Crohn’s-like Enteritis in X-Linked Agammaglobulinemia: A Case Series and Systematic Review

Abstract

BACKGROUND:

X-linked agammaglobulinemia (XLA) is an inherited primary immunodeficiency that usually manifests clinically with recurrent sinopulmonary infections. Gastrointestinal manifestations are mostly driven by acute infections and disturbed mucosal immunity, but there is a notable prevalence of inflammatory bowel disease (IBD). Differentiating between XLA-associated enteritis, which can originate from recurrent infections, and IBD can be diagnostically and therapeutically challenging.

OBJECTIVE:

This study presents a critical appraisal of the clinical, radiological, endoscopic, and histological features associated with XLA-associated Crohn disease (CD)–like enteritis.

METHODS:

We report 3 cases and performed a systematic review of the literature describing the diagnoses and outcomes.

RESULTS:

An XLA-related enteropathy presented in adolescence with an ileocolonic CD-like phenotype without perianal disease. Abdominal pain, noninfectious diarrhea, and weight loss were the most common symptoms. Imaging and endoscopic findings closely resemble CD. However, histologically, it presents without nodular lymphoid hyperplasia and only 2 studies reported the presence of granulomas. In addition, in XLA-associated enteritis, immunohistochemistry showed the absence or marked reduction in B cells and plasma cells.

CONCLUSIONS:

An XLA-associated enteritis is a distinct pathological process that presents clinically in a manner similar to ileocolonic CD. It is important to evaluate for infectious diarrhea, which is common in XLA and can mimic IBD clinically. Complete multidisciplinary evaluation is, therefore, recommended for XLA patients with persistent gastrointestinal symptoms. Although more research is needed, therapeutic selection for XLA-associated enteritis is like that of IBD, and the possible risk of drug interactions and complications from increasing immunosuppression should be considered.

INTRODUCTION

X-linked agammaglobulinemia (XLA), also known as Bruton disease, is a primary immunodeficiency disease. It has an X-linked recessive inheritance pattern with mutations in the Bruton tyrosine kinase (BTK) gene on chromosome Xq21.3-Xq22, accounting for 85% of cases of congenital agammaglobulinemia. The BTK gene encodes a cytoplasmic nonreceptor protein tyrosine kinase that belongs to the Tec kinase family and plays a fundamental role in B-cell receptor signaling and development. This results in the absence of mature B cells in the peripheral blood and markedly reduced levels of serum antibodies.¹ The XLA has been recognized since 1952, and over 600 different mutations of the BTK gene have been reported in the literature. The global estimated incidence of XLA ranges from 1:100,000 to 1:200,000 live births.^2–4

Despite recent clinical advances, there are still widespread limitations regarding the timely diagnosis of XLA.⁴ There is no standard screening and XLA patients are not identified clinically because newborns are either asymptomatic or have symptom heterogeneity.^3,5,6 The large variations in symptomatic presentation and associated complications lead to a diagnostic delay ranging from 24 to 84 months.^4,7,8 In addition, genetic testing was lacking in 39% of centers queried in a recent survey.⁴ Nevertheless, owing to increased awareness, genetic screening, and advocacy by national registries, this disease is increasingly being recognized.⁸ Associated signs and symptoms involving different organ systems have been reported, albeit on a limited basis. Systemic involvement of this disease most often manifests as recurrent otitis media, pneumonia, gastroenteritis, meningitis/encephalitis, pyoderma gangrenosum, and chronic liver disease.^2–4,7–9

The most reported gastrointestinal (GI) manifestations of XLA include intermittent or chronic diarrhea, gastroenteritis, or malabsorption.^3,7–9 Malignant change, predominantly found in the GI tract, has been described in several studies and is a potential complication.^8,10,11 Whereas recurrent infections, including Giardia or Campylobacter species, may play a role in some of these GI symptoms, a subset of patients develop a chronic Crohn disease (CD)–like condition in the absence of acute infection.^12–14 Of XLA patients reported in the U.S. Immunodeficiency Network (USIDNet) registry, CD had been diagnosed in 3.4% of the 128 patients registered.¹⁵ Unlike classic inflammatory bowel disease (IBD) with polygenic pathogenesis, individuals with XLA harbor a single gene aberration, uniquely dictating the disease process.^16–18 Published reports from colonoscopies of XLA patients document an active chronic enterocolitis.^14,19 Bowel resection specimens show strictures mimicking CD, although plasma cells and mature B cells are notably absent, histopathologically.^12,20,21 To better characterize clinicopathological findings of CD-like enteritis in XLA and the clinical outcomes, we report 3 affected patients and perform a systematic review of the literature.

METHODS

In addition to describing 3 cases, a systematic review was performed. Scopus, PubMed Central, and Google scholar queries with a search string (“x linked agammaglobulinemia” OR “Bruton’s disease” OR “monogenic IBD” AND “pathology” AND “endoscopy”) shortlisted 242 nonduplicate studies describing GI manifestations in XLA. The related articles function in PubMed and citing articles function in Google Scholar was also used to broaden the search; no language restrictions were made. Full-text appraisal of the searched results yielded 11 studies fulfilling the inclusion criteria (ie, with endoscopically and pathologically detailed CD-like enteritis, known XLA diagnosis, and therapeutic outcomes). Studies without disease-specific pathological evidence or only describing neoplastic or adenomatous transformation were excluded. Figure 1 illustrates the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)–based search outcomes. Further, the genomic locations and severity predictions have been extracted from ClinVar and combined annotation-dependent depletion database.²²

FIGURE 1.

Literature search flow diagram, generated from http://prisma.thetacollaborative.ca/.

RESULTS

Case description

Case 1.

A 20-year-old man with a family history of XLA was diagnosed with XLA at the age of 3 years. Genetic studies demonstrated a nonsense mutation p.Q380*, c.1138C >T at exon 13 of the BTK gene. He has been treated with intravenous immunoglobulin (IVIG) since diagnosis. Throughout his life, he has experienced sinopulmonary infections and failure to thrive (weight < third percentile of age in early childhood). He had several episodes of diarrhea throughout childhood and adolescence during which no specific infectious agent or other cause was identified. He was otherwise without any other significant GI symptoms.

He presented to the hospital with a 3-week history of abdominal pain, diarrhea, and loss of appetite leading to a 5-kg weight loss. Notably he did not complain of any non-GI symptoms. Workup was negative for infectious enterocolitis but revealed a C-reactive protein (CRP) of 22 mg/L (normal 0–5 mg/L), an erythrocyte sedimentation rate (ESR) of 81 mm/h (normal 0–15 mm/h), albumin of 3.6 g/dL, and a stool calprotectin 993 μg/G (normal < 120 μg/G). A computed tomography scan demonstrated terminal ileitis with probable stricture (Figure 2). Endoscopic evaluation revealed scattered aphthae in the stomach, duodenum, and rectosigmoid colon as well as inflammation at the ileocecal valve. Biopsy confirmed active duodenitis with focal crypt architectural distortion, cryptitis, scattered crypt apoptotic bodies, crypt eosinophilic microabscesses, as well as active ileocolitis with granulation tissue. A preliminary diagnosis of CD was made; however, before starting biologic therapy, he presented to the emergency room with symptomatic ileal stricture and underwent ileocolic resection. The resected specimen showed a stricture of the terminal ileum (Figure 3, A) with fat wrapping (Figure 3, B). Sections from the terminal ileum showed transmural active chronic ileitis, with ulceration, abscess formation, pyloric gland metaplasia, and neural and muscular hypertrophy (Figure 3, C, D). Peyer patches were notably absent, and no granulomas were seen. Immunohistochemical stains showed an absence of both CD20+ B cells (Figure 3, E) and CD138+ plasma cells (Figure 3, F). The appendix showed involvement by the inflammatory process, whereas the cecum was spared.

FIGURE 2.

Computed tomography scan coronal view (case 1) shows terminal ileitis with thickening of the bowel wall and probable stricture (arrows).

FIGURE 3.

(A) Ileocecal stricture (between arrowheads) with (B) fat wrapping (between arrowheads). (C) Transmural chronic inflammation, ulceration (10× hematoxylin-eosin [H&E] stain; arrowheads) and (D) pyloric gland metaplasia (400× H&E stain; between arrowheads). (E) Absence of CD20+ B cells (40×); compare with CD (inset; 40X). (F) Absence of CD138+ plasma cells (40×); compare with CD (inset; 200×).

Following surgery, the patient was started on infliximab for the management of his CD. A follow-up upper GI endoscopy and colonoscopy 1 year later demonstrated mildly active nonspecific ileitis, whereas the distal colon and rectal mucosae appeared normal. Immunohistochemical stains confirmed an absence of CD20+ mature B cells, CD79a early B cells, and plasma cells. Microorganism stains (acid-fast bacilli, Gomori methenamine silver, and immunohistochemical stains for cytomegalovirus) were negative. He has continued infliximab treatment with sustained clinical improvement, although with a continual demonstration of a short segment of terminal ileitis on both colonoscopy and magnetic resonance enterography.

Case 3.

A 13-year-old boy with no family history was diagnosed with XLA at the age of 3 years. Genetic studies demonstrated a frameshift deletion p. lys558fsX, c. 1673_1680delAATTTCCA at exon 17 of the BTK gene. Throughout his life, he experienced recurrent sinonasal infections, and he has been managed with IVIG replacement since diagnosis. He presented to the hospital with a week-long history of intermittent fever, aphthous stomatitis, diffuse small and large joint pain, and intractable abdominal pain associated with nonbloody and nonmucinous diarrhea and a 5-kg weight loss. His height and weight were under the 35th and 20th percentiles, respectively. Laboratory evaluation revealed a CRP of 158 mg/L (normal 0–5 mg/L), an ESR of 71 mm/h (normal 0–15 mm/h), hypoalbuminemia of 2.7 g/dL, and markedly elevated stool calprotectin of 2,792 μg/G (normal < 120 μg/G). Magnetic resonance enterography did not demonstrate any active inflammation, narrowing, or obstruction. The endoscopic evaluation revealed patchy mildly active inflammation in the esophagus, terminal ileum, and right colon, whereas the distal colon and rectum appeared normal. Biopsies showed focal erosion in the terminal ileum and mild active colitis with cryptitis and focal crypt abscess, but no evidence of chronic inflammation. No granulomas were seen. Immunohistochemical stains showed the absence of mature CD20+ B cells, although rare CD79a+ early B cells and CD138+ plasma cells were identified (Figure 4). Extensive evaluation for infectious etiologies, including the plasma-based, microbial cell–free DNA Karius test, was negative. Capsule endoscopy showed patchy erythema and ulcerations with exudate most prominent in the distal duodenum and jejunum (Figure 5), consistent with CD. He was initially managed with oral budesonide that resolved abdominal pain, diarrhea, mouth sores, and arthralgias. He achieved near-normalization of his ESR, CRP, and albumin with vedolizumab prescribed for long-term management.

FIGURE 4.

Biopsy from the terminal ileum, arrowhead shows (A) focal erosion (100× H&E stain), and biopsy from the left colon, arrowhead shows (B) a focal crypt abscess (200× H&E stain). Lymphocytes within the lamina propria are predominantly (C) CD3+ T cells with (D) absent CD20+ B cells, (E) rare CD79a+ early B cells, and (F) rare CD138+ plasma cells.

FIGURE 5.

Capsule endoscopy demonstrates numerous, exudate-covered ulcerations with surrounding erythema and edema primarily in the proximal-to-mid small bowel. Representative images show (A) edematous mucosa with ulceration and evidence of bleeding in the proximal small bowel and (B) deep ulceration (arrow) in the jejunum.

Case 3: USIDNet XLA registry.

Registries across the globe report a 19% to 41% incidence of GI symptoms in XLA, yet histopathological reports are sparse. The USIDNet is a national registry with over 5786 patients of primary immunodeficiencies in the United States. We performed a query of USIDNet for XLA patients with reported GI manifestations, seeking patients with IBD or IBD-like illnesses and for whom histopathology from the GI tract was available. One patient was located. The resulting patient presented with pneumonia at 13 years of age and was diagnosed with agammaglobulinemia after an initial workup revealed absent immunoglobulins and absent CD19+ B cells. Genetic studies demonstrated a missense mutation p. Pro566Leu, c. 1697C> T at exon 17 of the BTK gene. He did well on IVIG for several years but began to lose weight at 17 years of age and then developed recurrent aphthous stomatitis. He did not report diarrhea, but his trough immunoglobulin levels and pneumococcal antibody titers fell despite shortened intervals and increased dosing of IVIG. His initial endoscopy did not support IBD, but follow-up colonoscopy 3 years later demonstrated severely active ileitis with ulceration of the terminal ileum. He achieved both clinical and endoscopic remission with ustekinumab.

Literature review

Table I summarizes the reported clinical, genetic, imaging, endoscopic, and histological features. The median age at developing CD-like enteritis was 15 years (±5.2 years), although 1 report did not specify an age and 2 studies only stated that the symptoms developed while the patient was a teenager.

TABLE I.

Clinical, radiological, and histopathological findings in all cases

Study	Age at enteritis diagnosis (y)	Clinical findings (enteritis)	Radiological findings	Endoscopic findings	Pathological findings
Case 1	20	Abdominal pain, diarrhea, small bowel obstruction, weight loss	CT (age 20): terminal ileum thickening, probable stricture MRE (age 20): terminal ileum/cecal thickening	Colonoscopy (age 21): ileocecal valve inflammation	Ileocecal resection (age 20): transmural active chronic inflammation, stricture, pyloric gland metaplasia
Case 2	13	Abdominal pain, diarrhea, weight loss Acute arthropathy	MRE (age 13): negative for inflammation	Capsule endoscopy (age 13): duodenal/jejunal CD	Colonoscopy (age 13): focal erosion in the terminal ileum, focal active colitis, no evidence of chronic inflammation
Case 3	17	Weight loss, aphthous stomatitis	NR	Colonoscopy (age 20): severely active ileitis	Colonoscopy (age 20): severely active ileitis with granulation tissue at terminal ileum
Eggert et al, 196923	13	Epigastric abdominal pain, frequent stools, partial small bowel obstruction	Small bowel x-ray (age 13): regional enteritis	Proctoscopy (age 13): normal	Partial small bowel resection ×2 (age 13): active chronic enteritis with thickening of bowel wall, strictures, ulceration
Abramowsky et al, 198820	16	Diarrhea, weight loss, obstruction	Radiology studies (age 16): inflammation of distal jejunum and ileum	Colonoscopy (age 13): nonspecific chronic inflammation of terminal ileum	Ileocecal and small bowel resection (age 24): thickening of small wall with stricture, healed ulcers, prominent lymphoid infiltrate of lamina propria, clubbing of small intestinal villi, and gastric gland metaplasia, but no transmural inflammation. Prior ileal resection (age 16) — similar findings as above
Teahon et al, 199424	NR	Weight loss, abdominal pain	NR	NR	Jejunum resection: nonspecific transmural inflammation with multiple strictures
Washington et al, 199612	13	Clinical features of CD, not further specified	NR	Small bowel biopsy (age 12): nonspecific changes	Small bowel resection (age 13) and ileum resection (age 13): small bowel strictures with fissuring necrosis
Cellier et al, 200021	22	Chronic abdominal pain, diarrhea, weight loss	X-ray and CT (age 22): ileitis with multiple stenosis of terminal ileum	Retrograde push enteroscopy (age 24; symptom free): no evidence of inflammation, tissue PCR negative for enterovirus	Ileocecal resection (age 22): ileum with irregular transmural inflammation, thickened wall, strictures, ulceration, crypt abscesses, granulomas. PCR positive for enterovirus in inflamed portion of bowel
Nahum et al, 201413	2	Fever, perianal ulcers, bloody stool (age 2) Left-sided abdominal pain, tenderness (age 13)	Bowel contrast (age 13): filling defect midjejunum CT (age 13): focal small bowel thickening and possible submucosal process—CD-like	Gastrointestinal studies (age 2): thickening of the bowel wall and numerous pseudopolyps	Colonoscopy (age 13): distorted villous architecture, crypt hyperplasia Jejunal resection (age 13): transmural inflammation, ulceration, pseudopolyps, cryptitis, crypt distortion, hypertrophy of muscularis propria
Davey et al, 201425	Teen	Abdominal pain, weight loss, diarrhea	CT (age 21): small bowel thickening, edema, fat stranding and fistulization	Colonoscopy and capsule endoscopy (teen): ileitis, ileocecal inflammation, and ulceration.	Small bowel resection (age 21): florid transmural inflammation, histiocytes/(suppurative granulomas), and adenopathy.
Pac et al, 201714	Teen	Abdominal pain, weight loss	NR	Colonoscopy: ulcerations and aphthae in terminal ileum	Colonoscopy: mild to moderately active chronic inflammation of transverse and sigmoid colon
Çekiç et al, 201926	8	Abdominal pain, fever, weight loss, and oral ulcers	MRE (age 8): jejunal thickening and luminal stenosis with prestenotic dilation	Colonoscopy: ileocecal and colonic mucosal active chronic inflammation.	Proximal jejunal resection (age 8.8): histologically consistent with CD, after progression/relapse on infliximab
Crowley et al, 202017	15	Abdominal pain, weight loss	NR	NR	Colonoscopy (age 15): mixed chronic inflammation of colon suggestive of collagenous colitis
King et al, 202127	15	Abdominal pain, emesis, and anorexia	Abdominal US and MRE (age 15): terminal ileitis with stenosis	Colonoscopy: ileocecal narrowing and ileitis	Colonoscopy (age 15): active chronic ileitis consistent with CD-like disease. Right hemicolectomy post progression (age 15.3): later (age 16) neoterminal ileitis, prepyloric deep ulcers, and duodenitis but with colonic sparing

CT, Computed tomography; MRE, magnetic resonance enterography; NR, not reported; PCR, polymerase chain reaction; US, ultrasound.

Among all the studies, common findings include abdominal pain, weight loss, diarrhea, and obstructive symptoms.^{13,14,17,20,21,23–27} Of the 9 cases with radiological imaging, 4 showed enteritis (44%), 3 showed stenosis or probable stricture (33%), and 3 showed small bowel wall thickening (33%). Of the 12 cases with reported endoscopic findings, 9 cases showed inflammation of the distal small bowel (75%), 1 case showed thickening of the small bowel with numerous pseudopolyps (8%, site unspecified), 1 case had a normal proctoscopy (8%), and 1 showed nonspecific changes (8%). Common microscopic findings on biopsy and resection from all the patients included active mucosal inflammation (including fissure, ulceration, and erosion) in 8 cases (57%) and transmural inflammation (including stricture and bowel wall thickening) in 6 cases (43%). Table II elaborates the disease-specific characteristics along with clinical and therapeutic outcomes of these subjects.

TABLE II.

Disease-specific characteristics, extraintestinal manifestations, biomarkers, and clinical outcomes

Study	GI Disease Characteristics	Immunohistochemistry	Microbiology and biomarkers	EIM	Therapeutic interventions	Clinical outcomes
Case 1	Fistulizing ileocolonic disease: present Perianal disease: absent Granulomas: absent Mucosal NLH: absent	B cells: CD19−, CD79a− T cells: CD8+, CD4+ Plasma cells: CD138−	Stool calprotectin: 993 μg/G	Arthritis/arthralgia: absent Dermatological EIM: absent Aphthous stomatitis: absent	IVIG ileocolonic resection Infliximab	Clinical remission on infliximab.
Case 2	Fistulizing ileocolonic disease: absent Perianal disease: absent Granulomas: absent Mucosal NLH: absent	B cells: CD20−, CD79a rare T cells: CD4+, CD8+ Plasma cells: CD138 rare	Stool calprotectin: 2792 μg/G Microbial cell—free DNA: negative	Arthritis/arthralgia: present Dermatological EIM: present Aphthous stomatitis: present	IVIG Oral budesonide Vedolizumab	Clinical remission on vedolizumab
Case 3	Fistulizing ileocolonic disease: absent Perianal disease: absent Granuloma: absent Mucosal NLH: absent	B cells: NR T cells: NR Plasma cells: NR	NR	Arthritis/arthralgia: absent Dermatological EIM: absent Aphthous stomatitis: present	IVIG Ustekinumab	Clinical and endoscopic remission on ustekinumab
Eggert et al, 196923	Ileum strictures: present Perianal disease: absent Granulomas: NR Mucosal NLH: NR	Lymphocytes: present Plasma: absent	Stool O&P: negative	Arthritis/arthralgia: present Dermatological EIM: present Aphthous stomatitis: NR	IVIG and corticosteroids Terminal ileum resection	Chronic relapsing disease without remissions
Abramowsky et al, 198820	Fistulizing ileocolonic disease: present Perianal disease: NR Granulomas: NR Mucosal NLH: NR	B cells: CD19− T cells: CD4++ Plasma: NR	Bacterial, fungal, mycobacterial C/S and microscopy: negative	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	Prednisone Sulfasalazine Jejunum and right hemicolectomy IVIG	Clinical remission with IVIG, postsurgical resection
Teahon et al, 199424	Stricturing jejunal disease: present Perianal disease: NR Granuloma: NR Mucosal NLH: NR	B cells: NR T cells: NR Plasma: NR	NR	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	Elemental diet Jejunal resection	NR
Washington et al, 199612	Stricturing ileocolonic disease: present Perianal disease: absent Granulomas: absent Mucosal NLH: absent	B cells: NR T cells: NR Plasma: absent	NR	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	IVIG Ileum resection	Clinical remission with IVIG, postsurgical resection
Cellier et al, 200021	Stenosing ileocolonic disease: present Perianal disease: absent Granuloma: present Mucosal NLH: NR	B cells: absent, (CD22): rare T-cells: CD8++, CD4+ Plasma cells: NR	CMV, HHV, Enterovirus C/S: negative Enterovirus PCR: positive	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	IVIG Ileocecal resection	Clinical remission with IVIG, postsurgical resection
Nahum et al, 201413	Stenosing ileojejunal disease: present Perianal disease: present Granuloma: absent Mucosal NLH: absent	B cells: NR T cells: NR Plasma cells: NR	History of resolved giardiasis. Bacterial, protozoal, and fungal microscopy: negative	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	Jejunum resection	Clinical remission after surgical resection
Davey et al, 201425	Fistulizing ileocolonic disease: present Perianal disease: NR Granuloma: present Mucosal NLH: NR	B cells: NR T cells: NR Plasma cells: NR	Giardia: negative Tuberculosis, Whipple’s disease: negative	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	IVIG Mesalazine Ileum resection Infliximab	Clinical remission on infliximab
Pac et al, 201714	Fistulizing ileocolonic disease: absent Perianal disease: NR Granuloma: NR Mucosal NLH: NR	B cells: NR T cells: NR Plasma cells: NR	Stool O&P and cysts: negative Campylobacter, Clostridium, Salmonella, and Shigella: Negative	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	IVIG Corticosteroids Sulfasalazine Azathioprine	Clinically optimal response on azathioprine
Çekiç etal, 201926	Fistulizing ileocolonic disease: present Perianal disease: NR Granuloma: NR Mucosal NLH: NR	B cells: NR T cells: NR Plasma cells: NR	Stool O&P, C/S: negative CMV PCR: negative Giardia, Campylobacter: negative ESR: 29 mm/h CRP: 9.9 mg/dL Albumin: 2.7 g/dL	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: present	IVIG Corticosteroids Azathioprine Adalimumab Infliximab Jejunum resection Vedolizumab	Clinical remission on vedolizumab
Crowley et al, 202017	Stricturing ileocolonic disease: present Perianal disease: NR Granuloma: NR Mucosal NLH: NR	B cells: rare (CD20) T cells: NR Plasma cells: NR	ASCA: negative ANCA: negative	Arthritis/Arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	Exclusive enteral nutrition Methotrexate	Transitioned to adult services
King et al, 202127	Stricturing ileocolonic disease: present Perianal disease: NR Granuloma: NR Mucosal NLH: NR	B cells: NR T cells: NR Plasma cells: NR	History of resolved Campylobacter jejuni diarrhea Stool C/S: negative Stool calprotectin: 913 μg/G	Arthritis/arthralgia: NR Dermatological EIM: NR Aphthous stomatitis: NR	IVIG Right hemicolectomy Vedolizumab	Clinical and endoscopic remission on Vedolizumab

ANCA, Antineutrophil cytoplasmic antibody; ASCA, anti–saccharomyces cerevisiae antibody; CMV, cytomegalovirus; C/S, culture and sensitivity; EIM, extraintestinal manifestations; HHV, human herpes virus; NR, not reported; O&P, ova and parasites; PCR, polymerase chain reaction.

Infectious enteritis was specifically excluded in all but 1 study in which Cellier et al²¹ described a case of regional enteroviral enteritis in a 22-year-old man. Interestingly, enterovirus was identified by tissue polymerase chain reaction in the inflamed area with granuloma, but not in the normal mucosa or on a follow-up endoscopy when the patient was asymptomatic. The absence of granulomas or giant cells was specifically documented in 7 cases (77%), whereas granulomas were not discussed in the remaining 4 cases. The composition of the inflammatory cells was evaluated in several of the reported cases. Five cases reported a complete absence of plasma cells, and 1 case (our case 2) showed the presence of rare CD138+ plasma cells. Mature B cells were not identified in any of the 3 cases in which this was reported. Two cases (Cellier et al²¹ and our case 2) reported rare early B cells, and 2 cases reported the absence of early B cells.

As iterated by Barmettler et al,³ this phenotypic atypicality may be related to rare hypomorphic variants in XLA,⁶ at least hypothetically. For example, our case 2, which showed rare CD138+ plasma cells and CD79a+ B cells, had a frameshift mutation whereas our case 1 with a complete absence of these cells had a nonsense mutation. BTK gene mutation was not reported by Cellier et al.²¹ Similarly, a recent study typified this phenomenon in which an adolescent male with stricturing small bowel CD presented with a novel BTK variant p.N484K, c.1452G>T and a total lymphocyte count of 1.85 × 10⁹/L, but with very low levels of B cells.¹⁷ Still, the exact phenotypic projection in relation to specific type of mutation in BTK remains unknown.^2,28 Table III characterizes the genetics and closely matching severity predictions of cases included in this study.

TABLE III.

Genetic variants and severity predictions

Study	Genomic location	Amino acid substitution	Nucleotide substitution	Exon	Protein domain	Type of mutation	Interpretation (ClinVar)	CADD Score (maximum)
Case 1	GRCh38 X:101357548	p.Q380*	c.1138C>T	13	TK	Nonsense	Pathogenic	36
Case 2	GRCh38 X: 101353940–101353947	p. K588fsX	c.1673_1680delAATTTCCA	17	TK	Frameshift	Likely pathogenic	-
Case 3	GRCh38 X:101353923	p. P566L	c.1697C>T	17	TK	Missense	Conflicting interpretation	28.5
Nahum et al,13	GRCh38 X:101358670	p. S309P	c.925T>C	11	SH2	Missense	Novel (no data)	26.2
Cekic et al,26	GRCh38 X:101353936	p. R562*	c.1684C>T	17	TK	Nonsense	Pathogenic	32
Crowley et al,17	GRCh38 X:101356166	p. N484K	c.1452G>T	15	TK	Missense	Novel (no data)	22.4
King et al,27	GRCh38 X:101360588	p. W252*	c.756G>A	8	SH3	Nonsense	Pathogenic	36

CADD, Combined annotation-dependent depletion.

Whereas GI infections and dysbiosis have long been posited to be part of the pathogenesis for IBD, there does not seem to be any robust data implicating that infection predisposes to an IBD diagnosis in XLA patients. Barmettler et al³ reported a 90% and a 19.5% incidence of enteritis and IBD, respectively, in 200 XLA males. However, in most studies, it does not appear that XLA patients characterized with IBD also were coded with infectious enteritis.^3,4,9,15 Lougaris et al⁸ reported pathogen isolation in 18.5% of 200 episodes of GI manifestations, in which 49%, 24%, 19%, and 5% were the incidence of Giardia, Salmonella, Campylobacter jejuni, and Escherichia coli, respectively. Nahum et al¹³ reported an episode of giardiasis in a toddler with XLA, who presented 6 months later with a CD-like picture. King et al²⁷ reported a resolved episode of C. jejuni diarrhea in an adult who developed a CD-like clinical picture 3 years later. Two other studies did mention Giardia and C. jejuni infection in their cohort but excluded infectious enteritis in patients with IBD.^12,14

DISCUSSION

Genome-wide association studies (GWAS) have established an IBD-like phenotype that is associated with monogenic aberrations in primary immunodeficiency, and up to 67 genetic variants have been identified in this disease process.^17,18 A recently published long-term XLA study reports a 52.4% incidence of GI symptoms.⁸ In contrast to classic IBD, the pathophysiology, extent, and severity of GI involvement and the age of disease onset are quite variable in monogenic IBD.^17,29 Treatment strategies are borrowed from classic IBD, albeit with suboptimal outcomes.^29,30 Recent advances in genomics and immunology have brought monogenic IBD to the center stage, yet the atypical endoscopic and histological findings and confounding infections and biologic drug treatments create diagnostic and therapeutic challenges. Thus, such cases are classified as IBD-like, which may lead to missed opportunities in precision medicine.^{3,12,13,18,29,30} The IBD-like phenotype in XLA has been linked to inadequately understood changes in the microbiome including altered immune tolerance, increased microbial translocation, or stimulation of an aberrant response to active infection.^27,29 Recently, a disinhibited NLRP3-mediated release of proinflammatory mature interleukin 1-beta (IL-1β) and IL-18 signaling due to BTK deficiency has been proposed as a mechanism of the CD-like process in XLA.³¹

Our review of XLA endoscopic biopsy and resection specimens revealed a wide spectrum of morphology, including crypt apoptosis resembling acute graft versus host disease or drug toxicity, and the lack of plasma cells resembling common variable immunodeficiency disease (CVID). Active duodenitis with eosinophilic microabscess, mild and focal blunted villi, epithelial and lamina propria inflammation, and apoptotic bodies were also found. Taken together, this can reflect a spectrum of differentials including peptic duodenitis, celiac disease, CD, CVID, or autoimmune enteropathy.^32,33 Moreover, a striking prevalence of gross and microscopic features resembling CD was consistently noted. Grossly, XLA-related enteritis presents with a fistulizing and stricturing disease pattern with abscess formation, mesenteric fat wrapping, and transmural ulceration. Similarly, segmental activity with neutrophilic cryptitis, transmural inflammation, muscular and neuronal hypertrophy is the noted histological determinant.^12,34,35

With a lack of diagnostic clarity in distinguishing CD from XLA-associated enteritis, it is also possible that these conditions can coexist. However, the immunobiology of CD is suggestive of its complex CD4+ helper T-cell–mediated pathogenesis in which genetic, immunological, and microbial factors disturb the balance between effector and regulator T cells. In the realm of polygenic, mainly T-cell–mediated ailments, the proinflammatory tumor necrosis-factor alpha/nuclear factor kappa B (TNF-α/NF-κB)–mediated signaling is a major pathological cytokine and an immunogenic trigger for granulomagenesis. Moreover, the TNF-α/NF-κB driven immunopathology has led to the development and approvals of TNF-α inhibitors, which are promising targeted therapeutics for CD.^16,36,37 Conversely, XLA is a defect in adaptive immunity with a complete absence of mature B cells and low to absent lymphoid tissue, but with preserved T-cell function and a potentially disinhibited NLRP3-meditated proinflammatory mature IL-1β and IL-18 signaling, which could drive the CD-like phenotype.^31,38 Epithelioid granulomas were reported in 2 patients in the context of XLA-associated enteritis. One patient had enterovirus enteritis and the other had multifactorial septic and aseptic complications, both presumably indicate an appropriately functioning cellular immunity.³⁸

Mucosal immune response in IBD is crucially driven by nodular lymphoid hyperplasia (NLH), which histologically represents as lymphoid aggregates with prominent germinal centers,^39,40 but in XLA associated enteritis, studies report absence of prominent lymphoid germinal centers, which further highlights a distinct immune mechanism of the disease.^32,33 Similar observations regarding NLH are made in a recent study, albeit without any mention about the presence of granulomas.³² Although the exact pathogenesis of granuloma is poorly understood, it is significant as a predictive biomarker in CD as well as in CVID.^34,41 Therefore, the absence or presence of granuloma along with NLH portends key diagnostic and therapeutic implications in XLA-associated enteritis, and absent immunohistochemical staining for plasma cells or B cells can further serve as a diagnostic aid.^32,33,39

Therapeutically, the outcomes of immunoglobulin treatment in XLA have been efficacious and proven through multiple randomized control trials, and clinical studies do suggest effective therapeutic response and cessation of GI symptoms with IVIG therapy in XLA patients.^14,42 Conversely, clinical studies of TNF-α inhibitors have failed to demonstrate a robust and durable clinical response in XLA-associated enteritis and, therefore, are hesitantly prescribed.^26,27,29 Tumor necrosis factor-alpha blockade also hinders the formation and maintenance of granulomas and, thereby, has a potential to cloud histological interpretation of IBD specimens.^37,43,44 Nevertheless, biologics may be needed, but should be cautiously prescribed because typical IBD treatments may increase the risk of unfavorable outcomes through furthering immunosuppression, and selective therapeutic targeting is recommended owing to the convoluted nature of mucosal immunity.^43,45

Whereas our case 1 has been safely managed on infliximab,²⁵ vedolizumab, a humanized monoclonal antibody against α4β7 integrin, used in case 2, provides another therapeutic option.^26,27 This integrin is required for gut-specific homing of leukocytes and vedolizumab inhibits leukocyte binding to endothelial surfaces and extravasation into affected tissues. Two recent case reports have suggested the efficacy of this medication in patients with XLA, also its gut-specific properties, may lessen risks of immunosuppression.²⁷ Our case 3 documents the first report of clinical and endoscopic remission in XLA-associated enteritis via ustekinumab therapy. Ustekinumab is a selective agent that blocks IL-23 cytokine generated by dysregulated inflammasome activation due to BTK deficiency,^31,45,46 and has also been implicated in the pathogenesis of CD.⁴⁷ Although ustekinumab has been tested in refractory autoimmune enteropathy and CVID,^48,49 a paucity of reports exists regarding its effectiveness in XLA-associated IBD. Nevertheless, both vedolizumab and ustekinumab are considered less immunosuppressive than TNF-α inhibitors, are less immunogenic, and elicit lower cross-reactivity with parenterally administered antibodies.⁵⁰ Surgical resection remains necessary in patients in whom segment of bowel inflammation is amenable to resection or for symptomatic stricture, obstruction, fistula, or abscess.^13,51

In conclusion, the reported 3.4% to 9.5% incidence of enteritis with IBD-like clinical characteristics in XLA stands in stark contrast to the reported 0.4% population prevalence of IBD and represents a formidable clinical challenge.^{3,4,15,17,18,29–31} It is critical to consider such a diagnosis in patients with known or suspected XLA or similar immunodeficiency with gastrointestinal symptoms or concerning laboratory findings. Moreover, contrary to observations regarding the early-life presentation of monogenic IBD,^18,29,30 our study points to XLA-associated enteritis as more likely presenting in adolescence.^{12,17,20,23,27} Symptoms at presentation include abdominal pain, diarrhea, weight loss, aphthous stomatitis, and arthropathy. Laboratory evaluation is also significant for elevated serum and stool inflammatory markers and hypoalbuminemia.²⁷ The XLA-related IBD tends to be ileocolonic, with imaging like that of classic CD. It also is more likely to have a stricturing and penetrating phenotype, oftentimes with fistula formation.⁵¹ Endoscopic evaluation macroscopically shows similar findings as classic CD. However, the absence of granuloma and the absence of NLH in the setting of the other microscopic findings of CD are more suggestive of XLA-related IBD. Further evidence from prospective and longitudinal studies will clarify pathogenesis, common GI and extraintestinal manifestations, natural history, and prognosis of XLA-related IBD, to help formulate efficacious therapeutic strategies.

What is already known about this topic?

Inflammatory bowel disease (IBD) in X-linked agammaglobulinemia (XLA) presents in a Crohn disease (CD)–like fashion but with an immunologically distinct pathogenesis. This often presents a diagnostic challenge because the clinical presentation overlaps with classic IBD or infectious enterocolitides. Therapy in such situations is tailored employing borrowed strategies from classic IBD, albeit with variable clinical outcomes.

What does this article add to our knowledge?

This study describes the clinical characteristics, diagnostic pitfalls, complications, and treatment challenges in patients with XLA-associated IBD. It typically presents with a CD-like fistulizing and stricturing disease process, but with lower incidence of granuloma formation, perianal involvement, or other extraintestinal manifestations. Unlike CD, therapeutic response with tumor necrosis factor–alpha inhibitors may be less durable and there is growing body of evidence advocating for using drugs with alternative therapeutic targets.

How does this study impact current management guidelines?

This study describes and systematically reviews the current and emerging evidence that can be utilized to optimally diagnose and tailor effective treatment strategies in XLA associated inflammatory bowel disease.

Abbreviations used

BTK

Bruton tyrosine kinase (gene)

CD

Crohn disease

CRP

C-reactive protein

CVID

Common variable immunodeficiency

ESR

Erythrocyte sedimentation rate

GI

Gastrointestinal

IBD

Inflammatory bowel disease

IL-1β

Interleukin 1-beta

IVIG

Intravenous immunoglobulin

NLH

Nodular lymphoid hyperplasia

TNF-α/NF-κB

Tumor necrosis factor-alpha/nuclear factor kappa B

USIDNet

U.S. immune deficiency network

XLA

X-linked agammaglobulinemia