Lupus Drug Research Articles

Drug induced lupus associated with Trastuzumab emtansine in a patient with metastatic breast cancer

Introduction Ado-trastuzumab emtansine (T-DM1) is employed in the treatment of patients with HER2-positive breast cancer. The most common side effects are fatigue, diarrhoea, anaemia, transaminase elevation and drug-induced thrombocytopenia. This report describes a patient with metastatic breast cancer who developed drug-induced lupus due to T-DM1. Case Report A 54-year-old woman was diagnosed with breast cancer in March 2018. She underwent modified radical mastectomy and axillary lymph node dissection (pT2N1aM0). Following supraclavicular lymph node metastasis in May 2018, she received 8 cycles of docetaxel, trastuzumab, and pertuzumab. In December 2020, the patient presented with axillary and intra-abdominal lymph node metastases, along with bone metastases observed on PET/CT scan. Treatment with T-DM1 and zoledronic acid was initiated. After 18 months on T-DM1, she developed drug-induced lupus. Her symptoms resolved with hydroxychloroquine treatment and discontinuation of T-DM1. Discussion Drug-induced lupus is a clinical syndrome that shares similar features with systemic lupus erythematosus (SLE). The majority of patients present with symptoms such as arthralgia and myalgia. Hydralazine and procainamide are high-risk drugs for drug-induced lupus. Symptoms usually develop after months or years of use, but may also develop suddenly. Our patient also received TDM-1 treatment for 18 months. We present a case of TDM-1-associated drug-induced lupus in a patient with metastatic breast cancer. This is the first case of TDM-1-related drug-induced lupus reported in the literature.

Biomarkers Associated with Drugs for the Treatment of Lupus Nephritis.

The constant updating of lupus drug treatment guidelines has led to a question. How can the efficacy of treatment be more effectively monitored? Systemic lupus erythematosus (SLE) is a complex autoimmune disease that often presents clinically with multi-organ involvement, and approximately 30% of patients with SLE develop lupus nephritis (LN). Therefore, it is important to better track disease progression and drug efficacy. Now, kidney biopsy is still the gold standard for diagnosing and guiding the treatment of LN, but it is invasive and expensive. If simple, non-invasive and effective biomarkers can be found, drug intervention and prognosis can be better monitored and targeted. In this review, we focus on LN and explore biomarkers related to LN therapeutics, providing clinicians with more possibilities to track the therapeutic effect of drugs, improve treatment options and assess patient outcomes.

Люпус-нефрит: сучасна парадигма лікування

Вовчаковий нефрит є найпоширенішим та життєзагрозливим проявом системного червоного вовчака і продовжує зумовлювати високий відсоток термінальної ниркової недостатності. У даному огляді описуються сучасне лікування вовчакового нефриту, а також нові терапевтичні стратегії. Діагностика ураження нирок при системному червоному вовчаку (люпус-нефрит), згідно з рекомендаціями ACR, базується на таких критеріях: клінічні та лабораторні прояви у вигляді протеїнурії > 0,5 г на добу (або більше 3 «+» при визначенні тест-смужкою) і/або наявність клітинних скупчень, включаючи скупчення еритроцитів і циліндрів (гемоглобінових, зернистих, тубулярних або змішаних). Додатковим критерієм є результати гістологічного дослідження біоптату нирки з підтвердженням наявності характерного для люпус-нефриту імунокомплексного ураження нирок. Тактика ведення пацієнтів із вовчаковим нефритом складається з двох послідовних фаз: початкової (індукційної) і підтримуючої, коли використовуються поєднання глюкокортикоїдів і імуносупресорів. Під час індукційної фази проводиться інтенсивне лікування глюкокортикоїдами в комбінації з іншими імунодепресантами для швидкого пригнічення імунокомплексного запалення нирок і припинення розвитку їх пошкодження. Метою даного підходу і головним завданням індукційної терапії є відновлення ниркової функції і індукція ремісії шляхом контролю імунологічної активності процесу. Підтримуюча терапія застосовується для закріплення ремісії і запобігання загостренням шляхом використання препаратів або режимів лікування з меншим ризиком ускладнень. Незважаючи на невтішні результати декількох недавніх досліджень, нові методи лікування, спрямовані на різні імунологічні шляхи, активно вивчаються при вовчаковому нефриті. Найбільш перспективним напрямком є терапія, спрямована на В-клітини. Поглиблення розуміння патогенезу вовчакового нефриту, розробка нових методів лікування та оптимізація дизайну клінічних випробувань забезпечать успішний розвиток і впровадження нових ліків при вовчаку.

Biomimetic properties and estimated in vivo distribution of chloroquine and hydroxy-chloroquine enantiomers.

Chloroquine and hydroxy-chloroquine already established as anti-malarial and lupus drugs have recently gained renewed attention in the fight against the Covid-19 pandemic. Bio-mimetic HPLC methods have been used to measure the protein and phospholipid binding of the racemic mixtures of the drugs. The tissue binding and volume of distribution of the enantiomers have been estimated. The enantiomers can be separated using Chiralpak AGP HPLC columns. From the α-1-acid-glycoprotein (AGP) binding, the lung tissue binding can be estimated for the enantiomers. The drugs have a large volume of distribution, showed strong and stereoselective glycoprotein binding, medium-strong phospholipid-binding indicating only moderate phospholipidotic potential, hERG inhibition and promiscuous binding. The drug efficiency of the compounds was estimated to be greater than 2 % which indicates a high level of free biophase concentration relative to dose. The biomimetic properties of the compounds support the well-known tolerability of the drugs.

Establishing Consensus Understanding of the Barriers to Drug Development in Lupus

Due to the extreme heterogeneity of lupus and the lack of consensus among stakeholders, pharmaceutical and biotechnology companies have had limited success in developing treatments for lupus. For this reason, the Lupus Foundation of America (LFA), researchers at the Center for the Study of Drug Development at Tufts University School of Medicine (Tufts CSDD) and an advisory committee of 13 international lupus experts collaborated to launch the Addressing Lupus Pillars for Health Advancement (ALPHA) project. To inform the ALPHA project, 17 in-depth interviews among lupus experts and a global survey among lupus drug development and clinical care professionals was conducted to identify, characterize, and prioritize fundamental barriers and validate findings. The global survey received 127 responses from experts across 20 countries. Results of the in-depth interviews and the survey findings were consistent. Top barriers to developing new medical treatments for lupus included the lack of a clear definition of the disease with respondents identifying 30 autoimmune conditions that may be lupus-related; lack of predictive biomarkers; flaws in clinical trial designs; and a lack of reliable outcome measures. The study findings encourage drug development professionals to validate disease-specific measures and to identify if specific symptoms are caused by lupus. This original research also provides a methodology that can be applied to highly heterogenous diseases where low consensus on diagnosis and treatment exists among drug development and health professionals.

Immunosuppressive Therapy of Pediatric Lupus Nephritis

Lupus nephritis is a disease caused by severe complications of Systemic Lupus Erythematosus which attacks the kidneys. Therapy that is usually given to lupus nephritis patients is immunosuppressants. To determine the pattern of immunosuppressive therapy in pediatric lupus nephritis, the effectiveness and drug interactions that can be generated from these therapies. This study was an observational study with a retrospective method by observing patients’ medical record. This study populations were all pediatric patients ≤18 years old who were diagnosed with late onset of lupus nephritis, being hospitalized at Surabaya Hospital and had an immunosuppressive therapy history. There were 30 patients who met the inclusion criteria in this study. The sample collecting used a purposive sampling technique. The research instrument in this study was the medical record of department of pediatric in hospital of east Indonesia, Namely Dr. Soetomo. From the medical record data, we obtained information regarding the pattern of immunosuppressants administration including dosage, route, frequency of therapy, drug side effects, and drug interactions of immunosuppressive therapy. All patients received Methyl Prednisolone (MP) pulse IV, oral prednisone and Cyclophosphamide (CPA) pulse IV, oral mycophenolatmophetil (MMF), and chloroquine. The individual dosage of treatment was determined according to patients’ individual conditions. Side effects of corticosteroid use were digestive tract disorders in 20% of patients, hyperglycemia in 10% of patients, hypertension in 67% of patients, and cushingsyndrome in 27% of patients. The side effects of using CPA were leukopenia in 7% of patients, Hepatotoxic in 3% of patients, and cystitishaemorrhage in 47% of patients. Side effects of using MMF were digestive tract disorders in 10% patients and leukopenia in 17% of patients. Drug interactions that found were prednisone-furosemide interactions in 60% of patients, prednisone-metformin in 10% of patients, and cyclophosphamide-allupurinol in 50% of patients. Dosage, route, and frequency of therapy for LN patients in Dr. Soetomo hospital was in accordance with the recommendations of the Clinical Practice Guide which was used as a reference in Dr. Soetomo hospital and several literatures. However, there were some patients with special conditions that requireda dosage adjustment of medication. In addition, it was necessary to monitor patients periodically for the possibility of side effects and drug interactions of immunosuppressive therapy.

Drugs for Lupus While Breastfeeding

Drugs for Lupus While Breastfeeding

Minireview: Prospect of Doxycycline in Systemic Lupus Erythematosus Treatment

Doxycycline has non-antibiotic effects which are necessary for lupus treatment, such as immunosuppressive, anti-inflammatory, and anti-depressive effects. This widely used drug is a promising one to be developed as lupus drug since doxycycline has no data of its microbial resistance and it is safe for maternity. The other benefit is that doxycycline has lower side effects than the current drugs for lupus treatment. It gives excellent chances for women with lupus to be pregnant and have healthy babies. This article contains the compilation data of doxycycline target sites beyond its beneficial activities for lupus and also its limitations. Finally, this data will be a background for doxycycline in lupus drug development.

A New Driver for Lupus Pathogenesis is conserved in Humans and Mice.

Lupus is experienced as an “aggressive and expansive” disease affecting patients’ activities of daily living, sense of self, and social functioning [1]. Currently there is no cure. Despite substantial efforts, the lupus drug development field has witnessed only one FDA-approved therapy in the last 50 years. There is an urgent need to better our understanding of the pathogenic mechanisms for lupus, and to develop novel therapeutic strategies for both cutaneous and systemic lupus erythematosus.

Updates in Lupus Genetics.

Our understanding on genetic basis of SLE has been advanced through genome-wide association studies. We review recent progress in lupus genetics with a focus on SLE-associated loci that have been functionally characterized, and discuss the potential for clinical translation of genetics data. Over 100 loci have been confirmed to show robust association with SLE and many share with other immune-mediated diseases. Although causative variants captured at these established loci are limited, they guide biological studies of gene targets for functional characterization which highlight the importance of aberrant recognition of self-nucleic acid, type I interferon overproduction, and defective immune cell signaling underlying the pathogenesis of SLE. Increasing examples illustrate a predictive value of genetic findings in susceptibility/prognosis prediction, clinical classification, and pharmacological implication. Genetic findings provide a foundation for better understanding of disease pathogenic mechanisms and opportunities for target selection in lupus drug development.

The Immunosuppressant Effect Comparation Between Ethyl Acetate and n-Butanol Fractions of Kalanchoe Pinnata (Lmk) Pers In 2,6,10,14 Tetramethylpentadecane-Treated Mice

Immunosuppressant drugs are the main treatment of lupus patient. The ACR and SLICC treatment guidelines are able to increase the quality of life, but the outcome is not satisfying since the off-label therapy of corticosteroids and cytotoxic drugs give a lot of side effects. Many breakthrough efforts still develop in order to find the safe and effective drugs for lupus, such as finding immunosuppressant drugs from natural resources. One of the potential resources is Kalanchoe pinnata (Lmk) Pers, which have immunosuppressant, anti-inflammatory, antinociceptive, and antioxidant effects. Thus, in the previous study, we found the effect of the aqueous extract of Kalanchoe pinnata (Lmk) Pers is active to repair the lupus manifestation in 2,6,10,14 tetramethylpentadecane (TMPD)-treated mice. Then, this research was focused on the in vivo immunosuppressant effect of a flavonoid-rich fraction of the extract which was consisted of the ethyl acetate (FE) and n-butanol (FB) fractions. The induction method and the extraction procedure were the same as the previous study and then the fractionation was performed by using liquid-liquid extraction. After 2-week treatment of both fractions, we obtained the differences in the total leukocytes, organ indexes, and also the spleen, kidney, and joint structure parameters. The total leukocyte of the FE group was 3,600±264 cells/mm3, which was lower than that in the FB group. The spleen and kidney indexes increased after the administration of FB fraction, while the FE fraction was not. At last, despite the histology observation of spleen resembled mild structural changes differences, the clear differences between both treatment groups occurred in the kidney and joint histology. The differences led to a conclusion that the FE fraction has the better immunosuppressant effect in TMPD-treated mice.

Complement-Targeted Therapies in Lupus

Systemic lupus erythematosus is a complex disease affecting most organs in the body. Deficiency of early components of the classical complement pathway is a key predisposing genetic factor for lupus in both mice and humans. Activation of the complement cascade downstream of C3 is a key factor in tissue inflammation and damage in lupus. Thus, lupus provides an interesting puzzle for how and when to block complement activation as a therapy. Interventions blocking C5, the alternative pathway, the lectin pathway, and the terminal membrane attack complex are all effective in treating murine models of lupus. Over 20 complement-directed therapies are in clinical trials for various diseases. Despite the promising results regarding efficacy of complement inhibition in murine lupus, the overall lack of effective therapies in lupus, and the availability of a number of complement inhibitors for human trials, there have been and currently are no trials of complement inhibitors for treating lupus. The complexity of lupus and the failure of many recent clinical trials in lupus have perhaps discouraged industry sponsors from testing their complement therapies in lupus. There may also be concern that blocking complement alone may not be effective in treating lupus as other inflammatory mediators are also involved in disease pathogenesis. Despite these possible confounders, it is clear that complement is a key mediator of tissue inflammation and damage in lupus. Complement inhibitors may not be effective at long-term chronic management of lupus, but would appear to be very attractive as an acute intervention during disease flares, especially in lupus nephritis. Ongoing efforts by the NIH and by the lupus organizations to bring new lupus drugs to patients will hopefully lead to clinical trials of complement inhibitors in lupus in the near future.

Lupus Biomarker Discovery, Validation, Approval, and Impact on Clinical Trials

Current estimates suggest that bringing a new therapeutic from the laboratory to the patient requires 16–17 years and US$4–5 billion. One of the challenges in lupus clinical trials is the dearth of available biomarkers to identify those most likely to respond, to demonstrate response, and to predict adverse events. The lupus biomarker discovery pipeline, much like the lupus pharmaceutical discovery pipeline, has seen many potential advances but enjoyed all too few ultimate successes. New lupus biomarkers are essential and certain to accelerate lupus drug discovery and to move “lupology” from being less of an art to being more of a science. There is no precise path to lupus biomarker validation, FDA approval is generally not required, a multidisciplinary team is essential to optimize success, and a commercial partner is almost required to move advances in academia through the translational process. Despite the relatively few successes to date, the trajectory for lupus biomarker discovery and validation is steep and more promising than ever. Tandem and synergic advances in lupus biomarker validation and approval of new lupus therapeutics are hopefully on the horizon.

Rituximab: the Lupus Journey

Since the 1950s, lupus has changed from being a life-threatening condition to being treatable in most cases thanks to the introduction of steroids, immunosuppressive drugs, dialysis and renal transplantation. However, apart from the introduction of mycophenolate mofetil, successful new drugs for lupus have been hard to find in the past two decades. In an assessment of our lupus nephritis cohort over the past 30 years (Croca et al., Rheumatology. 11; 50:1424-1430), we reported that both morbidity and mortality have changed little during this period, suggesting that we have optimized the use of corticosteroids and conventional immunosuppressive drugs. If we want to seek further improvement in outcome, new approaches will be necessary. In this review, we will focus on the use of rituximab in the treatment of systemic lupus erythematosus (SLE). Although not fully understood, it has become clear that B cells play a key role in SLE pathogenesis. They are implicated in the production of autoantibodies, presentation of autoantigen to T cells, T cell activation and cytokine production. In theory, B cell-targeted therapies which eliminate pathogenic B cells and promote the expansion and function of protective B cells, or both, should be beneficial (Rahman and Isenberg, N Engl J Med. 2008; 358:929–39), (Yildirim-Toruner and Diamond, J Allergy Clin Immunol. 2011; 127:303-12). Many open-label and registry studies do indeed report the successful use of rituximab in both renal and non-renal lupus. However, two major clinical trials using it failed to meet their end points. We review the road travelled by rituximab as a lupus treatment in the past 14 years and consider where the journey is heading. • Rituximab is a safe and effective treatment for refractory SLE patients. • Early treatment with Rituximab seems to be effective and can reduce steroid burden.

A case of membranous nephropathy and myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Membranous nephropathy (MN) may be a primary disease or secondary to autoimmune conditions such as systemic lupus erythematosus, infection (for example, with hepatitis B or C virus), cancer or drugs. In primary MN, crescents are rarely observed. Therefore, the presence of crescents suggests another underlying disease, for example lupus nephritis, anti-glomerular basement membrane disease or anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The coexistence of primary MN and ANCA-GN is rare. In the present case, a 51-year-old female with mild edema in the lower extremities for 1 year was admitted to hospital for renal biopsy. The serum test for myeloperoxidase (MPO)-ANCA was positive. The patient was diagnosed with stage 2 MN with crescentic glomerulonephritis type 3; however, no causal association was found between these two diseases in this case. Treatment was initiated with 500 mg methylprednisolone for 3 days followed by 40 mg of oral methylprednisolone together with 50 mg cyclophosphamide twice per day. One month following treatment, the biochemical data results of the patient had improved.

PReS13-SPK-1129: Biologic therapies in SLE

Biologic therapy has not made the breakthrough in the treatment of patients with systemic lupus erythematosus (SLE) that it has managed in patients with rheumatoid arthritis and psoriatic arthritis. However, there are distinct signs that this form of treatment is going to find a place in the pantheon of SLE therapy. Based on a better knowledge of the ethiopathogenesis of lupus drugs, which interfere with B cell activation notably, Benlysta and Atacicept have been reported in major clinical trials to be successful in terms of controlling disease activity and preventing flares respectively. In addition, although the formal clinical trials did not meet their primary endpoints (almost certainly because of problems with the designs of those trials) the use of B cell depletion in the form of rituximab is widely accepted and appears to be helpful and highly beneficial in aspects of lupus ranging from skin disease to severe proliferative glomerulonephritis. My colleagues and I have treated 120 lupus patients with rituximab and have reported that 90% of patients are in partial or complete remission at six months (Lu et al. Arthritis Care Res; 2009: 61, 482), though some questions remained unanswered. For example, why is it in some patients B cells return within two months and in other cases it may be many years? In addition, once the B cells have returned there is a highly variable length of time before the clinical features return. In spite of disappointing results with major clinical trials, at least two new clinical trials using rituximab, are about to start recruiting, the RING trial for patients with lupus nephritis who failed conventional therapy at six months and RITUXILUP which aims to treat lupus patients at the time of diagnosis with two infusions of rituximab followed by a low dose of mycophenolate the state of aim avoiding the use of oral steroids. In an open label study of 50 lupus nephritis patients given rituximab at the time of diagnosis followed by low dose mycophenolate, Condon et al (Ann Rheum Dis 2013. In press) have reported that just two out of 50 patients after two years have required oral steroids.

Systemic lupus erythematosus: an update on current pharmacotherapy and future directions

Introduction: In the last decade, the development of a number of potential drugs for lupus that target the pathogenesis of the disease at different levels has been witnessed. Despite a number of negative trials during this period, belimumab was recently approved for the treatment of adult seropositive lupus patients with mild-to-moderate disease activity.Areas covered: This review summarizes the results of the most recent drug trials in lupus and highlights the aspects that require further refinement and modification in order to facilitate positive results in new drug trials for lupus.Expert opinion: The success of a clinical trial depends on the efficacy of the study drug and its appropriate dosing. Several other factors play a major role in the success of trials, including the patient inclusion criteria, the choice of evidence-based study outcomes and endpoints and other aspects of study design that are described in this review.

Belimumab in systemic lupus erythematosus: an update for clinicians

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that is driven by autoantibodies that target multiple organ systems. B-lymphocyte stimulator (BLyS) and its receptors on B-cell subsets play an important role in autoimmune B-cell development and SLE pathogenesis. Targeted therapy with belimumab, the monoclonal antibody against BLyS, has shown clinical benefit in two large-scale, multicenter phase III trials leading to US Food and Drug Administration approval for patients with serologically positive SLE who have active disease despite standard therapy. This review will discuss the challenges in lupus drug development and clinical trials, the basics of B-cell pathogenesis in SLE, the recent lupus clinical trials of B-cell targeted treatments, and other potential targeted therapies under investigation for patients with lupus.

Belimumab Efficacy is ‘Mild’ but Market Potential Still Great†

Speaking for the inThought Expert Discussion Series in February, Dr George Tsokos mirrored the opinion of many lupus thought leaders: Human Genome Sciences (HGS) and GlaxoSmithKline's (GSK) belimumab (Benlysta®) was likely to be approved by the US FDA and, despite modest efficacy, will be used by a large proportion of lupus patients. Dr Tsokos praised HGS and GSK's clinical trial program for belimumab, noting that huge trials and unique trial endpoints were needed to demonstrate the drug's efficacy, allowing it to succeed where so many other lupus drugs have failed. Still, belimumab's trial design may not become standard in future lupus trials - questions about identification of appropriate lupus patients with active disease, trial endpoints, and subgrouping lupus patients remain. Although Dr Tsokos does not expect other agents currently being tested in lupus trials to be significantly more efficacious than belimumab, his research suggests that significantly better results could be obtained using agents targeting interleukin-17, spleen tyrosine kinase (SYK), and calcium/calmodulin-dependent protein kinase type IV (CaMKIV). In line with Dr Tsokos' comments and consistent with inThought's outlook for belimumab, the US FDA granted approval for belimumab in March 2011, making it the first new lupus drug to be approved in more than 50 years. inThought projects US sales of $1.1 billion for belimumab by 2017. † Adapted and reproduced from Weintraub B. Benlysta Efficacy is "Mild" but Market Potential Still Great: Anticipating U.S. Approval of the First Lupus Drug Since 1957. inThought Research, 2011 Feb 24.

After half-century's wait, approval paves path for new lupus drugs

After half-century's wait, approval paves path for new lupus drugs