Reactive arthritis: an unusual presentation of acute Clostridioides difficile colitis

Abstract

A 20-year-old Caucasian man with a history of psoriasis presented to the emergency department due to a 2-week history of severe polyarthralgia and a 3-week history of non-bloody diarrhoea. The initial workup 2 days prior in an urgent care clinic returned negative for all enteric pathogens including Clostridioides difficile nucleic acid amplification test. Investigations revealed colitis on CT and pseudomembranous colitis on colonoscopy. The aspirate returned positive for C. difficile toxin. Tissue biopsies of the ascending, transverse, sigmoid colon and rectum were negative for chronicity to suggest inflammatory bowel disease with extraintestinal manifestation as the aetiology of polyarthralgia, which had been the most likely differential diagnosis until that point. The biopsy confirmed the diagnosis of reactive arthritis in the setting of C. difficile colitis. The patient improved on treatment with naproxen and was referred to rheumatology where he was found to be HLA-B27 positive.

Background

Reactive arthritis is a rare presentation of acute Clostridioides difficile colitis and requires high level of clinical suspicion to definitively diagnose. It is classically seen with the organisms Salmonella, Shigella, Campylobacter, Chlamydia and Yersinia, with C. difficile cases cited roughly 50 times in the literature thus far.¹ Additionally, overlapping symptoms with inflammatory bowel disease associated arthropathy can make this diagnosis particularly difficult to make. Both reactive arthritis and inflammatory bowel disease related arthropathy have associations with Human Leucocyte Antigen (HLA)-B27.

Case presentation

A 20-year-old Caucasian man with a history of controlled psoriasis and no other family history of autoimmune disease presented to the emergency department with worsening severe polyarthralgia localised mostly to the elbows, wrists and ankles that began 2 weeks after the onset of non-bloody diarrhoea associated with chills, fatigue and night sweats. He had been having diarrhoea for 3 weeks and polyarthralgia for 2 weeks at the time of presentation to the emergency department. He denied oral antibiotic use within the past month. Physical examination revealed extreme tenderness to palpation of joints without erythema or swelling. He was seen 2 days prior at an urgent care clinic where the initial workup returned negative for C. difficile by nucleic acid amplification test, basic enteric panel, occult blood, tick borne illness, infectious mononucleosis, West Nile and a normal rheumatoid factor. Complete blood count (CBC) was normal and erythrocyte sedimentation rate (ESR) was elevated at 86 (tables 1–3). He was given prednisone at the clinic and returned home with plans to see rheumatology.

Table 1.

Laboratory values at time of presentation to urgent care facility and 2 days later at presentation to emergency department

Test	Urgent care facility	Hospital admission	Reference values
White blood cell	10.3	15.7	4.0–11.0 ×109/L
Haemoglobin	138	126	135-175 g/L
Platelets	372	329	140–400 ×109/L
ESR	86	73	0–15 mm/hour

ESR, erythrocyte sedimentation rate.

Table 2.

Autoimmune workup for differential of polyarthritis

Autoimmune testing	Urgent care facility	Hospital admission	Reference values
Rheumatoid factor quantitative	<15		0–29 IU/mL
Antinuclear antibody screen		Negative	Negative
Antineutrophil cytoplasmic antibody screen		Negative	Negative
Myeloperoxidase antibody		<0.2	<0.4 U (negative)
Proteinase 3 antibody		<0.2	<0.4 U (negative)
Saccharomyces cerevisiae antibody, IgG		<10.0	≤20.0 U (negative)

Table 3.

Workup for aetiology of diarrhoea at time of presentation to urgent care facility and 2 days later at presentation to emergency department

Infectious agent testing	Urgent care facility	Hospital admission	Reference values
Basic Enteric Pathogen Panel*	Not detected		Not detected
Toxigenic Clostridioides difficile (Pathogenecity Locus)	Not detected		Not detected
Giardia	Negative		Negative
Cryptosporidium	Negative		Negative
Lactoferrin for leukocytes, faecal		Positive	Negative
Babesia species, nucleic acid detection	Negative		Negative
Ehrlichia/anaplasma	Negative		Negative
Lyme disease	Non-reactive		Non-reactive
Mono screen	Negative		Negative
West Nile	Negative		Negative
Bacterial blood cultures		No growth	No range found

*Basic Enteric Pathogen Panel includes Campylobacter, Salmonella, Shigella, Vibrio, Yersinia enterocolitica, Shiga-like toxin 1, Shiga-like toxin 2, norovirus, rotavirus.

Investigations

A CT of the abdomen and pelvis with contrast obtained in the emergency department revealed abnormal nodular thickening involving the cecum and ascending colon with adjacent inflammation and stranding (figure 1). There was concern for inflammatory bowel disease in light of the patient’s history of psoriasis, colitis on CT at the time of presentation and the overall incidence of inflammatory bowel disease compared with the rarer reactive arthritis. Colonoscopy showed diffuse moderate inflammation of the entire colon suspicious for pseudomembranous colitis and no terminal ileum involvement (figure 2).

Figure 1.

CT with contrast showing abnormal nodular wall thickening involving the cecum (red arrow).

Figure 2.

Colonoscopy of ascending colon. Pseudomembranous colitis (white arrows).

Aspirate returned positive for C. difficile toxin at which point vancomycin was initiated. It was still more plausible at this point that his polyarthralgia was due to a previously undiagnosed inflammatory bowel disease flare, and not reactive arthritis following acute C. difficile colitis. However, tissue biopsy results of the colon confirmed the diagnosis of reactive arthritis in the setting of C. difficile colitis. The tissue report documented focal active colitis in the ascending colon, transverse colon, sigmoid colon and rectum with reactive lymphoid aggregates in the terminal ileum. There was no pathological evidence of chronicity to suggest ulcerative colitis or Crohn’s as the aetiology. This effectively ruled out inflammatory bowel disease with extraintestinal manifestation. Of note, joint aspiration was not done in this patient and the clinical diagnosis was made based on diagnostic criteria including (1) asymmetric oligoarthritis, (2) enteritis preceding the onset of arthritis and (3) presence of triggering infection evidenced by culture positivity. The patient began conservative management with naproxen leading to gradual improvement in symptoms. Additionally, he tested positive for HLA-B27 after referral to rheumatology, further supporting the diagnosis of reactive arthritis.

Differential diagnosis

In this case, it was difficult to distinguish reactive arthritis from inflammatory bowel disease (IBD) with extraintestinal manifestation. Colonoscopy revealing pseudomembranous colitis with C. difficile positive aspirate and an unremarkable tissue biopsy for IBD helped make the definitive diagnosis. The treatment regimen for reactive arthritis includes antibiotics for enteric infection coupled with non-steroidal anti inflammatory drug (NSAID) therapy, which when initiated early results in excellent prognosis.

Discussion

Enteric infections are seen in about 10% of symptomatic relapses of IBD.² Reactive arthritis is an inflammatory arthritis with clear infectious trigger, although pathogens cannot be recovered from the affected joint. It is considered a spondyloarthropathy, classically associated with Salmonella, Shigella, Campylobacter, Chlamydia and Yersinia.³ There have been roughly 50 cases of C. difficile reactive arthritis documented to this point, with this case report contributing to the expanding work of literature on this topic (table 4). The epidemiology of the disease varies in part due to the lack of definitive criteria for diagnosis across the world; however, it is more common in men under 40, with HLA-B27 positivity cited in 30%–50% of cases. Certain populations report an even higher percentage.^{4 5} The proposed pathophysiological mechanism involves autoimmune reactivity to bacterial antigens that gain access to joints and other tissues after invading the intestinal mucosa.⁶ As the cases of C. difficile colitis continue to rise in response to widespread antibiotic use and hospital-acquired infection, it is even more important to recognise the connection of reactive arthritis with C. difficile colitis. Formerly known as Reiter syndrome, reactive arthritis classically presented as a triad of conjunctivitis, urethritis and arthritis. We now understand its association with many extraintestinal manifestations including enthesitis, dactylitis, uveitis, cystitis or even mucosal ulcers and hyperkeratotic skin.⁷ Reactive arthritis is a rare presentation associated with C. difficile colitis that clinicians should be aware of, especially when a patient presents with severe polyarthralgia that develop within 1–4 weeks of a preceding enteric infection.

Table 4.

Reactive arthritis cases due to Clostridioides difficile documented from 2016 until

A case of reactive arthritis due to Clostridium difficile colitis8	Journal of Community Hospital Internal Medicine Perspectives	February 2016
Clostridium difficile enterocolitis and reactive arthritis: a case report and review of the literature9	Case Reports in Pediatrics	April 2016
Clostridium difficile associated reactive arthritis: a case report and literature review1	Anaerobe	April 2016
Clostridium difficile colitis leading to reactive arthritis: a rare complication associated with a common disease6	Journal of Investigative Medicine High Impact Case Reports	March 2018

Learning points.

• Reactive arthritis is classically associated with Salmonella, Shigella, Campylobacter, Chlamydia and Yersinia, with cases of enteric organisms such as Clostridioides difficile cited uncommonly in the literature.

• C. difficile colitis cases continue to rise with widespread antibiotic use, hospital-acquired infection and community-acquired infection without prior antibiotic use.

• It is important to recognise C. difficile as an aetiological agent of reactive arthritis, despite fewer number of cases documented.

• C. difficile is a known agent seen in relapses of inflammatory bowel disease, making it difficult to delineate between true reactive arthritis and inflammatory bowel disease with extraintestinal manifestation.

• Clinicians should suspect reactive arthritis when a patient presents with severe polyarthralgia developing within 1–4 weeks of preceding enteric or genitourinary infection.