common errors in the treatment of ibd: case studies gary r. lichtenstein, md david t. rubin, md

Common Errors in the Treatment of IBD: Case Studies

Gary R. Lichtenstein, MDDavid T. Rubin, MD

Gary Lichtenstein, MDDisclosures

Research, Advisory, and/or Honorarium

Some Common Errors in IBD Management1. Delay in diagnosis! This is not usually a gastroenterologist’s error.2. Steroids as initial therapy for mild to moderate UC- trust the

evidence!3. Using anti-TNF therapy as mono therapy- concomitant is favored

for most patients at least for induction.4. Avoiding surgery when it is needed. 5. Under dosing therapies:

– 5-ASA – focus on delivery– Thiopurines – understand metabolism and shunters– TNF – in some patients (maybe less than we would like to think)

6. Not vaccinating 7. Ignoring vitamin D8. Relying on “crisis management” rather than proactive monitoring

and control9. Dismissing patient interests in diet or complementary therapies

rather than working with them 10. Not referring to mental health professionals

Why Do Patients With IBD Not Respond To Their Medications?

Primary Nonresponse• Drug/mechanism just doesn’t work• Wrong diagnosis

– Infection– Ischemia– Crohn’s disease

• Wrong dose– Not enough– Too much?– pK issues

• Wrong delivery– Rationale

• Allergy/intolerance

Secondary Nonresponse• Change in dose (by you)• Change in delivery• Change in physiology

– Does disease changeover time?

• Intentional nonadherence– Episodic dosing strategy– Denial– Fear of therapy

• Unintentional nonadherence– Can’t afford medication– Inconvenient dosing regimen

Patient Case 1

Diagnostic Evaluation

• Female, age 23 yr; well until 5 mo ago

• Symptoms– Pain– Diarrhea (4–6 loose

stools/day)– 5-lb weight loss

• Physical examination– Tender RLQ– No mass

• Social History– Cigs: 1ppd x 5 yrs

• Laboratory values– WBC: 4,500 cells/µL– Hgb: 10.5 g/dL– CRP: 5.5 mg/dL– Albumin: 3.5 g/dL

• Colonoscopy– Terminal ileum and cecum with

numerous aphthous ulcerations– Biopsies c/w Crohn’s

• SBFT– Mild bowel-wall thickening with

slight narrowing in terminal ileum only

CRP = C-reactive protein; RLQ = right lower quadrant.

Initial Treatment• Diagnosis

– Mild-to-moderate ileocecal CD• Treatment goals

– Induce rapid, complete remission– Minimize the potential for side effects

• Treatment prescribed– Mesalamine 1.2 g TID

• Response– No clinical improvement after 3 weeks

Mesalamine is not FDA approved for the treatment of Crohn’s disease in the United States.

• What is the most appropriate treatment option in this patient ?

1. Continue mesalamine at a higher dose

2. Change to another 5-ASA derivative

3. Add a systemic corticosteroid –prednisone 40 mg orally daily

4. Switch to EC budesonide at 9 mg a day

Induction Nonresponder

Treatment Options for Mild - Moderate Crohn’s Disease

Step-Up according to severity at presentation or failure at prior step

AminosalicylateBudesonide

Corticosteroid

Anti-TNF

Disease Severity at Presentation

Severe

Moderate

Mild

Natalizumab

Thiopurine/MTX

AminosalicylateBudesonide/Thiopurine

Anti-TNF+/- Thiopurine/MTX

Induction

Maintenance

Sequential Therapies for Crohn’s Disease

Mild Moderate SevereAminosalicylates TNF antagonists

(IFX, ADA, CZP)Parental

CorticosteroidsAntibiotics Oral

Corticosteroids Bowel Rest

NatalizumabLocally Active Oral

CorticosteroidsAntimetabolites

(AZA,6-MP, MTX)Surgery

Conventional CD Therapy is Sequential

Treatment of IBD

I. Establish the Correct Diagnosis, Severity of Disease & Extent of Disease

Ulcerative Colitis versus Crohn’s Disease

Disease Distribution Severity of Disease

ACG GuidelinesDetermining Severity of Crohn’s Disease

Lichtenstein GR, Hanauer SB, Sandborn WJ. Am J Gastroenterol . 2009; 104(2):465-83 .

Mild to Moderate

Ambulatory without toxicity, no abdominal tenderness, painful mass, or obstruction

Moderate to Severe

Unresponsive to treatment for mild-to-moderate stage or with prominent fever, weight loss, anemia, abdominal pain and tenderness, or intermittent nausea or vomiting

Severe to Fulminant

Persistent symptoms on corticosteroids or with high fever, rebound tenderness, cachexia, or abscess

Remission

Asymptomatic, no inflammatory sequelae, responsive to medication or surgery, or not requiring systemic corticosteroids

Mesalamine Delivery Systems

MesalamineControlled-release Capsules

(Pentasa)

5-ASA 5-ASAN=N5-ASAN N

N=N

Sulfasalazine(Azulfidine)

NHSO2

Sulfapyridine

COOH

CH

Olsalazine(Dipentum)

5-ASA 5-ASA

Balsalazide Disodium Capsules

(Colazal)

(ABA)inert

carrier

NaOOC

OH

EthylcelluloseMicrospheres

Eudragit S/L

5-ASA

MMX technology

MesalamineGastro-resistant/pH

(Lialda)

MesalamineDelayed-release Capsules

(Asacol)

MesalamineGranulated formulation

(Apriso)

MesalamineRectal suspension

enema / suppository (Rowasa, Canasa)

5-ASA

5-ASA

NCCDS: Response to Therapy for Active Crohn’s Disease

NCCDS, National Cooperative Crohn’s Disease Study.Summers RW et al. Gastroenterology 1979;77:847-869

PatientsPatients(%)(%)

Weeks after RandomizationWeeks after Randomization00 55 1010 1515

Sulfasalazine 1 g/15 kg (5 g)Sulfasalazine 1 g/15 kg (5 g)

PlaceboPlacebo

6060

5050

4040

3030

2020

1010

00

7070

13%13%

Meta-Analysis: Mesalaminein Active Crohn’s Disease

P=0.005P=0.005

P=0.7P=0.7 P=0.5P=0.5

P=0.04P=0.04

Hanauer, Stromberg. Clinical Gastroenterology & Hepatology 2004

P=0.005P=0.005

P=0.7P=0.7

P=0.05P=0.05P=0.04P=0.04

-80

-70

-60

-50

-40

-30

-20

-10

0

Crohn's I

n=155

Crohn’s II

n=150

Crohn's III

n=310

Overall

n=615

Ch

an

ge

fro

m b

as

eli

ne

in

CD

AI

sc

ore

Pentasa® 4 g Placebo

-60

-50

-40

-30

-20

-10

0

Crohn's I

n=155

Crohn's II

n=150

Crohn's III

n=310

Overall

n=615

Pentasa® 4 g minus Placebo

Role of Antibiotics in Crohn’s Disease

• Widespread use despite insufficient evidence– Inadequate data for metronidazole and

ciprofloxacin as first-line therapy• May be useful in the management of

– Complications– Perianal disease– Small Intestinal Bacterial Overgrowth– Postoperative prophylaxis

• Little, if any, effect on small bowel disease• Potential for resistance and selective overgrowth

and Clostridium Difficile infection

Steroid Dependent

28%(n = 21)

Prolonged Response

32%(n = 24)

Surgery 38%

(n = 28)

Corticosteroid Therapy for Crohn’s Disease

Immediate Outcome*(n = 74)

1-YearOutcome(n = 74)

Complete Remission

58%(n = 43)

PartialRemission

26%(n = 19)

NoResponse

16%(n = 12)

*30 days after initiating corticosteroid therapy.

Faubion W, et al. Gastroenterology. 2001;121:225-260.

Budesonide in Active Ileal/Right Colonic Crohn’s Disease

0

10

20

30

40

50

60

70

80

53%

66%

51%

20%

62%

36%

10 Weeks1 16 Weeks38 Weeks2

Pat

ien

ts i

n R

emis

sio

n (

%)

CIR = controlled ileal release. *Mesalamine controlled-release capsules (Pentasa).

1. Rutgeerts P, et al. N Engl J Med. 1994;331:842-845. 2. Greenberg GR, et al. N Engl J Med. 1994;331:836-841. 3. Thomsen OO, et al. N Engl J Med. 1998;339:370-374.

PlaceboPrednisolone 40 mg

Mesalamine* 4 gBudesonide CIR 9 mg

Corticosteroids in Crohn’s disease

• Budesonide is first-line therapy for mild-moderate ileal or right colon disease– Maintenance therapy?

• Systemic steroids for moderate-severe disease

• High risk of steroid-dependence• Greatest risk of long-term side effects

– AGA Quality guidance• Attempt steroid weaning• Monitor for osteoporosis

Change of Therapy• Treatment

– EC budesonide 9 mg QD for 8 weeks• Outcome

– Remission attained at 5 weeks– Hgb: 11.2 g/dL– Mild facial acne– EC Budesonide successfully tapered to complete

cessation after 8 weeks• Plan

– Watchful waiting

Followup

• Followup – 2 weeks after cessation of EC Budesonide

symptomatic recurrence is noted– 6 BM / day with RLQ abdominal pain – Perianal drainage from a small fistula was noted

• Labs:– WBC- 13.0 x 109 / L– Hgb: 8.7 g/dL– ESR- 45 mm/hr– CRP - 22 mg/L

Recommendations

• Which of the following are appropriate at this time

1.) MRI enterography2.) CT enterography3.) Stool for C diff4.) Ask patient to stop smoking5.) 1 and 46.) 1, 3 and 4

Refractory IBD

• Establish the Correct Diagnosis, Severity of Disease & Extent of Disease

• Evaluate for Disease Complications • Evaluate for Enteric Infections• Use Optimal Medication Doses• Miscellaneous

• NonAdherence• Paradoxical Responses• NSAIDs• Cigarettes

Disease Complications

Abdominal / Pelvic Abscess CT abdomen and pelvis with oral and iv

contrast MRI pelvis with gadolinium

Mesenteric Venous Thrombosis CT abdomen and pelvis with oral and iv

contrast MRI pelvis with gadolinium

Enteric Infections

Bacterial Infections

CMV

Clostridium Difficile

Parasitic Diseases

“Pseudointractibility” of IBD

• CMV

• Clostridium Difficile

• NSAIDs

• Cigarette • Cessation in UC• Use in CD

MRI Enterography: Active Crohn’s Disease

T2 and Post-gad images demonstrating marked thickening and enhancement of TI. Note elevated T2 signal within and adjacent to TI (arrows) indicating active disease.

Followup

• Followup – Therapy was initiated with infliximab 5 mg /kg at 0,2,

and 6 weeks the every 8 weeks and also AZA 2.5 mg/kg was given (TPMT enzyme activity was normal).

– Oral Iron was given (Ferritin checked was 10 ng/mL).– Within a period of 3 months symptomatic remission

was noted.– Hgb - 11.0 grams– WBC- 9.9 g/dL– ESR- 12 mm/hr– CRP - 3.8 mg/L

CASE 2: The Patient Failing Thiopurine Therapy

Two Brothers with Ulcerative Colitis

• Patient #1: 18 yo with pancolitis, steroid responsive but steroid dependent. – TPMT normal– 6-MP started at 1.5 mg/kg– Unable to wean steroids below 15 mg

• Patient #2: 15 yo brother of patient #1, ulcerative proctitis, steroid resistant– TPMT normal– 6-MP started at 1.5 mg/kg– Not responding

Metabolism of Azathioprine and 6-Mercaptopurine

Azathioprine

6-Methyl-mercaptopurine

6-Mercaptopurine Thioinosinicacid

6-Thioguaininenucleotides

6-Thiouricacid

TPMT

HPRT

XO

Chan GL et al. J Clin Pharmacol. 1990;30:358.

Association Between Clinical Response andBoth 6-TGN and Intermediate Activity TPMT Genotype in

Pediatric Patients With IBD

Therapeutic Efficacy

Frequency of 6-TG level >235 (pmol/8 × 108 RBC) (%)

6-TG Quartiles

Frequency of response (pmol/8 × 108 RBC) (%)

41%

78%

Dubinsky MC et al. Gastroenterology 2000;118:705.

0

20

40

60

80

100

0–173 174–235 236–367 368–1,203

65

27

0

20

40

60

80

100

Response Failure

n=44 n=42 n=43 n=44

Freq

uenc

y of

Res

pons

e

Freq

uenc

y of

6-T

G le

vel

The Patient not Responding to Thiopurine• Confirm adherence, consider metabolites:

6-TG 6-MMP Possible cause Recommendation

undetectable undetectable Non-adherentorunderdosed

Understand why pt not taking med orincrease dose

Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11.





Low (<230) Low or undetectable

Non-adherent or underdosed

Discuss adherence, increase dose









Low (<230) High (>5700) 6-MMP shunter 1. Increase thiopurine, or

2. Consider allopurinol, or

3. Switch agents











3. Switch agents

“Therapeutic” (>230-<400) orHigh (>400)

Normal range or high

Primary non-responder

1. Assess disease2. Switch to different

mechanism


Brothers with Shunting

6-MP monotherapy

Pt TPMT 6-TGN 6-MMP ALT

1 23.0 137 13,477 114

2 19.7 301 12,796 141










3. Switch agents

“Therapeutic” (>230-<400) orHigh (>400)

Normal range or high

Primary non-responder

1. Assess disease2. Switch to different

mechanism


Practical Approach to Allopurinol and Thiopurine Combination Therapy

• Not for everyone! Be aware of safety concerns.• Choose patient (and MD) wisely:

– Active disease– Adherence with thiopurines– Subtherapeutic 6-TGn, supratherapeutic 6-MMP– Elevated LFTs or nausea may be present but not necessary

to consider this approach• Drop thiopurine to 25 mg (6-MP) or 50 mg (AZA)• Allopurinol 100 mg• Notify pharmacist!• CBC weekly for one month, then monthly…• Metabolites at week 3• Dose adjustment if necessary but in small increments

Govani and Higgins. J Crohns Colitis 2010;4(4):444-9.Sparrow, et al. J Crohns Colitis 2009;3(3):162-7.

Brothers with Shunting

Both patients responded quickly (within 2-3 weeks), have been in stable steroid-free remission for >2 years.

6-MP monotherapy 6-MP/allopurinol

Pt TPMT 6-TGN 6-MMP ALT 6-TGN 6-MMP ALT

1 23.0 137 13,477 114 422 -- 21

2 19.7 301 12,796 141 351 -- 25

• 21 year old male with a 4 year history of extensive small bowel CD treated with infliximab for the past 3 years presents with increasing cramping abdominal pain, 12 pound weight loss and diarrhea

• No recent travel or antibiotics• No previous abdominal surgery• SH: Does not smoke • FH: No FH of IBD• On infliximab 10mg/kg q 6 wk

Case 3

• PE shows a well appearing male in NAD with fullness in the RLQ

• Stool samples for enteric pathogens and C. diff negative

• MRE- 5cm segment of small bowel disease with small bowel dilation proximal to the area of involvement but w/o inflammation

• IFX level (trough: 9.0 mcg/ml)• ATI negative• LABS:

WBC – 8.6 KHgb – 12Ptlt- 334 KCRP- 3.3 (Normal < 4 mg/dl)

Case 3

Please choose the best management strategy1.Increase infliximab2.Add an antimetabolite (AZA/6MP/MTX) and continue infliximab3.Switch to adalimumab or certolizumab4.Switch to natalizumab5.Continue infliximab but evaluate for small bowel intestinal overgrowth, irritable bowel syndrome and consider surgical options6.Send for ileocecectomy

Case 3

ENT06169 10/07

Factors that Influence the PK of TNF Antagonists

Impact on TNF antagonist PK

Presence of ADAs Decreases drug concentration Increases clearanceWorse clinical outcomes

Concomitant use of immunosuppressives

Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes

Low serum albumin concentration Increases drug clearanceWorse clinical outcome

High baseline CRP concentration Increase drug clearance

High baseline TNF concentration May decrease drug concentration by increasing clearance

High body size May increase drug clearance

Sex Males have higher clearance

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.

ENT06169 10/07

Clinical Outcomes of Patients With Detectable Human Anti-Chimeric Antibodies or Subtherapeutic

IFX Concentrations

Response to testComplete/partial

response (%)P value

Detectable HACA Increase IFX 1/6 (17) <0.004

Change anti-TNF 11/12 (92)

Subtherapeutic concentrations

Increase IFX 25/29 (86) <0.016

Change anti-TNF 2/6 (33)

Afif W, et al. Am J Gastroenterol. 2010; 105:1133-1139.

HACA and IFX concentration testing impacted treatment decisions in 73% of patients and were a useful adjunct to clinical and

endoscopic/radiologic assessment

Aim• Examine the utility of measuring HACA and IFX concentrations and compare subsequent clinical management and response

• Therapeutic infliximab trough level (7 μg/mL) and short segment of fixed non-inflammatory disease

• Send to surgery and laparoscopic ileocecectomy performed

• Treated postop with metronidazole 500mg po bid for 3 months as well as 6MP

• Doing well 10 months postop with colonoscopy demonstrating 2 isolated aphthous erosions in the neoterminal ileum

Followup: Case 3

P<0.001P<0.001

P = ns

Vermeire et al. Gut 2007;56;1226-1231

• “an IFX level of <4 μg/ml measured 4 weeks after the first infusion had a PPV of 81% to detect the development of high ATIs during the later course of treatment”

• “an IFX level of >15 μg/ml measured 4 weeks after the first infusion was 80% predictive for the absence of ATIs during later follow-up.”

Week 4 serum level and subsequent ATI titre

“Therefore, IFX levels measured early after the first infusion of IFX (at 4 weeks) are a good prognostic parameter for development of immunogenicity.”

Drug Levels Predict Immunogenicity: Serum IFX at Week 4 After an Infusion Predicts Eventual

Appearance of ATI’s in Episodic Dosing

Patients With Sustained ATI Associated With LOR

Vande Casteele N, et al. Am J Gastroenterol. 2013. DOI:10.1038/ajg.2013.12.

P<0.001

Time to IFX Discontinuation Due to LOR

Vande Casteele N, et al. Am J Gastroenterol. 2013. DOI:10.1038/ajg.2013.12.

Log-rank P=0.006

Transient ATI (n=12)

Sustained ATI (n=35)

Years of IFX follow-up

AAA Formation Lowers Adalimumab Trough Serum Levels

• 92% of the patients with a trough serum concentration measured below the threshold for detection were positive for AAA

Med

ian

AD

A T

R

(μg

/mL

)

0

2

6

8

12

42.1

(n=9)

Week 4

10

6.1(n=58)

0.6(n=8)

8.9(n=53)

Week 12

0.1(n=8)

Week 24

8.8(n=37)

0.02(n=3)

11.1(n=46)

Week 54

0.05(n=10)

5.8(n=30)

TherapyDiscontinuation

AAA (+)AAA (-)

Reprinted from Gastroenterology 137(5), Karminis K, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in

Crohn's disease, 1628-1640. Copyright 2009, with permission the AGA Institute.

Proposed Treatment Algorithm in the Setting of Loss of Response

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.

High titers

Low titers

De-escalation

Change drug class

(no benefit from dose

escalation)

Drug escalation

Switch within class

HighClearance

Drug escalation or switch

ImpactClearance

SwitchHighClearance

Drug escalation or switch

ImpactClearance

High titers

Low titers

Subtherapeutic

Therapeutic

Subtherapeutic & normal CRP

Negative & ADAs (+)

Positive

Drug

ADAs

LOR

Can Antibodies to Biologic Therapies Be Overcome?

• 5 patients with loss of response to infliximab, undetectable infliximab trough levels, and positive antibodies to infliximab on 2 occasions

• Antimetabolite therapy added without changing dose of infliximab– Methotrexate (2); Thiopurine (3)

• ATI titer decreased and trough IFX levels rose over 1-5 months

• Clinical response reestablished

Ben-Horin S. CGH 2013;11:444-7

Conclusion

• Reactive Therapeutic Drug Monitoring effective for optimization of AntiTNF therapy in NonResponders

• Most data studied with Infliximab- but likely applies to other antiTNF agents– Adalimumab– Certolizumab Pegol

• Future prospective trial needed to define Proactive Drug monitoring

CASE 4

• 24 year old woman with newly diagnosed Crohn’s disease of the colon, ileum and perianal skin tags with a small simple fistula– Anemic– Elevated CRP

• Treated with infliximab and azathioprine• Excellent response and clinical remission• Laboratory values return to normal

CASE 4 - continued

• After 6 months of continuous therapy, requests to stop azathioprine

• 6 weeks later, has blood per rectum, loose stools

• Steroids started

• Infliximab given early at higher dose

• No improvement

CASE 4 - continued

• What happened here?

• Colonoscopy performed: – complete mucosal healing– Small irritated skin tag with friability– Fistula not draining

CASE 4 – continued - oops

• 4 months later

• Diarrhea, frank hematochezia– Anemic– CRP elevated again

• C. diff negative

• Therapeutic assessment– Infliximab level elevated (16 ug/ml)– No antibodies to infliximab

Interpretation of Infliximab Levels and Antibodies to Infliximab in a Patient Losing Response

Infliximab Level Antibodies to Infliximab

Treatment recommendation

Elevated Absent Switch treatment mechanism

Elevated Present Unclear, consider switching to another

TNF-inhibitorNot elevated Absent Adjust dose, interval of

infliximabNot elevated Present Switch to another

TNF-inhibitor

Afif, et al. Am J Gastroenterol. 2010 ;105(5):1133-9.

Switching Between TNF Inhibitors: Rheumatoid Arthritis Experience

• Response to a second inhibitor is lower relative to first 1

• Response to a second inhibitor will be comparable if initial discontinuation was due to adverse events 1, 2

• Patients who do not respond to 2 TNF inhibitors are not likely to respond to a third 2

1. Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R292. Solau-Gervais et al. Rheumatology. 2006;epub ahead of print.

Non-Anti-TNF Mechanisms of Management for the Patient Failing anti-TNF Therapy

Confirm Inflammation First

Crohn’s Disease• Natalizumab• Methotrexate• Surgery

– Including staged approaches or diversion for induction of remission

• Bowel rest

• Less evidence:– Mycophenolate– Tacrolimus

Ulcerative Colitis

• Cyclosporine• Tacrolimus• Surgery

Don’t Forget about Clinical

Trials!

BrainBone marrow Gut

MadCAM-1

a4b7

VCAM-1

a4b1

endothelium

leukocyte

integrins

addressins

natalizumab

Vedolizumab, rhuMab-beta7

natalizumab

PF-00547659

Leukocyte Trafficking Inhibition

Updated Utilization and Safety Results of Natalizumab in CD and MS

(TOUCH, CD INFORM, TYGRIS & Pregnancy Registry Studies)

• 118,100 patients have received globally (post-marketing) as of 6/30/2013– Predominantly MS patients

• PML (Progressive Multifocal Leukoencephalopathy)– Rare but serious – 410 cases reported globally as of 01-Oct-

2013; 23% have died– Longer duration and prior immunosuppressant use increases

risk– Risk for patients treated 24-36 months similar to rates seen in

clinical trials – Limited safety data beyond 4 yrs of treatment– No known treatment or prevention interventions for PML

https://medinfo.elan.com (accessed 12-Dec-2011); PML Incidence according to Elan Pharmaceuticals at 04-Nov-2013.

Recommendations for JCV Antibody Testing

• Testing prior to treatment with natalizumab• If positive, consider retesting.

– If confirmed, option is treatment with natalizumab for 9-12 months

• If negative, may treat with natalizumab, retest every 6 months– If converts to positive, stop therapy

• The benefit and safety of a drug holiday and restarting after “resetting” the exposure has not been tested in Crohn’s disease

• Vedolizumab (expected approval Q2 2014) does not have PML associated with it.

CASE 4 - conclusion

• JCV antibody negative

• TOUCH program

• Natalizumab initiated (300 mg IV q month)

• Stable remission returns

• Ongoing monitoring– Repeat JCV antibody assessment q6 months

What happens to the patients who receive natalizumab in the current post-TNF paradigm?

Chicago Experience

Sakuraba et al. Inflamm Bowel Dis 2013; ;19(3):621-6.

SUMMARY: Avoiding Errors in IBD

• Clarify diagnosis and the presence of inflammation when making treatment adjustments

• “Optimize” therapy – delivery, metabolism and pK

• Rule out confounders• Don’t stay within class if the mechanism

has clearly failed• Remember surgery

common errors in the treatment of ibd: case studies gary r. lichtenstein, md david t. rubin, md

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