Antirheumatic Biologic Agents Research Articles

HEMATOLOGIC MANIFESTATIONS OF RHEUMATOID ARTHRITIS IN A TERTIARY CARE HOSPITAL

Hematological manifestations of rheumatoid arthritis (RA) are very common. Blood dyscrasias and other hematological abnormalities are sometimes the rst sign of rheumatic disease. In addition, novel anti-rheumatic biological agents may cause cytopenias. It is crucial that hematologists be aware of these presentations so that they are diagnosed and treated in a timely manner. A logical approach using easily available tests should allow straightforward decisions about diagnosis and therapy to be made, even in patients with some of the rarer hematological manifestations. An observational study was done in RA patients in a tertiary care hospital to study the prevalence and the type of hematologic manifestations from a pathologist's perspective. It was observed that anemia is the most common hematologic nding seen in RA, iron deciency being the commonest cause of anemia, however hemolytic anemia was not seen. Leucocytosis was more common with predominant neutrophilia. Elevated platelet count, bicytopenia and pancytopenia were observed in RA along with raised ESR. Coagulation parameters were however within normal range. Bone marrow ndings (where studied) included tuberculosis and plasma cell neoplasm. Summary: This study was conducted to estimate the proportion of patients with hematological abnormalities as the manifestation of RA and to study the nature of these various hematological problems, so that the empirical treatment can be started and also to inform the clinical rheumatologists about the common and rarer hematological manifestations of RA.

The Prevalence of Hypersensitivity Reactions to Antirheumatic Biological Agents and Results of the Skin Tests: Experience of a Tertiary Referral Allergy Center in Turkey

Objective: The use of biological agents (BAs) has increased dramatically for inflammatory diseases and this increase has led to a rise in hypersensitivity reactions (HSRs). The symptoms and diagnostic tools for HSRs are not standardized. We aimed to analyze the prevalence of HSRs to anti-rheumatic BAs and to evaluate the usefulness of skin tests (STs) as a diagnostic tool. Materials and Methods: Our study was conducted at the Ege University Medical Faculty, Department of Internal Medicine, Division of Allergy and Clinical Immunology and Division of Rheumatology, Izmir, Turkey. Four hundred sixty patients who received BAs between Jan 1st, 2015, and Jan 1st, 2016, were reviewed in this retrospective cross-sectional study. The prevalence of HSRs was retrospectively evaluated. Ten patients with HSRs were evaluated with STs containing commercially available culprit drugs. The data was collected from hospital records. The age, sex, atopic diseases, primary rheumatic diseases, and anti-rheumatic therapies of the patients were recorded. Results: Two hundred fifty patients were treated with rituximab (RTX), 45 with infliximab, 40 with tocilizumab (TOC), 36 with golimumab, 35 with etanercept, 34 with abatacept, 15 with certolizumab, and 5 with adalimumab. Fifty reactions with RTX and two reactions with TOC were infusion-related (IRRs). Ten HSRs were observed. Eight patients had immediate (7 immediate systemic reactions and 1 local injection site reactions), and 2 had late-onset cutaneous reactions. We detected the ratio of IRRs as 11.3%, immediate HSRs as 1.73%, IgE-mediated reactions as 1.08%, and anaphylaxis as 0.86%. STs were positive in 5 of 8 patients with immediate HSRs. Four of them had anaphylaxis, and remarkably, 3 of these had positive STs. None of the ten patients had high levels of specific IgE and only four had atopic diseases. Total IgE levels were not high and specific IgE levels were not positive in the presence of HSR to BAs (p=0.039). Conclusion: Five of the 8 (62.5%) patients with immediate reactions had positive STs, which suggested IgE-mediated reactions. The prevalence of HSRs to BAs was less than the ones mentioned in the literature.

Certain perspectives about the use of corticosteroids for managing hospitalized patients with rheumatic diseases.

The administration of cortisone to a bedridden patient with rheumatoid arthritis (RA) 70years ago was a transformative event in modern medicine. We have since struggled to balance the near-miraculous anti-rheumatic with the yet all-too-frequent devastating side effects of glucocorticoids (GC). With the current availability of newer disease-modifying and biologic anti-rheumatic agents, we were rather surprised to note that 94% of sick hospitalized patients with systemic rheumatic diseases at our medical center were on corticosteroids during a 3-month observation period. Comparing contemporary with past practices from historical references, we confirmed a perhaps paradoxical trend of increasing steroid usage in certain contexts over the years. Sixty-seven percent of our hospitalized lupus patients were started on GC of greater than 30mg prednisone equivalent compared with 50% in the 1950s. Seventy-five percent of our RA inpatients had their GC dose increased on discharge. Both (2/2) our new RA patients were started on GC, compared with 69% in the 2000s and just 36% in the 1990s. This likely reflects both improved abilities to keep sick patients alive and inability of other anti-rheumatic therapies to consistently induce or sustain disease remission compared with the usually highly efficacious yet inexpensive GC in these particular patients. Administration of glucocorticoids to ill, often infected, patients with systemic rheumatic diseases remains more art than science. Current perspectives view glucocorticoids as considerably less salutary than previously thought; we are still challenged to keep our patients from developing preventable complications. These observations emphasize the need for more and better therapeutic alternatives to glucocorticoids. There are now several examples-disease-modifying and biologic medications for RA and biologics for lupus and vasculitis-that suggest the possibility of caring for our patients without the historical reliance on corticosteroids. We have made enormous progress since steroids were first offered to a patient with RA in 1948. We are hopeful the future will bring us interventions of comparable or better efficacy that are safer.

The impact of seropositivity on the effectiveness of biologic anti-rheumatic agents: results from a collaboration of 16 registries.

RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting. We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time. Among the 27583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction <0.001). The adjusted hazard ratios for seropositive compared with seronegative patients were 1.01 (95% CI 0.95, 1.07) for TNFis, 0.89 (0.78, 1.02)] for TCZ, 0.80 (0.72, 0.88) for ABA and 0.70 (0.59, 0.84) for RTX. Adjusted differences in remission and low disease activity rates between seropositive and seronegative patients followed the same pattern, with no difference in TNFis, a small difference in TCZ, a larger difference in ABA and the largest difference in RTX (Lundex remission difference +5.9%, low disease activity difference +11.6%). Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis.

Thyroid Autoimmunity and Function after Treatment with Biological Antirheumatic Agents in Rheumatoid Arthritis.

With the increased pro-inflammatory response in both rheumatoid arthritis and thyroid autoimmune diseases, treatment with biological antirheumatic agents (BAAs) of the former may affect the course of the latter. In hepatitis C and cancer patients, treatment with biological agents substantially increases the risk of developing thyroid autoimmunity. As the use of BAAs in the treatment of rheumatoid arthritis is increasing, this review aimed to investigate if such use affected thyroid status in rheumatoid arthritis patients. We conducted a systematic literature search and included six studies with a total of 311 patients as well as three case reports. The patients were treated with tumor necrosis factor-α inhibitors (infliximab, etanercept, or adalimumab) or the monoclonal CD20-antibody rituximab. There was a non-significant trend of slight improvement of both thyroid function and autoantibody status: a reduction of thyroid peroxidase and thyroglobulin antibody concentrations, and a reduction of thyrotropin levels in hypothyroid patients. Despite the small number of studies, they presented compliant data. The BAAs used in rheumatoid arthritis thus did not seem to negatively affect thyroid status in patients with rheumatoid arthritis and can be considered safe with regard to thyroid autoimmunity. However, the well-established association between rheumatic diseases and thyroid autoimmunity necessitates continued monitoring of thyroid function in patients with rheumatoid arthritis. Each new BAA should be scrutinized for its effect on thyroid as well as other autoimmune diseases in order to establish concise recommendations for patient follow-up for each agent and each disease.

Thyroid-specific changes following treatment with biological therapies in patients with rheumatic diseases.

Biological anti-rheumatic agents (BAA) may induce autoimmune phenomena. Evidence on thyroid-specific effects of these agents is relatively limited. We studied prospectively, over 3 years, 36 rheumatic patients treated with BAA (18 Infliximab and 18 Rituximab) and no prior exposure to biological therapies (group-1), with respect to their thyroid function, thyroid antibody titers, and thyroid ultrasonographic parameters, such as left inferior thyroid artery peak systolic velocity (ITA PSV), left thyroid lobe vascularity index (TL VI), and echogenicity. Twenty-eight rheumatic patients treated with disease-modifying anti-rheumatic drugs and/or glucocorticoids (group-2), 21 rheumatic patients not receiving any treatment (group-3), and 49 healthy individuals (group-4) were used for comparison. Thyroid function and autoantibody titers were not significantly altered at any stage irrespectively of the administered BAA, previously unknown autoimmune thyroid disease (AITD) status, and/or concomitant treatment with glucocorticoids. Left ITA PSV was significantly increased in group-1 patients (mean ± SD start: 25.5 ± 14.1 cm/s vs. end: 29.8 ± 11.1 cm/s, p = 0.038 and p < 0.001, respectively). Six group-1, 7 group-2, and 3 group-3 patients developed reduced thyroid echogenicity during follow-up (start: p = 0.003 and end: p < 0.001). Left ITA PSV, left TL VI, and echogenicity changes were not related to alterations in thyroid volume, thyrotropin hormone levels, and/or underlying AITD. Infliximab and Rituximab do not cause any alterations in thyroid function and/or autoimmunity, even in patients with previously undiagnosed AITD. Elevated left ITA PSV and reduced thyroid echogenicity may be early features signaling progression to AITD in patients treated with BAA.

AB0478 Systematic safety review of five biologic antirheumatic drugs

BackgroundDecision-making regarding therapeutic intervention depends on various factors, including knowledge of the risk-benefit profile of each agent. The relative safety of antirheumatic biologic agents is difficult to assess because of...

FRI0099 Obese patients with rheumatoid arthritis have reduced response rates to biologic anti-rheumatic agents: a comparison between european and american ra patients

BackgroundObesity in RA patients has been associated with an increased risk of comorbidity, total joint replacement, pain, disability, high medical costs and impaired quality of life. One study has suggested...

Two cases of viral reactivation from resolved hepatitis B in patients with rheumatoid arthritis who received biologic antirheumatic agents

Two cases of viral reactivation from resolved hepatitis B in patients with rheumatoid arthritis who received biologic antirheumatic agents

Disease activity in rheumatoid arthritis patients at initiation of biologic agents and 1 year of treatment: Results from the Swiss SCQM registry

ObjectiveIn Switzerland, the prescription of biologic antirheumatic agents in rheumatoid arthritis (RA) patients is not limited by stringent requirements from health authorities. The goals of this study were to: determine the characteristics of the Swiss patients at the initiation of biologics, compare them with other countries and evaluate whether different disease activity levels at initiation of therapy, resulting from distinct access to these treatment, influence their effectiveness. MethodsThis is a retrospective cohort study of RA patients followed in the Swiss register (SCQM-RA). Two thousand and sixty patients treated with biologics were retrieved. We present the disease characteristics and the patients’ demographic data, at initiation and some effectiveness data after 1 year of treatment. ResultsTwo thousand and sixty patients treated with biologics were retrieved. At initiation of treatment, the mean disease activity DAS (SD): 4.4 (1.4), number of previous antirheumatic treatments: 1.1, functional status HAQ: 1.1 (0.7) and median duration of illness: 5.5 years were significantly lower than in other published registries. The mean DAS: 3.3 (1.4) 1 year after initiation of therapy also appears lower than in other countries. Additionally, patients treated more recently (after 2005) had a significantly higher improvement in mean DAS. ConclusionsData from the Swiss RA registry demonstrate that biologics are prescribed at a lower level of disease activity and after fewer prior DMARD failures than in most other countries, a practice that seems to correlate with overall lower absolute levels of disease activity and better patient outcomes after 1 year of treatment.

Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis

BackgroundThe availability of increasing numbers of biological agents for the treatment of rheumatoid arthritis (RA) offers several therapeutic options. While all biologicals have proven effective in trials, very limited direct...

Comparative Effectiveness of Rheumatoid Arthritis Therapies

Physicians and patients must choose between several therapeutic interventions for rheumatoid arthritis and need to compare the available therapeutic options. Although randomized, placebo-controlled trials are essential to establish the efficacy of a new treatment, they are not much help when it comes to selecting the best therapy for an individual patient. Comparative effectiveness research (CER) is set to provide direct comparisons between therapeutic strategies. CER attempts to weigh the benefits against the potential harms of a particular intervention. Furthermore, CER may help identify specific patient subgroups that are more likely to benefit from a particular therapy or at increased risk of adverse events. Several study designs are available for CER, including pragmatic trials, indirect comparisons using meta-analysis, and observational studies. Understanding the strengths and weaknesses of each design improves the interpretation of the results. In this article, I illustrate CER principles using examples from the literature on biologic antirheumatic agents.

Targeting Cytokines, Chemokines and Adhesion Molecules in Rheumatoid Arthritis

The therapy of rheumatoid arthritis (RA) was revolutionized by basic research studies and biopharmaceutical development of the first generation of anti-rheumatic biologic agents (i.e. biological response modifiers), which targeted the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). Further studies resulted in biological response modifiers that have also targeted activated T- and B-lymphocytes both of which play a prominent role in RA pathogenesis and disease progression. Despite the relatively impressive RA diseasemodifying effects of these biologic agents during the post-FDA approval period, there are reports of moderate to severe adverse events associated with their continuous use. Additionally, there is accumulating evidence indicating that antirheumatic biologic agents, while dampening RA disease activity as measured by the American College of Rheumatology (ACR) criteria in clinical trials or other arthritis disease activity instruments employed in studies after approval of these anti-rheumatic medicines by the FDA do not entirely halt the erosive joint cartilage and bone destruction characteristic of RA. There is also still some uncertainty as to how long the available anti-rheumatic biologics can be continuously employed as RA therapies. Since the development of TNF-α/IL-1/IL-6 anti-rheumatic biologics, several additional cytokines with pro-inflammatory activity as well as their receptors, which initiate upstream pathophysiologic effects, have been identified and characterized. In several cases, these cytokines have been cloned and sequenced. Thus, cytokines, such as IL-7, IL12/IL-23, IL-15, IL-16, IL-17/IL-18, IL-19/IL-20/IL-22 and IL-32, have been implicated in arthritis development in animal models of RA and measurements in synovial tissue and synovial fluid obtained from patients with RA also suggested a role for them in RA disease progression, if not in its pathogenesis. There has also been compelling evidence that cytokines with chemokine-activity and adhesion molecules also play a crucial role in RA via their capacity to recruit and retain leukocytes, macrophages, monocytes and endothelial-cell complexes in RA synovial joints. Taken together, non-TNF-α/non-IL-1/non-IL-6 cytokines, chemokines and their receptors as well as adhesion molecules appear to be worthwhile targets for drug development in RA.

Stem cell transplantation in rheumatoid arthritis

The therapeutic potential of high dose cytotoxic therapy and stem cell transplantation (SCT) in severe rheumatoid arthritis (RA) was originally supported by animal studies and serendipitous clinical cases where allogeneic and autologous procedures were shown to ameliorate and potentially cure the disease. Phase I and Phase II clinical studies established the feasibility, safety and efficacy of autologous stem cell mobilisation and transplantation. Although it was clear that the effects of high dose chemotherapy and autologous SCT could safely achieve profound responses, sustained control of disease usually required the reintroduction of disease modifying agents. Responses were improved with dose escalation of the conditioning regimen, and also with post-SCT therapy, such as rituximab, but were not observed with graft manipulation. Phase III studies were attempted, but recruitment was compromised by the increasingly widespread use of biological anti-rheumatic agents. Autologous SCT is now only reasonably considered in relatively rare patients whose disease has resisted conventional and biological treatments, and small numbers of cases continue to be registered with the EBMT. Occasional patients treated with allogeneic and syngeneic SCT continue to stimulate academic interest, particularly as some appear to be cured, but significant logistical and toxicity issues mean that routine and widespread application is unrealistic. In summary, SCT continues to have a limited therapeutic potential in rare patients with RA refractory to modern therapy and sufficient fitness for the procedure. From a scientific perspective, ablation of the dysfunctional rheumatoid immune system and its reconstruction with SCT has provided useful insights into the pathophysiology of RA.

Biologic therapies in rheumatoid arthritis.

Our growing understanding of the immune response mechanism has created a wave of novel biologic agents for the treatment of rheumatoid arthritis. The domain of biologic agents includes: 1) Recombinant regulatory cytokines; 2) engineered molecules and monoclonal antibodies that target proinflammatory cytokines; 3) monoclonal antibodies against lymphocyte cell-surface proteins; 4) fusion proteins and monoclonal antibodies that block the second signal and induce anergy; 5) vaccines comprised of specific proteins from lymphocytes and antigen presenting cells; 6) monoclonal antibodies that block intercellular adhesion; and 6) gene therapy whereby antiarthritis genes are introduced directly into the joint. Most treatments remain under investigation; however, in 1998 two antagonists of tumor necrosis factor were approved marking the first approvals of antirheumatic biologic agents. For the first time anti-rheumatic therapies are being designed instead of borrowed.