Coeliac disease: the current role of pathology (II) Refractory coeliac disease

Luigi Terracciano

What is Refractory coeliac disease ?

Refractory sprue or refractory coeliac disease (RCD) is defined by:

persistent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for 6 -12 months

Refractory coeliac disease

An high rate of progression to lymphoma (> EATL)

Unique biochemical and immunologic features

Heterogeneous group whereas collagenous sprue accounts for 30-50% of cases

Most patients with collagenous sprue die from disease or require corticosteroids, other immunsuppressive agents or total parenteral nutrition to survive

High prevalence of autoimmune conditions (2-12 fold

> than coeliac disease)

Prevalence of refractory sprue among patients with coeliac disease

The real prevalence of RCD is unknown but is probably rare

0.7% - 1.5% of patients with Coeliac Disease (non-referral population-based cohorts)

More common in women

Most cases diagnosed after age 50

West J. Celiac Disease and Its Complications: A Time Traveller’s Perspective Gastroenterology 2009 136: 32-4

Rubio-Tapia A, Murray JA. Classification and management of refractory coeliac disease

Gut 2010 59: 547-557

Presentation of Refractory Sprue/Refractory Coeliac Disease

Persistent diarrhoea, abdominal pain, and involuntary weight loss

Multiple vitamin deficiencies

Anaemia, fatigue, malaise

Refractory Coeliac Disease Patients

The majority of patients with RCD experience initial clinical improvement on a GFD, but, after a period of remission, develop disease refractory to gluten abstinence (‘secondary RCD’)

Patients who have no initial response to a GFD (‘primary RCD’ or ‘unclassified sprue’)

The first step in the diagnosis of RCD is to confirm the initial diagnosis of CD

Confirm gluten abstinence

Rule out other causes of villous atrophy

Response to GFD

Clinically - a marked symptomatic improvement may occur within several days of starting GFD

Mucosal improvement may continue for 2 years or more

Causes of Villous Atrophy Coeliac disease

Tropical sprue

Giardiasis

Infectious enteritis

Small bowel bacterial overgrowth

Microscopic colitis

Eosinophilic gastroenteritis

Graft-versus-host disease

Cow's milk and soy protein enteropathy

Abetalipoproteinaemia

Small bowel ischaemia

Intestinal lymphoma

Tuberculosis

Crohn's disease

Parasitic infestation

Severe malnutrition

Adult onset autoimmune enteropathy

Common Variable Immunodeficiency

HIV enteropathy

Chemotherapy and radiation enteritis

Pathology work-up Abnormal Intraepithelial Lymphocyte Detection

Double CD3/CD8 immunohistochemistry

T cell receptor clonal rearrangement by PCR

Immunophenotyping using flow cytometry

Refractory Coeliac Disease

Clonal intraepithelial lymphocytes? >50% IELs with abnormal immunophenotype (CD3+ CD8-) by IHC > 20% ‘aberrant’ IELS (express cytoplasmic CD3ε, but lack surface expression CD3, CD4 and CD8) by flow cytometry Clonal T cell receptor gene rearrangement by molecular analysis

Refractory Coeliac

Disease Type 1

Refractory Coeliac

Disease Type 2

No Yes

CD3 CD8

From Cellier C et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet. 2000;356:203

CD3 CD8

NORMAL

ABNORMAL

Gut, 2007; 56: 1373 - 1378.

Five-year survival was higher in the type 1 group (96 vs 58 %).

Most deaths (half) were due to development of T-cell lymphoma

No patient with type 1 disease developed type 2 disease

Treatment Options

RCD type 1 - prednisone, budesonide or combination of prednisone and azathioprine are beneficial

No established treatments for RCD type 2

Chemotherapeutic drugs alone or high-dose chemo followed by autologous stem cell transplantation for selected patients with RCD type 2

Future novel therapies, such as interleukin 15 blockade ?

Al-Toma A, Goerres MS, Meijer JW, et al. Cladribine therapy in refractory celiac disease with aberrant T cells. Clin

Gastroenterol Hepatol 2006;4:1322e7; quiz 1300.

Al-toma A, Visser OJ, van Roessel HM, et al. Autologous hematopoietic stem cell transplantation in refractory celiac disease

with aberrant T cells. Blood 2007;109:2243-9

Al-Toma A, Verbeek WH, Visser OJ, et al. Disappointing outcome of autologous stem cell transplantation for enteropathy-

associated T-cell lymphoma. Dig Liver Dis 2007;39:634-41

Yokoyamaa S, Watanabea, Satob N et al. Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in

transgenic mice that overexpress IL-15 in enterocytes. PNAS 2009:106:15849–15854

Common Variable Immune Deficiency

CVID can display features similar to those of coeliac disease

Villous atrophy in 24% to 53% of duodenal samples from patients

Increased IELs (53%).

CVID patients often show markedly decreased to absent plasma cells (CD 138 useful)

Daniels JA et al. Gastrointestinal Tract Pathology in Patients with Common Variable Immune Deficiency (CVID) – A Clinicopathologic Study and Systematic Review Am J Surg Pathol 2007;31:1800–1812

Autoimmune Enteropathy

Rare cause of intractable diarrhoea associated with circulating gut autoantibodies and a predisposition to autoimmunity.

Adults and children

Histologically similar to coeliac disease with increased IELs and villous blunting

IgA and IgG anti-enterocyte antibodies

Other organ-specific autoantibodies

No coeliac-related autoantibodies

Steroid responsive

From: Akram S, Murray JA, Pardi DS et al. Adult Autoimmune Enteropathy: Mayo Clinic Rochester Experience. Clin Gastroenterol Hepatol 2007;5:1282–1290

Collagenous sprue

Rare form of small bowel enteropathy.

Pathologic lesion consists of subepithelial collagen deposition associated with variable alterations in villous architecture.

Characterised clinically by chronic diarrhoea and progressive malabsorption.

It has traditionally been associated with significant morbidity

- 7 cases of collagenous sprue.

- Clonal TCR gamma configurations were found in 5/6

- 3 of these patients died from malnutrition.

- 5 new cases of collagenous sprue and extensive literature review

- 13/30 patients known to have died from complications of disease

AJSP 24(5):676-687, May 2000

The Lancet - Vol. 356, Issue 9225, 15 July

2000, P 203-208

12 cases (4 males), 41-84 yrs

6 patients improved clinically with combination of GFD and immunosuppressant drugs; histologic improvement in 3/6.

1 patient died of another illness, 2 died of CS complications. No lymphoma.

4 had CD

AJSP 2009;33:1440–1449

Collagenous sprue

Coeliac sprue

• Flat or nearly flat mucosa with crypt

hyperplasia and increased

intraepithelial lymphocytes (IELs)

CD3+ CD8+

• Positive serologic tests : tTG,

antiendomisial, antigliadin abs

• DQw2 and DQ8

• Clinical, biochemical and

morphologic response to a gluten-

free diet regimen

Collagenous sprue

• Flat or nearly flat mucosa with mild

or absent crypt hyperplasia and

increased intraepithelial

lymphocytes (IELs) CD3+ CD8 +/-

• Collagen band

• > Serologic test negative

• no DQw2

• Incomplete or absent response to a

gluten-free diet regimen (refractory

sprue)

Masson’s Trichrome

Lamina propria cells and capillaries entrapped in collagen

Varying degrees of villous atrophy

Sirius Red _ subepithelial collagen deposition

Sirius Red _ subepithelial collagen deposition

CD3

CD8

CD8

IgH-FR3 TCRg Rearrangement IgH-FR1

Beta-Globin= QC

100

Size (bp)

139

150

160

200

247

300

339

350

400

450

Almost no B-cells Polyclonal TCR-g rearrangement

Seminested multiplex-PCR for B- and T-cell rearrangement

Collagenous sprue

Histology • Layer of subepithelial collagen thicker than 12mm into the lamina propria

• Entrapment of cellular elements is a mandatory diagnostic criterion

• Crypt atrophy more frequent than crypt hyperplasia

• Intraepithelial lymphocytosis may be absent (>25 IELs per 100 epithelial cells)

• Hyperchromasia of the crypt epithelium

• Subcrypt inflammation and even crypt abscesses

• If collagen deposits are found in ther small bowel, similar deposity may be

concomitantly present in colonic (ie, collagenous colitis) and/or gastric

mucosa: further endoscopic assessment and biopsy elsewhere in GI tract

Zhao X, Arch Pathol Lab Med, 2011

Small bowel histology Gastric histology (4/7 bx) Colonic histology (7/9 bx)

Collagenous sprue Collagenous gastritis Collagenous colitis

Lymphocytic colitis

Collagenous sprue Chronic gastritis No biopsy

Collagenous sprue Lymphocytic gastritis Normal colonic biopsy

Collagenous sprue No biopsy Normal colonic biopsy

Collagenous sprue Collagenous gastritis Collagenous colitis

Collagenous sprue Normal antral biopsy No biopsy

Collagenous sprue No biopsy Collagenous colitis

Collagenous sprue No biopsy Collagenous colitis

Collagenous sprue No biopsy Collagenous colitis

Collagenous sprue Collagenous gastritis Collagenous colitis

Collagenous sprue Reactive gastropathy Collagenous colitis

Collagenous sprue

Ulcerative jejuno-ileitis

No biopsy No biopsy

TAKE HOME When patients fail to respond to GFD revisit and confirm initial diagnosis

of CD

Confirm adherence to GFD

Rare causes of villous atrophy should also be considered and ruled out.

• Recognition of RCD, and discrimination between RCD type 1 and 2, is important for prognosis and treatment.

• RCD is a potentially treatable condition, particularly type 1 variant.

• RCD type 2 is associated with a poorer prognosis and patients have a high risk of developing EATL.

Collagenous sprue:

• may be a histological pattern associated with several different immune-mediated GI diseases, most commonly CD

• may be associated with collagen deposition in other parts of GIT

• Most patients respond to a combination of GFD and immunosuppressive drugs

TEMPLATE REPORT

CLINICAL DETAILS

SITE & NO. OF BIOPSIES

COMMENT ON ORIENTATION

VILLOUS/CRYPT RATIO – NORMAL (type 1)/PARTIAL OR SUBTOTAL (type 2) / OR TOTAL (type 3)

INCREASED IELS –NORMAL/INCREASED (>25)

PRESENCE OF NEUTROPHILS, EOSINIPHILS, SUBEPITHELIAL COLLAGEN (> 10-20 micron and measure)

References

1. Zhao X, Johnson RL, Collagenous sprue: a rare, severe small-bowel malabsorptive

disorder Arch Pathol Lab Med. 2011 Jun;135(6):803-9

2. WeinsteinWM, Saunders DR, Tytgat GN, et al. Collagenous sprue—an

unrecognized type of malabsorption. N Engl J Med 1970;283:1297-301.

1. Vakiani E, Arguelles-Grande C, Mansukhani MM, et al. Collagenous sprue is not

always associated with dismal outcomes: a clinicopathological study of 19

patients. Mod Pathol. 2010;23(1):12–26.

2. Bagdi E, Diss TC, Munson P, Isaacson PG. Mucosal intra-epithelial lymphocytes in

enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac

disease constitute a neoplastic population. Blood. 1999; 94(1):260–264.

3. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and

enteropathy-associated T-cell lymphoma. Lancet. 2000;356(9225):203–208.

CD8 Phenotype in Refractory sprue

IEL phenotype is considered abnormal when the number of CD8+ IEL /

100 epithelial cells is less than 50% of CD3+ IEL / 100 epithelial cells

Cellier C, Lancet, 2000

23 complicated CD

18 Refractory Sprue: CD3+ CD8+ in 12/18 (67%)

CD3+ CD8- in 6/18 (33%)

5 EATL CD3+ CD8- in 3/5 (60%)

de Mascarel A, Am J Surg Pathol, 2008

CD8- 6/6 RCD Patey-Mariaud de Serre N, Histopathology, 2000

15/15 RCD Verkarre V, Gut, 2003

17/20 RCD Bagdi E, Blood, 1999

CD8 Phenotype in Refractory sprue

Refractory Sprue

Type 1 CD3+ CD8+

Type 2 CD3+ CD8- with clonal intestinal TCR g rearrangements and

clonal dissemination into the blood. Worse prognosis and strong

indicator for the development of overt T-cell lymphoma (cryptic T-cell

lymphoma, Green PH, N Engl J Med, 2007 )