Crohn's disease

Question 1

What environmental factors aggravate Crohn’s disease?

Answer 1

Environmental factors aggravating Crohn’s disease include: smoking 2X, higher if start early, hormonal contraception, meat diet, milk protein, omega-6 fatty acids, isoretinoin.

Question 2

What is the genetic basis of Crohn’s disease?

Answer 2

71 susceptibility loci on 17 chromosomes including at least 30 genes are associated with Crohn’s disease. concordance rate is 35% in monozygotic twins, 3% dizygotic with a 30 fold increased risk in siblings.20% of genetic variation is explained using all current susceptibility factors.
Many susceptibility genes overlap with those for mycobacterial infections and abnormalities in NOD2, CARD15, ATG16L1, JAK2, and STAT3 are prominent.

Question 3

What are the musculoskeletal complications of Crohn’s disease?

Answer 3

spondyloarthropathy, arthritis-colitic type, aseptic necrosis, hypertrophic osteoarthropathy, osteomalacia, myopathy,

Question 4

What antibodies are helpful in identifying inflammatory bowel disease?

Answer 4

Anti-Saccharomyces cervisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) are >80% specific for inflammatory bowel disease in patients with intestinal complaints.

Question 5

What diseases cause intestinal granulomas?

Answer 5

Granulomas are found on intestinal biopsy in Crohn’s disease, tuberculosis, Yersinia, Behcet’s disease, Whipple’s disease, and lymphoma.

Question 6

What are the usual presenting symptoms of Crohn’s disease?

Answer 6

Crohn’s disease usually presents after years of diarrhea, weight loss, abdominal pain, fever, with or without rectal bleeding.

Question 7

What are poor prognostic factors for Crohn’s disease?

Answer 7

Poor prognostic factors include onset age < 40, perianal or rectal disease, smoking, low education level, and initial requirement for glucocorticoids.

Question 8

What type of patients with Crohn’s disease are apt to develop strictures or fistula?

Answer 8

Intestinal strictures or fistulas are more common in Crohn’s disease with ilio colonic 9x or colonic involvement 6x, use of mesalamine or sulfasalazine in the first 90 days 2x, and perianal involvement.

Question 9

Why was the monoclonal antibody against alpha-4-integrin (nataizumab) which was effective in treating Crohn’s disease removed from the market ?

Answer 9

Up to 20% of patients on this drug develop PML (progressive multifocal leukoencephalopathy) due to JCV (John Cunningham virus).
nataizumab (Tizabri), a monoclonal antibody against alpha-4-integrin, Is expressed on all circulating leukocytes except neutrophils.

Question 10

What are the anti-inflammatory effects of anti-TNF treatment in Crohn’s disease?

Answer 10

Anti-TNF treatment in Crohn’s disease results in reducing stool TNF levels, and apoptosis of circulating monocytes, and of intestinal T lymphocytes.
anti-TNF with azathioprine is more effective than ant-TNF alone or azathioprine alone (57%,47%, 30% remission rates).
Anti-TNF treatment in Crohn’s disease also improves iritis/uveitis, pyoderma gangrenosum, and fever.

Question 11

What is the risk of stopping scheduled infliximab treatment in Crohn’s disease?

Answer 11

Stopping scheduled infliximab treatment in Crohn’s disease has a 50% relapse rate, worse if male sex, absence of surgical resection, WBC > 6000, hemoglobin < 14.5, C-reactive protein >5, and fecal calprotectin > 300 µg per gram. Switching to adalimumab results in significantly more complications and relapses.

Question 12

Is budesonide (Entocort EC, Pulmicort, Uceris) C25H3406 safer or more effective than other forms of glucocorticoids in Crohn’s disease?

Answer 12

Budesonide is inferior to conventional glucocorticoids (prednisone C21H26O5) when used to induce remission in Crohn’s disease. More decrease in bone density occurs with budesonide.

Question 13

What immunomodulatory drugs proved to be no better than placebo in treating Crohn’s disease?

Answer 13

IgG4 anti-TNF (CDP571) , etanercept (soluble p75 TNF receptor), Onercept (soluble p55 TNF receptor), certolizumab pegol, and tofacitinib (JNK and p38 inhibitor) do not perform better than placebo in Crohn’s disease.

Question 14

How long does it take azathioprine to work in Crohn’s disease?

Answer 14

There is no difference between 6-mercaptopurine, azathioprine, and placebo in treating Crohn’s disease until after 17 weeks of therapy.

Question 15

What cytokines do CD4+ Th17+ cells secrete?

Answer 15

TNF alpha, IL-17. This pathway is active in psoriasis, autoimmune uveitis, juvenile idiopathic arthritis, rheumatoid arthritis, and Crohn’s disease.

Question 16

How many genes participate in metabolic pathways leading to type 1 diabetes, rheumatoid arthritis, and Crohn’s disease?

Answer 16

There are at least 149 genes in diabetes type I, 189 in rheumatoid arthritis, and 277 in Crohn’s disease that participate in functional pathways that predict disease susceptibility.
Use genotypic data from the welcome trust case control Consortium on 14,000 Caucasian UK patients and 3000 controls with 7 diseases; Crohn’s, rheumatoid arthritis, type I diabetes, hypertension, type II diabetes, bipolar disorder. Looked at 1415 genes, 20,309 snips within 10 KB of the genes.

Question 17

What biochemical pathway abnormalities are common to both Crohn’s disease and type I diabetes?

Answer 17

Second order cytokine pathways are abnormal in Crohn’s disease and type I diabetes

Question 18

What hepatobiliary complications occur in Crohn’s disease?

Answer 18

Hepatobiliary complications include sclerosing cholangitis (3%), cholelithiasis (30-50%), fatty liver(20-50%)

Question 19

What ocular complications occurring Crohn’s disease?

Answer 19

Ocular complications (10%) include uveitis (2%), iritis, episcleritis (2.5%), scleromalacia(4% of episcleritis), corneal ulcers, retinal vascular disease, Crohn keratopathy.
Crohn's disease may be a contraindication to laser refractive surgery.

Question 20

How strong is the evidence linking vascular disease to Crohn’s disease?

Answer 20

Unusual blood/vascular complications said to occur more frequently include thrombocytopenic purpura, thrombophlebitis and thromboembolism, arteritis and arterial occlusion, polyarteritis nodosa, Takayasu arteritis, cutaneous vasculitis, anticardiolipin antibody, hyposplenism.
Based on case report studies often during anti-TNF treatment.

Question 21

How strong is the evidence linking neurological disease to Crohn’s disease?

Answer 21

Unusual neurological complications include peripheral neuropathy (0.7%), myelopathy, vestibular dysfunction, pseudotumor cerebri, myasthenia gravis, cerebral vascular disorders.
All associations are based on case studies in very sick patients or during anti-TNF treatment.

Question 22

What cardiac complications related to Crohn’s disease?

Answer 22

Unusual cardiac disorders reported as related include pericarditis, myocarditis, endocarditis heart block. Case report studies only, standardized mortality ratio not significant.

Question 23

What is the incidence of anti-TNF induced lupus in Crohn’s disease?

Answer 23

In 2012 review of 23,458 patients treated with adalimumab for rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and Crohn’s disease drug-induced lupus developed in 0.1 events/100 patient years in ankylosing spondylitis with lesser frequency in rheumatoid arthritis, JIA psoriatic arthritis, psoriasis, and Crohn’s disease.

Question 24

What are some pulmonary manifestations of Crohn’s disease?

Answer 24

Bronchiectasis, chronic bronchitis, interstitial lung disease, bronchiolitis obliterates with organizing pneumonia (BOOB) sarcoidosis, macrobiotic lung nodules, pulmonary infiltrates with eosinophilia, serositis, pulmonary embolism.
Based on case reports. Typical granulomas seen in bronchial mucosa, detailed studies show asymptomatic defects>healthy controls.

Question 25

What cytokines are active at sites of enthesitis?

Answer 25

IL 17, IL 22.

Question 26

What cytokines are active in areas of gut inflammation In Crohn’s disease?

Answer 26

IL 17, TNF, INF gamma.

Question 27

What are the major innate immunity problems in Crohn’s disease?

Answer 27

Dysfunctional innate immunity in Crohn’s disease includes disturbance of the mucosal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response, autophagy, and impaired recognition of microbes by pattern recognition receptors.

Question 28

What are the adaptive immunity changes in Crohn’s disease?

Answer 28

Adaptive immune defects include imbalance between effector and regulatory T cells and cytokines, and migration and retention of leukocytes.

Question 29

What is the pattern of Crohn’s disease within families?

Answer 29

Earlier disease onset occurs in offspring of parents with Crohn’s disease, and the firstborn is most often afflicted in discordant monozygotic twins.

Question 30

What is the proportion of genes sharing between ulcerative colitis, and Crohn’s disease?

Answer 30

17 of the loci in Crohn’s disease are shared with the 47 loci in ulcerative colitis.

Question 31

What type of gut bacteria characterizes Crohn’s disease?

Answer 31

Bacterial flora in Crohn’s disease shows increased intra-mucosal bacteria, with more adhesive species. Mycobacteria are often implicated but directed treatment is ineffective.
The incidence of Crohn’s disease increases when low incidence groups move into high incidence areas.
Firmicutes and Bacteroidetes phyla are overrepresented in Crohn’s disease.

Question 32

What is the normal distribution of bacteria within the small and large intestines?

Answer 32

Thousands of mostly anaerobic species from 4 bacterial fila colonize the human gut with a steep stomach-acid driven, proximal-distal gradient.

Question 33

What Is the Role of NOD2 in Crohn’s disease?

Answer 33

NOD2 (nucleotide-binding oligomerization domain-containing protein 2) a.k.a. CARD15 is an intracellular pattern recognition receptor that recognizes muramyl dipeptide. It contains 2 caspace recruitment domains and activates the NF-kBeta transcription factor.
Unaffected relatives of patients with Crohn’s disease who share the NOD2 defect have gut permeability abnormalities.

Question 34

What is the effect of NOD2 polymorphisms in Crohn’s disease?

Answer 34

NOD2 polymorphisms in Crohn’s disease are associated with weakened inflammatory cytokine response towards muramyl dipeptide and ineffective autophagy with increased IL10 transcription. Failure of autophagy is linked to decreased T cell responsiveness.

Question 35

What is ustekinumab?

Answer 35

Ustekinumab (Stelera) is a human monoclonal antibody that binds to the common p40 subunit of IL-12(p40 p35) and IL-23(p40 P19) thus interfering with signaling.
Side effects include infection risk, posterior reversible encephalopathy syndrome, URI, headache, fatigue.

Question 36

What are the indications to use ustekinumab?

Answer 36

Ustekinumab works in psoriatic arthritis: 24 week response rate 42% vs 22% for placebo. Also works in ankylosing spondylitis, psoriasis developing during TNF treatment of IBD, and for inducing remission inTNF resistant Crohn’s disease( 41.7% vs 27.4% for placebo).
Ustekinumab seems to work better after 4-6 months of disease, indicated more for maintenance rather than induction therapy.

Question 37

How many genes are common to both psoriasis and Crohn’s disease?

Answer 37

In one study of over 2000 patients with psoriasis in 2000 with Crohn’s disease and 10,000 controls, 11 susceptibility loci outside the HLA region are common to both. .
JAK2, Janus Kinase 2
ZMIZ1 Zinc Finger MIZ-Domain containing 1
PRDX5 peroxiredoxin 5
SOCS1 suppressor of cytokine signaling 1
STAT3 signal transducer and activator of transcription 3
YDJC,22q11
FUT2 fucosyltransferase 2
IL23R IL 23 receptor
IL12B interleukin 12B
REL avian reticuloendotheliosis viral oncogene homolog
TYK2 tyrosine kinase 2

Question 38

What is the rate of serious infections (events/100 patient years) in patients with Crohn’s disease treated with adalimumab?

Answer 38

In 2012 review of 23,458 patients treated with adalimumab, opportunistic infections developed < 0.1 events/100 patient years , but serious infections developed in 6.7 Crohn’s disease, 4.6 in rheumatoid arthritis, 2.8 psoriatic arthritis, 2 JIA, 1.7 psoriasis, and 1.4 ankylosing spondylitis.

Question 39

What pathways are important in Crohn’s disease but not rheumatoid arthritis or type I diabetes?

Answer 39

Pattern recognition pathways,B cell activation pathway, hematopoetic cell lineage pathway,neutrophil activation abnormalities are common in Crohn’s disease,