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REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1208-1213

Biologics: a target therapy of lupus nephritis: a systematic review


1 Internal Medicine Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Internal Medicine Department, Ministry of Health, Menoufia, Egypt

Date of Submission17-Feb-2019
Date of Decision03-Apr-2019
Date of Acceptance08-Apr-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Alaa N AbdAlla
Damanhour City, Al-Behera Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_42_19

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  Abstract 

Objective
To review the use of biological management of lupus nephritis (LN).
Data sources
A systematic review of Medline (PubMed, Medscape, Science Direct, and EMF-Portal) and Internet was conducted on all articles published from 2006 to 2017.
Study selection
English-language reports on biological management of LN were searched. The initial search presented 150 articles, where 30 satisfied the inclusion criteria.
Data extraction
Articles not reporting on biological management of LN in the title or abstract were not included. A total of five independent investigators extracted data on methods.
Data synthesis
Comparisons were made by structured review, with the results tabulated. Overall, seven studies were about traditional therapy, 14 about biological therapy, and seven about evidence-based treatment for LN.
Findings
The various biological agents consisted of anti-B-cell therapies targeting either B-cell surface antigens or B-cell survival factors, anticytokines antibodies, and novel drugs intervening in B-T cell costimulation. Use of leflunomide in LN was found to be equally efficacious and safe at least in short term and in refractory LN. Immunosuppressive treatment should be guided by renal biopsy, and treatment aimed at complete renal response.
Conclusion
Biologicals, especially rituximab, although still off the shelf as an induction agent, can be used for resistant LN. Overall, treatment has to be individualized, multidisciplinary, and holistic to prevent loss-of-organ function.

Keywords: biologics therapy, evidence, lupus nephritis, traditional therapy


How to cite this article:
Shoeib SA, Elshebini EM, AbdAlla AN. Biologics: a target therapy of lupus nephritis: a systematic review. Menoufia Med J 2019;32:1208-13

How to cite this URL:
Shoeib SA, Elshebini EM, AbdAlla AN. Biologics: a target therapy of lupus nephritis: a systematic review. Menoufia Med J [serial online] 2019 [cited 2020 Feb 24];32:1208-13. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1208/274277




  Introduction Top


Lupus nephritis (LN) is the most common severe manifestation of systemic lupus erythematosus (SLE) with increased risk of death and end-stage renal disease [1]. Approximately 50–80% of patients with lupus erythematosus experience LN. Evaluating renal function in patients with SLE to detect any renal involvement early is important because early detection and treatment can significantly improve renal outcome. Renal biopsy should be considered in any patient with SLE who has clinical or laboratory evidence of active nephritis, especially upon the first episode of nephritis [2]. The principal goal of therapy in LN is to normalize renal function or, at least, prevent the progressive loss of renal function. Treatment choice is different according to the pathologic lesion. It is important to treat extrarenal manifestations and other variables that may affect the kidneys [3]. A biopharmaceutical, biologic medical product is any medicinal product manufactured in and extracted from biological sources. Biologics comprise a heterogeneous group of pharmaceutical products, including blood or blood components, allergenic, vaccines, cell or gene therapy products, tissues, recombinant therapeutic protein, and living cells used in cell therapy. The official Food and Drug Administration definition of 'biological products' or 'biologics' as 'any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man' [4]. Biologics should be tested in LN owing to the adverse effects of current immunosuppressive regimens. Most of the damage observed in SLE is related to the use of glucocorticoids. Biologic therapy might be of interest to reduce the rate of renal flares, which are quite common despite maintenance immunosuppression with low-dose glucocorticoids, azathioprine, or mycophenolate mofetil (MMF), and to avoid the deleterious effect on long-term renal outcome, mainly in case of nephritic flares [2]. Therefore, the aim of this work was to review the use of biologics in the management of LN.


  Materials and Methods Top


Data sources

A systematic review on the recent advances in the use of biologics in the management of lupus nephritis using Medline (PubMed, Medscape, Science Direct. EMF-Portal) and Internet was conducted on all articles published from 2006 to 2017. During research, focus was on traditional therapy of lupus nephritis/Biologics Target Therapy of Lupus Nephritis/Evidence-based treatment for lupus nephritis. Additional records were identified by reference lists in retrieved articles. The search was established in the electronic databases from 2006 to 2017.

Study selection

Eligible articles were published in peer-reviewed journals and written in English. Articles not reporting on the recent advances in the use of biologics in the management of LN in the title or abstract were not included. Full-text articles were screened, and the final inclusion decisions were made according to the following criteria: original studies, systematic reviews or meta-analyses, primary or first-line treatment, treatment success, complications, and adverse effects described.

Data extraction

Articles not reporting on the use of biologics in the management of LN in the title or abstract were not included. A total of five independent investigators extracted data on methods, health outcomes, and traditional protocol. Surveys about symptoms and health without exposure assessment, report without peer-review, not within national research programme, letters/comments/editorials/news, and studies not focused on exposure from the management of LN were excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid [5].

US Preventive Services Task Force [5] classification is as follows:

  1. Level I: Evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: Evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might be regarded as this type of evidence
  5. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Study quality assessment

Quality of all the studies was assessed. Important factors included study design, ethical approval, calculation of evidence power, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was done with the results tabulated. A total of seven studies were about the traditional therapy of LN, 14 about biologics target therapy of LN, and seven about evidence-based treatment for lupus nephritis.


  Results Top


Study selection and characteristics

A systematic review on the recent advances in the use of biologics in the management of lupus nephritis using Medline (PubMed, Medscape, Science Direct. EMF-Portal) and Internet was conducted on all articles published from 2006 to 2017. Articles not reporting on traditional therapy of LN, biologics target therapy of lupus nephritis, and evidence-based treatment for LN in the title or abstract were excluded. A total of five independent investigators extracted data on methods, health outcomes, and traditional protocol. Potentially relevant publications were identified. Of them, nine articles were excluded as they did not fulfill our inclusion criteria, and 30 studies were reviewed as they met the inclusion criteria. Regarding the two studies, which were cohort studies (1, 3), that come in the second level regarding the pyramid of EBM, we found that treatment choice is different according to the pathologic lesion. It is important to treat extrarenal manifestations and other variables that may affect the kidneys. In addition, three randomized control studies (2, 4, 7) that come in level I or (level A) reported that prednisone is a corticosteroid commonly used to treat inflammatory manifestations of SLE. Methylprednisolone is a corticosteroid used in much the same manner as prednisone. In addition, two prospective studies (8 and 9) come in level II-2 or (level B), and they revealed that patients with active LN should avoid pregnancy, because it may worsen their renal disease and because certain medications used in the treatment may be teratogenic [Table 1]. Additionally, two cohort studies (10 and 11) that come in the second level regarding the pyramid of EBM found various biological agents consisting of anti-B-cell therapies and anticytokines antibodies and novel drugs intervening in B-T cell costimulation. In addition, six randomized control studies (12, 13, 14, 15, 16, and 17) that come in level I or (level A) reported that ocrelizumab, epratuzumab, and belimumab were used in the treatment if SLE. Other drugs investigated in SLE and LN are mizoribine, mainly in Japanese population, where it did not offer any benefit when compared with steroid alone. In addition, six prospective studies (18, 19, 20, 21, 22, and 23) that come in level II-2 or (level B) revealed that plasmapheresis acts by rapidly removing pathogenic antibodies and has been used as add-on therapy to baseline immunosuppression of mainly cyclophosphamide (CYC) and steroids, to improve outcome in LN [Table 2]. However, three cohort studies (24, 25, and 26) that come in the second level regarding the pyramid of EBM reported the guidelines developed by organizations such as the Kidney Disease. Moreover, two prospective studies (27 and 28) that come in level II-2 or (level B) indicated that the Kidney Disease Improving Global Outcome (KDIGO) guidelines advise dose target for MMF of 3 g/day, whereas American College of Rheumatology (ACR) recommends 3 g/day for non-Asians and 2 g/day for Asians. However, two randomized control studies (29 and 30) that come in level I or (level A) reported that ACR recommends the use of steroids plus MMF in class V LN with nephritic range proteinuria, whereas DIGO recommends to choose any of CYC/MMF/AZA/CNI along with steroids in class V LN [Table 3].
Table 1: Traditional therapy of lupus nephritis

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Table 2: Biologics target therapy of lupus nephritis

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Table 3: Evidence-based treatment for lupus nephritis

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  Discussion Top


The principal goal of therapy in LN is to normalize renal function or, at least, to prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion. It is important to treat extrarenal manifestations and other variables that may affect the kidneys [3]. Corticosteroid therapy should be instituted if the patient has clinically significant renal disease. Prednisone is a corticosteroid commonly used to treat inflammatory manifestations of SLE. Methylprednisolone is a corticosteroid used in much the same manner as prednisone, but it has less mineralocorticoid effects and should be considered in patients with edema [4]. On the basis of beneficial effects in other nephropathies, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have been routinely used to treat proteinuria in LN. The diet should be altered according to the presence of hypertension, hyperlipidemia, and renal insufficiency [6]. Drugs that affect renal function, including NSAIDs, should be avoided. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal disease [5],[7]. Regarding biologics target therapy of lupus nephritis, in the quest of using targeted therapy in SLE and LN, various biological agents have been investigated mainly in uncontrolled studies with the purpose of reducing toxicity and improving efficacy of non-specific immunosuppression in the current use [8]. The anti-B-cell-targeted therapies that have been investigated are rituximab (RTX) [9]. Other targeted therapies investigated included abatacept and atacicept [10]. RTX is a chimeric anti-CD20 MAB composed of the murine variable regions against CD20 and the human IgG Fc constant region. Weidenbusch et al. [11] found that although RTX depleted peripheral CD19 B-cells, anti-dsDNA titers, and C3/C4 levels, it did not transform into superior clinical outcomes. Zheng et al. [12] found that RTX was able to induce complete or partial remission in 74% of the patients who were refractory to current first-line drugs in severe LN. Other drugs investigated in SLE and LN are as follows: mizoribine mainly in Japanese population where it did not offer any benefit compared with steroid alone and used with tacrolimus [13],[14]. Use of leflunomide in LN was found to be equally efficacious and safe as CYC at least in short term and also in refractory LN [15] However, at present, it does not fare better than current first-line immunosuppression in LN but has a role to play in refractory/resistant disease [17]. Angiotensin inhibitors/blockers are effective in reducing proteinuria in diabetic nephropathy and other proteinuric glomerular diseases [18]. Stem cells have also been investigated as possible treatment for SLE, especially in severe form of the disease and LN in both mice and humans [19],[20]. The exact mode of benefit of stem cells is not known, but it may be owing to differentiation of these cells into renal cells or owing to their anti-inflammatory, immunomodulatory, antifibrotic, antiapoptotic, antioxidative, regenerative, and paracrine effects [21]. Guidelines developed by organizations such as KDIGO, ACR, and the European League against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) are important and handy to use [22]. Overall, immunosuppressive treatment should be guided by renal biopsy and treatment aimed at complete renal response. All these major guidelines advise immunosuppression with either CYC or MMF combined with steroids in class III/IV LN [23]. ACR guidelines advocate to prefer MMF in class III/IV LN, especially in African Americans and Hispanics [24]. The KDIGO and EULAR guidelines advise dose target for MMF of 3 g/day, whereas ACR recommends 3 g/day for non-Asians and 2 g/day for Asians [25]. Euro lupus regimen is recommended as alternate to MMF by EULAR/ERA-EDTA in severe LN, whereas ACR recommends Euro lupus regimen in patients of European descent [26],[27].


  Conclusion Top


Owing to the current treatment, LN has evolved from incurable to a disease that can be controlled with trade-off between improved outcomes and therapy-related adverse events. Biologicals, especially RTX, although still off the shelf as an induction agent, can be used for resistant LN. Overall, treatment has to be individualized, multidisciplinary, and holistic to prevent loss-of-organ function.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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