DOI: https://doi.org/10.21203/rs.3.rs-1613205/v1
Background: Anti-TNF-α antibody has been an efficient therapy for managing ulcerative colitis (UC). However, IgA vasculitis may be a rare complication that occurs during inflammatory bowel disease (IBD) or after TNF blocker treatment.
Case presentation: We report a 14-year-old female patient with a history of purpuric skin lesions and UC. Two months prior to the current admission, she developed canker sores with fever, which was alleviated after the application of clindamycin hydrochloride. One month prior to the current admission, she was diagnosed with UC because of her abdominal pain and severe bloody diarrhoea. Ten days before admission, she developed a bilateral lower extremity purpuric rash. After admission, her abdominal symptoms mildly improved with glucocorticoids and infliximab. However, soon after, she developed two episodes of severe haematochezia and markedly aggravated purpura on the extensor side of both lower extremities. Following colonoscopy examination and intestinal IgA staining, she was diagnosed with IgA vasculitis, which induced severe haematochezia. We decided to continue the original treatment. After the fifth dose of infliximab, the gastrointestinal symptoms disappeared, and the purpuric rash resolved after 1 month.
Discussion and conclusion: IgA vasculitis is a rare adverse effect of extraintestinal manifestations of UC, appearing at any age. IgA vasculitis is triggered by infections, specific drugs (infliximab, adalimumab, etanercept) and malignancy. The abdominal and intestinal manifestations of UC and IgA vasculitis may overlap, making it difficult to diagnose IgA vasculitis. Therefore, colonoscopy and intestinal biopsy with IgA staining are useful to detect intestinal involvement of IgA vasculitis.
Anti-TNFα therapy, such as infliximab, is widely used to induce prolonged remission of moderate to severe ulcerative colitis (UC) in adults [1, 2]. It is also used to replace or reduce the dose of glucocorticoids in the treatment of complicated UC [3]. IgA-mediated vasculitis, which is potentially severe but rare [4], has been reported to occur after anti-TNF therapy, including adalimumab [5–7], infliximab [7–10], and etanercept [11–13]. IgA-mediated vasculitis typically manifests with cutaneous vascular purpura, joint pain, abdominal pain, and kidney impairment [14]. Anti-TNFα therapy can cause severe IgA-associated vasculitis, including skin necrosis [15], rectal bleeding, and neurological dysfunction leading to progressive motor deficits [16]. Adalimumab and infliximab treatment for inflammatory bowel disease caused IgA vasculitis in six cases with ages ranging from 12 to 69 years [5, 6, 8–10, 17]. Henoch-Schönlein purpura (HSP) onset after anti-TNF therapy ranged from one day to more than 18 months, with a mean delay of 9.84 months [18]. Herein, in contrast to reported IgA vasculitis induced by TNF blockers, we report a case of advanced IgA vasculitis with severe haematochezia and rash after the introduction of infliximab (IFX) in a 14-year-old female adolescent with UC.
In September 2021, a previously healthy 14-year-old Chinese girl initially presented with canker sores and fever, which was cured by clindamycin hydrochloride 5 days later. One month later, she suffered from repeated abdominal pain, relieved by bowel movements with haematochezia 3–8 times per day. The patient also experienced dizziness, weakness, afebrile pallor, nausea, vomiting with sour regurgitation, chest discomfort, joint pain, photosensitivity and perineal ulcerations. Ten days before admission to our hospital, she experienced cutaneous vascular purpura on the lower limbs and was admitted to a tertiary medical institution. Laboratory data revealed a leukocyte count of 10.49×109/L with 72.6% neutrophils and a haemoglobin level of 84 g/L. Colonoscopy showed typical UC manifestations with pancolonic lesions. Based on clinical features, biochemical features, and endoscopy examination, the female adolescent was diagnosed with severe UC. The patient received mesalazine and methylprednisolone, and then methylprednisolone was tapered and gradually switched to oral and rectal mesalazine once the abdominal pain and haematochezia were alleviated.
In December 2022, the patient was admitted to our hospital because she was still experiencing intermittent abdominal pain, blooding diarrhoea, and fever. On admission, her BMI (BMI 13.43 kg/m2, weight 37 kg, height 166 cm) was significantly lower than that of girls of the same age. Laboratory data showed a WBC of 11.16×10^9/L, neutrophil levels of 7.86×10^9/L, haemoglobin levels of 69 g/L, HCT 22.3%, CRP levels of 10 mg/L, ESR of 11 mm/h, HBP levels of 92 g/L, TNFα levels of 27 pg/mL and calprotectin levels of 592.1 µg/g. Tests for antinuclear antibodies, rheumatoid factor and antineutrophil cytoplasmic antibodies were negative. Tests for Epstein–Barr virus, cytomegalovirus, HIV, and hepatitis B and C virus infections were also negative. Because of severe UC activity, high inflammatory index and moderate anaemia, the patient received intravenous (IV) methylprednisolone 2 mg/kg/day on Day 1 (regarded as Day 1), antibiotics, and supportive RBC suspensions. On Day 7, she had her first IFX treatment (200 mg). Seven days later, because of the rapid resolution of haematochezia, methylprednisolone was decreased to oral methylprednisolone tablets of 1 mg/kg/day. On Day 9, the patient received the second IFX 200 mg treatment. However, the next day (Day 10), the patient had massive bloody stools with increased heart rate (HR) (her highest HR was 125 bpm) and decreased blood pressure (BP) (her lowest BP was 87/51 mmHg). Therefore, oral methylprednisolone was changed to intravenous systemic methylprednisolone 1.5 mg/kg/day. After administration of rehydration support, RBC suspension transfusion and haemostatic treatment, she recovered soon, but the skin lesions were aggravated (Fig. 1). On Day 19, the patient received the third IFX 300 mg treatment, and three days later (Day 22), the patient received a colonoscopy revealing inflammatory mucosal hyperplasia and shallow ulcers in the descending colon and rectum, which had improved more than 1 month ago (Fig. 2A). Colonoscopy also revealed mucosa with a visible vascular pattern (Fig. 2B). Blood tests showed an increased haemoglobin level of 91 g/L and normal CRP and ESR results. Due to symptom stabilisation and improvement of the inflammatory index, on Day 27, intravenous methylprednisolone 1.5 mg/kg/day was changed to oral methylprednisolone 1 mg/kg/day. The patient received IFX 300 mg with the fourth dose. The patient experienced another bout of severe haematochezia on the same day, which was immediately alleviated by the treatment described above, so oral methylprednisolone 1 mg/kg/day was changed to intravenous methylprednisolone 1 mg/kg/day. On Day 28, the patient received an emergency endoscopy. We observed a 3–5 cm post-hemorrhagic scab (Fig. 3A) far from the anal margin and an improved mucosal lesion with no sigmoid colon or rectum ulceration. Simultaneously, direct intestinal tissue immunofluorescence revealed IgA staining of vessel walls (Fig. 3B). Based on these findings, IgA vasculitis was diagnosed, and IFX was suspected of playing a role in triggering the progression of intestinal vasculitis-associated haematochezia.
IFX was not discontinued because of her improved skin rash and intestinal mucosa. The patient no longer had haematochezia after Day 30, and oral methylprednisolone was gradually tapered and discontinued on Day 90. At more than 4 months of follow-up, although she received two additional IFX treatments (Day 81 and Day 109), neither caused further haematochezia. The skin lesions resolved approximately 2 months after admission to our hospital. Laboratory data revealed that faecal calprotectin, WBC, haemoglobin, HCT and albumin levels improved after the second bout of severe haematochezia (Fig. 4). The patient had improved nutritional status evidenced by weight from 37 to 48 kg and BMI from 13.27 to 17.65 kg/m2.
IgA vasculitis induced by anti-TNF therapy is rare [16], and systemic IgA vasculitis with extracutaneous involvement is rarer [18]. Here, we describe an unusual case of severe haematochezia in a paediatric patient with UC and IgA vasculitis after receiving infliximab. In our case, before hospitalisation, the female patient already had purpuric skin lesions. After hospitalisation, immediate control of haematochezia after haemostatic drug and glucocorticoid administration was shorter than the 3 to 5 days needed to control UC-associated haematochezia suggested by the AGA clinical practice guidelines on the management of moderate to severe UC [19]. Thus, we suspected that UC was not the primary contributor to the acute haematochezia. Due to the purpuric skin lesions and the rapid resolution of her haematochezia, IgA vasculitis with digestive involvement was diagnosed. This is the first report showing the anti-TNF-related progression of digestive involvement in patients with UC and IgA vasculitis to the best of our knowledge.
In general, vasculitis is not commonly observed in gastrointestinal (GI) biopsies of patients with IgA vasculitis [20]. The observed GI findings include neutrophil infiltration within the small bowel and colon, with the duodenum most commonly affected [20]. This is consistent with our observations regarding our patient. She had oesophageal and gastroduodenal involvement with colon and rectal ulcers. Streptococcal infection is the most frequent trigger for IgA vasculitis [21]. The preceding oral cavity infection (canker sore) may have triggered the development of IgA vasculitis. The IgA vasculitis was then exacerbated by infliximab treatment, which could be implicated according to the French drug reaction assessment method [22]. The treatment with systemic steroids probably decreased the severity of the vasculitis that was exacerbated by infliximab, leading to a partial resolution of the digestive symptoms. The decrease in systemic steroids may have contributed to the exacerbation of the intestinal vasculitis, leading to acute rectal bleeding. In addition, the atypical intestinal mucosal lesion caused by IgA vasculitis that was observed in our case might have developed due to adequate intravenous methylprednisolone, which significantly improved intestinal submucosal vasculitis.
The pathophysiology of the paradoxical digestive system reactions induced by the anti-TNF therapy is unclear. An imbalance in cytokines secondary to TNF inhibition may also have contributed to the side effects. Specifically, inhibition of interferon-α (IFN-α) production from plasmacytoid dendritic cells by TNF was reversed after anti-TNF therapy, resulting in increased IFN-α levels in the intestinal mucosa and skin [23]. Increased IFN-α stimulates and activates T cells, which leads to TNF and IL-17A production and thus exacerbates intestinal inflammation. In addition, anti-TNF therapy interrupts the effect of TNF-promoted T regulatory cell survival and proliferation [24], which is also proposed to be responsible for IgA vasculitis acute exacerbation, leading to severe haematochezia. In this study, we could not ascertain whether the abovementioned aetiologies of IgA vasculitis contributed to the disease process in our patient or whether a de novo inflammatory pathway contributed to the disease onset.
We decided not to withdraw the current infliximab treatment regimen after the first flare-up of HSP. According to the clinical practice guidelines [19], the AGA suggests using intravenous methylprednisolone in hospitalised patients with severe acute UC. After remission, the AGA suggests early use of biological agents, including infliximab or vedolizumab, rather than adalimumab. Our patient tolerated infliximab well after the second bout of severe haematochezia and had clinical, endoscopic, and histological improvement as we continued infliximab treatment and slowly stopped the steroids. It is difficult to exclude alternative drug-induced acute exacerbation of HSP in our patient because drug interactions are a potential confounding factor since this patient was taking drugs in addition to anti-TNF agents, including mesalazine and methylprednisolone. These two drugs have been reported to induce HSP-related adverse effects, including erythema multiforme [25], acute tubulointerstitial nephritis [25] and gastrointestinal perforation [26].
In the recent decade, where anti-TNF therapy has expanded, further guidance on clinical management of new-onset complications is needed. Depending on the clinical presentation, we believe HSP-related organ impairment is not an absolute contraindication for anti-TNF inhibitor therapy, and reinstatement of therapy may even be considered.
Immunoglobulin A
Infliximab
Ulcerative Colitis
Tumour Necrosis Factor
Inflammatory Bowel Disease
Henoch-Schonlein purpura
Body Mass Index
White Blood Cell
Haematocrit
C-Reactive Protein
Erythrocyte Sedimentation Rate
Heparin-Binding Protein
Human Immunodeficiency Virus
Red Blood Cell
Heart Rate
Blood Pressure
Gastrointestinal
Interferon
Interleukin-17
American Gastroenterological Association
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No conflict of interest exists in submitting this manuscript, and all authors have approved the manuscript for publication. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript.
Authors’ contributions
JL designed the manuscript and collected data; YX, JL, and CX interpreted the data; JL and YY wrote and edited the manuscript; all authors have read and approved the final manuscript.
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Verbal and written consent for this case report was obtained from the girl’s father. Proof of consent to publish from this patient and her father can be requested at any time.
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Author details
Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.