Conventional treatment of Crohn’s disease (CD) has been problematic in terms of efficacy and adverse effects. Infliximab, trade name Remicade, is an anti-tumor necrosis factor-α (TNF-α) human-mouse chimeric IgG1 monoclonal antibody that acts therapeutically by antagonizing TNF-α, a pro-inflammatory factor that plays a key role in the pathogenesis of CD immune inflammation. Infliximab is the first novel biologic agent approved by the US FDA for the treatment of CD, and has been used around the world for nearly 10 years. A randomized controlled study has confirmed the efficacy of infliximab in inducing and maintaining remission and the safety of its use in active CD and CD combined with enterocutaneous, anal or rectovaginal fistula, which was further confirmed by numerous clinical studies abroad. In the past year, we have accumulated some experience in the use of infliximab for the treatment of CD. Drawing on the consensus opinions of foreign countries [6-8], combined with the experience and actual situation in China, and discussed by the Collaborative Group of Inflammatory Bowel Disease of the Chinese Society of Gastroenterology, we hereby propose the following recommended protocol for the treatment of CD with infliximab.
Induction of remission.
1, Moderately to severely active CD, who are ineffective or hormone-dependent after regular treatment, i.e., corticosteroids or immunosuppressants (e.g., azathioprine, etc.), or who cannot tolerate (contraindications or serious adverse reactions).
2, CD combined with enterocutaneous fistula, anal fistula or rectovaginal fistula, who have been ineffective with regular treatment (including antibiotics, immunosuppressants, etc.).
Maintenance of remission.
Patients mentioned above, who are effectively treated with infliximab or who achieve remission.
Other indications for infliximab that have been recommended abroad in recent years are: CD in children; certain extra-intestinal manifestations of CD; active CD with severe disease, who have not used corticosteroids but clinically wish to get better as soon as possible. There is no domestic experience in this area.
The recommendation of the indication is based on the evidence of clinical studies and considering the benefit-risk ratio and cost-benefit ratio of infliximab application, combined with the preliminary application experience and actual situation in China. A large number of foreign clinical studies [1-5] and the preliminary application experience in China proved that infliximab has positive efficacy in inducing and maintaining remission in the treatment of CD. However, the following major problems exist in the application of infliximab for the treatment of CD: it is not effective in all patients; the long-term efficacy and safety of long-term treatment have yet to be studied in depth.
II. Contraindications.
Contraindications to the use of infliximab for the treatment of CD include: ① Active infection, chronic infection or recent history of recurrent infection. Among them, special attention should be paid to tuberculosis infection (including active and latent tuberculosis infection) and hepatitis B virus infection in China. ②Congestive heart failure. ③ malignant neoplasm (including current and past history). (iv) Demyelinating lesions of the nervous system. ⑤ Allergy to rat-derived protein components. ⑥Pregnancy.
The specific criteria for determining tuberculosis infection and hepatitis B virus infection are described as follows.
Tuberculosis infection: The incidence of tuberculosis is significantly higher in patients treated with infliximab than in the general population, which is closely related to the activation of latent tuberculosis infection during infliximab treatment. Therefore, a detailed history of TB and a thorough examination for TB, including routine chest radiographs and PPD skin tests, must be performed before applying infliximab. The different conditions found in the examination should be treated accordingly as follows: (i) those with chest radiographs suggestive of active tuberculosis or strong positive PPD skin test should be treated with regular anti-tuberculosis therapy and cured by identification before use. ②People with chest radiographs suggestive of old tuberculosis or a history of tuberculosis who have not received standard treatment should be treated with anti-tuberculosis prophylaxis before using infliximab, and anti-tuberculosis prophylaxis should be used together with infliximab (start infliximab after 2 months of isoniazid treatment and continue with isoniazid for 4 months). (3) China is a country with a relatively high prevalence of tuberculosis, and a negative chest radiograph or a non-strongly positive or even negative PPD skin test cannot confirm the absence of latent tuberculosis infection. The relevant guideline in the United Kingdom [9] recommends that for people at high risk of tuberculosis infection, isoniazid should be used as preventive anti-tuberculosis treatment for 6 months in combination with infliximide treatment even if no latent tuberculosis infection is detected. This guideline has been adopted in Hong Kong for local residents and can be used as a reference; ④ Those with a previous history of tuberculosis who have received standard treatment and have been certified as cured can start infliximab therapy directly.
Hepatitis B virus infection: The safety of infliximab in patients with chronic viral hepatitis B is not known. Before using infliximab, serum hepatitis B virus (HBV) markers and liver function should be routinely checked, and HBV-DNA should be quantified in HBsAg-positive patients. (2) For HBsAg-positive patients with normal transaminases and HBV-DNA <103 copies/ml, there is no consensus on whether antiviral therapy should be given, and these patients should be closely monitored for changes in liver function during treatment with infliximab.
III. Methods of use.
(i) Dose and duration of induction and maintenance of suetiolysis.
1. 5 mg/kg of infliximab is given at weeks 0, 2 and 6 as induction remission; the same dose is given every 8 weeks thereafter as long term maintenance therapy.
2. If the patient does not respond to the first 2 doses of treatment, infliximab is no longer given; if the response to treatment decreases or the response to treatment is lost, the dose can be increased to 10 mg/kg or the original dose is maintained and the dosing interval is shortened to 4~7 weeks.
3. Those who are receiving corticosteroids or/and immunosuppressive therapy before the use of inflixim should continue the original treatment when starting inflixim therapy. After achieving complete clinical remission, the hormone should be gradually reduced to discontinued depending on the clinical response. Immunosuppressants should be combined with infliximab as long as they are tolerated in patients previously treated with immunosuppressants.
(ii) Regarding maintenance therapy.
Clinical studies have demonstrated that long-term regular use of infliximab can be effective in maintaining remission. On the contrary, if the drug is given intermittently according to the change of symptoms, not only the efficacy decreases, but also the adverse effects increase [10]. Therefore, long-term regular maintenance therapy with regular dosing is currently advocated. However, the long-term use of infliximide is quite costly, so some studies have used infliximide as a transition to discontinue infliximide and continue maintenance with immunosuppressive drugs after the disease has completely resolved and hormones can be stopped [5]. Although further clinical studies are needed to confirm the efficacy of this therapy in maintaining remission, it can be used as a reference for current clinical practice.
(iii) Clinical observations.
1. Assessment of efficacy.
(1) The assessment indexes mainly include: disease activity index (simplified CDAI or Best CDAI) or fistula condition (amount of impotent tube drainage and number of closures); endoscopic ulcer size and mucosal healing; serum inflammatory indexes (C-reactive protein and erythrocyte sedimentation rate).
(2) The efficacy assessment was divided into: remission, effective, and ineffective (see Ref. 11 for details).
2. Observation of adverse reactions.
3.Follow-up items: symptoms and signs, blood test, C-reactive protein, erythrocyte sedimentation rate before each dose; liver function and chest X-ray as needed; colonoscopy is recommended to be performed 4 weeks after the third dose of induction remission and once a year during the maintenance treatment course (depending on the condition).
IV. Adverse reactions and precautions.
(a) Drug infusion reactions: incidence 3%-10%, serious reactions 0.1%-1%. It is believed that the production of anti-influenza antibody is closely related to the drug infusion reaction. Infusion reactions occur during drug infusion and within 2 h of stopping infusion. The infusion rate should not be too fast, and the infusion reaction can be prevented by giving antihistamines and corticosteroids 30 min before infusion to those who have experienced infusion reaction to infliximide. The infusion reaction should be suspended and treated according to the extent of the reaction, and the infusion can be continued after the reaction is completely relieved, but the infusion rate should be slower. Most patients can finish the drug infusion after the above treatment.
(ii) Late allergic reaction (serum sickness-like reaction): the incidence is 1%-2%. The clinical manifestations are muscle pain, arthralgia, fever, skin redness, urticaria, pruritus, facial and hand and foot edema and other reactions similar to serum sickness. Treatment: ①Symptoms can mostly subside spontaneously, if necessary, short-term corticosteroid treatment; ②For those who have had delayed allergic reactions, corticosteroids should be given orally 30 min before and after drug administration; ③For those who still have recurrence with the above treatment, drug administration should be stopped.
(iii) Autoantibodies and drug-related lupus erythematosus: It has been reported that up to 40% of treated patients develop serum antinuclear antibodies and 15% develop anti-double-stranded DNA antibodies. The incidence of drug-related lupus erythematosus is about 1%, which generally manifests as arthritis, polyplasmacythemia, butterfly-like erythema, etc. Rarely, there is renal or central nervous system invasion, and it usually resolves rapidly after drug discontinuation. Because autoantibody production is rare in those who develop drug-related lupus erythematosus, autoantibody production is not a contraindication to continuing infliximab treatment. If drug-related lupus erythematosus develops, the drug should be discontinued.
(iv) Infections: Opportunistic infections can involve almost all organs of the body, and the most common are respiratory and urinary tract infections; infectious microorganisms include various non-specific and specific bacteria, as well as fungal infections. Some studies have shown that serious infections occurring in the context of infliximab therapy are more often seen in those using concomitant corticosteroids. Therefore, it is important to strictly exclude infections before administration and to closely monitor the occurrence of infections during administration. For those who have serious infections such as pneumonia or sepsis during administration, it is advisable to continue treatment with infliximab after 3-6 months of complete control of the infection. The occurrence of tuberculosis infection during treatment with infliximab has been reported worldwide. Tuberculosis can occur after the second or third dose, or within 1 to 2 years after the first injection, with the average time of occurrence being 123 d. Tuberculosis is often manifested as extrapulmonary tuberculosis (>50%) and is often accompanied by a process of dissemination [5]. Therefore, the occurrence of tuberculosis infection after infliximab treatment should be highly guarded, and thorough screening for active and latent tuberculosis infection and appropriate treatment before treatment are essential, and regular follow-up and close monitoring of tuberculosis infection must be performed during drug administration. In case of elevated transaminases or/and elevated HBV-DNA during treatment, it is advisable to add antiviral therapy at the same time.
(v) Increased risk of lymphoma and other malignancies: This relates to the safety of long-term use of infliximab, which is again the most controversial issue at present. There is neither sufficient evidence to support an increased risk of lymphoma or other malignancies nor sufficient evidence to completely exclude this possibility. The presence of lymphoma or other malignancies (including past history) should be excluded prior to treatment, and regular follow-up monitoring is required during treatment.
(vi) Other: Demyelination-like syndrome, optic neuritis, transverse myelitis, multiple sclerosis, and Guillain-Barre syndrome have been reported in patients treated with infliximide; they can aggravate pre-existing moderate or severe congestive heart failure. Therefore, the above-mentioned patients are contraindicated, and most of them can recover from the above-mentioned complications during treatment by discontinuing the drug and treating them accordingly.
(vii) Safety in pregnancy: Until more safety evidence is available for use in pregnancy, it is recommended that pregnancy should be avoided during treatment and discontinued if pregnancy occurs during treatment.
New goals in the treatment of Crohn’s disease and ulcerative colitis: mucosal healing.
Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). Mucosal healing has long been an important goal of IBD treatment. However, most conventional treatments have failed to achieve the goal of mucosal healing. The use of biologics has changed this perception, as they not only provide rapid symptomatic relief but also promote and maintain mucosal healing.
Currently, the severity of lesions and post-treatment changes in the terminal CD colon and ileum are mainly assessed by colorectal microscopy. However, there is no accepted endoscopic standard. Because ulceration is the main manifestation of intestinal mucosal inflammation in IBD, disappearance of ulcers after treatment is the endoscopic criterion for mucosal healing used in the majority of studies to date, although the presence of mild active inflammatory changes, such as mild congestion, granular changes, or aphthous ulcers, may be tolerated.
Better mucosal healing can be achieved with infliximab treatment. Complete mucosal healing cannot be achieved with hormonal therapy. The mucosal healing effect of immunosuppressive agents such as azathioprine (AZA) requires a longer treatment period. In a subgroup study comparing the efficacy of regular versus on-demand treatment with infliximab in the ACCENT I study, mucosal healing was achieved in 29% of the regular group after 3 induction treatments at 10 weeks, compared with only 3% of the on-demand group. Following regular maintenance treatment every 8 weeks, 44% of patients in the group achieved mucosal healing at 54 weeks compared to 18% in the on-demand group. in the SONIC study, 30.1% of patients in the infliximab group alone achieved mucosal healing at 26 weeks, significantly higher than the 16.5% in the AZA alone group.
Mucosal healing can alter the impact of the natural course of Crohn’s disease. CD alternates clinically between relapse and remission, with progressive complications occurring during the course of disease progression. approximately 80% of patients require surgical treatment during their lifetime, and 20% to 70% of patients (depending on follow-up time) require reoperation after surgery due to postoperative relapse with complications. In the last decade or so, a growing number of prospective and retrospective studies have been reported on the impact of mucosal healing on the natural course of CD. A recent prospective study showed that 70.8% of patients with mucosal healing maintained remission in first-visit CD patients treated with either “step-up” or “step-down” therapy, while only 27.3% of those who did not achieve mucosal healing maintained remission. Mucosal healing has the potential to prolong hormone-free remission, reduce complications, and decrease surgical rates. This means that mucosal healing has the potential to slow down and stop the natural progression of CD.
The rationale for the traditional “step-up” treatment regimen has been questioned in recent years, as it is considered difficult to reverse when the lesion has progressed to severe structural destruction or even complications. An earlier randomized controlled placebo study of children requiring glucocorticoid therapy at first treatment found that the 2-year follow-up rate of hormonal remission was significantly higher in the 6-mercaptopurine group than in the placebo group, suggesting that early application of immunosuppressive agents may improve outcomes. In recent years, most studies have found that TNF-α monoclonal antibodies appear to be more effective in children and adolescents than in adults. In a well-known study of “step-up” versus “step-down” therapy, newly diagnosed patients with active CD were divided into a “step-down” group and an “step-up” group. “In the former group, infliximab was given in combination with AZA at the beginning, while in the latter group, the treatment was traditionally started with glucocorticoids, followed by AZA and then infliximab. The follow-up was 2 years. The remission rates after discontinuation of hormones were 60.0% versus 35.9% and 61.5% versus 42.2% at week 26 and 52, respectively, and the ulcer healing rates were 73.1% and 30.4% in the two groups after 2 years of follow-up (P=0.0028), with 7 cases requiring surgery for intestinal complications in the latter group but none in the former. The fact that early aggressive pharmacological treatment leads to better clinical outcomes and higher mucosal healing rates seems to be gaining acceptance. That is, early aggressive pharmacological treatment may be more helpful in modifying the natural course of CD.