Complicated Whipple’s disease and endocarditis following tumor necrosis factor inhibitors

Table 1 Frequency of the symptoms at the time of diagnosis of Whipple’s disease

	Patient group I	Patient group II	Patientgroup III
Patients (n)	41	61	1059
Therapy with TNFI	+	-	-
Therapy with non- biological DMARD	+	+	-
Signs or symptoms
Arthritis	85.4%	88.5%	70%-90%
Fever	53.6%	44.3%	35%-60%
Weight loss	36.6%	42.6%	80%-96%
Diarrhea	35.3%	54.1%	70%-85%
Endocarditis	12.2%	1.6%b	0.16%b
Pericarditis	12.2%	3.3%	0.08%b
IRIS	16%	22.9%	0%

All patients treated with non-biological disease modifying anti-rheumatic drugs (DMARDs) or tumor necrosis factor alpha inhibitor (TNFI) had experienced arthropathy or arthritis before the start of the therapy. In patient group III, few patients were treated with non-biological DMARDs (mostly steroids), but none were treated with TNFI. In 16 patients (reference 22), some symptoms (neurologic or eye symptoms) are not explicitly stated. The percentage of neurologic or eye symptoms of the analyzed patients were comparable (20% in group I (n = 25), 21.3% in group II (n = 45), and 10%-25% in group III).

^bP < 0.01 vs group I. IRIS: Immune reconstitution inflammatory syndrome.

Table 2 Summary of cases treated with tumor necrosis factor alpha inhibitor and later diagnosis of Whipple’s disease

Patients (n)(sex, age, yr)	TNFI/time from treatment start of TNFI to diagnosis of WD	Other DMARDs	Clinical picture at the time of diagnosis of WD (after TNFI treatment)	Therapy for WD/outcome	Ref.
1 (F, 33)	Etarnecept; 6 mo	NSAID, MTX	Chronic inflammation, ankylosing spondylitis, arthritis, diarrhea, fever, weight loss	CFA + CTM; resolution	[12]
1 (M, 57)	Etarnecept; “mo“	Leflunomide, MTX	Endocarditis, aortic valve replacement	DCN, HCQ; resolution	[13]
1 (M)	Etanercept; not stated	Steroids, others not specified	Arthralgia, diarrhea, others not specified, IRIS after Abx	Long-term steroids, resolution	[14]
1 (M, 70)	Etarnecept; 19 mo	NSAID, sulfasalazine, MTX	Ankylosing sacroiliitis, endocarditis, dyspnea, fever, aortic valve replacement	DCN, CTM, HCQ; resolution	[15]
3 (M, 51-76)	Infliximab/2, etarnecept/2 “yr“	Steroids, MTX, gold, leflunomide, cyclophos-phamide, cyclosporine	IRIS after Abx, fever, 3 arthritis, pseudotumor orbitae	3 long-term steroids; 1 blindness; 1 jejunal perforation; 1 death after 3 yr	[16]
1 (M, 46)	Infliximab, adalimumab; 28 mo	MTX, steroids	Ankylosing sacroiliitis, fever, T. whipplei septicemia, diarrhea	CFA + CTM; resolution	[17]
1 (M, 35)	Etarnecept; 2 mo	None	Purpura, scurvy, diarrhea, pancolitis, granulomas, T. whipplei septicemia, arthritis	CTM; resolution	[18]
5 (4 M, 1 F, 38-67)	Etarnecept/4, infliximab/2, adalimu-mab/2; 2, 4, 9, 26, 85 mo	NSAID, MTX, abatacept, rituximab, chloroquine, steroids, leflunomide	Aortic endocarditis, 4 arthritis, 3 T. whipplei in blood or septicaemia, 3 weight loss, 2 diarrhea, 2 pericarditis, 2 meningitis, diarrhea, hemorrhagic colitis, lymphadenopathy	1 DCN 4 DCN + HCQ All with favorable outcome	[19]
1 (M, 34)	Infliximab; 0, 5 mo	NSAID, steroids, azathioprine, MTX	Erythema nodosum, diarrhea, weight loss, fever, sigmoido-vesical fistula, arthritis, lymphadenopathy	CTM; resolution	[20]
1 (M, 47)	Adalimumab; “mo“	MTX, steroids, leflunomide	Arthritis, recurrent fever, cough, weight loss	CFA + CTM; resolution	[21]
16	TNFI not specified; time not stated	Most had other immuno-suppressants	Immunosuppressants: 43% deterioration, 32% temporary relief, then deterioration, 25% ineffectiveness; TNFI: 2 patients with endocarditis	Not specified	[22]
1 (M, 62)	Etarnecept; “short“	NSAID, steroids, MTX	Polyarthritis, pericarditis, cutaneous lesions; T. whipplei septicaemia	Penicilllin G, CTM; persisting cutaneous lesions; DCN + HCQ; resolution	[27]
1 (F, 58)	Not specified; 24 mo	No data available	Arthritis	No data available	[28]
1 (M, 53)	Not specified; 12 mo	No data available	Pericarditis, polyarthritis, lower limb edema	No data available	[29]
1 (M, 67)	Etarnecept; “short“	MTX, steroids, sulfasalazine, leflunomide	Pericarditis, pulmonary hypertension, arthritis, candida esophagitis, segmental ulcerative intestinal lesions, episcleritis, fever	CFA + CTM; Stopped because of diarrhea; Cefixim, steroids, resolution	[23]
1	Etarnecept; not stated	No data available	No data available	No data available	[30]
2 (M, 42, 53)	Etarnecept/2, adalimu-mab/2; 13, 14 mo	NSAID	Deterioration of arthritis, spondylising arthritis, diarrhea, weight loss	1 DCN + HCQ, Sulfadiazin; 1 DCN + HCQ; 2 resolution	[24]
1 (M, 64)	Etarnecept; 6 mo	Steroids, MTX	Spondylising arthritis, multisegmental spondylitis, arthritis, weight loss, Giardia lamblia infection	CFA + CTM; Persistent inflamma-tion, then DCN +HCQ; resolution	[25]
1 (M, 52)	Etarnecept, adalimumab, infliximab; 24 mo	Steroids, MTX	Rash, hemiplegia, dysarthria, facial palsy, cognitive sequelae, headache, decrease of executive functions, arthritis, diarrhea, weight loss, lymphadenopathy	CFA + CTM, amelio-ration, but remaining cognitive sequelae, headache	[26]

CFA: Ceftriaxone; CTM: Cotrimoxazole; DCN: Doxycycline; F: Female; HCQ: Hydroxychloroquine; IRIS: Immune reconstitution inflammatory syndrome; M: Male; MTX: Methotrexate; NSAID: Non-steroidal anti-inflammatory drugs; steroids: Corticosteroids; TFNI: Tumor necrosis factor alpha inhibitor; WD: Whipple’s disease; DMARD: Disease modifying anti-rheumatic drug; T. whipplei: Tropheryma whipplei.

Table 3 Whipple’s disease related symptoms and outcome after therapy with tumor necrosis factor alpha inhibitor

Sign or symptom1	Patients (n)
Total number of severe complications	49 (1.88 complications per patient)
Total number of affected patients	26 out of 41 patients (63%)
Fever, septic temperatures	16
T. whipplei septicaemia, T. whipplei in blood	6
Pericarditis	5
Endocarditis (many with valve replacement)	5
IRIS	4
Spondylitis (multisegmental)	4
Colitis, fistula, perforation	4
Neurologic symptoms, meningitis	3
Severe skin manifestation	3
Lymphadenopathy	2
Severe eye complications, blindness	2
Ankylosing sacroiliitis	2
Pulmonary hypertension	1
Outcome
Severe sequelae or death	3/19
Blindness	1
Neurological symptoms
(cognitive sequelae, dysfunction)	1
Death	1
Resolution or favorable outcome	16/19
Not specified/no data	22

¹Many patients experienced arthritis, weight loss or diarrhea as specified in Table 2. IRIS: Immune reconstitution inflammatory syndrome; WD: Whipple’s disease; T. whipplei: Tropheryma whipplei.

Table 4 Lack of reliability of standard diagnostic procedures in patient group I: Different situations ("settings") of the diagnostic procedures

Setting	Diagnostic procedurefor suspected WDbefore TNFI therapy	Diagnostic procedurefor suspected WDafter TNFI therapy	Patients (n) (reference)
1	Duodenal biopsy PAS neg	Duodenal biopsy PAS neg PCR pos	3 [19,21,25]
2	Duodenal biopsy PAS neg	Duodenal/small bowel biopsy PAS pos (PCR not performed )	3 [19,20,25]
3	“Duodenal mucosa normal“	Duodenal/jejunal PAS pos PCR pos	1 [23]
4	Duodenal biopsy PAS neg	Explanted heart valve PCR pos	1 [13]
5	Duodenal biopsy PAS neg PCR neg	Explanted heart valve PCR pos	1 [15]
6	None performed	Duodenal biopsy PAS pos PCR pos	3 [17,24,26]
7	None performed	Duodenal biopsy PAS neg PCR pos	2 [12,27]
8	None performed	Colonic biopsy PAS pos Stool, blood, CSF PCR pos	1 [18]
Total	9/9 PAS negative or mucosa normal	5/13 intestinal biopsies PAS neg	15 patients,
	1/1 PCR negative	8/13 intestinal biopsies PAS pos 10/10 intestinal PCR pos	13 reports

PAS: Periodic acid-Schiff staining; PCR: Polymerase chain reaction; TFNI: Tumor necrosis factor alpha inhibitor; WD: Whipple’s disease. Details are not stated in 23 patients (references 14, 16, 22, 28-30). neg: Negative; pos: Positive.

Table 5 Lack of reliability of standard diagnostic procedures in patient group I: Summary of all diagnostic tests n (%)

	PAS-stain	PCR-test
	False negative	False negative
Before TNFI therapy	9/9 (100)	1/1 (100)
After TNFI therapy	5/13 (38.4)	0/10 (0)
Total	14/22 (63.6)b	1/11 (9.1)
	True positive	True positive
Before TNFI therapy	0/9 (0)	0/1 (0)
After TNFI therapy	8/13 (61.6)	10/10 (100)
Total	8/22 (36.4)b	10/11 (90.9)

^bP < 0.01 vs periodic acid-Schiff staining (PAS)- and polymerase chain reaction (PCR)-tests. TFNI: Tumor necrosis factor alpha inhibitor.