Children who clinically respond to adalimumab therapy appear to have improved linear growth similar to that seen with infliximab. Malik et al. conducted a retrospective physician survey through the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) in which they collected information on anthropometry and treatment information. Of the 70 patients included in the survey, 36 had been treated with adalimumab and had sufficient growth data at 3 points in time to assess growth. Of these patients, 34 (94%) had prior treatment with infliximab. Despite prior medical therapy, the authors demonstrated improved linear growth comparing growth 6 months prior to initiation of adalimumab to the first 6 months on adalimumab therapy. Of the 17 children who were Tanner stage 1–3 at the start of adalimumab, there was a significant increase in the height Z score after 6 months of adalimumab.

Veerappan et al. prospectively assessed markers of bone formation and resorption in children with Crohn’s disease treated with adalimumab and compared their findings to those in control children without IBD. All of these children had previously been treated with immune suppressive therapy, most of whom had had prior treatment with infliximab. They found an increase in bone formation markers (osteocalcin and procollagen type 1 N-terminal propeptide) at 1 and 3 months after starting adalimumab. They also found increased osteoblast differentiation after 6 months, which the authors suggested was likely related to new bone formation.

In addition to efficacy and safety, pain with adalimumab injection is important to address, since this can impact patient adherence. Pain at the adalimumab injection site has been reported in both pediatric and adult studies. Hirai et al. conducted a survey of patient satisfaction with adalimumab self-injection [11]. They surveyed 124 patients (age 13–70 years) who were currently receiving adalimumab therapy. The majority of patients (88%) reported pain at the injection site, 28% of whom had “strong pain” at the injection site. Strategies that patients reported to help alleviate pain included “slow injection” and “warming the drug solution with their palms.”

There was one report of mixing lidocaine into adalimumab prior to injection to minimize pain at the injection site. Ayala and colleagues presented findings of a study in which they recruited pediatric and adult patients treated with adalimumab who experienced pain and anxiety or were younger [12]. They added 0.2 ml of 1% lidocaine directly into the prefilled syringes of 0.8 ml adalimumab. They tested this in 15 patients who reported decreased pain at the injection site.

The CLASSIC I and CLASSIC II trials investigated the efficacy of adalimumab in patients who were anti-TNF therapy naïve with moderate to severe Crohn’s disease [24, 25]. CLASSIC I first evaluated adalimumab as an induction therapy. This multicenter, randomized, double-blind, placebo-controlled trial enrolled 299 patients receiving loading doses of adalimumab in three different dose groups vs. placebo, with the primary endpoint being differences in rates of remission (defined by Crohn’s Disease Activity Index [CDAI] [33] scores of < 150) at week 4 [24]. Patients were randomized to receive loading dose regimens at weeks 0 and 2 of placebo, adalimumab 40 mg/20 mg, 80 mg/ 40 mg, or 160 mg/ 80 mg. Based on pharmacokinetic data obtained in trials for rheumatoid arthritis, the investigators anticipated a target dose of 40 mg every other week for efficacy in Crohn’s disease. A dose group above and below that target was selected (20 mg every other week and 40 mg weekly or 80 mg every other week), and the loading doses were selected based on early dosing pharmacokinetic data. At week 4, rates of remission were 18% in the 40 mg/20 mg group (p = 0.36), 24% in the 80 mg/40 mg group (p = 0.06), 36% in the 160 mg/80 mg group (p = 0.001), and 12% in the placebo group. Differences in response when compared with placebo achieved significance as early as week 1 in the 80 mg/40 mg group. This study demonstrated that induction therapy with adalimumab is more effective than placebo, with the best tested loading dose being 160 mg/80 mg at weeks 0 and 2. Additionally, adalimumab was well tolerated, with similar rates of adverse events across groups, except for injection site reactions, which occurred more frequently in the ADA groups.

The CLASSIC II trial evaluated adalimumab for maintenance therapy in moderate to severe Crohn’s disease in patients who were naïve to anti-TNF therapy and then responded to ADA, for a total of 56 weeks [25]. This trial was a continuation of CLASSIC I and enrolled 276 of the 299 patients from CLASSIC I. All patients who entered CLASSIC II from CLASSIC I received 40 mg ADA at week 0 (week 4 of CLASSIC 1) and week 2. At week 4, the 55 patients who had achieved remission at weeks 0 and 4 were re-randomized to receive placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly. The primary endpoint was again defined as a CDAI score <150. At week 56, 79% of patients in the 40 mg every other week and 83% of patients in the 40 mg weekly were in remission vs. 44% of the placebo group (p < 0.05). At week 4, 204 patients who had not achieved remission at week 0 and week 4 entered a separate open-label arm and received 40 mg every other week. Patients in this arm could escalate to 40 mg weekly for a flare or non-response. In this arm, 71 continued on 40 mg every other week, while 60 had dose escalation to 40 mg weekly. At the end of 56 weeks, 46% of patients in this arm were in remission. Additionally, 65% had a 100-point clinical response, and 72% had a 70-point clinical response. The rates of patients achieving 70-point clinical response were not significantly affected by concomitant use of immunosuppressant therapy. Thus adalimumab is more effective than placebo as maintenance therapy in adults with Crohn’s disease.

The CHARM trial was a randomized, double-blind, multicenter placebo-controlled trial that studied adalimumab for the maintenance of remission in patients who had responded to induction therapy with adalimumab [23]. This study permitted concomitant use of a stable dose of immunosuppressant therapy, 5-ASA therapy, Crohn’s disease-related antibiotics, and steroids and included adults with moderate to severe Crohn’s disease. This study also included patients who had previously been on a TNF antagonist, so long as it was more than 12 weeks prior to screening, and excluding those with primary non-response. Eight hundred and fifty-four patients enrolled and received open-label adalimumab loading doses of 80 mg and 40 mg at week 0 and week 2, respectively. Patients were then assessed and stratified at week 4 based on response (decrease in CDAI score of 70 or greater), and 58% of patients were randomized to placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly up to 56 weeks. Patients who experienced a flare or non-response were allowed to switch to 40 mg every other week after week 12. Two primary endpoints were evaluated as percentages of the randomized responder arms achieving remission at weeks 26 and 56 (defined as CDAI score <150). At week 26 the rates of remission were 17, 40, and 47% in the placebo, adalimumab 40 mg every other week, and adalimumab 40 mg weekly groups, respectively. At week 56, these rates were 12, 36, and 41%, respectively. This demonstrated that each adalimumab group achieved significantly greater rates of remission when compared pairwise with placebo (p < 0.001). Differences between the two adalimumab treatment groups did not achieve significance (P = 0.22 at week 26 and p = 0.34 at week 56). Differences in the rates of remission between treatment and placebo groups were seen as early as week 6, and most patients (81%) in the treatment groups who achieved remission at week 26 remained in remission at week 56, compared to 48% in the placebo group. Adalimumab achieved superiority to placebo regardless of concomitant use of immunosuppressive therapy or prior use of TNF-antagonists. Adalimumab was also demonstrated to be steroid sparing, with both treatment groups having a greater percentage of patients achieving steroid-free remission at 26 weeks (p < 0.001 for each treatment group vs. placebo) and 56 weeks (p < 0.001 for the 40 mg every other week group vs. placebo, p = 0.008 for adalimumab 40 mg weekly vs. placebo). This study demonstrated that treatment with adalimumab 40 mg every other week or 40 mg weekly is an effective therapy for maintenance of remission in adults with Crohn’s disease. Recently, data regarding remission rates at 4 years has been released using data from the CHARM trial and its open-label extension, ADHERE [23, 29, 34]. These studies demonstrated good durability of response, with 54% of patients who achieved remission at 1 year still in remission at 4 years [29].

The GAIN trial was a 4-week, randomized, double-blind, placebo-controlled trial designed to ascertain adalimumab efficacy in inducing remission in Crohn’s disease patients with symptoms despite infliximab therapy or an inability to take infliximab secondary to adverse events [26]. In this study 325 adults with moderate to severe Crohn’s disease who were either intolerant to infliximab or had initially responded but then lost response to infliximab were randomly assigned to receive placebo or adalimumab 160 mg at week 0 and 80 mg at week 2. Patients who did not ever respond to infliximab were excluded. At week 4, 21% of adalimumab-treated patients vs. 7% of placebo-treated patients achieved remission defined as CDAI<150 (p < 0.001). Rates of 70-point response in adalimumab vs. placebo at weeks 1, 2, and 4 were 35% vs. 21%, 52% vs. 33%, and 52% vs. 34%, respectively, with statistically significant response seen at week 1. Total CDAI scores were also significantly lower in the adalimumab group vs. placebo at weeks 1, 2, and 4. Subgroup analysis revealed that adalimumab demonstrated efficacy regardless of concomitant immunosuppressive therapy, previous intolerance to infliximab, previous loss of response to infliximab, previous intolerance of and loss of response to infliximab, or presence of antibodies to infliximab. Based on this study, adalimumab is safe and effective for use in patients with Crohn’s disease who had previously responded and discontinued infliximab due to adverse events or a loss of response, but no conclusions can be drawn about infliximab primary non-responders.

The EXTEND trial is the first randomized, double-blind, multicenter placebo-controlled trial investigating the efficacy of adalimumab in the induction and maintenance of mucosal healing in adults with moderate to severe ileocolonic Crohn’s disease [27]. One hundred and thirty-five patients received open-label adalimumab 160 mg at week 0 and 80 mg at week 2. At week 4, 129 patients who remained in the study were randomized to receive maintenance therapy with adalimumab 40 mg every other week or placebo. Patients who experienced flares or non-response could receive open-label adalimumab 40 mg every other week, with the potential to increase dosage to 40 mg weekly. Absence of mucosal ulceration at week 12 was defined as the primary endpoint. Mucosal ulceration was defined as a score of least two on the ulcerated surface subscore of the Simple Endoscopic Score for Crohn’s Disease (SES-CD) [35] in at least one of five ileocolonic segments. Secondary endpoints assessed included mucosal healing at week 52, Crohn’s Disease Endoscopic Index of Severity (CDEIS) [36] remission (defined as a score of 4 or less) at week 12 and week 52, and CDAI remission (score<150) and response (100-point reduction and 70-point reduction in CDAI score) at week 12 and week 52. The primary endpoint of mucosal healing at week 12 was achieved in 27% of the continuous adalimumab group compared to 13% of the induction/placebo group (p = 0.056). This p-value improved to 0.046 when applying a prespecified per-protocol analysis which excluded some patients for major protocol deviations. Secondary endpoint analysis at 52 weeks revealed that 24% of the adalimumab-continuous arm and none of the induction/placebo arm achieved mucosal healing (p < 0.001). Similarly, all secondary endpoints achieved statistically significant superiority of continuous adalimumab compared to induction/placebo at week 52. At week 12, CDEIS remission rates and CDAI remission rates of the continuous adalimumab group achieved statistical superiority over the induction/placebo group, but not for CDEIS 75% responders nor CDAI score reductions of > 100 or >70. Ultimately this study demonstrated superiority of adalimumab maintenance therapy in mucosal healing of adults with moderate to severe Crohn’s disease at 52 weeks, but not at 12 weeks post-induction. Despite the lack of statistical superiority of adalimumab on mucosal healing at week 12, this could be due to the lingering efficacy of the induction therapy that all participants received or that mucosal healing in patients with severe disease takes longer than 12 weeks. Overall this study demonstrates that adalimumab is efficacious in mucosal healing in addition to its established efficacy in clinical response and remission in Crohn’s disease.

An additional randomized controlled trial (POCER) has evaluated the efficacy of adalimumab in preventing disease recurrence in patients with Crohn’s disease who have undergone intestinal resection surgery [28]. This study was a randomized, prospective, open-label trial that included 51 patients with ileal or ileocolonic Crohn’s disease who underwent an intestinal resection. Patients were randomized to receive adalimumab, azathioprine, or mesalamine following surgery for a period of 2 years. For the adalimumab arm, subcutaneous injections were administered as a loading dose of 160 mg/80 mg at weeks 0 and 2, respectively, followed by maintenance dosing of 40 mg every 2 weeks. The azathioprine arm received 2 mg/kg daily, while the mesalamine group received 3 g daily, divided in three doses. The primary outcome of this study was the proportion of patients with clinical and endoscopic remission at 2 years post-surgery using multiple previously developed scales, with a secondary outcome being a quality of life assessment via the previously validated IBDQ [28, 37]. After the 2-year study period, 1 of 16 patients treated with adalimumab (6.3%), 11 of 17 patients treated with azathioprine (64.7%), and 15 of 18 patients treated with mesalamine (83.3%) experienced endoscopic recurrence. These values represent an OR = 0.036 for adalimumab compared to azathioprine and OR = 0.013 for adalimumab compared to mesalamine. Perhaps due to small sample size, there was no significant difference in endoscopic recurrence between azathioprine and mesalamine, with an OR = 0.367. With regard to clinical recurrence, using the scale proposed by Hanauer et al. [38], 2 of 16 adalimumab-treated patients (12.5%) had clinical recurrence, while 11 of 17 in the azathioprine arm and 9 of 18 in the mesalamine arm had clinical recurrence for odds ratios of 0.078 and 0.143, respectively [28]. These results were also reflected by using a CDAI >200, which results in clinical recurrence of 6.3% vs. 70.6% for OR = 0.028 and 6.3% vs. 50% for an OR = 0.067. Again, there was no significant difference in azathioprine vs. mesalamine when using these scales to measure clinical recurrence. Remission, defined as CDAI score <150, occurred in 15/16 of the adalimumab group compared with 4/17 in the azathioprine group (OR = 0.021) and 6/18 in the mesalamine group (OR = 0.033), with no difference between the azathioprine and mesalamine groups. Very similar outcomes were obtained when analyzing the secondary endpoint of quality of life using the IBDQ. Thus, adalimumab was shown to be superior to azathioprine and mesalamine in the prevention of disease recurrence in adults with Crohn’s disease who underwent intestinal resection.

The efficacy of adalimumab in ulcerative colitis was established primarily through two different phase-three clinical trials, ULTRA-1 (Ulcerative Colitis Long-Term Remission and maintenance with Adalimumab) and ULTRA-2 [30, 31]. ULTRA-1 was a multicenter, randomized, double-blind, placebo-controlled trial that lasted 8 weeks [30]. This enrolled adult patients with moderate to severe ulcerative colitis who had been treated with immunosuppressant therapy and/or corticosteroids but still had Mayo score [39] ≥6 and endoscopic subscore ≥2. All patients were naïve to anti-TNF agents. This study initially included 186 patients randomized to receive either placebo or induction therapy with adalimumab 160 mg at week 0 and 80 mg at week 4, followed by 40 mg maintenance dosing at week 4 and week 6. The protocol was amended to include a second treatment group with a regimen of 80 mg adalimumab at week 0, followed by 40 mg at weeks 2, 4, and 6 at the behest of European regulatory authorities. Ultimately, the primary endpoint of this study was assessed in 390 patients randomized to adalimumab 160 mg/80 mg/40 mg/40 mg, 80 mg/40 mg/40 mg/40 mg, or placebo. The primary endpoint was defined as clinical remission at week 8 as defined as Mayo score ≤2 with no individual subscore >1. At week 8, 18.5% of the 160 mg/80 mg group, 10.0% of the 80 mg/40 mg group, and 9.2% of the placebo group achieved remission (p = 0.031 for 160 mg/80 mg vs. placebo, p = 0.833 for 80 mg/40 mg vs. placebo). Serious adverse events occurred in 4.0% of the adalimumab 160 mg/80 mg group, 3.8% of the adalimumab 80 mg/40 mg group, and 7.6% of the placebo group. Evaluation of the primary endpoint leads to the conclusion that adalimumab 160 mg/80 mg induction dose followed by 40 mg every other week for 2 weeks is a safe and effective induction regimen for ulcerative colitis in adults when compared to placebo. Additionally, this study leads to the conclusion that loading doses of 80 mg/40 mg are not effective for induction of remission in ulcerative colitis.

ULTRA-2 was a randomized, double-blind, multicenter, placebo-controlled trial that included 494 patients with moderate to severe ulcerative colitis that were on immunosuppressant therapy and/or oral corticosteroids [31]. This study included both patients who had prior exposure to TNF-antagonists and those who had not. Patients were randomized to receive either placebo or adalimumab 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Remission in this study was also defined as Mayo score ≤2 with no individual subscore >1, with primary endpoints being remission at week 8 and week 52. The rate of clinical remission at week 8 was 16.5% of the treatment group vs. 9.3% of the placebo group, p = 0.019. At 52 weeks, the rates of clinical remission were 17.3% and 8.5% in the treatment and placebo groups, respectively, p = 0.004. Secondary analysis revealed that clinical response was achieved in 50.4% of the treatment group vs. 34.6% of the placebo group at week 8 and 30.2% of the treatment group vs. 18.3% of the placebo group at week 52, for p values of p < 0.001 at week 8 and p = 0.002 at week 52. In patients who were anti-TNF naïve, 21.3% of the treatment group and 11% of the placebo group achieved remission at week 8 and 22% vs. 12.4% at week 52 for p values of 0.017 and 0.039, respectively. For patients who had received prior anti-TNF therapy, rates of remission at week 8 were 9.2% in the treatment group vs. 6.9% in the placebo group and 10.2% in the treatment arm vs. 3% in the placebo arm at week 52, for p values of 0.559 and 0.039, respectively. This study demonstrated that adalimumab is superior to placebo for the induction and maintenance of remission in adults with ulcerative colitis, with markedly better efficacy in patients who are anti-TNF naïve compared to those with prior anti-TNF exposure. Recently, long-term data from adalimumab-treated patients in ULTRA-1, ULTRA-2, and the open-label extension ULTRA-3 has been published [32]. This study demonstrated that 199 of 600 patients randomized to receive adalimumab in the intent-to-treat analysis of ULTRA-1 and ULTRA-2 remained on adalimumab and demonstrated a rate of remission of 24.7% by partial Mayo score at week 208.

Approximately 18% of adult and pediatric Crohn’s disease patients who are primary responders will lose response to adalimumab, with an annual risk of over 20% per patient-year, and 37% will require dose intensification, with an annual risk of nearly 25% [40]. The importance of drug levels has been emphasized in several studies evaluating endpoints such as mucosal healing, and endoscopic and clinical indicators of disease [41–48]. Typically drug levels are evaluated with either HMSA or ELISA, which have been found to be roughly equivalent [49]. Several groups have proposed different drug level thresholds to achieve mucosal healing, with levels as low as 4.9 μg/mL (via ELISA) [44] and as high as 8.14 μg/mL (HMSA) [43] being proposed. One study proposes levels as high as 8–12 μg/mL [45]. Anti-adalimumab antibodies are thought to be primarily responsible for the observed loss of response [50, 51], with rates of anti-adalimumab antibody formation reported to range from 3% in the CLASSIC II trial [25] to as high as 21% [50]. Further, anti-adalimumab antibodies have been shown to be inversely associated with adalimumab drug levels and achievement of good clinical outcomes [42, 49]. More studies are needed to cement our understanding of the relationship between adalimumab levels, anti-adalimumab antibodies, and response, as not all studies have demonstrated such a clear relationship. One large cross-sectional study demonstrated no difference between mucosal healing rates in patients with anti-adalimumab antibodies and those without [45]. However, that comparison was made in patients who had adequate adalimumab drug levels, and the lack of separation could have been due to individuals overcoming the anti-adalimumab antibodies effect via other means. In addition to increasing drug levels, research has been done to investigate the effect of immunomodulators on the rate of formation of anti-drug antibodies [2]; however this data is limited to patients being treated with infliximab. Another proposed mechanism for loss of response is tissue inflammation itself acting to reduce levels of anti-TNF agents [47], although this is less well studied. Despite the importance of adequate drug levels in achieving remission in IBD, recent studies (TAXIT, TAILORX) using infliximab and adalimumab have demonstrated that there is no significant value in prospective drug monitoring during successful maintenance therapy and suggest that therapeutic drug monitoring should be used largely during induction or upon loss of response [52].

Two small phase 2 studies initially assessing certolizumab demonstrated that it is well tolerated and efficacious, but these studies failed to achieve their primary endpoint [64, 65]. Both were randomized, double-blind, placebo-controlled multicenter studies. One study evaluated the safety and efficacy of certolizumab in 92 adults with Crohn’s disease, who received certolizumab at doses of 1.25 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg or placebo [65], which was later adjusted. The 1.25 mg/kg arm was dropped based on efficacy results in a study of rheumatoid arthritis. The primary endpoint was clinical response (CDAI score reduction of at least 100 points) or remission (CDAI score ≤ 150) at 4 weeks. While the treatment groups and placebo groups all had similar percentages of patients achieving these endpoints at week 4 (47.8–60.0%), the 10 mg/kg group did demonstrate significant separation in remission at week 2 (47.1 vs. 16.0%, p = 0.041). The second phase 2 trial included 292 patients with moderate to severe Crohn’s disease randomized to 100, 200, 300, or 400 mg subcutaneous certolizumab or placebo at weeks 0, 4, and 8 [64]. This study again assessed response and remission as defined in the prior study but evaluated the endpoints at week 12. All treatment groups achieved significant separation from placebo at week 2, but this significance was not maintained. The 400 mg treatment group (roughly 6 mg/kg) maintained the highest response rate at all time points, with the most robust separation at week 10 with 52.8% vs. 30.1% for placebo (p = 0.006). However, this separation was lost in all groups at the primary endpoint analysis at week 12. It is not clear why a 700 mg (or 10 mg/kg) arm was not evaluated in phase 2.