throbber
Hügle et al. Pediatric Rheumatology (2017) 15:16
`DOI 10.1186/s12969-017-0147-3
`
`S H O R T R E P O R T
`Inflammatory bowel disease following
`anti-interleukin-1-treatment in systemic
`juvenile idiopathic arthritis
`Boris Hügle*, Fabian Speth and Johannes-Peter Haas
`
`Open Access
`
`Abstract
`
`Background: Inflammatory bowel disease can develop in the context of some rheumatic diseases in childhood,
`including juvenile idiopathic arthritis (JIA). Inflammatory bowel disease (IBD) is frequently associated with other
`immune-mediated diseases; however, systemic onset JIA (sJIA) has not previously been connected to IBD. Treatment of
`sJIA has significantly changed in recent years, possibly causing changes in inflammatory patterns. Therefore, data from
`the German Center for Pediatric and Adolescent Rheumtology from 2010 until 2015 were analyzed by retrospective
`chart review.
`Findings: Eighty-two patients with confirmed diagosis of sJIA were found. Of these, three were identified with a
`diagnosis of IBD confirmed by colonoscopy (two cases of Crohn’s disease, one case of ulcerative colitis) 0.8 – 4.3 years
`after diagnosis. All three were treated with IL-1 antagonists (anakinra in two cases, canakinumab in one case) and were
`well controlled for sJIA symptoms at time of diagnosis of IBD
`Conclusions: IBD seems to be a rare, but possible complication of sJIA. Treatment with IL-1 antagonists might be a
`relevant factor for a switch in the clinical phenotype of the underlying inflammatory process.
`Keywords: Systemic juvenile idiopathic arthritis, Inflammatory bowel disease, IL-1 Antagonists
`
`Findings
`is
`juvenile idiopathic arthritis (sJIA)
`Systemic-onset
`an autoinflammatory disease characterized by in-
`creased levels of interleukin(IL)-1 and IL-6 [1]. Ana-
`kinra and canakinumab are both medications used
`successfully in sJIA, aiming to neutralize the effects
`of IL-1 [2, 3].
`Inflammatory bowel diseases (IBD) are associated
`with several immune-mediated diseases, with almost a
`quarter of patients showing first symptoms during
`childhood or adolescence [4]. While unspecific mild
`bowel
`inflammation has been described in sJIA, IBD
`has not been observed as an extrarticular manifest-
`ation [5, 6].
`We present three pediatric cases with confirmed diag-
`nosis of sJIA who developed IBD diagnosed by histology
`and coloscopy during treatment with IL-1 antagonists.
`
`* Correspondence: huegle.boris@rheuma-kinderklinik.de
`German Center for Pediatric and Adolescent Rheumatology (GCPAR),
`Gehfeldstrasse 24, 82467 Garmisch-Partenkirchen, Germany
`
`Patients and Methods
`The database of the German Center for Pediatric and
`Adolescent Rheumatology was searched for all sJIA pa-
`tients (n = 82) with a confirmed diagnosis of IBD from
`2010 until 2015. Four patients were identified; one was
`excluded as histology showed only unspecific round-cell
`infiltrate. Chart survey was used to extract demographic
`data, date of diagnosis of sJIA and IBD, clinical and la-
`boratory data and medications.
`
`Case descriptions
`Clinical and laboratory data of the cases at time of
`diagnosis of sJIA and of IBD are described in Tables 1
`and 2, respectively. (Additional
`file 1: Table S1 and
`Additional file 2: Table S2).
`Case I is a Caucasian male. He presented at age 14 years
`and 10 months with high quotidian fever with associated
`diffuse exanthema, splenomegaly, mild pericardial effusion
`and polyarthritis. Infectious workup showed elevated IgG
`and IgM antibodies against Parvovirus B19. He did not
`complain about abdominal symptoms and had a normal
`
`© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
`International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
`reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
`the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
`(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
`
`

`

`Hügle et al. Pediatric Rheumatology (2017) 15:16
`
`Page 2 of 5
`
`Table 1 Demographics of the patients, clinical and laboratory data at time of diagnosis of sJIA, and time and dose of anti-IL-
`1 medication
`Patient
`Gender
`
`1
`m
`
`2
`m
`
`3
`f
`
`neg/neg/neg
`
`6.8
`
`Fever, rash, pleural
`effusion, hepatomegaly
`splenomegaly
`
`Elbows, hips, wrists
`16800/mm3
`(4800–10000)
`575000/mm3
`(150000–450000)
`297–1197 μg/l
`(30–400)
`3.36 mg/dl
`(0.2–1.0)
`-
`
`0.3 years
`
`Anakinra
`1.1 mg/kg
`
`ANA/RF/HLA-B27
`
`Age at diagnosis
`
`ILAR criteria for subtype
`
`Affected joints
`
`Leukocyte count
`
`Platelet count
`
`Ferritin
`
`C-reactive protein
`
`Bone marrow biopsy findings
`
`neg/neg/neg
`
`14.8
`
`neg/neg/n.d.
`
`15.8
`
`Fever, typical rash, splenomegaly,
`pericardial effusion
`
`Fever, rash, pericardial/pleural
`effusion, hepatomegaly
`
`Polyarthritis
`9100/mm3
`(4800–10000)
`294000/mm3
`(150000–450000)
`2926 μg/l
`(30–400)
`7.4 mg/dl
`(0.2–1.0)
`Negative
`
`Polyarthritis
`9100/mm3
`(4500–12500)
`208000/mm3
`(154000–386000)
`32722 ng/ml
`(22–322)
`28.54 mg/dl
`(<0.3)
`
`MAS
`
`2.2 years
`
`Canakinumab
`1.8 mg/kg
`
`Start of IL1-treatment, years after diagnosis
`
`0 years
`
`IL-1 agents, initial dose
`
`normal values in parentheses
`neg negative, n.d. not done
`
`Anakinra
`1.3 mg/kg
`
`bowel ultrasound except for splenomegaly. He received
`methylprednisolone pulse therapy and indomethacin and
`was started on anakinra, with rapid remission within
`3 months.
`After 11 months on anakinra he developed increasing ab-
`dominal pain and diarrhea. Stool cultures were negative.
`
`Colonoscopy showed ileitis and discontinuous inflamma-
`tion in the ascending colon. Histology confirmed granu-
`lomatous inflammation. With a diagnosis of Crohn’s
`disease he was started on azathioprine and prednisolone,
`while anakinra was tapered. He presented 3 months later
`with fevers and markedly elevated inflammatory parameters
`
`Table 2 Colonoscopy findings, clinical and laboratory data at time of diagnosis of IBD of the patients
`Patient
`1
`2
`3
`Time between diagnoses
`0.9 years
`4.4 years
`4.7 years
`of sJIA and IBD
`
`Time between start of
`Anti-IL1 agent and IBD
`
`0.9 years
`
`2.2 years
`
`4.4 years
`
`Anti-IL1 agents, dosage
`
`Anakinra, 1.3 mg/kg
`
`Canakinumab, 1.8 mg/kg
`
`Anakinra, 0.7 mg/kg
`
`Other medications
`
`None
`
`Cyclosporin A
`
`None
`
`Colonoscopy, macroscopic
`findings
`
`Colonoscopy, microscopic
`findings
`
`Active, ulcerous ileitis and colitis,
`consistent with Crohn’s disease
`Granulomatous inflammation
`
`Active colitis from sigmoid to coecum,
`consistent with Crohn’s disease
`Inflammatory infiltrate
`
`Colitis in colon descendens,
`consistent with ulcerative colitis
`
`Inflammatory infiltrate
`
`Diarrhea
`
`Present
`
`Macroscopic blood in stool Absent
`
`Ferritin
`
`CRP
`
`138 ng/ml
`(9–80)
`12.1 mg/dl
`(< 0.8)
`
`Calprotectin/stool
`
`Not available
`
`normal values in parentheses
`
`Present
`
`Absent
`
`154 ng/ml
`(30–400)
`4.67 mg/dl
`(0.02–1.0)
`877 μg/g
`(<50)
`
`Present
`
`Present
`
`10 ng/ml
`(30–400)
`0.44 mg/dl
`(0.2–1.0)
`1264 μg/g
`(<50)
`
`

`

`Hügle et al. Pediatric Rheumatology (2017) 15:16
`
`Page 3 of 5
`
`without diarrhea. After excluding systemic inflammation or
`infection, his colonoscopy was repeated and returned a re-
`sult of highly active Crohn’s disease. Treatment with inflixi-
`mab and methotrexate was started, leading to rapid and
`ongoing remission 8 months later.
`Case II
`is a Caucasian male, who presented at age
`15 years and 10 months with fevers, arthritis and exan-
`thema and developed polyarthritis, pericardial and pleural
`effusion within a few weeks. At that time, he had borderline
`positive IgM antibodies against Coxsackie virus, Adeno-
`virus and Epstein-Barr virus. He was treated with NSAID
`and steroids, but developed two episodes of macrophage
`activation syndrome, with recurrence on cyclosporin after
`the first episode. Three months prior to the second episode,
`he was diagnosed with Influenza A. Twenty-three months
`after diagnosis he was started on anakinra after methylpred-
`nisolone pulses which led to brief improvement. Three
`months later he presented with severe signs of systemic
`arthritis and elevated inflammatory parameters. Treatment
`with tocilizumab showed no improvement, but canakinu-
`mab – in addition to cyclosporine and low dose steroids –
`led to rapid and lasting remission over the next 2 years.
`After 24 months on canakinumab he presented with fa-
`tigue, arthralgias without arthritis and elevated C-reactive
`protein, with diarrhea and weight loss. Increasing doses of
`canakinumab and prednisolone did not lead to improve-
`ment. Infectious work-up showed again borderline posi-
`tive IgM antibodies against Coxsackie, but negative stool
`cultures. Colonoscopy showed active colitis extending
`from proximal sigmoid to the cecum with several, partly
`confluent ulcerations. The iliocecal valve was gaping, and
`the terminal ileum exhibited erythema and punch defects
`of
`the mucosal membrane. Duodenal biopsy showed
`edematous and coarse villi, with detachment of epithelium
`and mostly neutrophilic inflammatory infiltrate. Even
`without granuloma formation, this was interpreted as
`Crohn’s disease, supported by positive antibodies against
`Saccharomyces cerevisiae (ASCA). Canakinumab was dis-
`continued, and he was started on budenoside and inflixi-
`mab, which led to rapid remission, ongoing 18 months
`after diagnosis of IBD.
`Case III is a Caucasian male of mixed German and
`Turkish origin. He presented at age 6 years and 10 months
`with fevers, arthritis, exanthema, pleural effusion and oli-
`goarthritis. An extensive infectious workup showed no re-
`sult. He was treated with indomethacin, steroids and
`methotrexate. He presented 4 months later with arthritis,
`fevers and elevated inflammatory parameters. Treatment
`with steroids and etanercept showed no effect after 3
`doses, so he was switched to anakinra, leading to prompt
`improvement of clinical signs and laboratory parameters.
`He entered long lasting remission, but started to de-
`velop mild abdominal symptoms after 3 years on ana-
`kinra and methotrexate. Methotrexate was discontinued
`
`6 months later, and in the following months he showed
`increasing abdominal pain and blood in his stools. Stool
`cultures were negative. He received a colonoscopy 4 years
`after starting anakinra, which showed severe inflamma-
`tion of the colon descendens consistent with ulcerative
`colitis, with histology showing edema of the lamina pro-
`pria with inflammatory lymphocytic and neutrophilic in-
`filtrate, and also focal inflammation in the crypt walls.
`He was continued on low dose anakinra (0.5 mg/kg) and
`started on mesalazin and azathioprine, with ongoing
`mild gastrointestinal complaints on last follow-up.
`
`Discussion
`Here we present three patients with confirmed diagnosis
`of sJIA who developed signs of IBD on treatment with
`anti-IL1 agents, either anakinra or canakinumab. All cases
`fulfilled ILAR criteria for sJIA at the time of diagnosis,
`and none had any clinical signs of IBD at that time. Al-
`though the age range in these patients falls well within the
`described spectrum, the majority of patients with sJIA ini-
`tially present below the age of 5 years. All patients devel-
`oped typical manifestations of Crohn’s disease or
`ulcerative colitis, where monoclonal TNFα antibodies or
`DMARDS were required to gain disease control (for com-
`parison, see Table 3). The one patient receiving low-dose
`anakinra in fact continued to have low grade abdominal
`symptoms,
`possibly
`indicating
`an
`ongoing
`pro-
`inflammatory effect of anti-IL1 medication.
`Few reports exist of patients with sJIA developing IBD.
`Twenty-nine patients with various subtypes of JIA, includ-
`ing three with sJIA, have been linked to IBD on treatment
`with etanercept, and one on infliximab [7–9]. All three pa-
`tients developed Crohn’s disease between 5 and 12 years
`after diagnosis of sJIA on treatment with etanercept; all pa-
`tients went into clinical remission after discontinuation of
`etanercept and treatment of IBD. A recent survey from the
`German biologics registry did find IBD in eleven of 3,071
`patients with JIA, but none with sJIA [10]. Endoscopic
`studies on 27 JIA patients with gastrointestinal symptoms
`also found ulcerative colitis in five patients (19%), but none
`with sJIA [5]. Phenotypes of rheumatic diseases can evi-
`dently change over time, especially in childhood. sJIA
`changes from IL-1 driven acute febrile sJIA to IL-17 driven
`chronic active sJIA over time [1]. In endoscopic mucosal
`samples, IBD similarly exhibits a strong TH1 phenotype in
`early lesions and switches to a TH17 phenotype, with
`marked increase in IL-17A, and induction of IL-6 and IL-
`23; it can occur subsequent to different categories of JIA as
`well as spondyloarthropathies [11, 12].
`IBD, especially
`Crohn’s disease, is considered an NF-κB activation disorder
`as part of the spectrum of autoinflammatory diseases,
`where cross-overs have frequently been observed – a
`change of sJIA into an IBD phenotype therefore seems at
`least possible in theory [13]. In fact, a recent study of
`
`

`

`Hügle et al. Pediatric Rheumatology (2017) 15:16
`
`Page 4 of 5
`
`Table 3 Similarities to and differences between the presentation of systemic juvenile idiopathic arthritis and inflammatory bowel
`disease in children
`
`Onset of the disease
`
`Gastrointestinal symptoms
`
`Muskuloskeletal symptoms
`
`Skin manifestations
`
`Laboratory abnormalities
`
`Juvenile Idiopathic Arthritis
`Acute onset with high, quotidian fevers,
`
`Frequently abdominal pain, also nausea and
`anorexia
`
`Initially, mild oligoarticular arthritis, frequently
`severe polyarthritis over the course of the
`disease
`
`Initial presentation with evanescent, salmon-
`colored, cutaneous eruption
`
`Anemia, reactive thrombocytosis, markedly
`elevated erythrocyte sedimentation rate and
`C-reactive protein. Significantly elevated fer-
`ritin. Typically negative antinuclear antibodies
`and rheumatoid factor.
`
`Inflammatory Bowel Disease
`Typically subacute illness with fatigue, anemia,
`and weight loss. Occasionally more fulminant
`presentation.
`
`Loose stools and/or bloody diarrhea,
`abdominal pain, tenesmus
`
`Nonerosive, asymmetric arthritis, affecting the
`large joints, parallel to intestinal involvement
`
`Erythema nodosum, pyoderma gangrenosum
`
`Anemia, elevated erythrocyte sedimentation
`rate and C-reactive protein, depressed albu-
`min level, occult blood in the stool, elevated
`fecal calprotectin. Ferritin typically low or nor-
`mal. Typically negative antinuclear antibodies
`and rheumatoid factor.
`
`mucosal biopsies in 33 JIA patients with gastrointestinal
`symptoms included eight with sJIA, with two patients with
`mild eosinophilic infiltration in the colon, and one 4 year
`old patient with active gastrointestinal inflammation [6].
`All three patients were exposed to IL-1 antagonists when
`developing symptoms of
`IBD.
`IL-1 is known to be
`expressed at high levels in colonic biopsies from patients
`with IBD, supporting the hypothesis of a pro-inflammatory
`role. Animal models of colitis both in rabbits and rats im-
`prove with blockade of IL-1 [14]. However, recent mouse
`models show a differentiated role for IL-1α and IL-1β,
`where IL-1α, produced mainly by colonic epithelial cells,
`acts in an inflammatory fashion [15]. In comparison, IL-1β,
`produced mostly by myeloid cells, promotes healing and re-
`pair in colonic tissue; IL-1β deficient mice show more se-
`vere colitis with failure of
`repair mechanisms
`[16].
`Anakinra blocks both IL-1α and IL-1β, but in the mouse
`model described, experimental specific IL-1α antibodies
`were significantly more efficacious in reducing severity of
`colitis compared to external IL-1 receptor antagonist (IL-
`1RA). Canakinumab by design specifically targets IL1-β,
`with no effect on IL-1α. Disturbance of the IL1-1α/β equi-
`librium by these medications might possibly create a pro-
`inflammatory environment in the colon, leading to IBD in
`selected cases. Patients with active IBD have in fact been
`shown to have increased levels of IL-1RA [17]. So far, no
`clinical trials have been reported for IL-1 antagonists in
`IBD, but one case of IBD worsening with anakinra treat-
`ment has been described [18]. One patient with sJIA in a
`randomized clinical trial for anakinra did also in fact de-
`velop Crohn’s disease [19].
`Gastrointestinal symptoms in JIA are not uncommon,
`with several series describing results from gastrointestinal
`investigations [5, 6]. The majority of cases, including those
`with sJIA, show mild, nonspecific inflammation, frequently
`with a prominent eosinophilic infiltrate, with more severe
`
`inflammation in only a few cases. It is possible that the
`three cases presented here represent the extreme end of
`this spectrum. However, all three patients had ongoing, se-
`vere abdominal manifestations over several months while
`sJIA symptoms were well controlled. The three patients
`had extensive infectious work-up during diagnosis, which
`showed positive IgM antibodies for various pathogens,
`whose impact on the disease progression and change in
`phenotype is unclear.
`This is a case series; therefore, any conclusions about
`an underlying pathological mechanism would be prema-
`ture. The impact of medications on the development of
`IBD is unclear: the interval between IL-1 blocker treat-
`ment and IBD manifestations is highly variable, and it is
`possible that methotrexate withdrawal in case 3 lead to
`uncovering of a previously subclinical IBD. However,
`three cases of IBD in a single tertiary center cohort of
`82 patients argues against mere coincidence.
`In summary, this is the first report of sJIA patients de-
`veloping IBD in temporal connection with IL-1 antagon-
`ist treatment. It is not clear if these cases are coincident,
`represent a change in patterns of inflammation of sJIA
`or are a consequence of
`treatment. Further efforts
`should aim at collecting more patients and elucidating
`the underlying disease processes.
`
`Additional files
`
`Additional file 1: Table S1. Supplementary clinical and laboratory data
`for the patients at time of diagnosis of sJIA. (DOCX 23 kb)
`Additional file 2: Table S2. Coloscopy results of the 3 patients,
`translated and summarized from the German original. (DOCX 23 kb)
`
`Acknowledgements
`Not applicable.
`
`

`

`Hügle et al. Pediatric Rheumatology (2017) 15:16
`
`Page 5 of 5
`
`Funding
`This study was not supported by any outside funding.
`
`Availability of data and materials
`The datasets during and/or analyzed during the current study available from
`the corresponding author on reasonable request.
`
`Authors’ contributions
`BH designed the study, performed the data collection and the analysis. FS
`and JPH participated in the analysis and helped draft the manuscript. All
`authors read and approved the final manuscript.
`
`Competing interests
`The authors declare that they have no competing interests.
`
`Consent for publication
`Not applicable.
`
`Ethics approval and consent to participate
`The study was approved by the Ethics Committee of the Medical Faculty,
`Ludwig-Maximilians University Munich, Germany.
`
`Publisher’s Note
`Springer Nature remains neutral with regard to jurisdictional claims in
`published maps and institutional affiliations.
`
`Received: 28 September 2016 Accepted: 6 March 2017
`
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`17.
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