is common in SLE and has been reported in 37-75% (101-105) of patients. These low levels although incompletely understood are contributed to by decreased UV exposure, medications, corticosteroids, renal disease and the effect of pro-inflammatory cytokines (106). Photosensitivity, common in SLE, has been found to associate with very low levels (104) and lupus nephritis commonly associates with deficiency (odds ratio 13.3) (104). There are also ethnic variations to consider in the conversion to its active form (107).

In support of the role of vitamin D as an immunomodulator, it has been shown to block B-cell differentiation and proliferation and to decrease both the production of immunoglobulins (108, 109) and the expression of pro-inflammatory cytokines (110). Vitamin D decreases T-cell proliferation, shifting maturing cells toward Th2 and regulatory T-cell pathways and has been shown to suppress the differentiation of dendritic cells (crucial in the maintenance of self-tolerance)(111, 112). In SLE, low vitamin D associates with an interferon gene signature (via the inhibition of dendritic cell maturation), although supplementation did not appear to change the signature (111, 113).

There appears to be an inverse relationship between vitamin D levels and SLE disease activity (114-120). Recent studies of vitamin D supplementation are outlined in Table 4. For the most part, these studies demonstrate a modest effect on SLE disease activity with vitamin D supplementation. It is difficult to estimate the magnitude of this effect as these studies utilise many different dosing protocols. Vitamin D is widely accepted to be a safe medication and in the SLE studies there were no serious adverse events reported. Vitamin D therapy is safe with at least a modestly beneficial effect on disease activity. Although there are no specific recommendations in SLE regarding desirable vitamin D levels, in the general population, for individuals at risk of fracture, falls, autoimmunity or cardiovascular disorders, a level of at least 30-40 ng/ml is advised (121).

Dehydroeipandrosterone (DHEA)

Low levels of dehydroeipandrosterone, DHEA, the weak androgenic steroid, have been associated with many autoimmune diseases, including SLE, with evidence that it effects numerous cytokine and immunologic pathways (122-126). Prasterone, which is synthetic dehydroepiandrosterone, has been evaluated in numerous studies in SLE from the perspective both effect disease activity and bone metabolism (127-136). For the most part, clinical trials demonstrated a mild improvement in SLE disease activity. There is some anabolic effect on bone (in those who are postmenopausal), but not of the magnitude which would justify the therapy on this basis alone. Safety data were reassuring. It is worth noting that all of these studies were in females with no evidence to suggest that male patients would benefit from prasterone. In those who are post-menopausal concerns exist that an exogenous source of oestrogen could increase the risk of hormone sensitive malignancies. Prasterone, is prescribed at a dose of 200mg per day and frequently needs to be compounded. As a result of some androgenic properties therapy can associate with mild virilisation.

Corticosteroids

Developed by Hench et al. (137), corticosteroids exert potent anti-inflammatory and immunosuppressive effects by non-selectively reducing the expression of cytokines (IL-2, IL-6, TNF- and prostaglandins) and adhesion molecules, which in turn inhibit leukocyte, fibroblast and endothelial cell function. Although at times unavoidable and capable of powerful immunosuppression, corticosteroid therapy, in particular when chronic, produces a wide spectrum of adverse effects.

Patients receiving prednisone (the most commonly prescribed corticosteroid) at doses of ≥ 7.5 mg/day are more likely to develop organ damage, even after adjustment for disease activity and other variables. Thamer et al demonstrated a risk of developing organ damage which was increased by 50% in those exposed to an average daily prednisone dose of >6–12 mg/day when compared with those with low dose or no exposure (138). It has been estimated that an increase in mean prednisone dose of as little as 1 mg/day associates with a 3.8% increased risk of cataracts and 4.2% increase in osteoporotic fractures (139). Patients taking 20mg prednisone or more, have been shown to have a 5-fold increase in cardiovascular events (140). With each increase of 10 mg per day of prednisone, there is an 11-fold increase in the risk of serious infection (141). There is a dose- and time-dependent relationship between corticosteroid dosing and serum glucose (142). Hypertension, dyslipidemia, increased adiposity and reduced muscle mass have all also been associated with chronic corticosteroid use in addition to the adverse effect on bone metabolism and an increased risk of avascular necrosis.

Mycophenolate Mofetil

Mycophenolate mofetil which is a pro-drug of mycophenolic acid, inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme in the synthesis of guanosine nucleotides. Mycophenolate is the first line therapy in the management of lupus nephritis. It has similar efficacy to cyclophosphamide without the same toxicity profile (143) and appears to associate with a decreased risk of long-term flare when compared to azathioprine for maintenance. The Aspreva Lupus Management Study (ALMS) established that mycophenolate is equivalent to intravenous cyclophosphamide as induction therapy in lupus nephritis (144, 145). A post-hoc analysis of the induction phase of ALMS demonstrated improvements in non-renal disease, equivalent to that which was seen with cyclophosphamide (146). Mycophenolate has been shown to be superior to azathioprine for maintenance, although a European trial concluded that mycophenolate and azathioprine were equivalent in the ability to prevent renal flare after induction treatment with cyclophosphamide (although it is worth noting that there were numerically fewer flares in the mycophenolate group in this study)(147). Mycophenolate is a slow therapy, and response rates are only in the region of 50% at one year. At 24 weeks, Ginzler et al. demonstrated complete remission in only 16/56 (26.7%) patients (143). The pooled complete response rate in clinical trials was 36% with mycophenolate; 55% achieved partial response and subsequent relapses were described in 27% (148). These data indicate that many patients with lupus nephritis do not achieve remission in response to line therapy. A further limitation is that mycophenolate is teratogenic. With maternal exposure, a high number of foetal losses and a specific pattern of birth defects (cleft lip, external auditory canal atresia, trachea-oesophageal atresia and other anomalies) have been reporte
d (149).

Tacrolimus, a calcineurin inhibitor, has recently been shown to be additive to MMF as part of a multi-targeted approach (150-152), and in other studies, a viable alternative (153, 154). Tacrolimus is a therapeutic option in pregnancy (155).

Methotrexate

Methotrexate is a folate analogue which inhibits purine and pyrimidine synthesis, leading to adenosine release with anti-inflammatory and immunosuppressive effects. Although widely prescribed, methotrexate has been formally evaluated in SLE only in a small number of prospective case series (156-163) and in two randomised controlled trials (164, 165). The open label series demonstrated that for the most part, the drug was well tolerated, appeared to have a steroid sparing effect and to modestly decrease overall disease activity with particular improvements in cutaneous and articular disease. Carneiro et al. found that methotrexate (15-20 mg/week) was effective in cutaneous and articular disease and facilitated a reduction in prednisone dose (164). Fortin et al. also demonstrated a steroid sparing effect, with decreased disease activity. Patients in the methotrexate group reduced their average prednisone dose by 22% with decreased disease activity (revised systemic lupus activity measure (SLAM-R) declined by 1.41 points) although there was no significant difference demonstrated when the SLE disease activity index (SLEDAI) was used. For articular disease in particular, Rahman et al. demonstrated a 60% improvement in joint count with a SLEDAI reduction of 0.76 in the methotrexate group, compared to an increase of 2.05 amongst controls (163). For cutaneous disease refractory to anti-malarials and topical agents, methotrexate has been shown to be effective and is widely used (166-171).

Azathioprine

Azathioprine, also commonly prescribed in SLE, has largely been superseded by mycophenolate for the management of nephritis and has been shown to associate with a higher risk of renal flare. However, azathioprine becomes very useful in the management of nephritis in pregnancy, as the foetal liver cannot metabolise azathioprine to its active metabolites (172).

Biologic Therapies

B-Cell Therapies

Aberrant B-cell pathways are common in SLE with abnormal proliferation and maturation, prolonged life-span of auto-reactive clones and the production of antibodies targeting components of cellular nuclei (173). B-cells are involved in T-cell antigen presentation and cytokine release (interferon , IL-6 and IL-10, B-cell activating factor (BAFF), TNF α and a proliferation inducing ligand (APRIL)(173)) in addition to the formation of autoantibodies. As a result of these pathways, B-cell therapies have long been considered attractive agents. Many B-cell targets have been considered in SLE, outlined in Figure 1. Therapies have been developed which target CD-20 (ocrelizumab (174), rituximab (175)), CD-22 (epratuzumab (176, 177), BAFF (belimumab (178), blisibimod (179), tabalumab (180), briobacept and atacicept (181)). These agents, with the exception of belimumab, have been unsuccessful in clinical trials.

Belimumab, a fully humanised monoclonal antibody, which binds to soluble BAFF resulting in a decrease in the number of periph¬eral naive, transitional and activated B cells, is unique, as a B-cell therapy, in showing efficacy in randomised controlled studies (178, 182). It has been evaluated in two large, phase III, multi-centre, randomised, placebo-controlled trials (178, 182). The first of which, Navarra et al. demonstrated higher response rates with therapy at both 1 mg/kg and 10 mg/kg. More participants receiving belimumab had a reduction in SLEDAI of 4 points or more. Improved outcomes were observed with belimumab for the physician global assessment and using the British Isles lupus assessment group tool (BILAG) with belimumab therapy. Following this, Furie et al. (178) demonstrated similar, but less impressive results. Belimumab has been shown in subsequent analyses to be of most benefit in those with high disease activity despite usual therapy, serological abnormalities and steroid dependance (183). It may also be effective in lupus nephritis (184) but a phase 4 clinical trial has not yet been reported. Evaluating the 267 patients with lupus nephritis in the phase III trials there was a suggestion that belimumab in combination with mycophenolate mofetil may improve outcomes in renal disease (184).

Rituximab

Rituximab the chimeric monoclonal antibody targets CD 20 on B cells. This results in the depletion of mature B-cells and B cell precursors. Rituximab has not been shown to be effective in SLE clinical trials (175, 185). ‘Lupus Nephritis Assessment with Rituximab’ (LUNAR) evaluated rituximab (in addition to prednisone and mycophenolate mofetil) in 144 patients with active proliferative lupus nephritis (185). The primary and secondary effi¬cacy end points were not found to be significantly different between the placebo and the drug group in this phase III randomised controlled trial, although rituximab did associate with a numerically higher (not significantly significant) response rate (185). The ‘Exploratory Phase II/III SLE Evaluation of Rituximab‘ (EXPLORER) study evaluated patients with moderate to severely active non-renal SLE and noted no difference between those who received rituximab and the placebo group (175). Further, there was no reduction in flares demonstrated with rituximab therapy (186). Tew et al. further assessed the outcomes from the negative EXPLORER study and demonstrated certain abnormalities which did respond to therapy, including thrombocytopenia and hypocomplementenia, suggesting that B cell depletion may be beneficial to some patients with SLE (187). The rituximab trials in SLE have been criticised as being flawed in design (particularly for the high prednisone doses used) and many rheumatologists and nephrologists remain convinced that B cell depletion is important in nephritis in particular. A prospective cohort study evaluating a steroid-free regimen incorporating rituximab and mycophenolate has been reported by Condon et al. and has yielded promising results (188) with a formal trial underway. For steroid refractory haemolytic anaemia in SLE rituximab is commonly part of the therapeutic armamentarium (189).

The Future: New Drugs and Mechanisms of Interest.

The identification of interferonopathies, in addition to the longstanding recognition of an interferon gene signature in many SLE patients led to an increased interest in interferon pathways as therapeutic targets in SLE (190). Sifalimumab, a monoclonal antibody targeting interferon , was evaluated in a phase I randomised, controlled, dose-escalation study and yielded no significant difference in disease activity (191) although subsequent phase IIb study yielded more promising results (192). Rontalizumab (a humanised IgG1 anti-interferon  monoclonal antibody) failed to meet its primary or secondary end points (193). However, promising results were presented for a phase IIb randomised placebo trial of anifrolumab, which is an anti-interferon  receptor monoclonal antibody (194). Three-hundred and five patients with moderate to severe SLE were randomised to either 300mg, 1000mg or monthly placebo in addition to standard therapy. At six months 34% (up to 54.6% at 12 months) of the intervention group (at 300mg) met the primary end point compared to 17% in the placebo group, making this an exciting agent in development.

Interest is continuing into B cell therapies. SBI-087 is a Small Modular Immunopharmaceutical Protein™(SMIP™) drug that binds to CD20 and has been shown to deplete B cells in both SLE and RA (195). Another B cell agent of interest, Obinutuzumab has been tested in haematological diseases and is being trialled in lupus nephritis. Rigerimod, also known as P140 peptide, is a 21-mer linear peptide which comes from the small nuclear ribonucleoprotein U1-70K and was tested in SLE in an open-label, dose-escalation phase II study(196). A subsequent phase IIb, double-blind, randomised, pl
acebo-controlled clinical trial was undertaken in 204 SLE patients (197). In the intention to treat analysis, 53.1% who received 200 μg (p=0.048) were responders compared with 45.1% in those treated every 4 weeks (p=0.18) and 36.2% in the placebo group. P140 peptide is currently moving into a phase III clinical trial. HCDR1, another peptide-based therapy, was tested in a randomised, double-blind, placebo-controlled phase II clinical trial (340 patients enrolled) (PRELUDE) and failed to meet the primary endpoint (198).

T cell therapies are also of interest in SLE, although, to date, the studies evaluating these agents have been disappointing. Abatacept blocks CD80/CD86, preventing T-cell co-stimulation via the CD28 pathway. ACCESS included 134 patients with lupus nephritis and compared intravenous abatacept with cyclophosphamide versus cyclophosphamide only (199). The addition of abatacept to cyclophosphamide followed by azathioprine did not improve the outcome of lupus nephritis at 24 or 52 weeks. A further study evaluating abatacept (200), which also failed to meet its primary end point, demonstrated that the treatment associated with significant improvements in serological abnormalities and that amongst patients with nephrotic-range proteinuria, treatment resulted in a 30% greater reduction proteinuria.

Cytokine blocking agents are also of interest in SLE. Tocilizumab, commonly used in rheumatoid arthritis, is a humanised monoclonal antibody which inhibits IL-6 signalling. Tocilizumab has been evaluated in SLE, in a phase I study, and therapy was limited by neutropenia (201). Sirukumab a human, anti-soluble IL-6, monoclonal antibody was also evaluated in lupus nephritis and not found to be additive to standard therapy(202). PF-04236921, a fully human immunoglobulin G2 monoclonal antibody that binds and neutralises IL-6 and was evaluated in a phase II trial and did not meet its endpoint(203). However, subgroup analyses did demonstrate a response in those with high disease activity in particular.

Other agents of interest include the Janus Kinase inhibitors (tofacitnib, baricitinib). Tofacitinib is an oral Janus Kinase inhibitor that blocks signalling of cytokines implicated in the pathogenesis of SLE. To date, a response to therapy has been demonstrated in murine models (204), human studies are underway. Also of interest, the proteasome inhibitior, bortezomib which is widely used to treat multiple myeloma (targets plasma cells and blocks anti-apoptotic nuclear factor kappa B (NF-κB) activation, leading to the accumulation of proteins and subsequent apoptosis). In a small number of patients with refractory SLE, this agent was shown to decrease disease activity, in particular serological abnormalities, with a particular reduction in type I interferon activity (205).

Conclusion

SLE continues, despite therapeutic advancements, to associate with poor outcomes. With renal involvement, a large proportion of patients fail to achieve complete remission and a significant proportion go on to develop end stage kidney disease with a dramatic reduction in life expectancy (206, 207) (5). Although there are innumerable lessons to be learned from current management strategies, there is a major need for further agents. It is likely that given the diverse immunologic abnormalities at play in SLE, that future therapies need to be personalised to target specific pathways. Hopes for the future include further B cell agents, T cell agents, anti-cytokine agents and Janus Kinase inhibitors.

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