Primary and secondary nonresponse to infliximab: mechanisms and countermeasures

Introduction: Primary and secondary non-response to infliximab are common in patients with inflammatory bowel disease and remain a management challenge in clinical practice.

Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease. Data on proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm for evaluation and management of non-response to infliximab is provided. Preventative measures are also discussed. Relevant articles were identified after a literature search using PubMed. Search terms included ‘infliximab’, ‘loss of response’, ‘immunogenicity’, and ‘drug monitoring’. References of identified articles were also reviewed to identify additional references.

Expert opinion: A common cause for primary and secondary non-response include inadequate dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-drug antibody levels. Therapeutic drug monitoring should be done in patients losing response to infliximab. Use of drug monitoring proactively is still under debate.     

Cryptococcal meningitis in a patient treated with infliximab

Infliximab, a tumor necrosis factor-alpha inhibitor, is increasingly used for the therapy of different inflammatory conditions. We report the first case of cryptococcal meningitis in a patient treated with infliximab and other immunosuppressive agents, and review a further 5 reported cryptococcal infections. All of them involved fungal pneumonia. Outcome was favorable in all cases.     

Discontinuation of infliximab in rheumatoid arthritis patients in clinical remission

Biologic drugs are effective but are also expensive, and it is difficult to evaluate the duration of treatment. Infliximab, an anti-TNFα antibody, suppresses arthritic activity and inhibits bone destruction in patients with rheumatoid arthritis (RA). Here, we document that infliximab could be discontinued after clinical remission in RA patients. Among 172 patients with RA who reached clinical remission following infliximab (3 mg/kg) and methotrexate (MTX, >6 mg/w), nine patients with sustained remission discontinued it. Clinical assessment was based on a disease activity score (DAS) that included a 28-joint count/erythrocyte sedimentation rate (DAS28-ESR). The disease was assessed before and after the start of infliximab treatment, and concomitant drug treatment—in the order of corticosteroid, nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying anti-rheumatic drugs (DMARDs) other than MTX—was gradually discontinued. We considered patients for discontinuation of infliximab treatment after remission (DAS28-ESR < 2.6) had been sustained for more than 24 weeks. The nine patients able to discontinue treatment were all females, with a mean age of 53.8 years; eight patients were at stage I or II. The mean duration of disease was 28.7 months, and these patients were on corticosteroid treatment equivalent to a mean of 2.28 mg prednisolone (PSL). These nine patients all met the remission standard—that DAS28-ESR < 2.6 for ≥24 weeks) —and so their treatment with concomitant drugs was discontinued. After the discontinuation of infliximab, the mean period of sustained remission was 14.2 months and the longest period was 29 months. The duration of disease was significantly shorter and the points from Steinbrocker’s stage-classification were significantly lower in the infliximab-discontinued group than in the infliximab-continued group. Strategic reductions and/or discontinuations of concomitant treatment were performed in RA patients who attained clinical remission (DAS28 < 2.6) through treatment with infliximab and MTX. Nine patients successfully discontinued infliximab after maintaining clinical remission for more than 24 weeks. After infliximab was discontinued, clinical remission and suppression of joint destruction were maintained with MTX alone, especially in early RA patients.     

A case of planned pregnancy with an interruption in infliximab administration in a 27-year-old female patient with rheumatoid-factor-positive polyarthritis juvenile idiopathic arthritis which improved after restarting infliximab and methotrexate

We report a 27-year-old case of juvenile idiopathic arthritis (JIA) having been stopped infliximab during pregnancy. She was safely treated by infliximab therapy with premedications for preventing infusin reactions after her delivery, and then improved in the same manner as when she had been treated with infliximab therapy before pregnancy. As a result, it remains unclear whether or not we can use infliximab to control disease activities during pregnancy. In addition, it is also important to clarify whether or not premedications should be used when resuming infliximab treatment in such patients after pregnancy. These problems still remain controversial. More definitive data are needed in order to allow rheumatologists to better select the optimal TNF-alpha inhibitor therapy when treating pregnant JIA patients.     

祛疡清热汤治疗中重度溃疡性结肠炎疗效及对患者血清LPO与SCD-1表达的影响

目的:探讨祛疡清热汤对中重度溃疡性结肠炎患者血清中脂质过氧化物(LPO)与硬脂酰辅酶A脱氢酶(SCD-1)表达的影响。方法: 将84例中重度溃疡性结肠炎患者作为研究对象,依照随机数字表法将患者分为观察组和对照组,每组42例。对照组给予英夫利昔单抗治疗,观察组在对照组的基础上加用祛疡清热汤治疗,对比两组患者的临床疗效及不良反应的发生情况,以及在治疗前后T细胞群、LPO及硬脂酰-LPC/油酰-LPC(SCD-1)水平的变化情况。结果:经治疗结束后,两组患者均有一定疗效(观察组90.5% 与对照组73.8%,χ²=3.977,P<0.05),且不良反应发生率较低; 经治疗结束后,两组的Treg/Th₁₇相较于治疗前明显升高,且观察组的Treg/Th₁₇显著高于对照组,差异具有统计学意义(P<0.05); 经治疗结束后,两组患者血清中LPO明显下降,硬脂酰-LPC/油酰-LPC得到升高,且观察组的LPO与硬脂酰-LPC/油酰-LPC水平显著优于对照组,差异有统计学意义(P<0.05)。结论:采用祛疡清热汤治疗中重度溃疡性结肠炎具有较好的临床疗效,可调节血清LPO与SCD-1的表达水平,增强免疫功能。     

Esclerosis múltiple como efecto adverso de los agentes antifactor de necrosis tumoral alfa: una complicación infrecuente pero relevante de infliximab en la enfermedad de Crohn

Anti-tumor necrosis factor alpha (TNF-α) agents have been a great advantage in the treatment of inflammatory bowel disease. The safety profile of these agents is well-known and they can be considered safe when properly used. In clinical practice, the most important adverse events are infections. Other adverse effects are also possible but are much less frequent. However, because of the widespread use of these drugs, these uncommon adverse effects may also occur in clinical practice. We report one of these infrequent adverse events, multiple sclerosis, which is rare but important because of its severity. When neurological symptoms appear during treatment with anti-TNF-α, multiple sclerosis must be ruled out. The diagnosis and therapeutic management of this entity, led by a neurologist with our collaboration, required permanent cessation of anti-TNF-α therapy. Azathioprine, interferon, and even natalizumab, may be used as alternatives in patients who require therapy.