|Year : 2019 | Volume
| Issue : 4 | Page : 103-108
Biologics: A tectonic shift in the management of rheumatoid arthritis
Ramaswamy Subramanian1, Shiva Prasad2
1 Department of Rheumatology and Immunology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
2 Department of Rheumatology, Apollo BGS Hospital, Mysore, Karnataka, India
|Date of Submission||13-Jul-2019|
|Date of Acceptance||11-Aug-2019|
|Date of Web Publication||18-Oct-2019|
Dr. Shiva Prasad
Apollo BGS Hospital, Mysore, Karnataka
Source of Support: None, Conflict of Interest: None
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints which if ongoing, has a significant bearing in the quality of life and has a variety of systemic manifestation which reduces the overall life span due to an ongoing inflammatory process. There has been a shift in the management of RA right from the early identification of the disease to targeting the pathogenic mechanisms. The changing modalities with emphasis on remission and low disease activity in early RA should be the primary goal. Disease control of RA with the use of combination synthetic disease modifying anti-rheumatic drugs or in combination with biological agents have improved disease-related outcomes. This prevents the progression of disease, morbidity, and has a significant bearing on the overall economic productivity of the patient and the society. Costs of the biological drugs is a major hurdle in their usage. Introduction of biosimilars have lead to a decrease in the cost of the biological molecules and hence their use becoming more widespread. The purpose of this review is to highlight the changing treatment modalities with the advent of biological disease modifiers in RA and a rationale for their use. The strategy in the treatment of RA should be goal directed rather than just relief of symptoms.
Keywords: Biologics, disease activity indices, rheumatoid arthritis
|How to cite this article:|
Subramanian R, Prasad S. Biologics: A tectonic shift in the management of rheumatoid arthritis. APIK J Int Med 2019;7:103-8
|How to cite this URL:|
Subramanian R, Prasad S. Biologics: A tectonic shift in the management of rheumatoid arthritis. APIK J Int Med [serial online] 2019 [cited 2019 Dec 6];7:103-8. Available from: http://www.ajim.in/text.asp?2019/7/4/103/269564
| Introduction|| |
Rheumatoid arthritis (RA) is chronic disease process characterized by inflammatory joint symptoms with frequent exacerbations and remissions often leading to disability and loss of workdays, if left uncontrolled. Although there is no single unifying pathogenetic mechanism, rise in circulating inflammatory cytokines, aberrations in intracellular signalling pathways and alterations in the immune synapse often define the disease. Genetic susceptibility includes HLA DRB 1 gene association, shared epitope (SE) alleles; such as HLA-DRB1*01 and DRB1*04; and nonHLA gene single-nucleotide polymorphisms including PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4 have been described in the pathogenesis of RA. Established clinical disease is an outcome of this interplay between the susceptibility genes and “immune-cytokine” axis. The multitudes of steps in the pathogenesis of RA make the management of the disease challenging.
Early referrals' and early institution of disease-modifying anti-rheumatic drugs (DMARDs) have been found to be beneficial in controlling this disease. Combinations of conventional synthetic DMARDs (cDMARDs') through their multimodal mechanisms of action, if instituted early in the course of disease inches closer to the goal of sustained clinical remission of RA, which was elusive in the past., A biological product or a small molecule targeting the steps in the pathogenesis of this disease bridges this gap. The combination strategies include triple therapy methotrexate (MTX) plus sulfasalazine (SSZ) and chloroquine (CQ)/hydroxychloroquine (HCQ) or MTX + leflunomide (LEF).,
With the advent of biologics in the past two decades, there has been a tectonic shift in the management of RA, especially in the early stages of the clinical disease where the goal is clinical and serological remission seems achievable. It is in this endeavor, current treatment strategies are individualized to achieve a state of minimal disease activity (MDA) within a defined period which is otherwise called as “tight control” of RA. MDA is considered when a patient of RA on treatment satisfies 5 out of the following 7 domains - pain scale of ≤2, tender and swollen joint scores; ≤1 each, health assessment questionnaire (HAQ) of ≤ 0.5, physician (≤1.5), and patient global activity (≤2) indices together with erythrocyte sedimentation rate (ESR) of ≤20. The concept of tight control of disease was first proved in the TICORA (tight control of Rheumatoid Arthritis) trial and CAMERA (Computer Assisted Management for Early Rheumatoid Arthritis) supported this concept..,
In established RA, biologics have been proven to show radiological regression of joint erosions and is often used to manage certain extra-articular features of the disease. Untreated or poorly controlled RA has a significant impact on work disability and reduces life expectancy by over 5–10 years., The treatment strategy for RA is multidisciplinary with the active involvement of the Physical Medicine and Rehabilitation unit.
| Early Rheumatoid Arthritis and Very Early Rheumatoid Arthritis|| |
Inflammatory joint disease is associated with pain during periods of prolonged rest, usually lasting for >30 min. Together with a predilection for hand joints and the duration of persistent symptoms for >3 months typifies the clinical symptoms of RA. The presence of Rheumatoid Factor (RF) and anti-Citrullinated Peptide Antibody (ACPA) further aid in the diagnosis of RA. However, the American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria 2010, which is a weighted score prioritizes the joint counts and the presence of antibodies over the duration of symptoms. This has led to the shift to identifying the disease in the early stages wherein the diagnosis is based more on the complex. This criterion was primarily directed toward identifying the early disease and intent to treat with DMARDs'. Modalities such as Ultrasound with Power Doppler and Magnetic Resonance Imaging (MRI) help detect inflammatory synovitis and bone edema, which was elusive in the era of conventional radiography. Identifying early RA, i.e., before the development of radiological erosions provides a window of opportunity to prevent damage, deformity and morbidity over a longer period.
The stages of inflammatory arthritis progression from the development of signs and symptoms (duration <12 weeks) to the stage of persistent disease (approximately 2 years) categorizes early RA. Very early RA represents as symptom duration of the first 12 weeks is a potentially important therapeutic window, wherein patients with very early synovitis (as evidenced on ultrasonography/MRI) progress on to develop RA. It is in this period, with early aggressive therapy, it may be possible to halt the inflammatory process. In the remission phase of RA, there is resolution of inflammatory synovitis and bone edema. The thought behind identifying the early and very early RA is the intent to treat and prevent disease progression, if possible, also revert the disease.
| Treatment of Rheumatoid Arthritis|| |
Conventional DMARDs' (MTX, LEF, CQ/HCQ, SSZ) with or without glucocorticoids formed the backbone of the treatment of RA in the early stages in the pre-biologic era. The safety and efficacy of combination therapy in early RA has been demonstrated in the COBRA “Combinatie therapie Bij Rheumatoide Artritis” trial and the the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial., The outcome measures in RA is measured by the Disease Activity Score (DAS) for 28 joint counts and the American College of Rheumatology (ACR remission criteria) which is based on the percentage of improvement in joint counts, physician and patient global index, physical activity as indicated by the Health Assessment Questionnaire (HAQ) together with the laboratory changes in the Acute Phase Reactants (namely the ESR and C-reactive protein [CRP])., Early and aggressive are the two main approaches to reach the main therapeutic goals of RA which is dependent on the type, timing and the efficacy of treatment given. Prognostic factors (RF, ACPA, and SE positivity) disappeared when patients were treated aggressively and promptly as indicated in the BeST trial. Untreated or poorly controlled RA leads to major decrements in health-related quality of life and has an impact on the socioeconomic health of the patient and society in terms of work-related disabilities and loss of productivity. In addition to cDMARDs', various biologics have been approved in the treatment of RA and the choice of biologics is individualized based on outcome measures and safety so as prevent adverse events (AEs).
| Pathogenic Background of Use Of Biological Drugs|| |
The pathogenesis of RA [Figure 1] is a complex interaction between genetics, environment and autoimmunity; neither of them in isolation renders the disease. In an individual with a genetic risk which may be up to 80% in the case of SE (HLA-DRB1*04) and up to 3%–5% with non-MHC risk alleles, innate immune response to an inciting antigen is the first step in the pathogenesis of RA.,, Antigen-presenting cells (APCs), namely dendritic cells, macrophage-derived cytokines (interleukin [IL] 1, IL6 and tumor necrosis factor-alpha [TNF-α]) and B-cells present arthritic antigens to T-cells to initiate the release of IL-2 and interferon-gamma (IFN-γ). These cytokines infiltrate the synovial membrane leading to the progression of synovitis in RA. The pro-inflammatory cytokines (IL1, IL6, and TNF-α) play a dominant role in the pathogenesis of RA. Inflammatory cytokines play an important role in the immune synapse by facilitating activation of T-cells, B-cells, and promoting T-cell – B-cell interaction/T-cell-APC interaction (co-stimulation).
|Figure 1: Pathogenesis of RA. PTPN22: Protein tyrosine phosphatase, non-receptor type 22, PADI4: Protein Arginine Deiminase Inhibitor 4, STAT4: Signal transducer and activator of transcription 4, TRAF1-C5: Tumor necrosis factor-receptor associated factor 1/complement component 5, TNFAIP3: Tumor necrosis factor, alpha-induced protein 3|
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In addition to their effects on synoviocytes, osteoclasts and T-cell activation and infiltration, proinflammatory cytokines mediate systemic inflammatory response in the form of elevation in circulating acute phase reactants, cardiovascular disease progression, osteoporosis, and exacerbate fatigue and depression.,,
| Biological Disease Response Modifiers in Rheumatoid Arthritis|| |
Biological drugs are derived from natural sources – humans, animals, or microorganisms and are composed of sugars, proteins, or nucleic acids or complex combinations extracted from a living source by biotechnological methods. Biologic drugs include vaccines, blood, blood components, cells, allergens, genes, tissues, and recombinant proteins. They can be broadly divided into monoclonal antibodies, receptor modulators, or replacement/modulators of enzymes. Because these pharmaceutical products originate from a living system, immunogenicity remains a possibility that can either induce allergic reactions and/or alter the biological activities with clinical consequences.
Biologic disease response modifiers are used in the treatment of Crohn's disease, ulcerative colitis, RA, and other autoimmune diseases. Available biologics have revolutionized cancer treatment, delayed or reversed the course of immune-related conditions, changed the lives of people with rare diseases, and have offered hope for many patients who previously had no effective treatment options for their condition.
A biosimilar is a compound which demonstrates structural and functional similarities with comparable pharmacokinetic and pharmacodynamic properties to the originator compounds using sensitive indicators, for example, levels of cytokines, blood glucose, or white cell counts. A biosimilar is approved based on a showing that it is “highly similar” to a Food and Drug Administration (FDA)-approved biological product, known as a reference product. It may not have any clinically meaningful differences in terms of safety and effectiveness from the reference product.
Targets of treatment with respect to biologics in RA include inflammatory cytokines, namely TNF-α, IL-6 and IL-1, costimulatory molecules (CD28), and cellular targets (anti B cell). The therapeutic molecules used in RA are indicated in [Table 1].
| Screening|| |
In view of the risk of infections, especially tuberculosis (TB) reactivation, it is advisable to assess a patient's TB history and exposure. Screening for latent TB (mantoux/IFN-γ assays) is recommended for all biological agents, except rituximab, where clinical vigilance would suffice in view of the paucity of arguments pointing toward an elevated TB risk with this drug. In addition to history and detailed physical examination along with records of treatment with anti-tuberculous treatment, patients with a positive TB screening test should be assessed for active disease with a chest X-ray and treated with appropriate prophylactic TB therapy. Chemoprophylaxis for latent TB usually consists of isoniazid single therapy for 9 months, or alternatively, rifampicin for 4 months. In regions with TB drug resistance of >10% combination drug therapy must be considered. The caveats in the screening tests for TB in highly endemic regions is compounded by the use of MTX and steroids in RA, which together lead to alterations in T-cell functions leading to variability in results in the screening tests. HIV/hepatitis B surface antigen and hepatitis C virus are the other routine screening tests that are usually recommended before administration of biologicals.
| Anti-Tumor Necrosis Factor|| |
The first monoclonal antibody to Tumor necrosis factor-alpha (TNFα) developed for treating RA was infliximab. This chimeric antibody binds with high affinity to both soluble and transmembrane TNF and is able to reduce synovial inflammation, bone resorption, and cartilage degradation. The recommended dosage of 3 mg /kg could be increased up to 10 mg /kg in case of partial efficacy. Antibodies to infliximab have been observed in 7%–61% of patients and are associated with a low trough level of infliximab and secondary response failure. Their occurrence could be prevented by co-medication with MTX. ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Combination Therapy) trial and ASPIRE (Active controlled Study of Patients receiving infliximab for the treatment of Rheumatoid arthritis of Early onset) study provide evidence that infliximab is capable of slowing down structural joint damage., It is administered as an infusion, with a dosage adapted to patient weight at 5 mg/kg. Immunogenicity concerns, i.e., production of human anti-chimeric antibodies and infusion reactions are of concern with the use of infliximab.
Etanercept is a dimeric human tumor necrosis factor receptor p75-Fc fusion protein. It is given at doses of 25 mg biweekly or 50 mg/week doses as a subcutaneous injection. It can either be used as a monotherapy or in combination with MTX in early RA as evidenced by COMET (Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis).
Adalimumab is a recombinant fully human immunoglobulin G1 antibody and binds soluble and membrane TNF-α which may lyse membrane TNF-α cells. It is given as 40 mg subcutaneous injections every other week. Adalimumab was generally well tolerated as both concomitant therapy and monotherapy. Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab [ARMADA] trial showed improvements in the individual components of the ACR response were significantly greater with adalimumab 40 mg every other week plus MTX than with placebo plus MTX.
Certolizumab pegol (CZP) is a novel pegylated anti-TNF, consisting of a Fab′ attached to a 40kDa poly ethylene glycol (PEG) moiety. Attachment of PEG to the Fab′ increases the plasma half-life of CZP to ~2 weeks, allowing dosing every 2 or 4 weeks. The efficacy and safety of CZP in adult patients with active RA were established in three Phase III clinical trials, in which CZP was administered with MTX or as monotherapy.
Golimumab is a human monoclonal antibody which targets TNF-α and is used at doses of 50 mg or 100 mg every 4 weeks as a subcutaneous injection. The GO-AFTER trial evaluated patients with active RA despite prior treatment with conventional synthetic DMARDs (CS DMARDs') and ≥1 TNF inhibitor (s) (a particularly treatment-refractory cohort with long-standing disease) for their response to yet another TNF inhibitor, golimumab. The long-term efficacy data presented reveal that, despite refractory disease, 40% of randomized patients continued in the study through 5 years.
| Anti Interleukin-1|| |
Anakinra is a recombinant and slightly modified version of the human IL 1 receptor antagonist (IL-1ra) protein. Meta-analysis has shown that anakinra given at doses of 50 mg to 150 mg SC daily. Anakinra has a significant improvement in ACR20, HAQ, and ESR. The ACR20 response is maintained after 48 weeks of treatment. Anakinra shows higher episodes of treatment-related withdrawals than placebo. IL-1ra was generally well tolerated, with injection site reaction the most frequent AE.
| Anti Interleukin-6|| |
Tocilizumab (TCZ) is a humanized antihuman IL-6 receptor monoclonal antibody. It is given as an intravenous injection at dose 4 mg to 8 mg/kg/dose. TCZ is also significantly positioned as a promising treatment for patients with RA whose condition is poorly controlled by TNF inhibitors. TCZ is already widely used as a first-line biological DMARD in the same way as TNF inhibitors, but clinically, it also occupies a significant position as a second- and third-line biological DMARD. If a TNF inhibitor proves ineffective, changing the treatment target is a sensible decision, and although there are no directly comparative studies, it is possible that the percentage of patients achieving treatment response would be higher than had they been switched to another TNF inhibitor. In fact, disease activity can be controlled by TCZ in many patients whose condition has failed to respond to TNF inhibitors. TCZ is also highly rated as a second-line biological DMARD and is widely used in clinical practice.
The most commonly reported AEs were abnormal laboratory values (35.46/100 patient-years) comprising rises in the hepatic function markers alanine transaminase and aspartate aminotransaminase, decreased white cell count, decreased platelet count, and rises in blood cholesterol levels.
| Anti B-Cell|| |
Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody approved for the treatment of RA and relapsed or refractory, low-grade or follicular, CD20+ B-cell nonHodgkin's lymphoma. For RA rituximab is administered as a 1000 mg intravenous infusion on days 1 and 15. B-cells may function as antigen-presenting cells and provide important costimulatory signals required for CD4+ T-cell clonal expansion and effector functions. In addition, it is known that the synovial membrane in patients with RA contains an abundance of plasma cells (derived from B-cells) that produce RF and that positivity for RF is associated with more aggressive articular disease, a higher frequency of extra-articular manifestations, and increased mortality. AEs occur most frequently with the first infusion, for example infusion reactions.
| Adverse Effects of Biologics|| |
Postmarketing reports, most notably of infections and lymphoma, have heightened awareness of potential AEs, and have led to FDA-mandated label changes in the use of biologics.
Infections serious infections are well-known to occur in RA patients treated with both traditional DMARDs and TNF-α antagonists of which opportunistic infections such as TB, histoplasmosis, and sporotrichosis are a major concern. Of these, recommended guidelines for screening for latent/active TB is the only universally acceptable prebiologic evaluation in patient with RA using purified protein derivative tests or IFN-γ assays together with chest radiographs. Common bacteria have also led to serious infections and fatalities. The risk of infections differs in different cohorts though the risks with anti TNF-related infections seem to be maximum in the first 6 months of treatment. Rarer infections like JC virus-related progressive multifocal leukoencephalopathy has been associated with the uses of rituximab.
An increased incidence of lymphoma among patients with RA was reported before the introduction of the TNF-α antagonists, with an increased risk ranging from 2- to 25-fold. Careful longitudinal assessment of treated patients is necessary to assess the incidences of malignancies in RA patients treated with biologics. Till date, there is no increase in the incidence of malignancies in patients with autoimmune diseases treated with biologic drugs when compared to normal individuals.
Heart failures, systemic lupus erythematosus like syndrome and demyelination have known to occur, but the exact incidences of these with the use of biologics are yet to be determined.
| Duration of Treatment With Biologics|| |
Treatment responses can be monitored by the improvement in disease activity indices and ACR/EULAR remission criteria. The goal for each RA patient should be low disease activity or remission. In ideal circumstances, RA remission should be the target of therapy, but in others, low disease activity may be an acceptable target. For the target of remission, the number of tender and swollen joints, along with CRP and patient global assessment on a scale of (0–10) should all be ≤1 and for sustained remission, 6 months is mentioned as a time frame for the target-state of sustained remission.,
The use of biologics in RA is determined by the dosing intervals, vulnerability to adverse effects and economics. With the use of biologics, it is possible for the patients to appreciate rapid responses to treatment with weeks of initiation. Biologicals are effective in symptom relief and hasten improvement in quality of life and disease-related morbidities. Although a head-to-head comparison with each available biologic is not being discussed in this review, the choice of biologics is dependent on the frequency of usage, endemicity of infections, and the costs involved. There is almost a three-fold increase in the annual cost of treatment in a patient with RA on biologic. Dose escalation in the case of infliximab or a class switch, i.e., a biologic with a different mechanism of action has also been practiced in the event of nonresponsiveness.
| Conclusion|| |
There has been a paradigm shift in the treatment of RA from a pyramidal “step-up” approach to an inverse pyramidal “step-down” approach with frequent monitoring of disease activity to achieve a sustainable remission in RA, especially in early disease. CS DMARDs' remain the backbone of treatment of RA with biologics as add on therapy, especially in resource-deprived situations where institutional support for treatment is minimal or selective.
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Conflicts of interest
There are no conflicts of interest.
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