Biologic therapies for rheumatologic diseases, which are targeted at molecules involved in the mechanisms of the immune system, provide an alternative to the existing treatment methods of disease-modifying anti-rheumatic drugs and other immunosuppressive medications. However, the current drawbacks of biologic therapies, including the inconvenience of intravenous administration, the high costs of these drugs, and the adverse events associated with them, prevent their wide use as first-line medications. This review provides an update of the recent literature on the new biologic therapies available. The review concentrates on nine drugs: tocilizumab, rituximab, ofatumumab, belimumab, epratuzumab, abatacept, golimumab, certolizumab, and sifalimumab, which are used as therapies for rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, or vasculitis.

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

The development of biologics and small oral molecules has recently changed the scenario of pharmacologic treatment of systemic rheumatic diseases and it has become a real revolution. These drugs have innovative mechanisms of action, based on the inhibition of specific molecular or cellular targets directly involved in disease pathogenesis. This new scenario has lead to a regular update of the management recommendations of several institutions, such as those for Rheumatoid Arthritis treatment that address the use of conventional and biologic therapies including TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, IL-6 inhibitors (tocilizumab and sarilumab), biosimilars and small oral molecules (the JAK inhibitors tofacitinib and baricitinib). Monotherapy, combination therapy, treatment strategies (such as treat-to-target) and the targets of sustained clinical remission or low disease activity are the final goal of the guidelines for rheumatic patients management. In another condition represented by Axial Spondyloarthritis guidelines suggest to start first with non-steroidal anti-inflammatory drugs to improve lifestyle and reduce spine inflammation, but if this is not achieved in 2-4 weeks it is important to consider the use of local therapies (i.e. glucocorticoid injections) or to start biologic therapy such as TNF inhibitors and then eventually switching to another TNF inhibitor or swapping to IL-17 inhibitor. In the case of active Psoriatic Arthritis, guidelines suggest to start with non-steroidal anti-inflammatory drugs and even local glucocorticoid injections especially for oligoarthritis, then to start conventional therapies if lack of efficacy, and finally start biologics or small oral molecules in the presence of drugs toxicity, unfavorable prognostic factors and still active arthritis. In several cases, active Psoriatic Arthritis patients develop a complex clinical condition with comorbidities such as diabetes, inflammatory bowel disease and high risk of infections, and for this reason the American College of Rheumatology and the National Psoriasis Foundation have developed specific guidelines for their management. Biologic and new small molecules therapies are very expensive, but the availability of biosimilars offers the opportunity of reducing the treatment cost and significantly decreasing the cost of originators as well. In fact, we live in a period characterized by the need to rationalize costs of these drugs, to allow treating a higher number of patients and to maintain a homogeneous possibility of treatment choice. For these reasons, we need to follow scientific guidelines and patients' clinical conditions to choose the correct treatment, also based on the economic burden of therapies.

Inflammatory bowel disease, including its 2 entities ulcerative colitis and Crohn's disease, is a chronic medical condition characterized by the destructive inflammation of the intestinal tract. Biologics represent a class of therapeutics with immune intervention potential. These agents block the proinflammatory cascade that triggers the activation and proliferation of T lymphocytes at the level of the intestine, therefore reestablishing the balance between the pro- and anti-inflammatory messages. All 7 biologics showing clinical benefits in inflammatory bowel disease are monoclonal antibodies. The following systematic review discusses the pharmacokinetics and efficacy of the tumor necrosis factor blockers infliximab, adalimumab, certolizumab pegol, and golimumab. In addition, we describe the α4 integrin inhibitors natalizumab and vedolizumab, which are directed against cell adhesion molecules, as well as the interleukin 12/23 blocker ustekinumab.

Biologics or molecularly targeted drugs are often highly effective for the treatment of allergic diseases and other immunologic disorders, and they are relatively safe for short-term use as compared with conventional approaches such as the systemic use of corticosteroids. A number of studies published in 2021 consistently demonstrated their effectiveness and also revealed unanticipated findings. Among them, clinical trials for asthma and chronic obstructive pulmonary disease using biologics targeting thymic stromal lymphopoietin, IL-33, and IL-33 receptor demonstrated that these type 2 alarmin cytokines are also involved in non-type 2, noneosinophilic inflammation. Randomized controlled trials reporting the efficacies of 2 small-molecule oral drugs targeting Janus kinase-1 had a substantial impact on the management of atopic dermatitis. These drugs demonstrated superiority over dupilumab, which has previously demonstrated efficacy and is in wide use in clinical practice. As a concern, biologics are generally costly, and it should be noted that racial/ethnic minority populations may be less likely to receive biologics in the real world. Here, we have reviewed recent clinical trials and related topics dealing with the effects of biologics on allergic and immunologic diseases; in addition, we discuss how our understanding of the pathophysiology of these disorders has progressed.

Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

Introduction: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-α therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-α therapies (certolizumab pegol, golimumab).

Areas Covered: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments.

Expert Opinion: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects.

Schmitt et al.101 recently reviewed tolerability of biologic and nonbiologic therapies in a meta‐analysis. Tolerability assessed by withdrawals showed monthly withdrawal rates of 1·3% (range 0·5–1·6) for infliximab, 1·2% (0·6–1·9) for efalizumab, 0·4% (0·3–1·4) for etanercept and 0·3% for adalimumab. Additionally infusion reactions occurred in 2·1% of patients per month with infliximab. Serious adverse events occurred at a monthly rate of 1·1% with infliximab, 1·2% with efalizumab and 0·5% with adalimumab. Rates for etanercept could only be computed from the data for the 50 mg biweekly dose, and were 0·6%. Brimhall et al.102 conducted a meta‐analysis of adverse events of biologic therapies based on pooled short‐term trial data. They expressed a relative risk of adverse events and severe adverse events, compared with placebo. Risks for efalizumab were 1·15 (adverse events) and 1·43 (serious adverse events); for etanercept 1·05 (adverse events) and 1·17 (serious adverse events); and for infliximab 1·18 (adverse events) and 1·26 (serious adverse events). Of these, only the relative risk of adverse events with infliximab and serious adverse events with efalizumab reached an increased level of statistical significance. Adalimumab was not included in the analysis.
15.1 Tumour necrosis factor antagonist therapies
15.11 Infections: bacterial, mycobacterial, viral
Data from clinical trials indicate that infections are common, but overall rates of infection are no greater than with placebo.
Rheumatology registry data do suggest an increased risk of skin and soft tissue infections [adjusted incidence rate ratio 4·28, 95% confidence interval (CI) 1·06–17·17] compared with standard disease‐modifying antirheumatic drugs (DMARDs)100 and although these are poorly characterized, they have included erysipelas, cellulitis, furunculosis, folliculitis, paronychia and wound infections. An increased risk of herpes zoster has also been reported in rheumatology patients on TNF monoclonal antibody therapy, but not etanercept, from the German rheumatology registry: crude incidence rate per 1000 patient‐years 11·1 (95% CI 7·9–15·1) for the monoclonal antibodies, 8·9 (95% CI 5·6–13·3) for etanercept, and 5·6 (95% CI 3·6–8·3) for conventional DMARDs.103 When rates were adjusted for age, RA severity and glucocorticoid use, a significantly increased risk was still observed for treatment with the monoclonal antibodies (hazard ratio 1·82, 95% CI 1·05–3·15), but not etanercept or TNF antagonist therapy as a class. These findings are supported by cohort and case–control studies using data from the U.K. general practice research database and a U.S. health plan claims database which showed increased risk of herpes zoster with biologic therapy (infliximab, etanercept and anakinra) compared with DMARDs in patients with RA.104

The three licensed TNF(alpha) blocking agents (etanercept, infliximab, adalimumab) and the recombinant form of human interleukin-1-receptor antagonist (anakinra) have all been shown to be effective in patients with chronic rheumatic autoimmune diseases; they have also been associated with certain types of serious adverse events. As expected, much of the information on serious events have accumulated during the post-marketing period. Certain serious, but uncommon, adverse events have been observed with all three TNF(alpha) blocking agents, including serious bacterial infections, tuberculosis (TB) and certain opportunistic infections, demyelinating syndromes, and lupus-like reactions. These data suggest that these adverse reactions may be related to blockade of TNF(alpha) and may therefore represent class effects of these agents. However, the severity and degree of risk may not be the same with all three agents. Blockade of interleukin-1 activity with anakinra appears, at present, to be relatively safe. The safety profile of these products will continue to be developed through the use of the registry, periodic safety updates from the passive surveillance program, and safety data from controlled trials of biological therapy for other diseases. Physicians should minimize risks by patient selection and screening for opportunistic infections. Moreover, the choice of the biological agent must be tailored to minimize risks and maximize benefits.

Biological agents represent a major advance in the treatment of rheumatic diseases, most particularly in the prevention of irreversible structural damage. While generally well tolerated, their increasing use continues to reveal a variety of immune-mediated adverse effects. The most frequent adverse events are infusion reactions and injection site reactions, but despite their fairly common occurrence the precise mechanisms are not fully understood. Another adverse event that became appreciated early in the era of biologicals is the increased risk of Mycobacterium tuberculosis and other granulomatous infections in patients treated with tumor necrosis factor (TNFα) antagonists. Although it is evident that this enhanced susceptibility to intracellular infections must be due to immunosuppression arising from the blockade of TNFα, the mechanisms have not been fully elucidated; such an understanding is likely to provide important insights into the role of TNFα in granulomatous and other infectious diseases. In addition, the biologicals may paradoxically induce autoimmunity. The development of autoantibodies is seen in a considerable proportion of patients, but clinical autoimmune disease develops much less commonly, including systemic lupus erythematosus, multiple sclerosis and other demyelinating diseases, psoriasis, sarcoidosis, and interstitial lung disease. The mechanisms leading to their induction are very poorly understood, but an intriguing hypothesis is that interferon α provides a common link, at least for lupus, psoriasis and possibly sarcoidosis. Finally, the potential risk of infection with use of the biologicals is an issue that clinicians should always be aware of. These comments aside, the biologics are the most important advance in the treatment of rheumatic disease in the history of rheumatology and their usage has not only greatly helped patient care, but also provided key data on the immunobiology of the disease processes.

The advent of biologics brought a paradigm shift in ways to treat psoriatic patients because they have dramatic efficacy. At the same time, safety concerns about biologics have been raised. In this paper, we focus on the safety profile of biologics for psoriasis. As of 2017, six biologics are available in Japan. Two tumor necrosis factor-α inhibitors; infliximab and adalimumab, one anti-interleukin (IL)-12/23p40 antibody; ustekinumab, and IL-17 inhibitors; secukinumab, ixekizumab and brodalumab. Secukinumab and ixekizumab are anti-IL-17A antibodies. Brodalumab is an anti-IL17RA antibody. In this review, we pick up topics which have drawn attention regarding the safety of biologics and discuss them with recent published work.

Purpose Of The Review: As treatment options for Inflammatory Bowel Disease (IBD) expand each class of medication will have specific safety concerns and side-effect profiles that need to be considered for optimal treatment of patients. We will review the most recent safety data for the newly approved immunomodulator therapies for the treatment of IBD.

Recent Findings: There are a growing number of publications outlining safety concerns for medications used to treat IBD. We reviewed safety profile of anti-tumor necrosis factor antibodies (TNF) with specific attention to combination therapy (anti-TNF plus immunomodulator). Recent publications have demonstrated increased risk of serious infection and malignancy (lymphoma and overall cancer rates) in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immunomodulator monotherapy. Recent publications on Janus Kinase Inhibitors indicate an increased risk of infection, specifically Herpes Zoster, and increased risk of major cardiovascular events and venous thromboembolic events resulting in a black box warning for the medication. In contrast, anti-interleukin 12/23 agents and gut selective anti-integrin antibody agents have demonstrated a favorable side-effect profile with low rates of infection and malignancy. The latest class of medications to be approved, sphingosine 1-phosphate (S1P) receptor modulators, have cardiac and infectious precautions. The field of IBD treatment is rapidly evolving with several mechanistic classes of medications now available. While corticosteroids continue to be associated with the greatest, overall, safety risks, each of the newer mechanistic classes have unique safety concerns. In the future, as we gain more experience with these agents, we will need to continue to evaluate the safety profile of our therapies used alone or in combination to make informed treatment decisions with our patients.

Background: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers.

Methods: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk.

Results: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA.

Conclusion: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

The biologic era has greatly improved the treatment of Crohn's disease and ulcerative colitis. Biologics can however induce a wide variety of skin eruptions, especially those targeting the TNF-α and Th17 pathway. These include infusion reactions, eczema, psoriasis, lupus, alopecia areata, vitiligo, lichenoid reactions, granulomatous disorders, vasculitis, skin cancer, and cutaneous infections. It is important to recognize these conditions as treatment-induced adverse reactions and adapt the treatment strategy accordingly. Some conditions can be treated topically while others require cessation or switch of the biological therapy. TNF-α antagonists have the highest rate adverse skin eruptions followed by ustekinumab and anti-integrin receptor blockers. In this review, we provide an overview of the most common skin eruptions which can be encountered in clinical practice when treating IBD (Inflammatory bowel disease) patients and propose a therapeutic approach for each condition.

The use of biologic agents as therapies for atopic diseases such as asthma and atopic dermatitis has increased greatly in recent years. The biological agents used to treat atopic diseases are for the most part monoclonal antibodies that suppress the immune response and reduce inflammation by targeting particular cytokines or other molecules involved in Th1, Th2, or Th17 immune reactions. Various side effects and rare complications have been reported from these agents. In this review, we discuss mechanisms of various adverse effects for the biologic agents currently in use or in development for atopic and inflammatory diseases. Monoclonal antibodies targeting the Th1 and Th17 pathways have been associated with significant side effects, partially due to their ability to cause significant impairment in immune responses to pathogens because of the immunologic alterations that they produce. Biologicals targeting Th2-mediated inflammation have had fewer reported side effects, though many are new and emerging drugs whose adverse effects may remain to be fully elucidated with more use. Therefore, continued long-term safety monitoring is required. As with all therapies, the risks associated with side effects of biologics must be balanced against the benefits these drugs offer for treating atopic diseases. One of the most apparent benefits is the steroid-sparing effect of well-chosen biologic therapy used to treat severe atopic disease. In contrast with the quite favorable safety profile of currently available biologics that target the Th2-mediated immune response, chronic systemic corticosteroid use is associated with significant side effects, many of which impact the majority of patients who are placed on long-term steroid therapy.

Introduction: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-α therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-α therapies (certolizumab pegol, golimumab).

Areas Covered: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments.

Expert Opinion: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects.

Biologic treatments--including five TNF-α inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy.

Introduction: More than 15 years after its introduction, there is still no agreement as to whether anti-TNF treatment increases the risk of developing infections, cardiovascular or neurological diseases, or auto-antibodies. Anti-TNF drugs reduce inflammation and sub-clinical atherosclerosis in rheumatoid arthritis (RA) patients, but they also alter their lipid profiles and can lead to the development of severe infections. Furthermore, as they increase the risk of developing demyelinating diseases, are not recommended in patients with multiple sclerosis or related disorders. The authors searched the Medline database for English language articles concerning the adverse events of anti-TNF drugs published between 1998 and December 2019, and have summarized their contents relating to infections, malignancies, cardiovascular diseases, autoimmunity and neurological diseases. Patients should be fully informed of the increased risks associated with anti-TNF drugs, and physicians should know how to treat them.

Areas Covered: This review considers these safety concerns, their possible underlying causes, and other aspects that are important in clinical practice.

Expert Opinion: Growing concern about the safety of anti-TNF drugs underlines the need to ensure that all clinicians are capable of taking appropriate preventive and therapeutic action.

Purpose Of Review: The landscape for treatment of rheumatic diseases is ever evolving, with several new drugs recently approved across diseases and more in the pipeline. This timely review aims to highlight the latest literature on long-term safety profiles of salient established and emerging biologic (b) and targeted synthetic (ts) disease modifying antirheumatic drugs (DMARDs).

Recent Findings: The risk of infection remains elevated with the use of most b and tsDMARDs, with specifically risk of hepatitis B reactivation with rituximab and zoster infection with JAK inhibitors (JAKi). The results of the ORAL surveillance trial led to new black box warnings for JAKi and evoked critical risk-benefit discussions surrounding JAKi and DMARDs overall.

Summary: Such well conducted trials are needed to gather long term comparative safety data of DMARDs. In the interim, real world observational studies also have a role to play in our understanding of long-term drug safety, provided that detailed attention is paid to minimize biases inherent in observational studies.

Background And Aims: Recent studies raise concern for increased risk of major adverse cardiovascular events (MACE) with Janus kinase (JAK) inhibitors used to treat immune-mediated inflammatory disorders (IMIDs). We aimed to examine MACE risk with licensed biologics and small molecules used commonly between IMIDs: inflammatory bowel disease, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis.

Methods: Data were obtained from systematic searches (from inception to May 31, 2022) in PubMed, Embase, Ovid Medline, Scopus, Cochrane Central, and ClinicalTrials.gov. Studies that assessed a predefined MACE (myocardial infarction, cerebrovascular accident, unstable angina, cardiovascular death, or heart failure) risk in those ≥18 years of age with IMIDs treated with anti-interleukin (IL)-23 antibodies, anti-IL-12/23, anti-tumor necrosis factor α antibodies (anti-TNF-α), or JAK inhibitors were included in a network meta-analysis using a random-effects model with pooled odds ratios (ORs) reported with 95% credible intervals (CrIs) by drug class and disease state.

Results: Among 3528 studies identified, 40 (36 randomized controlled trials and 4 cohort studies) were included in the systematic review, comprising 126,961 patients with IMIDs. Based on network meta-analysis of randomized controlled trials, regardless of disease state, anti-TNF-α (OR, 2.49; 95% CrI, 1.14-5.62), JAK inhibitors (OR, 2.64; 95% CrI, 1.26-5.99), and anti-IL-12/23 (OR, 3.15; 95% CrI, 1.01-13.35) were associated with increased MACE risk compared with placebo. There was no significant difference in the magnitude of the MACE risk between classes or based on IMID type.

Conclusions: Anti-IL-12/23, JAK inhibitors, and anti-TNF-α were associated with higher risk of MACE compared with placebo. The magnitude of the increased MACE risk was not different by IMID type. These results require confirmation in larger prospective studies.

Purpose Of The Review: As treatment options for Inflammatory Bowel Disease (IBD) expand each class of medication will have specific safety concerns and side-effect profiles that need to be considered for optimal treatment of patients. We will review the most recent safety data for the newly approved immunomodulator therapies for the treatment of IBD.

Recent Findings: There are a growing number of publications outlining safety concerns for medications used to treat IBD. We reviewed safety profile of anti-tumor necrosis factor antibodies (TNF) with specific attention to combination therapy (anti-TNF plus immunomodulator). Recent publications have demonstrated increased risk of serious infection and malignancy (lymphoma and overall cancer rates) in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immunomodulator monotherapy. Recent publications on Janus Kinase Inhibitors indicate an increased risk of infection, specifically Herpes Zoster, and increased risk of major cardiovascular events and venous thromboembolic events resulting in a black box warning for the medication. In contrast, anti-interleukin 12/23 agents and gut selective anti-integrin antibody agents have demonstrated a favorable side-effect profile with low rates of infection and malignancy. The latest class of medications to be approved, sphingosine 1-phosphate (S1P) receptor modulators, have cardiac and infectious precautions. The field of IBD treatment is rapidly evolving with several mechanistic classes of medications now available. While corticosteroids continue to be associated with the greatest, overall, safety risks, each of the newer mechanistic classes have unique safety concerns. In the future, as we gain more experience with these agents, we will need to continue to evaluate the safety profile of our therapies used alone or in combination to make informed treatment decisions with our patients.

Autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and others, are characterized by dysregulation of various aspects of normal immunity and inflammation. Biologic agents targeting key components of the dysregulated immune response have dramatically improved patient outcomes and transformed treatment paradigms for a number of systemic inflammatory autoimmune diseases. Despite their excellent efficacy, because they do affect normal immune responsiveness, biologic agents can potentially be associated with a variety of adverse effects. Important potential adverse effects related to the use of biologic agents include immunosuppression, which might result in outcomes such as infection, and autoimmunity, that could result in paradoxical inflammation or even autoimmune disease. In this article the current clinical evidence and immunologic mechanisms of the adverse effects related to biologic agents are discussed.

Background: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies.

Aims: To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations.

Sources: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family.

Content: Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti-Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles-mumps-rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made.

Implications: Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy.

BACKGROUND &

Aims: Management of immune-mediated inflammatory diseases often requires lifelong immunosuppression. Increasing numbers of older patients have inflammatory diseases and are particularly vulnerable to risks of immune suppressive therapies-particularly infections and malignancies.

Methods: We systematically searched PubMed/Medline and Embase to identify eligible studies that examined the safety of biologic therapies in older patients with immune-mediated inflammatory diseases (inflammatory bowel disease, rheumatoid arthritis, psoriasis). Included studies provided information on patients who began receiving therapy with a biologic agent when they were older than 60 years and a control population (either younger users of biologics or older patients who did not use biologics). Information of on overall pooled rates of infections, malignancy, and mortality were extracted. A DerSimonian and Laird random effects model was used to calculate pooled odds ratios (ORs) and 95% CIs.

Results: Our meta-analysis included 14 unique studies that comprised 4719 older users of biologics, 13,305 younger users of biologics, and 3961 older patients who did not use biologics. The pooled prevalence of infections in older and younger users of biologics was 13% and 6% respectively, yielding a pooled random effects odds ratio of 2.28 (95% CI, 1.57-3.31). Older age was associated with a significant increase in risk of malignancy (OR, 3.07; 95% CI, 1.98-4.62) compared to younger age. Older users of biologics had a 3-fold increase in risk of infection compared to patients who did not use biologics (OR, 3.60; 95% CI, 1.62-8.01), but there were no significant differences in odds of malignancy (0.54, 95% CI, 0.28-1.05) or death (OR, 1.52; 95% CI, 0.44-5.28) compared to older patients who did not use biologics.

Conclusion: In a systematic review and meta-analysis of studies on the safety of biologic therapies in older patients with inflammatory diseases, we found that older users of biologic agents have an increased risk of infections compared with younger users or older patients who do not use biologics. Large, prospective cohort studies are needed to examine safety of biologic therapy in older patients with immune-mediated diseases.

Biologics are generally either custom-designed monoclonal antibodies against specific target cells (e.g. B-cells) or target cytokines (e.g. tumour necrosis factor, TNF) or they are receptor constructs (fusion proteins) based on naturally-occurring cytokine or cell receptors. Biologics are mostly used in adult rheumatology but are increasingly used in paediatrics. There are significant concerns about safety and also about cost. The main safety concerns are about increased risk of infection and malignancy. The use of TNF antagonists is associated with increased risk of serious infections with intracellular organisms, particularly mycobacteria, but also intracellular bacteria, fungi and Pneumocystis. B-cell antagonists like rituximab can cause progressive multifocal leukoencephalopathy. IL-6 antagonists are associated with increased rates of common bacterial infections and the complement pathway antagonist eculizumab with meningococcal infection. The risk of some infections associated with biologics can be reduced, by screening patients starting TNF antagonists for latent tuberculosis and giving them cotrimoxazole prophylaxis against Pneumocystis, and by immunising against VZV, hepatitis B, meningococci and pneumococci. However, the risk of the biologics causing serious infection in children is unknown and needs study. Children should not be started on the biologics without careful consideration of the risks and without fully informed consent.

Purpose Of Review: The introduction of tumor necrosis factor-alpha antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged.

Recent Findings: These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosus-like syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-alpha antagonists.

Summary: Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required.

Context: Tumor necrosis factor (TNF) plays an important role in host defense and tumor growth control. Therefore, anti-TNF antibody therapies may increase the risk of serious infections and malignancies.

Objective: To assess the extent to which anti-TNF antibody therapies may increase the risk of serious infections and malignancies in patients with rheumatoid arthritis by performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapy.

Data Sources: A systematic literature search of EMBASE, MEDLINE, Cochrane Library, and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through December 2005. This search was complemented with interviews of the manufacturers of the 2 licensed anti-TNF antibodies.

Study Selection: We included randomized, placebo-controlled trials of the 2 licensed anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis. Nine trials met our inclusion criteria, including 3493 patients who received anti-TNF antibody treatment and 1512 patients who received placebo.

Data Extraction: Data on study characteristics to assess study quality and intention-to-treat data for serious infections and malignancies were abstracted. Published information from the trials was supplemented by direct contact between principal investigators and industry sponsors.

Data Synthesis: We calculated a pooled odds ratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalization) in anti-TNF-treated patients vs placebo patients. We estimated effects for high and low doses separately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of anti-TNF antibodies. For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months.

Conclusions: There is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy. The formal meta-analysis with pooled sparse adverse events data from randomized controlled trials serves as a tool to assess harmful drug effects.

Biologic treatments--including five TNF-α inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy.

Biological agents represent a major advance in the treatment of rheumatic diseases, most particularly in the prevention of irreversible structural damage. While generally well tolerated, their increasing use continues to reveal a variety of immune-mediated adverse effects. The most frequent adverse events are infusion reactions and injection site reactions, but despite their fairly common occurrence the precise mechanisms are not fully understood. Another adverse event that became appreciated early in the era of biologicals is the increased risk of Mycobacterium tuberculosis and other granulomatous infections in patients treated with tumor necrosis factor (TNFα) antagonists. Although it is evident that this enhanced susceptibility to intracellular infections must be due to immunosuppression arising from the blockade of TNFα, the mechanisms have not been fully elucidated; such an understanding is likely to provide important insights into the role of TNFα in granulomatous and other infectious diseases. In addition, the biologicals may paradoxically induce autoimmunity. The development of autoantibodies is seen in a considerable proportion of patients, but clinical autoimmune disease develops much less commonly, including systemic lupus erythematosus, multiple sclerosis and other demyelinating diseases, psoriasis, sarcoidosis, and interstitial lung disease. The mechanisms leading to their induction are very poorly understood, but an intriguing hypothesis is that interferon α provides a common link, at least for lupus, psoriasis and possibly sarcoidosis. Finally, the potential risk of infection with use of the biologicals is an issue that clinicians should always be aware of. These comments aside, the biologics are the most important advance in the treatment of rheumatic disease in the history of rheumatology and their usage has not only greatly helped patient care, but also provided key data on the immunobiology of the disease processes.

Purpose Of Review: The landscape for treatment of rheumatic diseases is ever evolving, with several new drugs recently approved across diseases and more in the pipeline. This timely review aims to highlight the latest literature on long-term safety profiles of salient established and emerging biologic (b) and targeted synthetic (ts) disease modifying antirheumatic drugs (DMARDs).

Recent Findings: The risk of infection remains elevated with the use of most b and tsDMARDs, with specifically risk of hepatitis B reactivation with rituximab and zoster infection with JAK inhibitors (JAKi). The results of the ORAL surveillance trial led to new black box warnings for JAKi and evoked critical risk-benefit discussions surrounding JAKi and DMARDs overall.

Summary: Such well conducted trials are needed to gather long term comparative safety data of DMARDs. In the interim, real world observational studies also have a role to play in our understanding of long-term drug safety, provided that detailed attention is paid to minimize biases inherent in observational studies.

Background: Uncertainty exists concerning the risk of infection and cancer associated with biologic therapies in elderly patients with inflammatory bowel disease (IBD).

Aims: To identify, synthesise and critically appraise the available evidence on the topic.

Methods: We systematically searched Medline/PubMed, Embase and Scopus, through October 2019, and recent conference proceedings, to identify studies investigating the risk of serious infections, opportunistic infections, any infection and cancer in elderly IBD patients (>60 years) exposed to biologics as compared to those unexposed to biologics. Two reviewers independently extracted study data and assessed each study's risk of bias. We examined heterogeneity, and calculated summary effect estimates using fixed- and random effects models. Quality of evidence was determined with GRADE.

Results: We included 15 studies (one post hoc analysis of a randomised trial, nine cohort and five case-control studies). Elderly IBD patients treated with biologics were at increased risk of developing serious infections (random effects summary relative risk: 2.70, 95%

Ci: 1.56-4.66; seven studies; I  = 57%) and opportunistic infections (3.16, 1.09-9.20; four studies; I  = 73%). The occurrence of any infection (1.67, 0.51-5.43; five studies; I  = 75%) and cancer (0.90, 0.64-1.26; nine studies; I  = 0%) was not significantly affected. Nevertheless, our confidence in the effect estimates is rather limited; the quality of evidence is low to very low.

Conclusions: Biologics are likely to increase the risk of serious and opportunistic infections in old IBD patients. Large prospective studies are needed to further assess the biologic treatments' long-term safety profile in this population.

The introduction of biologic therapy for the treatment of IBD has substantially changed its management. The safety concerns associated with biologic therapies include the increased risk of infection, autoimmunity, development of lymphoma and demyelinating disease, and the risk of worsening heart failure. There are several strategies for minimizing the risks associated with biologic therapies. Pretreatment strategies include taking a proper history from the patient, physical examination of the patient, screening for latent tuberculosis and ruling out sepsis. Vaccination of patients against vaccine preventable diseases is also recommended. During treatment, patients should be closely monitored and any symptoms that develop should be dealt with early. Education of physicians and patients is also important to allow the early detection of any adverse events.

Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--are more biologically potent than alpha-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn's disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB(4) produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.

Clearly there is much evidence to show that under well-controlled laboratory and dietary conditions fatty acid intake can have profound effects on animal models of autoimmune disease. Studies in human autoimmune disease have been less dramatic; however, human trials have been subject to uncontrolled dietary and genetic backgrounds, infection and other environmental influences, and basic trial designs have been inadequate. The impact of dietary fatty acids on animal autoimmune disease models appears to depend on the animal model and the type and amount of fatty acids fed. Diets low in fat, essential fatty acid-deficient, or high in n-3 fatty acids from fish oils increase the survival and reduce disease severity in spontaneous autoantibody-mediated disease, whilst linoleic acid-rich diets appear to increase disease severity. In experimentally-induced T-cell-mediated autoimmune disease, essential fatty acid-deficient diets or diets supplemented with n-3 fatty acids appear to augment disease, whereas n-6 fatty acids prevent or reduce the severity. In contrast, in both T-cell and antibody-mediated auto-immune disease the desaturated and elongated metabolites of linoleic acid are protective. Suppression of autoantibody and T lymphocyte proliferation, apoptosis of autoreactive lymphocytes, and reduced pro-inflammatory cytokine production by high-dose fish oils are all likely mechanisms by which n-3 fatty acids ameliorate autoimmune disease. However, these could be undesirable long-term effects of high-dose fish oil which may compromise host immunity. The protective mechanism(s) of n-6 fatty acids in T-cell- mediated autoimmune disease are less clear, but may include dihomo-gamma-linolenic acid- and arachidonic acid-sensitive immunoregulatory circuits such as Th1 responses, TGF beta 1-mediated effects and Th3-like responses. It is often claimed that n-6 fatty acids promote autoimmune and inflammatory disease based on results obtained with linoleic acid only. It should be appreciated that linoleic acid does not reflect the functions of dihomo-gamma-linolenic and arachidonic acid, and that the endogenous rate of conversion of linoleic to arachidonic acid is slow (Hassam et al. 1975, 1977; Phylactos et al. 1994; Harbige et al. 1995). In addition to effects of dietary fatty acids on immunoregulation, inflammation as a consequence of immune activation in autoimmune disease may also be an important mechanism of action whereby dietary fatty acids modulate disease activity. In conclusion, regulation of gene expression, signal transduction pathways, production of eicosanoids and cytokines, and the action of antioxidant enzymes are all mechanisms by which dietary n-6 and n-3 fatty acids may exert effects on the immune system and autoimmune disease. Probably the most significant of these mechanisms in relation to our current understanding of immunoregulation and inflammation would appear to be via fatty acid effects on cytokines. The amount, type and balance of dietary fatty acids and associated antioxidant nutrients appear to impact on the immune system to produce immune-deviation or immunosuppressive effects, and to reduce immune-mediated inflammation which will in turn affect the susceptibility to, or severity of, autoimmune disease.

Omega-3 polyunsaturated fatty acids (PUFA) have demonstrated anti-inflammatory properties, while Omega-6 have pro-inflammatory effects, and the balance between the two is an important aspect of healthy nutrition. Over the last 30 years, however, the Western diet has shifted largely from Omega-3 to Omega-6 consumption. Uncontrolled aberrant and chronic inflammation is a leading component of many common diseases, including arthritis, cardiovascular diseases, neurodegenerative diseases, cancer, obesity, autoimmune diseases, and infective diseases. Eicosanoids derived from Omega-6 participate in the inflammatory process, while Omega-3 PUFA have the opposite effect. Many favorable effects of Omega-3 are believed to result from their anti-inflammatory properties, but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have inhibitory effects on immune cells and reduce proinflammatory cytokine release. All these mechanisms can be beneficial in autoimmunity. No effective preventions or definite cures for autoimmune diseases are yet known because pathophysiology is also unclear. Omega-3 fatty acid supplementation is associated with a significant reduction in disease activity in several autoimmune diseases, like type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Studies of viral diseases, including COVID-19, show improvement in symptom severity, recovery prognosis, and probability of survival with the use of Omega-3. Finally, the evidence of the beneficial effect of Omega-3 on metabolic diseases associated with aging is persuasive; various studies have demonstrated that their consumption improves lipids, fatty liver disease, obesity, cognitive function, and cardiovascular complications of chronic kidney disease (CKD). Omega-3 PUFA have also been shown to support an anti-inflammatory effect in older age and to have favorable effects on age-related disease's complications, frailty, and mortality. A healthy Omega-6/3 PUFA ratio should be targeted for the modulation of low-grade inflammation, as well as for the prevention of immune dysregulation and complications of uncontrolled inflammation triggered by infections, development, and progression of autoimmune disorders, and the consequences of oxidative stress due to aging. There is still a need for randomized clinical studies to validate current evidence supporting supplementation with correct doses of Omega-3 PUFA in autoimmune and chronic disease prevention.

The problem of treating inflammatory bowel disease continues to be a topic of great interest for researchers. Despite the complexity surrounding their treatment and strategies to prolong periods of remission, there is a promising exploration of various compounds that have potential in combating inflammation and alleviating symptoms. Selenium, calcium, magnesium, zinc, and iron are among these compounds, offering a glimpse of hope in the treatment of IBD. These essential minerals not only hold the promise of reducing inflammation in these diseases, but also show the potential to enhance immune function and possibly influence the balance of intestinal microflora. By potentially modulating the gut microbiota, they may help support overall immune health. Furthermore, these compounds could play a crucial role in mitigating inflammation and minimising complications in patients with IBD. Furthermore, the protective effect of these compounds against mucosal damage in IBD and the protective effect of calcium itself against osteoporosis in this group of patients are notable.

As well represented by the impaired immune function of malnourished individuals encountered in developing countries and the incidence of specific diseases following local nutrient deficiencies, nutrition and immunity have been linked to each other for centuries while the specific connection between dietary factors and autoimmunity onset or modulation is a more recent acquisition. Autoimmune diseases manifest limited prevalence rates in developing countries while numerous immunity-related claims have been proposed in the field of functional foods. Nevertheless, over the past years multiple lines of evidence have supported a major role for specific dietary factors (including vitamin D, vitamin A, selenium, zinc, omega-3 fatty acids, probiotics, and flavanols) in determining the immune responses involved in infections, allergies, and autoimmune diseases. Interestingly, the link between nutrition and autoimmunity may well contribute to the geoepidemiology observed for numerous conditions. In general terms, most data that will be discussed herein were obtained in experimental or animal models while human data from real-life clinical settings or randomized clinical trials remain largely unsatisfactory. Our current knowledge on the beneficial impact of nutrition on autoimmunity prompts us to encourage the search for evidence-based nutrition to support the everyday diet choices of patients.

The hypothesis that oxidative stress favours flogistic and immune processes inducing autoimmune rheumatic diseases (ARDs) and their complications is still under discussion. In this review we take into consideration both the aetiopathological role of the diet in such diseases and the possible efficacy of dietary supports as adjuvants for the usual specific therapies. Moreover, we shall examine the hypothetical pathophysiological role of oxidative stress on ARDs and their complications, the methods for its evaluation and the possibility of intervening on oxidative pathways by means of nutritional modulation. It is possible that in the future we will be able to control connective pathology by associating an immuno-modulating therapy ('re-educating') with natural products having an anti-oxidant activity to current immunosuppressive treatment (which has potentially toxic effects).

Despite an incomplete overall understanding, nutrition plays an important role in connective tissue disease. Assessment of patients with connective tissue disease for nutritional status and metabolic disturbances may significantly contribute to patient outcomes. Several studies have indicated the multifactorial role of macronutrients, micronutrients, and supplements in the setting of connective tissue disease. There is additional evidence regarding the roles of weight, obesity, and malnutrition. This contribution reviews a growing body of data regarding nutrition in the development and treatment of various connective tissue diseases, including systemic lupus erythematosus, dermatomyositis, and systemic sclerosis.

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.

Accumulating research evidence suggests that nutrition might be implicated in the risk of development and in the management of autoimmune disease, including rheumatoid arthritis (RA), characterized by immune-inflammatory response. Nutrition can have direct roles through the provision of pro- or anti-inflammatory foods, and indirect roles through management of co-morbidity management. The review updates on the evidence relating RA risk and management with focus on specific foods such as fish and diets/dietary patterns such as the Mediterranean diet, fasting and elimination diets and oral nutritional supplements including omega-3 polyunsaturated fatty acids (PUFA). Evidence on herbs and spices, beverages, Vitamin D, and probiotics is also reviewed. Diet has been shown to improve disease activity through reducing inflammation and oxidation and through its beneficial effects on the gut microbiota. Based on the existing evidence, it is recommended that as an adjunct to medical treatment, nutrition therapy for RA should be based on an anti-inflammatory Mediterranean diet (MD) supplemented with at least twice a week consumption of oily fish and/or omega-3 PUFA supplements at 2 g/day. The need for rheumatologists to work more closely with registered dietitians in the management of patients particularly in supporting a well-balanced diet according to individual needs, is highlighted.

Rheumatoid arthritis (RA) is a systemic, autoimmune disease characterized by joint involvement, with progressive cartilage and bone destruction. Genetic and environmental factors determine RA susceptibility. In recent years, an increasing number of studies suggested that diet has a central role in disease risk and progression. Several nutrients, such as polyunsaturated fatty acids, present anti-inflammatory and antioxidant properties, featuring a protective role for RA development, while others such as red meat and salt have a harmful effect. Gut microbiota alteration and body composition modifications are indirect mechanisms of how diet influences RA onset and progression. Possible protective effects of some dietary patterns and supplements, such as the Mediterranean Diet (MD), vitamin D and probiotics, could be a possible future adjunctive therapy to standard RA treatment. Therefore, a healthy lifestyle and nutrition have to be encouraged in patients with RA.

Vitamin D plays a key role in in calcium homeostasis and, thus, provides an important support in bone growth by aiding in the mineralization of the collagen matrix. However, vitamin D performs various immunomodulatory, anti-inflammatory, antioxidant and anti-fibrotic actions. Autoimmune diseases result from an aberrant activation of the immune system, whereby the immune response is directed against harmless self-antigens. Does vitamin D play a role in the pathophysiology of autoimmune diseases? And, if so, what is its role? In the last decade, researchers' interest in vitamin D and its correlations with autoimmune diseases has considerably increased. We conducted a literature review, covering the period January 1, 2009 through March 30, 2019, in PubMed. We analyzed more than 130 studies in order to find a correlation between vitamin D levels and its effect upon several autoimmune diseases. The analysis demonstrated an inverse association between vitamin D and the development of several autoimmune diseases, such as SLE, thyrotoxicosis, type 1 DM, MS, iridocyclitis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, seropositive RA, polymyalgia rheumatica. International multicenter study could allow us to confirm the data already present in the literature in the single clinical studies and to evaluate when to effectively supplement vitamin D in patients who do not take corticosteroids.

Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--are more biologically potent than alpha-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn's disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB(4) produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.

Vitamin D plays a key role in in calcium homeostasis and, thus, provides an important support in bone growth by aiding in the mineralization of the collagen matrix. However, vitamin D performs various immunomodulatory, anti-inflammatory, antioxidant and anti-fibrotic actions. Autoimmune diseases result from an aberrant activation of the immune system, whereby the immune response is directed against harmless self-antigens. Does vitamin D play a role in the pathophysiology of autoimmune diseases? And, if so, what is its role? In the last decade, researchers' interest in vitamin D and its correlations with autoimmune diseases has considerably increased. We conducted a literature review, covering the period January 1, 2009 through March 30, 2019, in PubMed. We analyzed more than 130 studies in order to find a correlation between vitamin D levels and its effect upon several autoimmune diseases. The analysis demonstrated an inverse association between vitamin D and the development of several autoimmune diseases, such as SLE, thyrotoxicosis, type 1 DM, MS, iridocyclitis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, seropositive RA, polymyalgia rheumatica. International multicenter study could allow us to confirm the data already present in the literature in the single clinical studies and to evaluate when to effectively supplement vitamin D in patients who do not take corticosteroids.

Rheumatoid arthritis (RA) is a systemic, autoimmune disease characterized by joint involvement, with progressive cartilage and bone destruction. Genetic and environmental factors determine RA susceptibility. In recent years, an increasing number of studies suggested that diet has a central role in disease risk and progression. Several nutrients, such as polyunsaturated fatty acids, present anti-inflammatory and antioxidant properties, featuring a protective role for RA development, while others such as red meat and salt have a harmful effect. Gut microbiota alteration and body composition modifications are indirect mechanisms of how diet influences RA onset and progression. Possible protective effects of some dietary patterns and supplements, such as the Mediterranean Diet (MD), vitamin D and probiotics, could be a possible future adjunctive therapy to standard RA treatment. Therefore, a healthy lifestyle and nutrition have to be encouraged in patients with RA.

The impact of dietary interventions such as specific types of diet or nutritional supplements in rheumatoid arthritis (RA) has been subject to increased attention in recent years. The recognition of the unmet need to better understand the effects of specific dietary interventions on disease outcomes in RA, along with the growing patient interest on lifestyle interventions beyond pharmacotherapy, have informed the undertaking of this narrative literature review. The benefits of the Mediterranean Diet (MD) have been shown in various studies, although only a limited number of trials focus specifically on RA. Based on the studies reviewed, the MD may provide benefits in reducing pain and swollen and tender joints in RA patients. There is more and better evidence that n-3 polyunsaturated fat (PUFA) supplementation has the potential to reduce inflammation and provide clinical benefit, possibly slowing progression to pharmacotherapy. Yet, many of these studies to date are limited in their methodology; this being partly a reflection of the complexity of the research questions being addressed. Consequently, the conclusions that can be robustly drawn from their results are restricted. With a focus on clinical trials on the MD and fish oil supplementation, this review critically appraises the evidence, discussing the findings of studies in the wider context of impact on RA outcomes, methodological challenges, and practical points to consider as part of the routine care of RA patients.

Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.

To date, there is no robust evidence of increased risk of malignancy with TNF antagonists in patients with psoriasis. Data from clinical trials are reassuring, and there is no indication from registry data in rheumatology populations of increased risk of solid tumours and lymphoma with TNF antagonist therapy as compared with standard DMARDs to date.126 However, uncertainty and conflicting evidence remain around the possible increased risk of lymphoma, possibly because lymphomas are more common in patients with severe RA. Bongartz et al.127 carried out a meta‐analysis of nine trials of patients with RA treated with infliximab or adalimumab. The data included 3493 patients who received TNF antagonist treatment and 1512 patients who received placebo and demonstrated a pooled odds ratio for malignancy of 3·3 (95% CI 1·2–9·1). This paper raised a variety of methodological concerns128129–130 which included lack of adjustment for duration of exposure to TNF antagonist therapy, inclusion of open‐label extension data for biologic therapy with no comparable placebo data, infliximab induction doses exceeding labelled dose in approximately 50% of patients and an unexpectedly low rate of malignancy in the control arms. In addition, both infliximab and adalimumab have been rarely associated with hepatosplenic T‐cell lymphoma.131 This rare, aggressive, and usually fatal tumour has occurred in adolescents and young adults with Crohn’s disease who were also receiving treatment with azathioprine or mercaptopurine.132–136 There are also reports of cases of early onset of lymphoma after introduction of TNF antagonist therapy137, 138 and regression of lymphoma following withdrawal of TNF antagonist therapy.137, 139
With respect to skin cancer, data on TNF antagonists in RA are inconsistent. Pharmacovigilance data on 1440 patients with RA treated with etanercept from clinical trials (3530 person‐years total exposure time) did not show any link between squamous cell carcinoma (SCC) development and etanercept.140 Lebwohl et al.141 carried out a retrospective analysis of 1442 patients with RA treated with etanercept for up to 5 years and similarly found no increased incidence of SCC (observed four SCCs, expected 5·9–13·1). However, an increased risk of nonmelanoma skin cancer (NMSC) (odds ratio 1·5, 95% CI 1·2–1·8) and a trend towards increased risk of melanoma (odds ratio 2·3, 95% CI 0·9–5·4) has recently been reported in a large (> 13 000 patients) observational study comparing rates of malignancy in patients with RA on biologic therapies with population rates (drug‐specific data from this analysis are given in the relevant section below).139

Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.

Background: TNF inhibitors (TNFi) effectively treat rheumatoid arthritis but may increase patient risk of some malignancies, particularly lymphomas or skin cancers.

Methods: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to conduct a case-control study in patients with rheumatoid arthritis (2007-2015). Cases were individuals with a first cancer diagnosed in SEER registries (ages 66-99, 22 cancer sites, = 10,263). Skin cancer cases [nonmelanoma skin cancer (NMSC, = 501), basal cell carcinoma (BCC, = 161), squamous cell carcinoma (SCC, = 150)] and cancer-free controls ( = 30,475) were selected from Medicare beneficiaries residing in SEER areas. Cases and controls had prior Medicare claims-based evidence for rheumatoid arthritis, and TNFi exposure was ascertained from part B and part D claims. Logistic regression was used to estimate adjusted odds ratios (aOR).

Results: TNFi exposure was present in 16.2% of controls and 12.8% to 33.7% of cancer cases, varying by site. TNFi use was associated with increased risk of NMSC overall (aOR 1.32, 95% confidence interval 1.06-1.63), non-Hodgkin lymphoma (NHL) overall (1.28, 1.06-1.56) and, specifically, follicular lymphoma (2.63, 1.63-4.24). TNFi exposure was not associated with other SEER cancer sites, BCC or SCC specifically, or other common NHL subtypes.

Conclusions: Among older adults with rheumatoid arthritis, TNFi exposure was associated with elevated risk of NMSC and NHL, driven specifically by follicular lymphoma. Exposure was not associated with increased risk for other cancer sites.

Impact: Our results support a role for TNF in lymphomagenesis. Given the association with NMSC, patients initiating TNFi therapy may benefit from skin cancer screening and sun protection measures.

Biologic treatments--including five TNF-α inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy.

Analysis of the malignancy rate in combined controlled and uncontrolled portions of studies has demonstrated that types and rates are similar to what is expected in the general U.S. population based on the SEER database and suggests no increase in rates over time. Whether treatment with ENBREL (etanercept) might influence the development and course of malignancies in adults is unknown. Melanoma and Non-Melanoma Skin Cancer (NMSC) Melanoma and non-melanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL (etanercept). Among 15,401 patients treated with ENBREL (etanercept) in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of melanoma was 0.043 cases per 100 patient-years. Among 3306 adult rheumatology (RA, PsA, AS) patients treated with ENBREL (etanercept) in controlled clinical trials representing approximately 2669 patient-years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient-years versus 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult PsO patients treated with ENBREL (etanercept) in controlled clinical trials, representing approximately 283 patient-years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years versus 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with ENBREL (etanercept). Periodic skin examinations should be considered for all patients at increased risk for skin cancer. Pediatric Patients Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including ENBREL (etanercept). Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma.

To date, there is no robust evidence of increased risk of malignancy with TNF antagonists in patients with psoriasis. Data from clinical trials are reassuring, and there is no indication from registry data in rheumatology populations of increased risk of solid tumours and lymphoma with TNF antagonist therapy as compared with standard DMARDs to date.126 However, uncertainty and conflicting evidence remain around the possible increased risk of lymphoma, possibly because lymphomas are more common in patients with severe RA. Bongartz et al.127 carried out a meta‐analysis of nine trials of patients with RA treated with infliximab or adalimumab. The data included 3493 patients who received TNF antagonist treatment and 1512 patients who received placebo and demonstrated a pooled odds ratio for malignancy of 3·3 (95% CI 1·2–9·1). This paper raised a variety of methodological concerns128129–130 which included lack of adjustment for duration of exposure to TNF antagonist therapy, inclusion of open‐label extension data for biologic therapy with no comparable placebo data, infliximab induction doses exceeding labelled dose in approximately 50% of patients and an unexpectedly low rate of malignancy in the control arms. In addition, both infliximab and adalimumab have been rarely associated with hepatosplenic T‐cell lymphoma.131 This rare, aggressive, and usually fatal tumour has occurred in adolescents and young adults with Crohn’s disease who were also receiving treatment with azathioprine or mercaptopurine.132–136 There are also reports of cases of early onset of lymphoma after introduction of TNF antagonist therapy137, 138 and regression of lymphoma following withdrawal of TNF antagonist therapy.137, 139
With respect to skin cancer, data on TNF antagonists in RA are inconsistent. Pharmacovigilance data on 1440 patients with RA treated with etanercept from clinical trials (3530 person‐years total exposure time) did not show any link between squamous cell carcinoma (SCC) development and etanercept.140 Lebwohl et al.141 carried out a retrospective analysis of 1442 patients with RA treated with etanercept for up to 5 years and similarly found no increased incidence of SCC (observed four SCCs, expected 5·9–13·1). However, an increased risk of nonmelanoma skin cancer (NMSC) (odds ratio 1·5, 95% CI 1·2–1·8) and a trend towards increased risk of melanoma (odds ratio 2·3, 95% CI 0·9–5·4) has recently been reported in a large (> 13 000 patients) observational study comparing rates of malignancy in patients with RA on biologic therapies with population rates (drug‐specific data from this analysis are given in the relevant section below).139

Malignancies, including lymphoma. In clinical trials at different indications, the observed malignancy rate (lymphoma and non-lymphoma) was lower in control than in infliximab-treated patients, but the latter did not exceed the rates expected for the general population according to the Surveillance, Epidemiology and End Results (SEER) database of the US National Cancer Institute. In the EXPRESS phase III trial in psoriasis, three patients (1%) with non-melanocytic skin tumours were reported in the infliximab group, compared to none among the placebo-treated patients.170 In clinical trials for different indications, lymphomas were observed more frequently in patients receiving infliximab than in subjects on placebo. Most lymphomas associated with TNF antagonists are non-Hodgkin's lymphomas, with a mean time to onset of 10 to 21 months. It should be noted that, in clinical trials, patients on placebo usually had a shorter time of follow-up than patients treated with active drug. In registries for rheumatoid arthritis, lymphomas were observed more frequently in patients treated with TNF antagonists than in the general population. Lymphomas were also observed more frequently in rheumatoid arthritis patients receiving standard disease-modifying antirheumatic drugs. In patients with Crohn's disease treated with infliximab or adalimumab, a rare variant of aggressive hepatosplenic lymphoma has been observed. Similar types of lymphoma have also been observed in patients treated with azathioprine or 6-mercaptopurine. The majority of patients who developed hepatosplenic lymphoma during treatment with TNF antagonists had also been treated or were treated concomitantly with azathioprine or 6-mercaptopurine. The overall reporting rates for lymphomas from post-marketing experience with TNF antagonists (0.02–0.03 events per 100 patient-years) do not indicate an increased risk when compared to the expected rate of lymphomas from the SEER database (0.07 events per 100 patient-years in a 65-year-old population).180
Although it is presently unknown whether psoriasis patients treated with TNF antagonists have a higher risk of lymphoma or skin cancer, a potential risk for the development of lymphoma or other malignant diseases cannot be excluded based on current knowledge. It should be noted, however, that patients with psoriasis, similar to patients with rheumatoid arthritis, have a higher baseline lymphoma risk compared to the general population143 and may also carry an increased risk of developing skin cancer due to previous UV phototherapy, particularly PUVA, and to the use of immunosuppressive drugs, such as ciclosporin.95,96 As a result, all patients, particularly those with an intensive immunosuppressive therapy in their medical history, as well as psoriasis patients with prior PUVA therapy, should be evaluated for non-melanoma skin cancer both before and during TNF antagonist therapy.

Even in the absence of TNF blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Hepatosplenic T-cell Lymphoma (HSTCL) Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE (infliximab). These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of reported REMICADE (infliximab) cases have occurred in patients with CD or UC and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use REMICADE (infliximab) alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with REMICADE (infliximab) monotherapy from the clinical trial data [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ]. Skin Cancer Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including REMICADE (infliximab) [see Adverse Reactions (6.3) ]. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.

The potential risk of lymphoma induction by the TNF inhibitors is a much-debated issue. As discussed previously, patients with psoriasis may have an increased risk of lymphoma (particularly Hodgkin's lymphoma and cutaneous T-cell lymphoma).
While a consensus panel of experts reviewing the clinical trial evidence concluded that the overall risk of malignancies including lymphoma was not increased over baseline levels in patients with rheumatoid arthritis being treated with TNF inhibitors,
A large observational study of patients with rheumatoid arthritis demonstrated an increased risk for the development of nonmelanoma skin cancer (odds ratio 1.5, 95% confidence interval 1.2-1.8) and a trend toward increased risk of melanoma (odds ratio 2.3, 95% confidence interval 0.9-5.4) in patients treated with biologic agents (largely the 3 TNF inhibitors). Importantly, this large study also demonstrated no increased risk of any other types of solid cancers.
These findings contrast with the results of a meta-analysis of rheumatoid arthritis studies examining patients treated with adalimumab and infliximab, which revealed an increased risk of solid cancers.
but most of these reports have been in patients with rheumatoid arthritis, which is itself known to be associated with vasculitis.
All of the TNF inhibitors are pregnancy category B.
Safety issues specific for individual TNF agents
Adalimumab is the newest of the TNF inhibitors, and available safety data are more limited than for etanercept or infliximab. Adalimumab injections can lead to painful injection site reactions in up to 15% of patients. These reactions usually resolve spontaneously within the first 2 months of therapy.

Objectives: Rheumatoid arthritis (RA) is associated with an increased risk of lymphoma linked to activity of the disease. Immunosuppressive drugs have been suspected to induce an additional risk. Since, NK cells have been recently shown to participate to anti-lymphoma immunosurveillance, we aimed to assess if anti-TNF might impact their anti-lymphoma activity.

Methods: NK cells have been assessed ex vivo in patients with RA treated with methotrexate (MTX) with or without anti-TNF. Phenotype has been studied by flow cytometry and function has been assessed after NKp30-cross linking. NK have been cultured 6 days in presence of anti-TNF, TNF-R inhibitors or controls and phenotype has been studied. Then cytotoxicity against 2 B non-Hodgkin lymphoma cell lines [Farage (EBV+) and SU-DHL4 (EBV-)] was assessed.

Results: Exposure to anti-TNF was associated with a decreased activation of NK cells. NK cells exhibited an impaired function in patients treated with anti-TNF compared to patients treated with MTX alone as assessed by the percentage of degranulation (20.9% [18.5-32.9] vs 31.3% [21.5-49.1], p = 0.04) and a decreased IFN-γ secretion ((17.4% [8.9-25.9] vs to 29.7% [22.5-43.1], p = 0.007). In vitro, exposure to anti-TNF impaired NK cells function and impacted negatively anti-lymphoma activity. These effects may be the consequence of inhibition of TNFR1 signaling.

Conclusions: Thus, even if meta-analysis of randomized controlled trials and of registries have not demonstrated to date an increased risk of lymphoma with anti-TNF, cautious must be pursued concerning this possible side effect in patients with long-term anti-TNF exposure.

Biologic treatments--including five TNF-α inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy.

Background: Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine the cancer risk of RA patients using different types of DMARDs and analyze their relationship with tumor mutational burdens (TMBs) reflecting immunogenicity. Methods: A thorough search of PubMed, EMBASE, Web of Science, and Medline was conducted up to 20 August 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies in comparison with the general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR). Results: From a total of 22 studies, data on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and four regions were available. Overall cancer risks were 1.15 (SIR 1.15; 1.09-1.22; < 0.001) and 0.91 (SIR 0.91; 0.72-1.14; = 0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking csDMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50-2.09; < 0.001), a 2.15-fold lymphoma risk (SIR 2.15; 1.78-2.59; < 0.001), and a 1.72-fold melanoma risk (SIR 1.72; 1.26-2.36; = 0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 from those taking csDMARDs and bDMARDs, respectively. Conclusion: We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMBs were not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA. Interpretation: Changes were similar in cancer risk after different immunosuppressive treatments, and there was a lack of correlation between SIRs and TMBs. These suggest that we should look for causes of increased risks from the RA disease itself, rather than using different types of DMARDs.

The potential risk of lymphoma induction by the TNF inhibitors is a much-debated issue. As discussed previously, patients with psoriasis may have an increased risk of lymphoma (particularly Hodgkin's lymphoma and cutaneous T-cell lymphoma).
While a consensus panel of experts reviewing the clinical trial evidence concluded that the overall risk of malignancies including lymphoma was not increased over baseline levels in patients with rheumatoid arthritis being treated with TNF inhibitors,
A large observational study of patients with rheumatoid arthritis demonstrated an increased risk for the development of nonmelanoma skin cancer (odds ratio 1.5, 95% confidence interval 1.2-1.8) and a trend toward increased risk of melanoma (odds ratio 2.3, 95% confidence interval 0.9-5.4) in patients treated with biologic agents (largely the 3 TNF inhibitors). Importantly, this large study also demonstrated no increased risk of any other types of solid cancers.
These findings contrast with the results of a meta-analysis of rheumatoid arthritis studies examining patients treated with adalimumab and infliximab, which revealed an increased risk of solid cancers.
but most of these reports have been in patients with rheumatoid arthritis, which is itself known to be associated with vasculitis.
All of the TNF inhibitors are pregnancy category B.
Safety issues specific for individual TNF agents
Adalimumab is the newest of the TNF inhibitors, and available safety data are more limited than for etanercept or infliximab. Adalimumab injections can lead to painful injection site reactions in up to 15% of patients. These reactions usually resolve spontaneously within the first 2 months of therapy.

Even in the absence of TNF blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Hepatosplenic T-cell Lymphoma (HSTCL) Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE (infliximab). These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of reported REMICADE (infliximab) cases have occurred in patients with CD or UC and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use REMICADE (infliximab) alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with REMICADE (infliximab) monotherapy from the clinical trial data [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ]. Skin Cancer Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including REMICADE (infliximab) [see Adverse Reactions (6.3) ]. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Introduction: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-α therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-α therapies (certolizumab pegol, golimumab).

Areas Covered: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments.

Expert Opinion: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects.

Accumulating research evidence suggests that nutrition might be implicated in the risk of development and in the management of autoimmune disease, including rheumatoid arthritis (RA), characterized by immune-inflammatory response. Nutrition can have direct roles through the provision of pro- or anti-inflammatory foods, and indirect roles through management of co-morbidity management. The review updates on the evidence relating RA risk and management with focus on specific foods such as fish and diets/dietary patterns such as the Mediterranean diet, fasting and elimination diets and oral nutritional supplements including omega-3 polyunsaturated fatty acids (PUFA). Evidence on herbs and spices, beverages, Vitamin D, and probiotics is also reviewed. Diet has been shown to improve disease activity through reducing inflammation and oxidation and through its beneficial effects on the gut microbiota. Based on the existing evidence, it is recommended that as an adjunct to medical treatment, nutrition therapy for RA should be based on an anti-inflammatory Mediterranean diet (MD) supplemented with at least twice a week consumption of oily fish and/or omega-3 PUFA supplements at 2 g/day. The need for rheumatologists to work more closely with registered dietitians in the management of patients particularly in supporting a well-balanced diet according to individual needs, is highlighted.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterised by immune dysregulation affecting multiple organs. Current anti-inflammatory treatments used in SLE are associated with unwanted side-effects. Dietary supplementation has been suggested as a safe and effective addition to conventional treatment, but evidence of efficacy in SLE or preventing associated comorbidities is uncertain.

Methods: We identified literature on clinical trials focused on nutritional interventions in SLE aiming to improve inflammation and comorbidities. A systematic-type search on Embase, Medline, and the Cochrane Library, was conducted to identify nutritional interventions among SLE patients in the past 15 years that met our inclusion criteria.

Results: We identified 2754 articles, of which 14 were eligible for inclusion based on our set criteria and were subsequently quality assessed. Vitamin D or E supplementation was associated with respective improvement of inflammatory markers or antibody production, but not disease activity scores in most studies. Despite their expected synergistic actions, the addition of curcumin on vitamin D supplementation had no additional effects on disease activity or inflammatory markers. Trials of omega-3 fatty acid supplementation presented significant reductions in ESR, CRP, disease activity, inflammatory markers, and oxidative stress, and improved lipid levels and endothelial function, while a low glycaemic index (GI) diet showed evidence of reduced weight and improved fatigue in patients.

Conclusions: Different dietary guidelines can therefore be implicated to target specific SLE symptoms or therapeutic side-effects. This systematic review highlights the scarcity of larger and longer in duration trials with homogenous methodologies and verifiable outcomes to assess disease progression.

Context: The impact of various dietary interventions on rheumatoid arthritis (RA), characterized by immune-inflammatory response, has been subject to increased attention.

Objective: A systematic review was conducted to update the current knowledge on the effects of nutritional, dietary supplement, and fasting interventions on RA outcomes.

Data Sources: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with prespecification of all methods, Medline and Embase were systematically searched for relevant articles.

Data Extraction: Data were extracted by 2 independent reviewers.

Results: A total of 70 human studies were identified. Administration of omega-3 polyunsaturated fatty acids at high doses resulted in a reduction in RA disease activity and a lower failure rate of pharmacotherapy. Vitamin D supplementation and dietary sodium restriction were beneficial on some RA outcomes. Fasting resulted in significant but transient subjective improvements. While the Mediterranean diet demonstrated improvements in some RA disease activity measures, outcomes from vegetarian, elimination, peptide, or elemental diets suggested that responses are very individualized.

Conclusion: Some dietary approaches may improve RA symptoms and thus it is recommended that nutrition should be routinely addressed.

Background: In 2013, the group of Cicero Coimbra, Brazil, reported the clinical efficacy of high doses of vitamin D3 in patients suffering from autoimmune skin disorders ("Coimbra protocol", CP). However, hypercalcemia and the subsequent impaired renal function may be major concerns raised against this protocol.

Methods: We report for the first time for a broad spectrum of autoimmune diseases in 319 patients (mean age (±SD) 43.3 ± 14.6 years, 65.5% female, 34.5% male) safety data for high doses of orally applied vitamin D3 (treatment period: up to 3.5 years) accompanied by a strict low-calcium diet and regular daily fluid intake of at least 2.5 L.

Results: Mean vitamin D3 dose was 35,291 ± 21,791 IU per day. The measurement of more than 6100 single relevant laboratory parameters showed all mean values (±SD) within the normal range for total serum calcium (2.4 ± 0.1 mmol/L), serum creatinine (0.8 ± 0.2 mg/dL), serum creatinine associated estimated GFR (92.5 ± 17.3 mL/min), serum cystatin C (0.88 ± 0.19 mg/L), serum TSH (1.8 ± 1 mIU/L), and for 24 h urinary calcium secretion (6.9 ± 3.3 mmol/24 h). We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively.

Conclusions: Our data show the reliable safety of the CP in autoimmune patients under appropriate supervision by experienced physicians.

Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.

Nuclear Factor Kappa-Β (NF-kB) is recognized as one of the main inflammatory pathways in the Autoimmune Disease (AD) Rheumatoid Arthritis (RA), which exhibits high levels of inflammatory cytokines such as IL-1, TNFa and IL-6 linked to bone erosion and disease progression. NF-kB is also the most studied pathophysiological mechanism in RA, however, over the last few decades, a more recently discovered Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), also linked to NF-kB activation and bone erosion, has been the topic of interest for research in the area of AD management. As the non-discriminative long term suppression of the NF-kB pathway by pharmacological agents in the management of RA has been linked with a number of side effects and with the discovery of the RANKL mechanism, which may present a more targeted approach to the management of the AD, there has been renewed interest in research on the potential impact of nutritional interventions influencing the NF-kB pathway, RANKL as well as RA disease outcomes. Existing research highlights the potential utility of nutrients such as Omega 3 and Vitamin D, which may lower NF-kB activation in RA. There is, however, a gap in the knowledge of the effects of nutritional interventions on pathophysiological mechanisms contributing to RA and a more robust systematic analysis of whether nutrients or specific vitamins can have an effect on the NF-kB and RANKL main drivers of pathology in RA. Findings from this study suggest the potential of Vitamin D supplementation in lowering the levels of RANKL and related markers/cytokines such as Th17 cell levels, OPG/RANKL ratio and CXCL10 pathway, which may present as a viable nutrition intervention for the management of RA. The methodology of this review involved a Systematic Search of the Literature with a Critical Appraisal of papers. It incorporated three tranche searches of 1. review, 2. animal/in vitro and 3. intervention peer reviewed research published in the last 10 years, resulting in a total of 119 papers. Results provide an overview of the NF-kB pathway, a detailed mechanistic examination of the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL) which is linked to bone erosion, and finally a review of nutritional interventions relating to this mechanism of pathophysiology. The accepted papers were critically appraised using SIGN50 for human studies and the ARRIVE guidelines for animal studies; the narrative was and the extracted information coded into key themes.