Multisystem Autoimmune Inflammatory Disease, Including Colitis, Due to Inborn Error of Immunity

A 14 -year-old girl presented to pediatric rheumatology with an 18-month history of symmetrical small and large joint pain and was subsequently diagnosed with rheumatoid factor–negative polyarticular juvenile idiopathic arthritis. Her medical history included transient pancytopenia 6 months earlier, mild chronic thrombocytopenia, and an evaluation by gastroenterology 18 months before for recurrent abdominal pain and intermittent diarrhea. The latter was diagnosed as functional abdominal pain on the basis of a negative white cell scan result, normal endoscopy findings, absence of fecal occult blood, lack of inflammatory markers, and complete resolution of symptoms once known patient stressors were addressed. Persistent bloody diarrhea began 4 months after celecoxib treatment was initiated to treat the arthritis. Subsequent evaluation revealed a highly elevated fecal calprotectin level (>2500 μg/g) and negative anti–Saccharomyces cerevisiae immunoglobulin A (IgA) and immunoglobulin M (IgM) antibody levels. An endoscopy at 16 years of age revealed circumferential pancolitis, with a normal appearing terminal ileum and normal perianal area. Histopathologic findings of the ileum biopsy specimen were normal, whereas the whole length of the colon revealed moderate to marked chronic active inflammation with erosion, cryptitis, and crypt abscess formation, characteristic of ulcerative colitis. However, a single mucosal granuloma was found in the colon. Therefore, it was not possible to entirely exclude Crohn disease, and a diagnosis of IBDU was favored. An upper endoscopy revealed fungal (Candida) esophagitis. The patient did not tolerate methotrexate treatment of arthritis and IBDU and therefore was transitioned to a combination of leflunomide and mesalamine. Although the GI disease went into clinical remission, she continued to have active arthritis, and anti–tumor necrosis factor (TNF) therapy was added to her treatment regimen.

Review of infectious history revealed that between the ages of 3 and 9 years, the patient had recurrent prolonged bronchitis and chronic recurrent middle ear infections requiring repeated bilateral myringotomy tube insertions, tonsillectomy, and adenoidectomy and had zoster after uncomplicated chickenpox infection without previous immunization. The family history was remarkable for psoriasis and psoriatic arthritis affecting several family members on the paternal side. Her sister had recurrent middle ear and sinus infections and uncomplicated varicella twice. Her mother had rubella infections twice, and her maternal grandmother had leukemia, and there was also a case of autoimmune thyroiditis on the maternal side.

Laboratory test results revealed low immunoglobulin levels with normal albumin levels, lack of isohemagglutinins determining abnormal IgM isotype polysaccharide responses, and low switched memory B-cell levels (Table 1), fulfilling the laboratory criteria for CVID. Interestingly, the patient had preserved protective antibody titers to a wide variety of vaccine antigens (measles, rubella, diphtheria, tetanus) and good response to the conjugated pneumococcal vaccine. Test results for antinuclear antibodies and extractable nuclear antigen antibodies were negative. An extensive immunology workup ruled out other IBD and Candida infection–related primary immunodeficiencies, including chronic granulomatous disease by the nitro blue tetrazolium test, an inborn error of interleukin 17 immunity by enumeration of T helper 17 cells by flow cytometry, and complement deficiencies by measuring classic, alternative, and mannose-binding lectin complement activities. Test results for anti-adrenal antibody and anti-thyroid peroxidase antibody were negative, making mucocutaneous candidiasis and autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia unlikely.

In view of the clinical history and immune investigation abnormalities, we considered an IEI, and a trio of whole-exome sequencing analyses (including mother, father, and proband) were performed as a part of the International Early Onset Pediatric IBD Cohort Study. Our patient was found to carry a heterozygous tumor necrosis factor receptor superfamily member 13B (TNFRSF13B), also known as transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), gene variant (C104R in second TACI-CRD2 domain, Chr17:16852187 A/G), which was confirmed by Sanger sequencing. This heterozygous pathogenic variant is associated with CVID and autoimmune disease development.^12–14 

On the basis of these findings, in addition to the combined biological disease-modifying antirheumatic and antiinflammatory therapy (adalimumab and mesalazine), we started intravenous immunoglobulin replacement therapy to prevent infections and recommended lifelong monitoring for additional autoimmunity and extra vigilance for infections as a global approach to care.

The history of multiorgan autoimmune disease, candidiasis, recurrent respiratory infections; the positive family history for infections and inflammatory diseases; and the abnormal immune investigations, including low immunoglobulin levels in the presence of chronic inflammation, resulted in a strong index of suspicion for primary immune regulatory disorder in our patient and provided important hints for IEI. An increased risk of developing autoimmune manifestations has been identified in various IEIs, caused by potential defects of peripheral tolerance to self-antigens and persistent infectious stimulation as a result of ineffective eradication of antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that can lead to tissue damage and autoimmunity.¹⁵ 

Endoscopic investigations were triggered by the onset of bloody diarrhea after the patient was exposed to celecoxib and revealed a variety of chronic IBDU features (notably a single granuloma in the setting of other endoscopic and histologic findings suggesting ulcerative colitis), which can be considered diagnostic of CVID-associated colitis or enteropathy.¹⁶  Other PID-related findings can include lack of plasma cells, lymphonodular hyperplasia, or unexpected infections, the latter of which was revealed in our patient (Candida esophagitis).

Approximately 30% of patients with CVID develop autoimmune complications, and 20% of those have preceding recurrent or unusual infections. Autoimmunity is most common in TACI gene (or TNFRSF13B) alterations, particularly the heterozygous C104R mutation, which was found in our patient.^11,13,17  TACI is a cell membrane receptor, and as a regulator, it affects multiple events in the immune response, including immunoglobulin G (IgG) and IgA class switch recombination, differentiation, and survival of plasma cells.¹⁷ 

Interestingly, the patient’s mother also carries the same TACI allele variant but without a detectable humoral immune defect. ClinVar describes TNFRSF13B variants as having conflicting interpretations of pathogenicity. The C104R variant, however, even in a heterozygous form, constitutes a risk factor for the development of CVID, possibly because of haploinsufficiency or dominant interference.^13,18,19 

Discovery of IEIs on a molecular genetic level has great importance in individualized treatment and long-term care of patients, including those presenting with colitis.²⁰  The primary treatment of CVID is antibody replacement therapy with either intravenous or subcutaneous immunoglobulin. Early diagnosis and optimal management is likely to result in improved quality of life and health outcomes. Anti-TNF therapy alone in our patient increases the risk of infection, and having an underlying PID increases this risk even more because recurrent bacterial infections occur in 90% of patients with CVID. As for malignancy, the incidence of leukemia and lymphoma in IBD is low, but concerns about hepatosplenic T-cell lymphoma and (Epstein -Barr virus–related) histiophagocytic lymphohistiocytosis have greatly influenced antiinflammatory therapy choices, such as the use of coimmunomodulators over the last decade.²¹  However, it is known that there is an increase in malignancy in CVID in general, with lymphomas being the most frequently reported (8%), and these patients have a 10-fold increased risk of gastric cancer as well.^10,11 

A clinical history of recurrent infections, low immunoglobulin levels despite chronic inflammation, histologic features that do not fit the usual pattern of disease, additional autoimmune inflammatory manifestations, poor response to conventional therapy, and/or a positive family history for infections or autoimmunity should prompt the physician to refer such patients to an immunologist.¹⁶  Treatment options for colitis in affected patients with CVID are the same as for patients with classic IBD and include corticosteroids, 5-aminosalicylic acid and azathioprine, or targeted biological therapies against TNF, interleukin 12 and/or interleukin 23, or α4β7 integrin, with careful monitoring for infections.¹⁶  Additional immunoglobulin replacement therapy may offer unstable patients protection from infectious complications and decrease autoimmunity-triggering pathogen load. In addition, we hypothesize that IgG replacement therapy might have immunomodulatory effects that could also ameliorate the autoimmune manifestations.²² 

We thank Dr Lori Connors for her help in the transition of the patient to adult care. We thank Dr Thomas Issekutz for his critical review and Anne Woolaver for formatting the article.

CVID

common variable immunodeficiency

GI

gastrointestinal

IBD

inflammatory bowel disease

IBDU

inflammatory bowel disease undetermined

IEI

inborn error of immunity

IgA

immunoglobulin A

IgG

immunoglobulin G

IgM

immunoglobulin M

PID

primary immunodeficiency

TACI

transmembrane activator and calcium-modulating cyclophilin ligand interactor

TNF

tumor necrosis factor

TNFRSF13B

tumor necrosis factor receptor superfamily member 13B