Seronegative spondyloarthropathy-associated inflammatory bowel disease

Table 1 Demographic, clinical, laboratory, therapeutic, and prognostic profiles in five seronegative spondyloarthropathy subgroups

Category	AS	PsA	ReA	EnA	JSpA
Demographic
Sex, M:F	3:1	1:1	5-10:1	1:1	ERA 3:1, JPsA 1:2
Age, yr	20-40	35-45	Any	20-40	< 16
Laboratory
HLA-B27	> 90%	Axial 50%-70%	60%-80%	Axial 50%-70%	ERA 40%-70%
		Peripheral 20%		Peripheral 20%	JPsA 10%
Clinical
Affected joints	Spine, sacroiliitis	Any area	Peripheral, sacroiliitis	Peripheral	Peripheral, sacroiliitis
Peripheral	30%, lower	Common, upper	Common, lower	Common, lower	Common, lower
Sacroiliitis	100%	50%	30% in urogenital	20%	40%-60% in ERA
Dactylitis	Uncommon	Common	Common	Uncommon	20% in JPsA
Enthesitis	Common	Common	Common	Uncommon	Uncommon
EAM common	Intestine, skin, uveitis	Intestine, skin, uveitis	Skin, uveitis	Intestine, skin, uveitis	Intestine, skin, uveitis
Treatment	Spinal physical therapy, NSAIDs/cDMARDs for peripheral SpA, biologics, JAKi	NSAIDs, avoid CS, cDMARDs for peripheral SpA, biologics, JAKi, PDE4i	NSAIDs, antibiotics for chlamydia-induced ReA, cDMARDs for peripheral SpA	Coxibs/cDMARDs for peripheral SpA, biologics, JAKi	Spinal physical therapy, NSAIDs/cDMARDs for peripheral SpA, biologics
Prognosis	Life-threatening EAMs with heart, intestine or neurological involvement	Comorbidities associated with more severe disease activity	Usually a self-limited disease	Rarely grave EnA in controlled intestinal activity	More spinal deformity and THR as compared with adult SpA or other JIA subtypes

AS: Ankylosing spondylitis; cDMARD: Conventional synthetic disease-modifying anti-rheumatic drug; Coxib: Cyclooxygenase-2 inhibitor; CS: Corticosteroid; EAM: Extra-articular manifestation; EnA: Enteropathic arthritis; ERA: Enthesitis-related; F: Female; IBD: Inflammatory bowel disease; JAKi: Janus kinase inhibitor; JPsA: Juvenile psoriatic arthritis; M: Male; NSAID: Non-steroidal anti-inflammatory drug; PDE4i: Phosphodiesterase 4 inhibitor; PsA: Psoriatic arthritis; ReA: Reactive arthritis; SpA: Spondyloarthropathy; JSpA: Juvenile-onset spondyloarthropathy; THR: Total hip replacement.

Table 2 Demographic, clinical, laboratory, therapeutic, and prognostic profiles in two main types of inflammatory bowel disease

Category	Ulcerative colitis	Crohn’s disease
Demographic
Sex, M:F	1:1	1:1
Age at onset in yr	30-50	10-40
Laboratory
ANCA	Common	Rare
ASCA	Rare	Common
Clinical
Origin/Location	Rectum/colon, rectum	Terminal ileum/any part
Distribution	Continuous	Skip lesions
Pathology
Inflamed thickness	Mucosa, submucosa	Transmural
Crypt abscess	Common	Uncommon
Granuloma	Rare	Common
Fissure	Uncommon	Common
Fibrosis	Rare	Common
Treatment	ASA, CS, IS, biologics, JAKi, S1PR modulator, surgery for refractory medical disease or malignancy	CS, IS, biologics, surgery for refractory medical disease, complication or malignancy
Prognosis	Complete remission in most patients, low surgical requirement	Prolonged remission in about 20% of patients, 10-yr surgical resection risk near 50%

ANCA: Anti-neutrophil cytoplasmic antibody; ASA: Aminosalicylate; ASCA: Anti-Saccharomyces cerevisiae antibody; CS: Corticosteroid; IS: Immunosuppressant; JAKi: Janus kinase inhibitor; SIPR: Sphingosine-1-phosphate receptor.

Table 3 Inflammatory bowel disease manifestation in ankylosing spondylitis patients receiving approved tumor necrosis factor inhibitor or Janus kinase inhibitor therapy published in the English literature

No.	Clinical trials, n	Countries involved in clinical trials	Cases, n	TNFi or JAKi	IBD manifestation events, flare-up and new-onset	IBD manifestation events per 100 patient-yr1	Ref.
1	7	Canada, Germany, Netherlands	366	IFX	1 CD	0.2	[38-44]
2	9	European nations, United Kingdom, United States	724	ETA	14 (8 CD, 6 UC)	2.0	[45-52]
3	5	France, Germany, Netherlands, United States, etc.	2026	ADA	14	0.7	[53-55]
4	3	Canada, Germany, Netherlands, United States, etc.	837	GOL	0	0	[56-58]
5	1	Belgium, Canada, France, Germany, Netherlands, United States	121	CZP	1 CD	0.2	[59,60]
6	1	Australia, Canada, European nations, United States, etc.	133	TOF	0	0	[61]
7	1	Australia, Canada, European nations, Israel, United States, etc.	211	UPA	1 CD	1.8	[62]

¹One point six events per 100 patient-years in placebo groups by pooling 1015 ankylosing spondylitis patients under clinical trials[38,42,45,46,47,49,52,54,56,59,61,62].

ADA: Adalimumab; AS; Ankylosing spondylitis; CD: Crohn’s disease; CZP: Certolizumab pegol; ETA: Etanercept; GOL: Golimumab; IBD: Inflammatory bowel disease; IFX: Infliximab; JAKi: Janus kinase inhibitor; No.: Number; Ref.: Reference; TNFi: Tumor necrosis factor inhibitor; TOF: Tofacitinib; UC: Ulcerative colitis; UPA: Upadacitinib.

Table 4 Demographic, clinical, laboratory, medication, course, and outcome profiles in 4 ankylosing spondylitis-associated inflammatory bowel disease patients from 2017 January to 2021 December[30]

No.	Age in yr and sex	1AS period in yr	Affected joints	Other EA	3BASDAI/2AS medication	HLA-B27/3ESR	IBD clinical manifestation	IBD entity/6severity	4IBD medication	Disease course, under ADA 40 mg q2w SCI	Final outcome
1	42, F	12	SI, spine, hip	Uveitis	7.6/NSAIDs	Positive/38	Rectal bleeding, BWL, anemia	UP/ moderate, MS 9	CS, mSAZ, ADA 40 mg q2w	No IBD relapse for 4.3 yr	AS in low activity with BASDAI 2.0-2.5, IBD in remission, MS 0
2	35, M	15	SI, spine, hip	Uveitis	8.8/NSAIDs, SAZ	Positive/80	Bloody diarrhea, BWL, fever, anemia	UC/severe, MS 12	CS, mSAZ, ADA 40 mg q4 to q2w	No IBD relapse for 4.8 yr	AS in low activity with BASDAI 2.5-3.0, IBD in remission, MS 1
3	45, M	14	SI, spine, hip	Nil	8.4/NSAIDs, SAZ	Positive/42	Bloody diarrhea, BWL, anemia, 5colon perforation	UC/severe, MS 11	CS, SAZ, ADA 40 mg q2w	No IBD relapse for 5.8 yr	AS in low activity with BASDAI 2.5-3.0, IBD in remission, MS 2
4	45, F	25	SI, spine, shoulder hip	Nil	8.1/NSAIDs, SAZ, MTX	Positive/35	Bloody diarrhea, BWL, anemia	UC/severe, MS 11	CS, SAZ, ADA 40 mg q4 to q2w	No IBD relapse for 5.3 yr	AS in low activity with BASDAI 2.5-3.0, IBD in remission, MS 1

¹AS duration before the inflammatory bowel disease (IBD) development.

²Methotrexate 15 mg per wk, salazopyrin 2 to 3 g/d, nonsteroidal anti-inflammatory drugs only with Coxibs after IBD diagnosis.

³At disease onset of IBD.

⁴High-dose corticosteroids (CS, 1-2 mg/kg/d prednisolone equivalent doses) for acute ulcerative colitis (UC), topical CS for active ulcerative proctitis, low-dose CS for UC maintenance.

⁵Perforation at the splenic flexure, under double barrel colostomy and abdominal abscess drainage.

⁶MS: Mayo score, 11-12 severe, 6-10 moderate, 3-5 mild, 0-2 remission.

Age at diagnosis of inflammatory bowel disease. ADA: Adalimumab; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BWL: Body weight loss; CS: Corticosteroids; ESR: Erythrocyte sedimentation rate (normal value ≤ 15 mm/h); F: Female; IBD: Inflammatory bowel disease; M: Male; mSAZ: Mesalazine; MTX: Methotrexate; No.: Number; NSAIDs: Nonsteroidal anti-inflammatory drugs; q2w: Every 2 wk; SCI: Subcutaneous injection; UP: Ulcerative proctitis; SAZ: Salazopyrin; SI: Sacroiliac; UC: Ulcerative colitis; WNL: Within normal limit.

Table 5 Classification of inflammatory bowel disease-associated peripheral arthritis

Category	Type 1 pauciarticular	Type 2 polyarticular
Prevalence	4% to 5% in IBD, higher in CD than UC	3% in IBD, higher in CD than UC
Joint manifestation
Involved numbers	< 5	≥ 5
Articular distribution	Large joint, asymmetric	Mainly small joint
Involved area with the decreasing frequencies	Knee, ankle, wrist, elbow, MCP, hip, shoulder, MTP, PIP	MCP, knee, PIP, wrist, ankle, elbow, hip, shoulder, MTP
Erosion/destruction	Absent	Present
Clinical course	Early in IBD disease course, acute and self-limiting (mostly under 10 wk)	Arthritis for months, episodic exacerbation for yr
Disease characters
IBD activity	Parallel with activity	Independent of activity
Other EIM	EN, uveitis	Uveitis
HLA association	HLA-B27, B35, DR*0103	HLA-B44
Treatment	Control of IBD activity, coxibs, CS, cDMARDs (SAZ 1st choice), TNF mAbs for refractory cases, JAKi for anti-TNF failure	Coxibs, CS, cDMARDs (SAZ 1st choice), TNF mAbs for refractory cases, JAKi for anti-TNF failure

CD: Crohn’s disease; cDMARD: Conventional disease-modifying antirheumatic drug; Coxib: Cyclooxygenase 2 inhibitor; EIM: Extra-intestinal manifestation; EN: Erythema nodosum; HLA: Human leukocyte antigen; IBD: Inflammatory bowel disease; JAKi: Janus kinase inhibitor; mAb: Monoclonal antibody; MCP: Metacarpophalangeal; MTP: Metatarsophalangeal; PIP: Proximal interphalangeal; PsA: Psoriatic arthritis; SAZ: Salazopyrin; S1PR: Sphingosine-1-phosphate receptor; TNF: Tumor necrosis factor; UC: Ulcerative colitis.

Table 6 Generic names and currently approved indications of biologics and small molecules from the United States Food and Drug Administration for ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis, and inflammatory bowel disease

Category	AS	PsA	JIA1	UC	CD
Biologics/TNFi
Etanercept	X	X	X
Infliximab	X	X		X	X
Adalimumab	X	X	X	X	X
Golimumab	X	X	X	X
Certolizumab pegol	X	X			X
Biologics/IL-17i
Ixekizumab	X	X
Secukinumab	X	X	X
Biologics/IL-12/23i
Ustekinumab		X	X	X	X
Biologics/IL-23i
Guselkumab		X
Risankizumab		X			X
Biologics/IL-1i
Canakinumab			X
Biologics/IL-6i
Tocilizumab			X
Biologics/anti-integrin mAb
Natalizumab					X
Vedolizumab				X	X
Biologics/anti-CTLA-4 mAb
Abatacept		X	X
Small molecules/JAKi
Tofacitinib	X	X	X	X
Upadacitinib	X	X		X
Small molecules/PDE4i
Apremilast		X
Small molecules/S1PR modulator				X

¹Tumor necrosis factor inhibitor, abatacept, tocilizumab and tofacitinib for polyarticular juvenile idiopathic arthritis (JIA), canakinumab and tocilizumab for systemic JIA, secukinumab and ustekinumab for juvenile psoriatic arthritis, secukinumab for enthesitis-related arthritis.

AS: Ankylosing spondylitis; CD: Crohn’s disease; FDA: United States Food and Drug Administration; IL: Interleukin; JAKi: Janus kinase inhibitor; JIA: Juvenile idiopathic arthritis; PDE4i: Phosphodiesterase 4 inhibitor; PsA: Psoriatic arthritis; S1PR: Sphingosine-1-phosphate receptor; TNFi: Tumor necrosis factor inhibitor; UC: Ulcerative colitis.