Enteropathic arthritis

Smith first described the connection between the intestines and joints in 1922. This was a patient with rheumatoid arthritis who experienced an improvement in joint symptoms following colectomy surgery (Peluso 2013).

At the end of the 1950s, Bywaters et al. and Mc Bride et al. wrote about the occurrence of enteropathic arthritis (EA) in patients with ulcerative colitis and chronic bowel disease (Peluso 2013).

In 1964, the American Rheumatism Association categorized arthritis associated with inflammatory bowel disease as a distinct clinical form.

Later, Wright and Moll classified enteroarthritis in the group of spondyloarthritides (Peluso 2013).

The first classification of EA, the so-called ESSG criteria, dates back to 1991 and was developed by the European Spondyloarthritis Study Group (Puchner 2012).

In 1998, Orchard et al. described the so-called "Oxford criteria" in Oxford (Sturm 2021). In 2001, these were supplemented by Smale et al. with a 3rd type, which also includes axial involvement (Zimmermann 2019).

The ASAS classification system was first presented by Rudwaleit et al. in 2009 (Zimmermann 2019).

Enteropathic arthritis (EA) is one of the spondyloarthritides (Braun 2017), which is an extraintestinal manifestation in patients with chronic intestinal diseases such as ulcerative colitis and Crohn's disease (Peluso 2013). No rigorous scientific definition of EA currently exists (Mayet 2015).

There are various classifications for differentiating an EA. The most commonly used are the Oxford criteria.

Oxford criteria:

- Type 1: Pauziarticular form with less than 5 joints

- Type 2: Polyarticular form involving 5 or more joints

- Type 3: Involvement with both axial and peripheral joints (Conigliaro 2016)

ESSG criteria (European Spondyloarthropathy Study Group):

• Inflammatory back pain or asymmetric synovitis or synovitis localized in the lower extremities must be present. In addition, one or more criteria of the 7 ESSG features are met: positive family history, psoriasis, chronic inflammatory bowel disease (IBD), urethritis or acute diarrhea or cervicitis, sacroiliitis, bilateral alternating buttock pain, enthesopathy (tendoostosis [Zeidler 2009]) (Zimmermann 2019).

ASAS criteria (Assessment of SpondyloArthritis international):

• The prerequisites for these criteria are chronic back pain lasting ≥ 3 months and a patient age of < 45 years at the onset of symptoms. Axial spondyloarthritis is divided into:
  • - radiographic axial SpA (corresponds to ankylosing spondylitis)
  • - Non-radiographic axial SpA (sclerosis or ankylosis is absent in the conventional X-ray image)
  • The criteria are met if imaging shows sacroiliitis plus ≥ 1 further sign of SpA or HLA- B27 plus ≥ 2 further signs of SpA.
• The signs of SpA are defined as: inflammatory back pain, psoriasis, uveitis, enthesis, IBD, dactylitis, arthritis, positive family history of SpA, elevated C-reactive protein, HLA- B27 positive, good response to non-steroidal anti-inflammatory drugs ( NSAIDs ) (Zimmermann 2019).

The joint involvement that occurs in chronic bowel disease is also divided into 2 subgroups:

• - axial group (including sacroiliitis with or without spondylitis)
• - Peripheral group (Peluso 2013 / Conigliaro 2016)

EA and inflammatory bowel disease share genetic, clinical, and immunological characteristics (Picchianti- Diamanti 2020).

There is a north-south gradient for the occurrence of chronic bowel disease and EA. Frequency peaks are observed in the 2nd - 3rd and 6th - 7th decade of life (Mayet 2015).

Men are more likely to develop Crohn's disease, and women are more likely to develop ulcerative colitis (Mayet 2015).

In patients with chronic bowel diseases such as Crohn's disease and C. ulcerosa, arthritis occurs in approximately 25% and sacroiliitis in approximately 15% (Herold 2022).

Patients with Whipple 's disease develop arthritis in approximately 60% and sacroiliitis in approximately 40% (Herold 2022).

Of the extraintestinal manifestations of inflammatory bowel disease, EA is the most common (Resende 2013).

- Chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease

- M. Whipple

- Z. n. gastrointestinal anastomosis surgery , also referred to as "bypass arthritis" (Herold 2022)

- Celiac disease (rare) (Kasper 2015)

- Gluten-sensitive enteropathy (Mayet 2015)

Both inflammatory bowel disease and spondyloarthritis are immune-mediated diseases. However, the specific pathogenic mechanisms are as yet unclear. Genetics certainly plays a role. There is also evidence that leukocytes and macrophages move back and forth between the gut and joints (Kasper 2015).

Currently, a multifactorial genesis consisting of environmental factors, genetics, and loss of immunological tolerance is most likely (Zimmermann 2019).

Clinically, enteropathic arthritis cannot be distinguished from idiopathic arthritis. Sometimes the arthritis already occurs - up to several years - before that of the chronic intestinal disease (Kasper 2015).

Symptoms may include:

- acute self-limited oligoarthritis

- chronic symmetrical polyarticular arthritis

- inflammatory back pain (Kasper 2015) that improves on exercise (Zimmermann 2019).

Erosions or deformities rarely occur in the course (Kasper 2015).

In order to make a diagnosis of EA, evidence of endoscopically or biopsy confirmed IBD is first required (Mayet 2015). In addition to the medical history and clinical examination, X-rays and CT scans are the main diagnostic tools (Herold 2022). As there is no specific marker for the detection of EA, EA is a diagnosis of exclusion (Mayet 2015).

• X-ray: Conventional X-rays can be used to differentiate the classic course of rheumatoid arthritis. Characteristically, no joint space narrowing, no erosions and no osteoporosis near the joint are detectable in peripheral joint involvement (Mayet 2015). In patients with Crohn's disease, 25 - 50 % show radiological signs of sacroiliitis (Sturm 2021) with:
  • - blurred joint contours
  • - irregular joint space widening
  • - osteolytic foci
  • - erosions
  • - syndesmophytes
  • - sclerosis
  • - ankylosis (Miehle 2000)
• Sonography: This non-invasive examination method is particularly suitable for the early detection of spondylarthritis. Characteristic features are:
  • - Bursitis
  • - synovitis
  • - Bone erosions
  • - Tendosynovitis
  • - Enthesis (Conigliaro 2016)
• MRI: MRI is the gold standard for diagnosing sacroiliitis (Conigliaro 2016). It allows a detailed characterization and also the extent of the disease to be shown.
• CT is also used to diagnose complications of sacroiliitis (Slobodin 2016).

Laboratory chemistry can detect the inflammatory and metabolic manifestations of inflammatory bowel disease (Kasper 2015), such as:

- non-specific inflammatory markers

- CRP elevated

- erythrocyte sedimentation rate (ESR) increased

- normochromic normocytic anemia (Conigliaro 2016).

Joint fluid also shows inflammatory processes (Kasper 2015).

The HLA- B27 gene is detectable in 30-70% of patients with inflammatory bowel disease (Kasper 2015)

- Joint pain of other etiology (Storm 2021)

- destructive arthritis of the hip (rarely occurring)

- Enthesopathy (extra-articular dolent inflammation of tendon attachment points).

- Dactylitis (Kasper 2015)

- Sacroiliitis in 10 - 25

- Spondylitis in 30 - 36 % (Conigliaro 2016).

Treatment requires close collaboration between rheumatologists and gastroenterologists (Peluso 2013).

Therapy consists of treating the precipitating underlying disease (Herold 2022), which may consist of:

- Steroids

- mesalazine

- Immunosuppressants such as:

- azathioprine

- methotrexate

- TNF alpha blockers for severe courses (Herold 2022) such as:

- Infliximab: Two phase 3 studies showed efficacy for arthritis, spondylarthritis, Crohn's disease and ulcerative colitis (Kucharzik 2021).

- Adalimumab

- Certolizumab (Kasper 2015).

In axial spondyloarthritides, sulfasalazine and methotrexate do not respond. These drugs should only be prescribed to patients with peripheral spondyloarthropathies (Sturm 2021).

For pain relief, acetaminophen (do not use with coexisting liver disease), metamizole , and low-potency opioids should be used (Sturm 2021).

NSAIDs can lead to exacerbation of IBD and are therefore recommended only for a limited time and in low doses (Mayet 2015).

Relapses of peripheral type 1 arthritis (see Oxford criteria under "Classification") usually occur with worsening of bowel symptoms, whereas axial disease (see "Classification") and peripheral type 2 arthritis tend to exist independently of bowel symptoms (Conigliaro 2016).

EA occurring in the setting of Crohn's disease usually shows complete remission. For one occurring in the setting of ulcerative colitis, remission is possible after 2-3 months. Overall, joint inflammation is rarely active for longer than 1 year, although recurrences do occur (Mayet 2015).

1. Conigliaro P, Chimenti M S, Ascolani M, Triggianese P, Novelli L, Onali S, Lolli E, Calabrese E, Petruzziello C, Pallone F, Perricone R, Biancone L (2016) Impact of a multidisciplinary approach in enteropathic spondyloarthritis patients. Autoimmunity Reviews 15 (2) 184 - 190
2. Herold G et al (2022) Internal Medicine. Herold Publishers 674
3. Hettenkofer H J, Droste U, Frenssen E, Hammer M, Hettenkofer H J, Kellner H, Miehle W, Miehle R K, Neudorf U, Perniok A, Sattler H, Schmidt K, Schneider M, Späth M (2003) Rheumatology: diagnosis - clinic - therapy. Georg Thieme Verlag Stuttgart / New York 27, 88, 93, 235
4. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 2178 - 2179.
5. Kucharzik T, Dignass A U, Atreya R, Bokemeyer B, Esters P, Herrlinger K, Kannengießer K, Kienle P, Langhorst J, Lügering A, Schreiber S, Stallmach A, Stein J, Sturm A, Teich N, Siegmund B (2021) Updated S3- guideline ulcerative colitis. AWMF No. 021 - 009
6. Mayet W J (2015) DGIM Innere Medizin: Enteropathic spondylparthritis in Crohn's disease and ulcerative colitis. ePedia Springer Medizin.
7. Miehle W, Fehr K, Schattenkirchner M, Tillmann K (2000) Rheumatology in practice and clinic. Georg Thieme Verlag Stuttgart / New York 643
8. Peluso R, Di Minno M N D, Iervolino S, Manguso F, Tramontano G, Ambrosino P, Esposito C, Scalera A, Castiglione F, Scarpa R (2013) Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. article ID: 6314408, 12 pages.
9. Picchianti- Diamanti A, Lorenzetti R, Chimenti M S, Luchetti M M, Conigliaro P, Canofari C, Benfaremo D, Bruzzese V, Lagana B, Perriconne R (2020) Enteropathic spondyloarthritis: results from a large nationwide database analysis. Autoimmunity Reviews 19 (2) 102457
10. Puchner R, Eichbauer- Sturm, Loisl D, Sautner J, Trieb K (2012) Rheumatology from practice: a short textbook of inflammatory joint diseases with case examples. Springer Verlag Vienna / New York 60
11. Resende G G, Lana C C D, Bortuluzzo B A, Goncalves C R, Braga da Silva J A, Ximenes A C, Bertolo M B, Ribeiro S L E, Keiserman M, Skare T L, Cameiro S, Azevedo V F, Vieira W P, Albuquerque E N, Bianchi W A, Bonfiglioli R, Campanholo C, Carvalho H M S, Duarte A P, Kohem C L, Leite N, Lima S A L, Meirelles S, Pereira I A, Pinheiro M M, Polito E, Rocha F A C, Santiago M B, de Fatima M, Sauma M de F L C, Valim V, Sampaio- Barros P D (2013) Enteropathic arthritis in Brazil: data from the Brazilian Registry of Spondyloarthritis. Rev Bras Reumatol. 53 (6) 452 - 459
12. Slobodin G, Rimar D, Boulmann N, Kali L, Rosenbaum M, Rosner I, Odeh M (2016) Acute sacroiliitis. Clin Rheumatol. 35 (4) 851 - 856
13. Sturm A, Areya R, Bettenworth D, Bokemeyer B, Dignaß A, Ehehalt R, Germer C, Grunert P C, Helwig U, Herrlinger K, Kienle P, Kreis M E, Kucharzik T, Langhorst J, Maaser C, Ockenga J, Ott C, Siegmund B, Zeißig S, Stallmach A (2021) Updated S3 guideline "Diagnostics and therapy of Crohn's disease" of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). AWMF Register Number: 021-004
14. Zeidler H, Michel B (2009) Differential diagnosis of rheumatic diseases. Springer Medizin Verlag Heidelberg 62
15. Zimmermann J M (2019) The quality of life of patients with inflammatory bowel disease (SPICE cohort) - What influence on quality of life does the presence of spondyloarthritis (according to the ASAS classification) have? Dissertation of the Department of Rheumatology and Immunology of the Medical Faculty of the Friedrich-Alexander-University Erlangen-Nuremberg for the degree of Dr.med.