Juvenile idiopathic arthritis is a common chronic childhood disease, with a prevalence of ∼1 per 1000 children. Arthritis can also be a manifestation of other inflammatory conditions, such as inflammatory bowel disease (IBD). Studies suggest a genetic influence in IBD, including mutations in CARD8. CARD8 is a negative regulator of the NLRP3 inflammasome, and mutations in this gene are hypothesized to induce gastrointestinal inflammation. However, few studies have evaluated this association and most have included a limited number of patients. We present a case of a pediatric patient with IBD-associated arthritis and a CARD8 mutation. Our patient is a 7-year-old female who was initially evaluated by rheumatology for right leg pain and an intermittent rash. She had clinically active arthritis on exam and was started on methotrexate with only slight improvement. Additional workup revealed sacroiliitis by imaging, elevated inflammatory markers, no anemia, and a variant of unknown significance in CARD8. Adalimumab was recommended but before medication initiation, our patient’s symptoms progressed to worsening joint pain, fatigue, fevers, nausea, vomiting, diarrhea, and hematochezia. Infectious testing was negative. Fecal calprotectin was >8000 µg/g. A colonoscopy revealed IBD most consistent with Crohn’s disease. Adalimumab was ultimately added, and she has responded well to combination therapy. This case report highlights the association between CARD8 mutations and IBD, especially in the setting of IBD-associated arthritis.
Juvenile idiopathic arthritis is a common chronic childhood disease, with a prevalence of ∼1 per 1000 children,1 that persists for longer than 6 weeks and presents before 16 years of age.2 Untreated juvenile idiopathic arthritis can result in significant long-term articular and extraarticular damage, as well as physical disability.3 Arthritis is also the most common extraintestinal manifestation of inflammatory bowel disease (IBD), commonly referred to as IBD-associated arthropathy, which is a subtype of enthesitis-related arthritis or juvenile spondyloarthritis (SpA).4,5 Research has shown an association between IBD and SpA, with asymptomatic sacroiliitis occurring in ∼30% of IBD patients.4,6 Studies suggest a genetic influence in IBD, especially early-onset IBD, including mutations in CARD8. CARD8 is a negative regulator in the NLRP3 inflammasome, and mutations in this gene are hypothesized to induce gastrointestinal (GI) inflammation.7 CARD8 is a 48-kDa peptide that has a similar structure to the genes, NOD1 (CARD4) and NOD2 (CARD15); mutations in these genes are known to be associated with Crohn’s disease (CD).8 This article presents the case of a 7-year-old female with a CARD8 mutation and IBD most consistent with CD who first presented with arthritis and an intermittent rash. Few articles discuss the association between mutations in CARD8 and IBD. Most have included a small number of patients and we could find no report that detailed an association in a pediatric patient. This case report supports an association between a CARD8 mutation and IBD in the setting of IBD-associated arthritis.
Case Report
A 7-year-old female was referred to our outpatient rheumatology department for evaluation of leg pain. She related that she first noticed swelling of her right knee a year ago, associated with leg pain that was worse in the morning and resulted in a limp. Her mother also reported a history of treatment of multiple presumed elbow fractures resolving after 2 to 3 weeks of casting and an intermittent facial rash that crossed the nasolabial folds. She denied abdominal symptoms such as nausea, vomiting, diarrhea, constipation, or mouth ulcers. She had a history of anemia but no current issues. Family history was notable for mother with Grave’s disease. Upon examination, she was at the eighth percentile for both height and weight. She had arthritis and decreased range of motion to her right elbow, as well as tenderness and limited range of motion to her right hip. Sacroiliac joint tenderness was difficult to appreciate because of generalized tenderness during hip/back examination. Her rash was not present on exam, but pictures showed an urticarial rash that crossed the nasolabial folds. With significant arthritis on exam, we started her on subcutaneous methotrexate (MTX) 15 mg/m2 (12.5 mg) once weekly and a 2-week course of oral prednisolone. Nonsteroidal antiinflammatory drugs were prescribed for symptom relief after completion of prednisolone. Additional workup revealed elevated inflammatory markers (erythrocyte sedimentation rate 37 mm/h [0–20 mm/h], C-reactive protein 6.19 mg/dL [0.0–0.5 mg/dL]), elevated platelet count (622 103/µL [140–440 103/µL]), normal hemoglobin and hematocrit, antinuclear antibody of 1:320 with negative extractable nuclear antigen antibodies, negative angiotensin-converting enzyme and lysozyme for sarcoidosis, negative Lyme enzyme-linked immunosorbent assays, and normal urinalysis. Pelvic x-ray was normal. X-ray of her right elbow reported no acute or old healing fractures, but did show mild elevation of the anterior fat pad with mild soft tissue prominence over the olecranon. Slit lamp exam was negative for uveitis.
Two weeks after her appointment, mother reported an ongoing limp with significant pain. Subsequently, we obtained MRI of her right hip, which showed bilateral sacroiliitis more prominent on the right side (Fig 1). With these findings, we recommended adding a tumor necrosis factor inhibitor, adalimumab; MTX was continued because of peripheral arthritis. We repeated laboratory work that showed a slight improvement of inflammatory markers, negative tuberculosis, and negative HLA-B27. We also ran a primary immunodeficiency genetic panel because of abnormal presentation, which showed 3 variants of uncertain significance: heterozygous CARD8 mutation variant c.867C > A (p.Ser289Arg), heterozygous OAS1 mutation variant c1042G > T (p.Glu348*), and heterozygous PIK3R1 mutation variant c.1273C > A (p.Leu425Ile). The OAS1 gene is associated with pulmonary alveolar proteinosis with hypogammaglobulinemia, and the PIK3R1 gene is associated with SHORT syndrome characterized by congenital anomalies, PI3K-δ immunodeficiency syndrome, and agammaglobulinemia, none of which fit this patient’s clinical presentation.
Coronal T2 weighted fat-saturated images of the right pelvis. Bone marrow edema consistent with sacroiliitis is prominent in the right sacrum and left ilium (asterisks), and possibly in the right ilium, as well (arrowhead).
Coronal T2 weighted fat-saturated images of the right pelvis. Bone marrow edema consistent with sacroiliitis is prominent in the right sacrum and left ilium (asterisks), and possibly in the right ilium, as well (arrowhead).
Before starting adalimumab, our patient developed worsening jaw and neck pain, inability to eat or drink, and intermittent fevers. She presented to her primary care provider and tested negative for severe acute respiratory syndrome coronavirus 2, influenza, and group A Streptococcus. After 5 days of fever, inability to open her jaw, and difficulty moving her neck, she returned to primary care and had repeat laboratory work done, which showed leukocytosis of 17 000/µL. She was thought to have a possible soft tissue infection of her neck and was started on amoxicillin-clavulanate. However, she was unable to tolerate the antibiotics because of vomiting, so she presented to the emergency department for further evaluation. Computed tomography of her neck showed cervical lymphadenopathy without drainable fluid collections or signs of necrosis. She was hospitalized for pain control and management of nausea and vomiting. Infectious workup including testing for respiratory viruses, Epstein-Barr virus, Bartonella, Toxoplasma, Mycobacterium, and serum fungal cultures was negative. She was subsequently discharged after her pain had improved and she was tolerating oral intake. At this time, she had been off MTX for 2 weeks because of fever. Fecal calprotectin resulted 2 weeks after discharge showing significant elevation at >8000 µg/g (<50 µg/g). Adalimumab was again recommended, and she was referred to gastroenterology. However, before medication initiation, our patient developed hematochezia, abdominal pain, weight loss, and fatigue. She was readmitted to the hospital. Evaluation found persistent elevation of inflammatory markers, several enlarged mesenteric lymph nodes but no overt inflammation of the small bowel on abdominal computed tomography, and scattered aphthous ulcers, though no granulomas were found on biopsy specimens obtained during colonoscopy/endoscopy (Fig 2). Her Paris classification was A1a (L2 + L4a) B1 with inadequate data over time to assess growth velocity.9 Anti-Saccharomyces cerevisiae antibodies were not obtained. Magnetic resonance enterography obtained 3 months later again demonstrated mesenteric adenopathy without small bowel inflammation. We restarted MTX, discontinued nonsteroidal antiinflammatory drugs, began adalimumab, and tapered corticosteroids. Her erythrocyte sedimentation rate normalized in 2 weeks and she demonstrated almost complete resolution of symptoms in 2 months.
A patchy area of moderately erythematous mucosa was found in the rectum, in the sigmoid colon, in the descending colon, in the transverse colon, in the ascending colon, and in the cecum. Histology demonstrated colitis with mild edema in the rectum, neutrophilic cryptitis with fibrinopurulent exudate consistent with nearby ulcer and mild edema in the sigmoid and descending colon, mild edema in the ascending and transverse colon, focal active colitis with mild edema in the cecum, and patchy, mild, nonspecific active chronic gastritis.
A patchy area of moderately erythematous mucosa was found in the rectum, in the sigmoid colon, in the descending colon, in the transverse colon, in the ascending colon, and in the cecum. Histology demonstrated colitis with mild edema in the rectum, neutrophilic cryptitis with fibrinopurulent exudate consistent with nearby ulcer and mild edema in the sigmoid and descending colon, mild edema in the ascending and transverse colon, focal active colitis with mild edema in the cecum, and patchy, mild, nonspecific active chronic gastritis.
Discussion
When a child presenting with arthritis has an atypical history, exam, or laboratory testing, it is essential to keep a broad differential diagnosis while also starting appropriate medications to treat inflammation quickly. Because of our patient’s atypical history and substantially elevated inflammatory markers, she underwent a thorough evaluation to rule out infectious or other autoimmune causes for arthritis. Our workup raised no concern for malignancy. With elevated inflammatory markers, sacroiliitis, CARD8 mutation, and elevated fecal calprotectin, IBD-associated arthritis became the most likely diagnosis and was confirmed by colonoscopy/endoscopy. This case contributes to the differential diagnosis of peripheral arthritis and sacroiliitis and highlights the importance of genetic testing and specifically CARD8 mutations in the setting of IBD-associated arthritis.
Clinical features and extraintestinal manifestations of IBD include GI symptoms, unexplained fevers, anemia, weight loss, erythema nodosum, pyoderma gangrenosum, oral ulcers, vasculitis, uveitis, and arthritis.4 Arthritis is the most common extraintestinal manifestation of IBD and can present with 3 distinct patterns of joint disease: oligoarticular, polyarticular, or axial.4 Oligoarticular arthritis seen in IBD typically affects large joints in the lower extremities and correlates with gut severity, whereas polyarticular arthritis tends to affect the upper extremities with a symmetrical distribution and is independent of GI activity.3,10 Recent studies evaluating GI inflammation and sacroiliitis demonstrate a correlation between mucosal inflammation and sacroiliac joint findings. One study displayed that pediatric enthesitis-related arthritis patients with sacroiliitis had higher fecal calprotectin levels than those without.11 Likewise, an adult study demonstrated that SpA patients with chronic gut inflammation had higher degrees of sacroiliac joint bone marrow edema.12 IBD has various known triggers such as genetic predisposition, immune system dysregulation, and environmental causes.13 Many studies prove a robust genetic association, noting that ∼5% to 15% of children with CD or ulcerative colitis have a positive family history of IBD.13 Studies have shown an association between NOD2/CARD15 mutations and CD in pediatric and adult populations; however, there is no known reported correlation between joint disease and/or sacroiliitis.14 More recently, there have been a few case reports noting the significance of IL-23R and early-onset CD.15 There is also a strong association between HLAB27 positivity and juvenile SpA, and is a risk factor for sacroiliitis in patients with IBD.8,16
Similar cases are rare in the literature. After an extensive literature review, there were no articles that identified the specific CARD8 mutation (c.867C > A [p.Ser289Arg]) in our patient. There are few reports discussing the association between CARD8 mutations and IBD. One study from Kastbom et al looked at the association between CARD8 mutations and HLA-B27 positive ankylosing spondylitis, reporting that the minor allele of CARD8-C10× is linked to a decreased risk of ankylosing spondylitis.17 Another study from Kastbom et al concluded that variants of CARD8-X were associated with a more complex disease course for rheumatoid arthritis patients.18 To our knowledge, this is the first report of an association between CARD8 mutations and IBD-associated arthritis in a pediatric patient.
Conclusions
At our patient’s follow-up appointment 2 months after adding adalimumab to MTX, she showed significant clinical improvement; she was able to ambulate well with no limitations and had adequate joint range of motion. From a GI perspective, she was still having intermittent abdominal pain but no hematochezia, diarrhea, nausea, vomiting, or fevers. We continue to monitor her closely to manage her medications and disease. This case illustrates that IBD-associated arthritis is an etiology of arthritis in the pediatric population. Early treatment with immunomodulatory medications is crucial to control disease activity and improve patient outcomes. This case also highlights the benefit of genetic testing in atypical arthritis presentations and the role of CARD8 mutations in association with IBD-associated arthritis. More research is needed on the role of CARD8 mutations in diseases such as pediatric sacroiliitis and IBD and the possibility of better targeted treatments.
Ms Gennaro and Dr Smitherman conceptualized and designed the case report, drafted the initial manuscript, and reviewed and revised the final manuscript for submission; Drs Maclin, Stoll, and Weiser all substantially contributed to conceptualizing the case report, acquiring data for the report, and critically reviewing and revising the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding. Support for Dr Smitherman was provided by the Rheumatology Research Foundation's Investigator Award.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
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