Safety of biologic agents after rituximab therapy in patients with rheumatoid arthritis

The safety of other biologic therapies in rheumatoid arthritis (RA) following B cell-depletion therapy with rituximab has not been established. This retrospective chart review of patients attending an outpatient rheumatology clinic aimed to assess the incidence of adverse events in patients receiving biologic agents to treat RA after an inadequate response or intolerance to rituximab. The charts of 22 patients (18 female; mean age 59 years) were reviewed. Duration of RA was >2 years. Before rituximab, patients had failed one (n = 10), two (n = 4) or three (n = 7) biologic therapies: 1 patient started on rituximab as a first-line biologic. Eighteen patients stopped rituximab due to an inadequate clinical response, while four patients stopped due to adverse events. The mean time to starting a new biologic after rituximab was 4 months, although five patients were started within 1 month of the last rituximab infusion. Abatacept (41%) was the most common biologic used after rituximab. The mean follow-up time from the last rituximab infusion was 14 months. Adverse events occurring after rituximab therapy, but before initiation of a new biologic, included disseminated herpes zoster and aseptic meningitis (both required hospitalization). Adverse events recorded after starting a new biologic post-rituximab included rash, carbuncle, upper respiratory tract infection, urinary tract infection, pneumonia, and eczema, but none was classified as serious. Most of these events occurred in patients receiving abatacept. In conclusion, in this retrospective analysis, no serious adverse events were recorded in patients who received biologic agents following rituximab therapy.     

Safety of biologic therapy in rheumatoid arthritis and other autoimmune diseases: focus on rituximab

OBJECTIVES: To review the safety of biologic agents used to treat rheumatoid arthritis (RA) and other autoimmune diseases, with a focus on rituximab. METHODS: Information was gathered from a search of the PubMed database and from major congress abstract listings through June 2007. RESULTS: Rituximab is approved for treating RA in patients with an inadequate response to TNF inhibitors and is under study in other indications for RA and other autoimmune disorders. The current safety profile of rituximab in RA is known from Phase II and III studies conducted preapproval, treating approximately 750 patients, as well as from long-term extension studies with repeated therapy. Clinical trials have established that the most common adverse events are infusion-associated reactions, seen in 29 to 40% of patients, most of which are mild to moderate and occur following the first rituximab infusion, with incidence and severity decreasing with subsequent infusions. Rates of infections and serious infections to date are within the range expected for RA patients treated with other biologic agents, but the longer term effects of B-cell depletion and the effects of repeated treatment on the risk of infections are uncertain. Information is limited for rituximab safety in other autoimmune disorders but current data do not suggest that there is a significant difference in adverse events from that previously reported. CONCLUSIONS: Rituximab is an important addition to the rheumatologist's armamentarium for the treatment of difficult RA and ongoing trials will determine its utility in other indications for RA and other autoimmune conditions. The true safety profile of rituximab will emerge as larger numbers of patients are treated in routine clinical practice.     

State-of-the-art: Immunosuppression and biologic therapy

Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn's disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn's disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn's disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids.     

Malignancy and biologic therapy in rheumatoid arthritis

PURPOSE OF REVIEW: Owing to the complex functions of the inflammatory response systems--potentially or clearly of importance in human carcinogenesis--that biological therapies interfere with uncertainty regarding their safety profile for malignancy is more or less expected. This uncertainty has been further sparked by the apparent discordance between trial data and observational studies of anti-TNF agents, and the methodological challenges inherent in addressing the safety profile of new drugs for delayed and multifactorial events like cancer. RECENT FINDINGS: This review provides a summary of the pattern of cancer seen in patients with rheumatoid arthritis not treated with biologics, and the currently published data on cancer risk following treatment with biologics in patients with rheumatoid arthritis, primarily anti-TNF therapy. SUMMARY: Published data currently do not exclude clinically important increased risks, nor do they refute beneficial effects. As per definition, much of the currently available safety data from trials or clinical practice do not capture the impact of either any effect that biological therapy might have on early events in carcinogenesis, or of sustained exposure to biologics. Beyond the risk of de-novo cancer development, several other clinically important aspects of cancer safety remain to be addressed, including issues of prognosis, progression, and relapse.     

Safety of biologic therapies during pregnancy in women with rheumatic disease

Inflammatory rheumatic diseases frequently affect women of childbearing age. Biologic therapy during pregnancy is an important topic that is yet unresolved. The majority of documented experiences are in case series, case reports, or registries. Tumor necrosis factor (TNF) inhibitors are now better known. Some evidence suggests that it is possible that differences between drugs regarding safety are associated with the structure and capacity to cross the placenta, but we are not aware of any study that supports unequivocally this statement. Most of the monoclonal antibodies are actively transferred to fetal circulation using the neonatal Fc receptor. Although this transfer does not appear to be associated with the risk of miscarriage, stillbirth, or congenital abnormality, the rate of premature births and lower birth weight may be increased. During fetal development, the neonatal period, and childhood, the immune system is constantly maturing. The ability to produce cytokines in response to infectious stimulus remains low for years, but is similar to that of an adult around the age of 3 years owing to the adaptive nature of the newborn’s immune system as a result of exposure to microbes. Therefore, exposure to TNF inhibitors may have serious consequences on the newborn, such as severe infections or allergic reactions. Regarding the former, an anecdotal case report described a fatal case of disseminated bacillus Calmette-Guérin (BCG) infection in an infant born to a mother taking infliximab for Crohn’s disease. Although the baby was born and progressed well initially, he died at 4.5 mo after he was vaccinated with BCG. Fortunately, serious infections do not appear to be frequent in newborns exposed to in utero biologic therapy. However, very limited short-term experiences are available regarding complications in an exposed fetus, and no data are available about long-term implications on the child’s developing immune system. Therefore, we must be aware of potential complications in later years. Although the clinical data to date are promising, no firm conclusions can be drawn about the safety of biologic drugs during pregnancy, and, without further evidence, guidelines that suggest these drugs should be avoided at the time of conception cannot yet be changed.     

Eruptive lentigines confined to psoriatic plaques following biologic therapy

Clinical Rheumatology -     

Surgical treatment of ulcerative colitis in the biologic therapy era

Recently introduced in the treatment algorithms and guidelines for the treatment of ulcerative colitis, biological therapy is an effective treatment option for patients with an acute severe flare not responsive to conventional treatments and for patients with steroid dependent disease. The reduction in hospitalization and surgical intervention for patients affected by ulcerative colitis after the introduction of biologic treatment remains to be proven. Furthermore, these agents seem to be associated with increase in cost of treatment and risk for serious postoperative complications. Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice in ulcerative colitis patients. Surgery is traditionally recommended as salvage therapy when medical management fails, and, despite advances in medical therapy, colectomy rates remain unchanged between 20% and 30%. To overcome the reported increase in postoperative complications in patients on biologic therapies, several surgical strategies have been developed to maintain long-term pouch failure rate around 10%, as previously reported. Surgical staging along with the development of minimally invasive surgery are among the most promising advances in this field.     

MDS: Refining existing therapy through improved biologic insights

Advances in therapy can essentially be measured using two parameters; introduction of a new agent which benefits an increased number of patients over prevailing treatments or more selective use of an existing drug by matching it to the biologic characteristics associated with response. In reviewing the therapeutic landscape of myelodysplastic syndromes (MDS), both should be applied to gauge the advances in therapy. While several new drugs are currently in clinical trials for the treatment of MDS, three drugs were approved for use in the last decade and sufficient time has elapsed to take stock of the benefit they have produced in the outcome of patients both in terms of survival and quality of life. For the two hypomethylating agents, response remains limited to 50% patients at best, and no strategy has evolved to allow for pre-selection of likely responders, however, 5-azacytidine has been associated with improvement in the survival of higher risk patients. The benefit of lenalidomide was found to be greater for del(5q) patients with transfusion dependent anemia and lower risk disease right from the start, although a quarter of the non-del(5q) patients also experienced complete transfusion independence with this agent. It is in this latter group of non-del(5q) cases that a strategy for potentially preselecting likely responders is suggested by the finding of an expression profile associated with response. In this paper, we will focus on defining our current understanding of the mechanisms of action of the existing FDA approved drugs in order to identify therapeutic strategies that are suitable for specific MDS subtypes. We expect that through advancing biologic insights, the use of such therapies will become more selective and refined.     

Safety of infliximab and other biologic agents in the inflammatory bowel diseases

In many ways, infliximab has drastically altered expectations for medical therapy in IBD, and it is expected that adalimumab and certolizumab pegol with ultimately have a similar role. Patients initiating such therapy should be made cognizant of the potential risks of serious infection including opportunistic ones, such as TB and histoplasmosis; demyelinating disorders; CHF; and lymphoma. Proper selection of candidates for anti-TNF-alpha therapy is critical in maintaining a proper benefit-to-risk ratio.     

Dynamics of proinflammatory cytokines during biologic therapy of inflammatory bowel disease

Chronic inflammation in IBD is accompanied by an imbalance in the production of Tx1 and Tx2 cytokines. Imbalance of cytokine profile is important pathogenetic importance in chronic inflammatory process, since the formation of defective immune response to pathogenic agent promotes recurrence of the disease. Analysis of the dynamics of proinflammatory cytokines allows both the activity of inflammatory process and effectiveness. Increased levels of proinflammatory cytokines: TNF-alpha, IFN-gamma, IL-2, IL-5, IL-8, IL-12, IL-15 in serum of patients with IBD, indicate their possible involvement in the mechanisms of development of CD and UC. Increasing content of these cytokines is accompanied by increased activity of disease, which can be used in diagnose IBD activity.     

Safety of biologic treatments in solid organ transplant recipients: A systematic review

BackgroundThe development of biological treatments has transformed the management of a broad spectrum of autoimmune/inflammatory diseases. However, little is known about their use in solid-organ transplant recipients. This study aimed to evaluate complications occurring with biologic treatments in solid-organ transplant recipients.MethodsA systematic review of the literature was performed in the Medline, Embase and Cochrane databases, up to 01/10/2020, to identify published case reports or series reporting the use of biologic treatments in solid organ transplant recipients with chronic inflammatory diseases. We collected data on patient characteristics and reported complications.ResultsIn total, 57 articles were included, totalling 187 patients (141 liver, 42 kidney, 3 heart, and 1 liver-kidney transplant recipients). Inflammatory bowel diseases represented the most common indication for biologic treatment initiation (80.7%), followed by rheumatic diseases (7.5%), hereditary periodic fever syndromes (5.9%) and psoriasis (4.8%). Anti-TNFα were mainly used (77.5%; mainly monoclonal antibodies (70%) compared to soluble receptor etanercept (7.5%)), followed by the anti-α4β7 integrin, vedolizumab (27.3%) and the anti-IL-1R, anakinra (6.9%). Median treatment duration was 12 months. Infections occurred in 54 patients (28.9%) through 88 recorded events. No therapeutic or demographic factors were associated with occurrence of infection. Sixteen patients (8.6%) developed malignancies, and acute graft rejections occurred in 5 patients (2.7%). Among the 187 patients, 9 deaths were reported (4.8%).ConclusionsThis review assembles the largest number of published reports regarding the use of biological treatments in solid organ transplant recipients, providing data about their safety. Further comparative studies are needed to assess the safety of biological treatments in transplanted patients.     

Leucocytapheresis for inflammatory bowel disease in the era of biologic therapy

(Table is included in full-text article.)The development of biologicals such as infliximab to intercept TNF-alpha validates the current perception that certain cytokines are major factors in the immunopathogenesis of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. Furthermore, major sources of inflammatory cytokines include activated peripheral granulocytes and monocytes (GM), which in patients with IBD are elevated with increased survival time and are found in vast numbers within the inflamed intestinal mucosa. Hence, elevated GM should be appropriate targets of therapy in IBD. Accordingly, in recent years technologies such as the Adacolumn have been developed for selective depletion of elevated GM by extracorporeal adsorption (GMA). Published data show that GMA in patients with steroid-dependent or steroid-refractory IBD is associated with striking efficacy and tapering or discontinuation of steroids, whereas in steroid-na?ve patients GMA spared patients from steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse significantly suppressed relapse, thus sparing the patients from the morbidity associated with active IBD. First ulcerative colitis episode, steroid naivety and short disease duration seem to be good predictors of response to GMA and on the basis of our experience, GMA seems to have an excellent safety profile.