Development of crohn's disease following treatment for juvenile idiopathic arthritis in a nigerian child: Case report and review of literature.

Juvenile idiopathic arthritis (JIA) and Crohn's disease (CD) are diseases that are rarely seen in the black African child. CD has been reported to occur following therapy with etanercept in JIA patients. We report the case of a Nigerian child with JIA who developed CD following treatment for JIA. A 9-year-old male with JIA was referred to the pediatric gastroenterology unit of the Lagos University Teaching Hospital on the account of chronic diarrhea with occasional passage of bloody stools. He had been on prednisolone and methotrexate which had controlled the joint flares. Colonoscopy revealed extensive colitis, ulcers, abscesses, and ileocecal disease. Histology confirmed the CD. In view of the unavailability of the recommended treatment, namely biologics in the country and financial constraints; steroids; and sulfasalazine were added to his treatment regimen, and subsequently, he has made significant clinical improvement.

INTRODUCTION

Gastrointestinal (GI) disease appears to be one of the documented extra-articular manifestations of juvenile idiopathic arthritis (JIA).[1234] Similarly, joint involvement occurs in 16%–33% of children with inflammatory bowel disease (IBD) in the course of the disease.[124] However, the occurrence of JIA and Crohn's disease (CD) is rare, especially in children below the age of 16 years, and both conditions have only been reported in 12 Caucasian children.[1234] CD has been reported to occur following therapy with etanercept in JIA patients and rarely with the mercatopurines.[567] In Nigeria, methotrexate (MTX) is the therapeutic choice for most rheumatological conditions as it is affordable and readily available, unlike the biologics which are largely unaffordable and unavailable.

We report a male Nigerian child with JIA who developed CD following therapy with MTX and highlight the challenges in the management of this child in resource-poor countries.

CASE REPORT

The child was first seen at the age of 9 years at the Lagos University Teaching Hospital, Lagos, Nigeria, on the account of joint pains (knees and wrists) of 7 weeks' duration and swelling of the left wrist of 4 days' duration. There was no history of skin rashes, recurrent conjunctivitis, cough or chest pains, parents did not volunteer a history of poor growth, and developmental milestones were within normal limits. There was no family history of a similar illness. Essential physical finding at this time was a swollen and tender left wrist joint, and he weighed 18 kg (Z score-3SD). An assessment of JIA was made; he was referred to the rheumatology clinic where the diagnosis of JIA (oligoarticular type) was confirmed. Rheumatoid factor (nephelometry) was <20.0 IU/mL (reference range: 0–20.0 IU/mL), and antinuclear antibodies were negative. Induction of remission was commenced with oral steroids (prednisolone10 mg bd) and oral MTX (10 mg weekly). Prednisolone was tailed off gradually to 5 mg daily. After 6 months of therapy, oral MTX was discontinued and he was commenced on subcutaneous MTX 10 mg weekly. Vitamin D (1500 IU daily), calcium supplements, and omeprazole 20 mg daily were added to his treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) were given for breakthrough pains when needed.

One year after diagnosis, he was referred to the pediatric gastroenterology clinic on the account of recurrent abdominal pain which was cramping in nature, vomiting, diarrhea, intermittent passage of bloody stools, and weight loss of 1-month duration. Significant findings were a chronically ill child, who was pale, with a weight of 19 kg (Z score = −4.0) and a height of 134 cm (Z score = −0.7). There was no evidence of uveitis or skin rash. An abdominal examination revealed vague periumbilical tenderness, with no organomegaly, perianal tags, fissures, or fistula. Examination of the other systems was normal. Differential diagnoses at this time included IBD, NSAID-induced gastritis, and infective colitis.

Stool microscopy for ova and parasites was negative, and culture did not yield any growth. Abdominal ultrasound was normal. Packed cell volume was 28%. Retroviral screening and Mantoux test were also negative. A subsequent gastroscopy revealed Helicobacter pylori-negative gastritis and normal duodenal biopsies. An ileocolonoscopy showed extensive left- and right-sided colitis with ulcers and abscesses and an inflamed ileocecal valve [Figure 1]. Histopathologic examination of biopsies taken from the colon, caecum, and terminal ileum was diagnostic of CD [Figure 2]. The Pediatric CD Activity Index (PCDAI)[8] score was 50, indicating severe disease.

Figure 1

Colonoscopy findings show extensive left- and right-sided colitis with ulcers and abscesses

Figure 2

Transmural inflammation in the colon

In view of the clinical disease and current recommendations, the patient was to commence a biologic agent, i.e., infliximab. However, infliximab is unavailable in Nigeria; he was continued on prednisolone and MTX and sulfasalazine (250 mg bd was added to his regimen till date). The possibility of exclusive enteral nutrition was explored but was not pursued due to the unavailability of appropriate formulas in the country. Subsequently, the patient made significant clinical improvement, with a reduction in abdominal pain and frequency of diarrhea. PCDAI reduced to 25 within a month of treatment and was 10 at the last follow-up visit. Prednisolone was gradually tailed off, and he is presently on the subcutaneous MTX (10 mg weekly) and sulfasalazine (250 mg bd). He is gaining weight and now weighs 23 kg, with a height of 134.4 cm. He is to have his blood counts done every 2 months and a follow-up colonoscopy.

DISCUSSION

The occurrence of JIA and CD is rare, especially in children below the age of 16 years.[16789101112] To the best of the authors' knowledge, this is the first report of the coexistence of these two conditions in a Nigerian child.

Previous reports on JIA and CD have revealed 12 cases in Caucasian children between 1994 and 2011,[1910111213] but there remains a paucity of data on the occurrence of these conditions in black African children. These reports reveal that the interval between the diagnosis of arthritis and the development of CD is highly variable [Table 1]. A diagnosis of CD was made about a year after the diagnosis of JIA in our patient, and similar observations have also been reported previously.[13]

Table 1

Patients with Crohn’s disease and juvenile idiopathic arthritis reported in literature

Author	Years	n	Age/sex	Type	Disease location	Duration	Treatment	Other findings
Sung et al.	1994	1	14/male	Childhood stills disease	Colitis (with skip lesions and strictures)	2 months	Azathioprine, prednisolone
Scarpa et al.*	1997	1	16/male	Oligoarthritis	Transverse colon	2 months	Mesalazine	Turner syndrome
Ruemele et al.	2004		6/male	Oligoarthritis	Ileocolitis and perianal fistula		Infliximab (initially had etanercept)
Wiegening et al.	2010	1	11/female	Oligoarthritis	Ileocolitis	4 years	Adalimumab (initially had etanercept)
Oikonomou et al.	2010		17/female	Oligoarthritis	Ileocolitis	15 years	Adalimumab (previously etanercept, infliximab allergic)
Dallochio et al.	2010	5	17/female	Systemic	Left colon, anus	11 years	Infliximab (all)	Positive family history of CD in one patient
				Oligoarticular	Colon	9.5 years	Azathioprine (2)
				Polyarthritis	Stomach, duodenum, colon	10 years	Mesalazine (3)
				ERA	Esophagus, duodenum, ileocolitis	7.5 years		Two patients had anterior uveitis
				Oligoarticular	Duodenum, colon, anus	11.9 years
Tarkiainen et al.	2011	2	4/male 4/female	ERASeronegative polyarthritis	Ileum/colon Ileocolitis	3.6 years1.4 years	Infliximab (etanercept previously)	Maternal history of JIA

*Turner syndrome has been found to be associated with significant autoimmune antibodies and thus these patients are predisposed to Inflammatory Bowel disease. n=Number of patients, ERA=Enthesitis-related arthritis, JIA=Juvenile idiopathic arthritis, CD=Crohn’s disease, Others=Other associated findings, timing of diagnosis=Duration between JIA and onset of CD. Source: Katsanos et al. Adult-onset Still’s disease preceding Crohn’s disease. J Crohn’s Colitis (2013) 7, e93-8

In our patient, the possibility of NSAID or steroid-induced gastritis/colitis was considered, but the colonoscopy findings and histology were in keeping with IBD (CD). The absence of granuloma in this instance may be due to the use of the MTX therapy before the endoscopic procedure. Thus, colonoscopy and histopathology are able to differentiate the former conditions from CD. Arthritis as an extraintestinal manifestation of CD may present either as a monoarthritis or an asymmetric polyarthritis[11011] and increased fecal levels of lactoferrin and calprotectin, which indicate the presence of leukocytes in stool and thus intestinal inflammation can be used to identify JIA patients with underlying inflammation in the gut.[11011] Other tests such as abdominal ultrasound/computed tomography scan, magnetic resonance enterography to assess bowel thickness, and capsule endoscopy can also been done to screen for CD in JIA patients.[1] However, in many developing countries such as Nigeria, some of these tests are not readily available, affordable, or accessible. Determinants of the onset of CD following the diagnosis of JIA are unclear but may possibly be related to the type and severity of arthritis, other genetic, and environmental factors – HLA-B27 gene.[14910] It is important to look out for GI symptoms, and other symptoms such as fever, jaundice, and side effects of drug therapy when treating JIA patients.

It is interesting that this patient being a male child developed CD despite being on MTX and the reason for this remains unclear. Our patient developed CD 1 year after the commencement of the MTX therapy for JIA. There have been many reports in the literature of IBD occurrence in children and adults, following treatment with anti-tumor necrosis factor agents such as etanercept for various rheumatological conditions and the time frame for development of IBD following the use of these agents ranges from days to 5 years.[5671213] However, to the best of the authors' knowledge, this is the first report of IBD occurring in a child who had been on treatment with MTX for JIA. Previous literature has documented the protective effect of MTX in JIA even when used in combination with etanercept.[5]

In terms of therapy for JIA-associated CD, current guidelines recommend the use of biologic agents particularly infliximab, and in cases where this is ineffective, adalimumab may be an option, especially for the older children.[134] In Nigeria where biologic agents and formulas for enteric and elemental nutrition are not available, the treatment algorithm is to induce remission with steroids and maintain remission with azathioprine or MTX. Subsequent follow-up care includes monitoring of inflammatory markers such as erythrocyte sedimentation rate, C-reactive protein, and fecal calprotectin, and documentation of the PCDAI score.[8] This scoring tool is used to assess severity of and to monitor response to therapy in children.[8]

CONCLUSION

This report draws attention to the development of IBD following treatment of JIA with MTX in a Nigerian child and highlights the challenges of managing these conditions in a developing country with limited access to the currently recommended biologic agents. The importance of a high index of suspicion for the development of IBD and early referral to a gastroenterologist for further evaluation and management cannot be overemphasized.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.