© Springer International Publishing AG 2018
Adam S. Cheifetz and Joseph D. Feuerstein (eds.)Treatment of Inflammatory Bowel Disease with Biologics https://doi.org/10.1007/978-3-319-60276-9_44. Anti-TNF Therapy for Treatment of Extraintestinal Manifestations of Inflammatory Bowel Disease
(1)
Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
Extraintestinal manifestations (EIM) of inflammatory bowel disease (IBD) are common, affecting up to one half of IBD patients [1–7], and are of major clinical importance because of their impact on the health and quality of life of those affected. EIM of IBD can affect nearly any organ system with a range of severity from mild to debilitating. Patients may experience one or multiple EIM simultaneously, and the presence of one EIM increases the likelihood of developing other EIM [3, 6]. In some cases, the EIM may be more severe than the intestinal disease itself. While some EIM such as erythema nodosum and pauciarticular arthritis typically parallel luminal disease activity, others such as uveitis and ankylosing spondylitis may be active without concomitant intestinal disease [8, 9]. This pattern and the approach to treatment is further complicated by the fact that EIM of IBD may develop even before the onset of gastrointestinal symptoms [8].
Although EIM of IBD can affect nearly every organ system, the use of anti-TNF therapy has been examined in only a subset of manifestations and is of varying efficacy depending on the condition being studied. Most data regarding the use of anti-TNFs for EIM of IBD are retrospective and have focused on patients with Crohn’s disease (CD) rather than ulcerative colitis (UC). Nonetheless, for some extraintestinal conditions, the data for the use of anti-TNF therapy are robust.
Both infliximab and adalimumab can be effective in controlling certain EIM of IBD as will be reviewed below. Data for the use of certolizumab pegol and golimumab for EIM are lacking and, as has been the case for luminal disease, etanercept is probably less effective than infliximab and adalimumab, although data regarding this comparison are limited. A study outlining the Danish experience with infliximab from 1999 to 2005 noted that 80% of patients with CD and skin or joint symptoms had improvement or remission in symptoms [10], and similar overall response rates have been reported for adalimumab [11]. More recently, a systematic review of 9 interventional and 13 non-interventional studies also concluded that infliximab and adalimumab are effective for some classes of EIM including certain musculoskeletal, dermatologic, and ocular manifestations [12]. Consistent with this report, the 2016 ECCO consensus document on the use of anti-TNF drugs for the management of EIMs in IBD patients also noted anti-TNFs to be effective for certain EIMs and recommended considering their use in patients with spondyloarthropathy, arthritis, dermatologic manifestations such as pyoderma gangrenosum or erythema nodosum and uveitis [13].
Peripheral Arthritis
IBD-associated peripheral arthriti s is categorized into 2 distinct subtypes, termed type 1 and type 2. Type 1 peripheral arthritis often occurs acutely, affects the large joints (knees most commonly), and typically tracks with luminal disease activity. On the other hand, type 2 usually occurs independently of intestinal disease, affects multiple small joints (especially the metacarpophalangeal joints), and is more commonly chronic [8, 14].
In line with existing data that anti-TNF therapy is effective in the treatment of rheumatoid and psoriatic arthritis [15], available evidence suggests that anti-TNFs are effective in the treatment of IBD-associated peripheral arthritis. A prospective, open-label study of Crohn’s patients who had failed prior therapy (steroids, azathioprine, 6-mercaptopurine, or methotrexate) looked at patients with arthritis or arthralgia treated with infliximab (dosed either 5 mg/kg at 0 weeks for luminal disease or at 0, 2, and 6 weeks for fistulizing disease). The study showed that 61% (36/59) had improvement in their joint symptoms and 46% (27/59) of patients had symptom resolution [16]. In another study, 7 of 11 patients with Crohn’s disease and inflammatory arthralgia reported improvement after treatment with a single 5 mg/kg infusion of infliximab [17].
Although data for adalimumab are more limited, the CARE trial provides evidence for its use for IBD-associated arthritis. Of over 900 patients with CD studied, 20 of 82 patients who had baseline arthritis had resolution of their arthritis at the conclusion of 20 weeks of treatment with adalimumab [18].
Generally, anti-TNF therapy should be a leading consideration for treatment of peripheral arthritis in patients with indications for systemic therapy of luminal disease. In the absence of a need for luminal-directed systemic therapy, a decision to undertake anti-TNF therapy for IBD-associated peripheral arthritis should be made in consultatio n with a rheumatol ogist.
Axial Arthritis
Anklylosing spondylitis (AS) and sacroiliitis are associated with IBD, although they occur less frequently than peripheral arthritis and typically manifest independently of intestinal activity [8, 14].
The efficacy of anti-TNF therapy for AS in the absence of IBD is well established [19–22]. In a multicenter randomized placebo-controlled trial, 53% (18/34) of patient s with AS treated with infliximab (5 mg/kg at 0, 2, and 6 weeks) had symptomatic improvement at 12 weeks, compared to 9% (3/35) in the placebo group (p < 0.0001) [20]. An open-label follow-up study of the same cohort after 3 years of infliximab maintenance suggested that infliximab was effective in maintaining remission of AS [21].
The use of anti-TNF therapy for axial arthritis in patients with concomitant IBD is less well studied. The largest study of patients with both IBD and spondyloarthropathy compared 24 patients with Crohn’s (16 of whom had active disease) given infliximab (5 m/kg at 0, 2, and 6 weeks then 3–5 mg/kg every 5–8 weeks) to 12 patients with active Crohn’s on other treatments. Although there was a similar improvement in CDAI scores between the groups, the infliximab group had significantly better arthritis disease scores [23]. In a smaller cohort of 11 patients with Crohn’s-associated inflammatory lower back pain treated with infliximab, 7 saw benefit [17].
Adalimumab also appears to be effective in treating IBD-related axial arthritis [11, 18]. In the open-label CARE trial, for example, 15 of 16 patients with AS treated with adalimumab had resolution of their joint symptoms after 20 weeks of therapy [18].
Based on the available data, anti-TNF therapy should be considered for treatment of axial arthritis in patients in whom systemic therapy for luminal disease is warranted, and in conjunction with a rheumatologist for patients with IBD-associated axial arthritis who lack an indication for luminal-directed systemic therapy.
Uveitis
Although there are several ocular manifestations of IBD, only for uveitis does there exist a body of literature supporting treatment with anti-TNF therapy. This typical chronic condition that presents with eye pain, blurry vision, photophobia, and headaches can develop before or after the onset of bowel symptoms and frequently occurs concurrently with arthritis [8, 9, 24].
Although not considered first-line therapy, anti-TNF agents have an important role in treating uveitis. They counter the role of TNF in fueling ocular inflammation, as demonstrated in animal models and analyses of human ocular fluids [25]. Adalimumab, infliximab, and etanercept have been studied in uveitis; however, these studies include patients with refractory uveitis and are not limited to patients with underlying IBD [26–31]. Infliximab seems to be more effective than etanercept, and adalimumab may be more effective than etanercept as well.
In a 2005 study, data from 4 placebo-controlled trials and 3 open-label studies of patients with AS being treated with infliximab or etanercept were analyzed to assess outcomes of patients with concomitant anterior uveitis. Follow-up data on 397 patients demonstrated that patients treated with ant-TNF agents had 6.8 uveitis flares per 100 patient-years vs 15.6 in the placebo group. Flares were less frequent in those treated with infliximab than etanercept, although this finding was not statistically significant [27].
Similarly, a retrospective study of 17 children with chronic uveitis treated with high dose infliximab (10–20 mg/kg at varying intervals) showed a favorable response to the anti-TNF: 13 children had complete resolution of intra-ocular inflammation within 1–2 weeks of their first for second infusion, and the other 4 had resolution of symptoms after up to 7 infusions [28]. Another retrospective study of childhood uveitis (from conditions other than known IBD) in 21 patients with active recalcitrant uveitis also showed favorable though more limited responses to both etanercept and infliximab. Thirty-eight percent of those treated with inflix imab had a “good” response, defined by a 50% or greater reduction in corticosteroid and immunosuppressive use, while 54% had a moderate response in which either the corticosteroid or immunosuppressive was reduced by ≥50 [29]. Those treated with infliximab had a trend towards fewer complications and a higher rate of improvement of glaucoma and visual acuity than those treated with etanercept [29].
The data for adalimumab are more limited than for infliximab. A retrospective study of 18 children with chronic uveitis treated with adalimumab after failing other immunosuppressive therapies showed an 88% percent response rate as measured by the frequency of relapse. As in the other studies, most of these children had juvenile idiopathic arthritis, and none had IBD [26].
Although most of the available evidence for anti-TNF treatment of uveitis is from studies of uveitis unrelated to IBD, the data can certainly be extrapolated to uveitis associated with IBD and some smaller studies do show a benefit in this population. The decision to use an anti-TNF for refractory uveitis, however, should always be made in conjunction with an ophthalmologist.
Pyoderma Gangrenosum
Pyoderma gangrenosum (PG) is a rare chronic cutaneous ulcerating skin condition that is sometimes associated with pathergy [32]. The use of anti-TNFs for this EIM of IBD has not been widely studied; however, the quality of the data is among the most robust for EIM and clearly demonstrates a benefit.
In one of the few placebo-controlled randomized trials examining the use of anti-TNF therapy for the treatment of EIMs, infliximab was given to 13 patients with PG at 5 mg/kg as a single dose. Effectiveness compared to 17 placebo controls was evaluated at 2 and 6 weeks based on patient questionnaires and physician assessment. At week two, there was improvement in 46% of the infliximab group versus 6% of the placebo group. At that point, all non-responders were offered and accepted open-label infliximab. Sixty-nine percent (20/29) showed improvement at 6 weeks, with 21% (6/29) deemed in complete remission [33].
Retrospective studies show a more robust response, attributable in part to less limited dosing strategies. In one early retrospective study of 13 patients with moderate to severe PG treated with infliximab, 3 responded after induction dosing, the remaining 10 had response with ongoing dosing, and all patients were able to stop corticosteroids [34]. In a more recent study of 67 patients in Spain with PG (61.2% with underlying Crohn’s and 37.3% with UC), 31 were given infliximab (24) or adalimumab (7), with improvement of PG in 29 (93.5%) [35]. Furthermore, the results show that infliximab and adalimumab were definitive (i.e., no subsequent therapy was needed over the study period) 91.7% and 100% of the time, respectively [35].
It is important to recognize that there are also reports of “paradoxical” PG developing during treatment with infliximab [36–38]. In two cases, therapy was transitioned to cyclosporine or adalimumab with resolution of skin lesions [36, 38]. In another case of a patient with underlying RA, infliximab was transitioned to etanercept but the lesions persisted until their treatment with minocycline [37]. These cases suggest that paradoxical PG is not a class effect, but might instead be a manifestation of immune response to a particular biologic agent.
Erythema Nodosum
Erythema nodosum (EN) is a dermatologic condition consisting of subcutaneous, tender, red nodules that occur most commonly on the shins [32]. EN has been described in association with several systemic inflammatory conditions but, among patients with IBD, EN is most commonly associated with Crohn’s [8, 9]. Since the activity of EN typically parallels the activity of intestinal disease, first-line therapy focuses on treatment of the underlying IBD. When the intestinal disease responds, the EN typically remits as well [6]. However, successful treatment of idiopathic (and non-IBD-associated) EN with adalimumab has been reported [39]. In addition, as in PG, “paradoxical” EN has been reported with the use of infliximab [40].
Primary Sclerosing Cholangitis
Despite early reports of infliximab leading to biochemical improvement of comorbid primary sclerosing cholangitis (PSC) in patients with UC, this has not been borne out in subsequent work. A randomized double blind placebo-controlled trial of infliximab versus placebo in 10 patients with PSC did not show biochemical, symptomatic, or histologic differences between the two groups after 6 months [41]. Indeed, it is generally agreed that there is no role for infliximab in the treatment of PSC, although it may be appropriate for the treatment of UC in patients also affected by PSC.
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