CASE 1

• Dr Agnès Carlotti• Hôpital Tarnier-CochinService d’Anatomie PathologiquePr MC Vacher LavenuService de DermatologiePr MF Avril

• Man 62• Polyarthritis since 2000 and raised ESR• Rheumatoid factor-, Antinuclear

antibody-, HLA B 27-• No improvement with anti inflammatory

drugs, corticosteroids, methotrexate, etanercept

• March 2006: pericarditis• Treated by penicillin (2 weeks),

trimethoprim-sulfamethoxazole 4 weeks• Persistence of fever and development of

tender nodules on buttocks and right thigh

Subcutaneous Whipple’s disease

PAS

specific immunohistochemistry

Thanks to Dr Fenollar Marseille University

• 1907 George Hoyt Whipple: fatal illness with weight loss, chronic cough, fever, steatorrhea, polyarthritis « intestinal lipodystrophy »

• 1907 George Hoyt Whipple

• 1958: JC Sieracki: macrophage’s PAS inclusions • 1961: WC Chears: bacteria on electron microscopy• 1991: KH Wilson: partial amplification of the bacterial

16S RNA

• 1992: DA Relman: molecular identification of Tropheryma Whipplei

• 1997: A Schaffner culture of T Whipplei

Tropheryma Whipplei:• intracellular bacteria gram+ belonging to the

group of actinobacteria • Ubiquitous (soil, water…)

• Epidemiology: approximate annual incidence is less then 1/1 000 000

• Caucasian males (M/F ratio:8/1)• Mean age onset: 50

Clinical features++Gastro intestinal-weight loss: 80-90%,diarrhea: 70-85%,abdominal pain: 50-90%

• Extra intestinal manifestations:-arthralgias, arthritis: 70-90%-anemia: 75-90%-low grade intermittent fever: 40-60%-lymphadenopathy: 40-60%-hyperpigmentation: 40-60%-cardiac: 35-65%: pericardial friction rub, murmurs, ECG changes:

infectious endocarditis+negative blood cultures-pulmonary: 35-60%: chronic cough, pleuritic pain (differential

diagnosis: sarcoidosis)-central nervous system: 20-30%: cognitive changes, supranuclear

gaze palsy, altered levels of consciousness

Diagnostic Tools

• PAS positive foamy histiocytes on duodenal biopsy Endoscopy showing pale, yellow, focally eroded mucosa of duodenum,

• Electron microscopy: macrophages laden with phagosomes containing degenerated bacilli

• Specific PCR gene amplification• Specific immunohistochemistry• Cultivation of T. whippelii

The clinical course can be divided into two broad stages:

- a prodromal stage lasting 6 to 10 years: migratory polyarthralgias, adenopathy, and/or fever;

- a steady-state stage: weight loss, diarrhea, adenopathy, and/or neurologic symptoms.

15% of patients do not have the classical signs of the disease

This second stage can be further divided into • Classic WD : abdominal manifestations,

weight loss, weakness, chronic diarrhea, and abdominal pain,

• Generalized stage characterized by steatorrhea, cachexia, lymphadenopathy, hyperpigmentation, cardiovascular, pulmonary, and/or neurologic dysfunction.

• Immune reactions to T whipplei range from• -asymptomatic carriage (no host response,

PCR+) • -to a localized inflammatory reaction at the

site of initial infection (classic intestinal form)

• -to widespread, disseminated disease (sarcoidal and necrotizing [caseous] granu-lomatous responses, PCR+, PAS-

• -to generalized disease (diffuse foamy histocytosis, PAS+)

• Cutaneous manifestations in Whipple’s disease occur up to 21% of cases

• skin manifestations of Whipple’s disease can be classified into two groups of disorders:

• - malnutrition-related (72%) • -inflammatory, ‘‘reactive’’ (28%)

The most frequent skin manifestation: Addison’s disease-like hyperpigmentation (melanoderma)

-up to 46% of patients -late, generalized stage of WD. -exact pathogenesis of WD hyperpigmentation

is undefined:vitamin B12 deficiency/ malabsorption?, hypocortisolism secondary/ malnutrition?, and/or WD involvement of the adrenal cortex?

steady state stage cutaneous manifestations • Petechies or non thrombopenic purpura,

Scurvy (deficiencies vit C +/- vit K)• Acquired ichtyosis, palmoplantar

hyperkeratosis• Erythema nodosum-like lesions, frequently

antibiotic related• Papules, plaques or nodules• Lower leg and ankle edema

(hypoalbuminemia, lymphatic stasis)• Lupus like rash

• prodromal stage:cutaneous manifestations (rare)

• Dermatomyositis-like eruption• Erythroderma • Macular (morbiliform or reticulate) eruption• Urticaria• Rheumatoid nodule like

• Others: Psoriasiform dermatitis• Eczema like eruption• vasculitis

• Symptomatic, inflammatory cutaneous Whipple’s disease shows two patterns.

• -reactive dermatoses: macular and reticulate erythemas, dermatomyositis-like, lupus-like, psoriasiform, urticarial, eczema-like, vasculitic eruptions, and erythroderma +/-sarcoidal or lichenoid granulomatous inflammation : PCR+ generally PAS-

• -infiltrative dermatoses: scattered or numerous cutaneous or subcutaneous papules, nodules, plaques: rheumatoid nodules or erythema nodosum like PAS+

• Histological features of nodular/subcutaneous lesions associated with Whipple’s disease:

• mixed panniculitis mostly septal with neutrophils and macrophagesat steady state stage

• granulomatous sarcoidal dermatitis, at prodromal stage

• It is unknown whether normal skin in early WD harbors T whipplei identifiable by PCR?

• in the steady state, approximately one third of biopsy specimens of normal skin show PAS+ macrophages, indicating that skin is infected, albeit asymptomatically

• EN like lesions in WD differ from classic EN (mostly septal without any organisms within the lesions even associated with infective diseases )

• EN- like lesions of WD have more in common clinically, pathologically and immunologically with erythema nodosum leprosum (ENL), a specific type of reversal lesion seen in lepromatous leprosy patients

• Development of EN-like lesions is likely a consequence of the combination of

• -the presence of free T whipplei bacilli• -numerous dermal and subcutaneous T

whipplei laden macrophages• -lymphatic stasis (lymphangiectases)• -and immune reconstitution syndrome

(IRIS) after antibiotic therapy secondary to a dramatic decrease in the numbers of viable, replicating T whipplei

• Bibliography subcutaneous Whipple’s :-Good et al: Arthritis Rheum 1980-Kwee et al:JAAD 1987-Balestrieri et al:Br J dermatol 1996-Tarroch et al: J Cutan Pathol 2001 -J Schaller et al: J Am Acad Dermatol 2008