What tests should you use to assess small intestinal bacterial overgrowth in systemic sclerosis? Y. Braun-Moscovici¹, M. Braun², D. Khanna3, A. Balbir-Gurman1, D.E. Furst4

¹B. Shine Rheumatology Unit, Rambam ABSTRACT The pathogenesis of GIT involvement is Health Care Campus, Bruce Rappaport Objective. Small intestinal bacte- thought to include early vascular dam- Faculty of , Technion – Institute rial overgrowth (SIBO) plays a major age to the vasa nervorum of the nerves of Technology, Haifa, Israel; ² Institute, Beilinson Hospital, role in the pathogenesis of malabsorp- innervating the GIT. This leads to neu- Petach-Tikwa, Sackler School of Medicine, tion in SSc patients and is a source of rological dysfunction, particularly in- Tel Aviv University, Israel; great morbidity and even mortality, in volving autonomic pathways (4-5). The ³Director of University of Michigan those patients. This manuscript reviews activation of the immune system may Scleroderma Program, University of which tests are valid and should be contribute to neurological dysfunc- Michigan, Ann Arbor, Michigan, USA; used in SSc when evaluating SIBO. tion by production of antibodies which 4Director of Therapeutic Research, David Geffen School of Medicine, University of Methods. We performed systematic lit- specifically inhibit M3-muscarinic California, Los Angeles, USA. erature searches in PubMed, Embase receptor-mediated enteric cholinergic Yolanda Braun-Moscovici, MD and the Cochrane library from 1966 up neurotransmission (6). With damage to Marius Braun, MD to November 2014 for English language, innervation, smooth muscle atrophies Dinesh Khanna, MD, MS published articles examining bacterial and is eventually replaced by fibrotic Alexandra Balbir-Gurman, MD overgrowth in SSc (e.g. tissue which further leads to motility Daniel E. Furst, MD tests, breath tests, xylose test, etc). Ar- disorders of the GIT. At present, there Please address correspondence to: ticles obtained from these searches were is no single validated, objective, specif- Dr Daniel E. Furst, reviewed for additional references. The Geffen School of Medicine at ic test to assess the global involvement the University of California validity of the tests was evaluated ac- of the GI tract although the GIT2.0, a in Los Angeles, cording to the OMERACT principles of patient reported outcome measure has 1000 Veteran Ave, truth, discrimination and feasibility. been validated (7). Los Angeles, CA 90025, USA. Results. From a total of 65 titles, 22 Hypomotility of the small bowel may E-mail: [email protected] articles were reviewed and 20 were ul- cause intestinal pseudo-obstruction and Received on December 1, 2014; accepted timately extracted to examine the valid- small intestinal bacterial overgrowth in revised form on May 28, 2015. ity of tests for GI morphology, bacterial (SIBO). SIBO is one of the main patho- Clin Exp Rheumatol 2015; 33 (Suppl. 91): overgrowth and malabsorption in SSc. genetic factors of malabsorption which S117-S122. Only 1 test (hydrogen and methane is associated with 50% mortality over © Copyright Clinical and breath tests) is fully validated. Four 8.5 years, in SSc patients (8). Diagno- Experimental Rheumatology 2015. tests are partially validated, including sis of SIBO is problematic. Quantita- Key words: systematic literature jejunal cultures, xylose, lactulose tests, tive culture of small bowel contents is review, systemic sclerosis, and 72 hours fecal test. considered the gold standard, but the gastro-intestinal tract Conclusion. Only 1 of a total of 5 GI lack of standardisation of the normal tests of bacterial overgrowth (see above) bowel flora in the limits Competing interests: is fully validated in SSc. For clinical tri- its accuracy. A variety of indirect tests, D. Khanna has/had consulancy relationships als, fully validated tests are preferred, including breath tests and biochemical and/or has received research funding from although some investigators use par- tests based on bacterial of Bayer, Biogen Idec, Bristol Myers Squibb, Cytori, EMD Serono, Forward, Lycera, tially validated tests (4 tests). Further a variety of substrates, have been used Roche/Genentech, NIH/NIAID, NIH/NIAMS, validation of GI tests in SSc is needed. over the years in an attempt to facilitate PCORI, Scleroderma Foundation and the diagnosis of SIBO. Our aim is to Seattle Genetics. Introduction review the procedures used to evaluate D.E. Furst has received grant/research Involvement of the SIBO in SSc patients and to assess their support from AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novatis, Pfizer, (GIT) in SSc is extremely frequent; it validity. Roche/Genentech, and UCB; has received is a leading cause of morbidity and the consultancy fees from AbbVie, Actelion, third most common cause of mortality in Methods Amgen, BMS, Cytori, Janssen, Gilead, this disease. Oesophageal abnormalities We performed systematic literature GSK,NIH, Novatis, Pfizer, Roche/Genen- occur in up to 90% of patients, searches in PubMed, Embase and the tech, and UCB; and is on the Speaker’s Bureau (CME only) of AbbVie, Actelion, involvement can be documented in 50% Cochrane library from 1966 through and UCB. or more of patients and small bowel, co- November 2014 for English language, The other co-authors have declared no lonic and anorectal involvement occur published articles examining bacterial competing interests. in 50–70% of SSc patients (1-3). overgrowth and malabsorption in SSc.

S-117 Bacterial overgrowth assessment in scleroderma / Y. Braun-Moscovici et al.

The keywords used were systemic scle- rosis and scleroderma and they were combined with text words such as small bowel, bacterial overgrowth, malab- sorption, breath tests, small bowel cul- tures, xylose test, lactulose tests, oro- cecal transit test, hydrogen, glucose, gut. Case reports, case series with less than 8 patients, reviews, articles with non-separable data for SSc patients, du- plicates and articles in languages other than English were excluded. The titles and abstracts obtained were screened for inclusion by both a rheumatologist and a gastroenterologist. Titles and ab- stracts which included at least one va- lidity criterion were selected and the data were extracted from the complete articles. Articles obtained from these searches were reviewed for additional references (Fig. 1). Reviews were not Fig. 1. Medline search of publications on the use of the diverse procedures for small intestinal bacte- rial overgrowth assessment in systemic sclerosis. included but their reference lists were examined for additional articles. Table I. Omeract principles. The validities of the tests were evalu- ated as to whether they conformed to Face validity apparent but untested statistical validity (whether a test measures what it OMERACT (Outcome Measures in was meant to measure, in the subjective opinion of the scientist); Rheumatologic Clinical Trials) princi- Content validity the items on the test represent the entire range of possible items the test should ples (truth, discrimination and feasibil- cover; ity). The principles used to assess the Construct validity the extent to which operationalisations of a construct (e.g. practical tests truth, discrimination and feasibility of developed from a theory) do actually measure what the theory says they do; measures, which are accepted world- Criterion validity the correlation between the test and a criterion variable (or variables) taken as wide, are described in Table I. representative of the construct. It compares the test with other measures or outcomes (the criteria) already held to be valid; Results Convergent validity the degree to which a measure is correlated with other measures that it is Validated or partially validated tests theoretically predicted to correlate with; (Table II) 1. Jejunal culture Reproducibility requires stability when a measure is done repeatedly; Jejunal cultures are only partially vali- Sensitivity to change requires that when an effective drug is used, the measurement changes by a dated in SSc. statistically or clinically important amount; Three out 4 articles met inclusion/ex- Feasibility requires that a measure should be easy to perform, requires little time and clusion criteria and were extracted. The requires minimal amount of equipment. gold standard for diagnosis of bacterial overgrowth has been quantitative cul- studies, the prevalence of small intes- trols, found significantbacterial counts: ture of an aspirate of luminal fluid from tinal bacterial overgrowth (SIBO) was >10(5) colony forming units per ml the jejunum. Growth of 10 million or 30–62.5% in SSc patients exhibiting (cfu/ml) of jejunal fluid in 8 patients more organisms/ml in either aerobic or gastrointestinal symptoms; in these (33%) compared to none in the con- anaerobic conditions is the criterion for series, SIBO was defined as microbial trols. Seven out of these 8 patients had a positive culture. Problems with use concentration (>105 CFU/ml) in the je- also a positive breath test (10). By im- of jejunal cultures as a test for bacte- junal aspirate culture (9-11). plication, although no statistics were rial overgrowth include lack of stand- Content validity: the procedure was done, this study meets convergent con- ardisation of the collection method, the used in SSc pts with limited and diffuse struct validity. requirement for intubation of the upper disease and various disease duration (9, Criterion validity: criterion validity GI tract and their relative high cost. 10), thus meeting the criteria for con- for bacterial overgrowth were met. A tent validity. study performed in 20 unselected SSc Truth Construct validity: a study performed patients and 18 controls found posi- Face validity: the test meets the cri- in 24 SSc patients with symptoms of tive jejunal cultures (106 organisms/ml) teria for face validity in SSc. In a few malabsorption and in 9 normal con- in 7 SSc patients compared to none in

S-118 Bacterial overgrowth assessment in scleroderma / Y. Braun-Moscovici et al.

Table II. Validation of procedures used in systemic sclerosis (SSc) to assess small intestinal bacterial overgrowth.

Small bowel absorption tests Face Content Construct Criterion Reliability Sens. to Feasibility Assessment Used in Validated reproduc- change of. SSc in SSc ability

Jejunal cultures Yes Yes Yes Yes Yes Na ± Bacterial Yes partially overgrowth Hydrogen and methane breath tests Yes Yes Yes Yes Yes Yes Yes Bacterial Yes Yes overgrowth D-xylose test Yes Yes No NA Yes No ± Bacterial Yes partially overgrowth Lactulose test Yes Yes No NA ± Yes Yes permeability Yes partially 72-hour fecal fat test Yes Yes No NA ± Yes No absorption Yes partially the controls. The difference in bacterial it is not used frequently and will not be in 51 consecutive SSc patients as- counts between the two groups was sta- reviewed (15, 16). sessed the prevalence of SIBO (21): all tistically significant (9). patients underwent glucose hydrogen Sensitivity to change/discrimination. A. Hydrogen and methane breath tests and methane (H2/CH4) breath test, an- There are no studies in SSc assessing These are currently the most used diag- swered questionnaires about intestinal sensitivity to change or discrimination . nostic methods. Hydrogen breath tests symptoms, underwent oesophageal ma- reflect hydrogen which is produced by nometry, gastroscopy and biochemical Reliability and feasibility anaerobic bacteria in the small bowel, tests (ESR, haemoglobin level, total The presence of greater than one mil- is absorbed and then exhaled. It re- serum protein and albumin, ferritin, lion organisms/ml in either aerobic or quires 3 hours and is non-invasive. It is B12 and folic acid). Twenty-two pa- anaerobic conditions is convention- done after administering a carbohydrate tients (43.1%) had positive breath tests. ally regarded as the criteria for a posi- substrate (glucose, lactulose or xylose) Significant correlations were found tive culture. However, bacterial over- orally and a sequential­ end-expiratory between positive breath tests and di- growth, particularly due to coliforms breath is taken every 15 minutes­ for 3 arrhoea (p=0.0034), abdominal pain and enterococci, may occur in appar- hours. Sensitivity and specificity vary (p=0.0001), constipation (p=0.00001), ently healthy individuals with no evi- widely, in this case from 62% to 93% bloating (p=0.0246), GSS>5 (p=10­6), dence of malabsorption (12, 13) and so and from 78% to 100%, respectively Scleroderma health assessment score the clinical relevance of such a positive (15, 17-19). The procedure as well as (p=0.0086), ESR (p=0.003), haemo- result may be difficult to determine. the optimal substrate to use are quite globin (p=0.002), serum protein and Although anaerobic organisms are pri- well standardised, although the criteria albumin (p=0.066 and p=0.024 respec- marily associated with malabsorptive for considering a breath test as SIBO- tively), severe abnormal oesophageal syndromes, isolation and categorisa- positive or -negative are not fully estab- motility disorder (p=0.046). Eleven out tion of bacterial anaerobes are not rou- lished, hence the problems associated of 22 patients with SIBO underwent tinely performed in many laboratories. to the presence of false positive and small bowel manometry. The manom- The lack of standardisation of bacterial false negative tests. (20, 28). etry was abnormal in all of them (21). counts, the possibility of sampling er- The glucose hydrogen and methane test This test, therefore, meets construct va- rors, and the need for intubation have is validated in SS. lidity criteria. a negative impact on the reliability and Five out of five papers were extracted. Criterion validity: a study performed feasibility of the procedure. in 24 SSc patients with symptoms of Jejunal cultures are only partially Truth malabsorption and in 9 normal con- validated in SSc with poor feasibility Face validity: glucose hydrogen and trols, found positive breath tests in 7 and no data documenting sensitivity to methane breath tests meet the criteria out of 8 patients with significant bac- change or discrimination. for face validity (see above). Hydro- terial counts: >10(5) colony forming gen breath tests were found to be posi- units per ml (cfu/ml) of jejunal fluid 2. Breath tests tive in SSc patients with symptoms of compared to none in the controls (10). Various breath tests have been pro- SIBO (9, 10). This test meets requirements for crite- posed as non-invasive tests for small Content validity: the procedure was rion validity. intestinal bacterial overgrowth (SIBO). used in SSc pts with limited and diffuse Sensitivity to change/discrimination: Bile acids breath tests have reasonable disease and various disease duration (9, Sensitivity to change was assessed by content validity versus bacterial counts 10, 21-24), thus meeting the criteria for administrating octreotide in SSc pts from the jejunum (14). “Because this content validity. with bacterial overgrowth and in nor- test has poor sensitivity and specifity, Construct validity: a study performed mal controls. Hydrogen breath test was

S-119 Bacterial overgrowth assessment in scleroderma / Y. Braun-Moscovici et al. performed before and after 3 weeks went cellobiose/mannitol test, jejunal cecal flora are detectable. Most investi- treatment, Substantial symptomatic biopsies and xylose test. The passive gators accept that the first rise in H2 be and hydrogen breath excretion rate im- permeability of the small bowel was within 90 minutes of lactu­lose inges- provement was observed (23). normal in all patients, although, seven tion (32), although in some patients, Two other studies assessed efficacy of patients had a low xylose test result. an early rise in H2 greater than 20 ppm antibiotic treatment in patients with No correlation was found between im- above the baseline can be considered SIBO by performing glucose hydrogen paired xylose test and pathologic biop- as a measurement of OCTT rather than and methane (H2/CH4) breath test be- sies of jejunal mucosa in 17 consecu- SIBO (34) There are few data with re- fore and 1-3 and 6 months after treat- tive SSc pts. The authors’ conclusions spect to this test for detection of SIBO ment: normalisation of the tests was were that passive intestinal permeabil- in SSc (28, 32, 33, 35). achieved in 52.4% and in 42.8% of the ity is unaltered in systemic sclerosis, patients, respectively (21, 24). and that malabsorption, when it occurs, Truth Both sensitivity to change and discrim- is caused by other factors (11). Con- Face validity: Lactulose breath test ination criteria were met. struct validity criteria have not been meets the criteria for face validity. met for this test. Lactulose test was positive for SIBO in Reliability Criterion validity: there are no studies 46% of a cohort of 99 SSc pts evalu- The main limitations are lack of stand- in SSc patients evaluating criterion va- ated for GI involvement (36). ardisation, false negative results and lidity. Content validity: the test was per- inability to evaluate bacterial over- Sensitivity to change/discrimination: formed in limited and diffuse SSc pa- growth-related antibiotic sensitivity/ There are no studies in SSc patients tients with various disease duration resistance (18). evaluating sensitivity to change or dis- (32, 33, 35, 36), thus meeting the crite- crimination. ria for content validity. Feasibility Construct validity: although differ- Feasibility is reasonable. Reliability ences in bacterial overgrowth were Glucose hydrogen and methane breath The test it is not commonly performed found between 55 SSc patients and 60 test is validated in SSc. in clinical practice because it is not matched controls, construct validity widely available and has been large- was not tested (33). No other studies B. The D-xylose test ly replaced by hydrogen breath tests have examined construct validity in The D-xylose test is not validated and which are considered­ to be more ac- SSc. Construct validation has not been meets very few criteria in SSc. curate (29). In addition, disorders as- achieved for this test. The 14C D-xylose breath test depends sociated with impaired gastric empty- Criterion validity: there are no studies on the capacity of the intestinal bacteria ing may lead to false negative­ results, assessing criterion validity in SSc. to release 14C CO2 which is absorbed while rapid intestinal emptying may Sensitivity to change/discrimination: and ultimately eliminated­ in the breath lead to false-positive results (29, 30). Sensitivity to change of lactulose test where it can be quantified. Radioactive was assessed in a trial performed on 14C or the stable isotope 13C can be Feasibility 54 SSc pts and 60 matched healthy used to label 1 g of xylose. The sensi- The feasibility is relatively low. controls (33). Oral cecal transit time tivity of 14C d-xylose test ranges from The D-xylose test is essentially unvali- and the presence of SIBO were as- 14.3% to 95%, and specificity from dated in SSC as it does not meet con- sessed by a lactulose breath test. Pa- 40% to 94% (25, 26). struct, criterion validity, is not reliable, tients with SIBO were treated with Four out of 5 papers answered the is not discriminatory and has low fea- rifaximin 1,200 mg/day for 10 days. A criteria. sibility. second lactulose test was performed 1 month after the end of therapy. SIBO Truth C. Lactulose breath test was found in 30\54 SSc pts compared Face validity: the D-xylose test meets The lactulose breath test is only to 4\60 controls. Eradication of SIBO the criteria for face validity. The test partially validated in SSc. was achieved in 73.3% of patients, correlates with fecal fat and jejunal The lactulose hydrogen breath test with a significant reduction of symp- flora and was found to be abnormal in (LHBT) is the most widely used hy- toms in 72.7% of them (33). Sensitivty 13% of SSc patients (27, 28). drogen breath test. LHBT is a non-in- to change and discrimination has been Content validity: the procedure was vasive, inexpensive, and well-tolerated documented. used in SSc pts with limited and diffuse technique, able to assess oro-cecal disease and various disease duration transit time (OCTT) with accuracy (31- Reliability (11, 27, 28), thus meeting the criteria 33) and to detect SIBO (31, 32). The The criteria for a positive breath test are for content validity. intestinal flora ferment the lactulose, problematic and not well validated. The Construct validity: in a study aimed to resulting in the production of hydrogen reliability of the test was not validated assess the passive permeability of the and/or methane. The pres­ence of bacte- in SSc. Data extrapolated from other small bowel, 17 SSc patients under- rial overgrowth in the small bowel and conditions suggest a negative impact of

S-120 Bacterial overgrowth assessment in scleroderma / Y. Braun-Moscovici et al. diabetes mellitus, hypochlorhydria on stool collection and a complete dietary discriminatory and has low feasibility. the reliability of the test (37, 38). intake record. Additionally, some pa- The paucity of high quality studies re- tients with fat malabsorption have diar- garding GI involvement and use of new Feasibility rhoea and therefore accurate and com- technologies in SSC patients imposes The feasibility is reasonable. plete collection is difficult. serious limitations upon the ability to The lactulose breath test is partially The 72-hour fecal fat test is partially do the high quality trials needed to de- validated in SSc as neither criterion validated in SSc for face, content, crite- velop new therapies. validitiy nor construct validity have rion validity and sensitivity to change, There is need for more, well –planned been found. Reliability is not well doc- but construct validity and reliability studies and new, more accurate tests to umented. have not been examined and feasibil- assess SIBO in SSc. ity is low. In summary, we have outlined the pre- 3. The 72-hour fecal fat test sent available modalities for SIBO as- This test is partially validated in SSc. Discussion sessment in scleroderma and described Quantitative fecal fat tests measure and The prevalence of SIBO in SSC has the formal validity of those tests. report the amount of fecal fat which is been reported to be 30-62% (9, 10, There is a need for more validation in collected over a period of three days. 20, 22, 35). SIBO is associated with SSc for most of the tests. We hope the The fat content is extracted with sol- a greater prevalence of diarrhoea, ab- updated data presented will serve the vents and measured by saponification. dominal pain and gas-related symp- rheumatologic community to plan the Normally up to 7 grams of fat are found toms (bloating and abdominal tender- future studies needed to improve the un- when subjects ingest 100 grams of fat ness) and has a significant impact upon derstanding the full extent of GI involve- per day. In patients with malabsorption the patients’ quality of life and progno- ment in SSC and the future therapies. the amount of fat excreted is markedly sis (21). SIBO plays a major role in the increased. Two articles met inclusion/ pathogenesis of malabsorption in SSc References exclusion criteria and were extracted. patients. However SIBO assessment in 1. SJÖGREN RW: Gastrointestinal motility dis- SSC is not standardised. A standard- orders in scleroderma. Arthritis Rheum 1994; 37: 1265-82. Truth ised approach should lay ground to as- 2. SJÖGREN RW: Gastrointestinal features of Face validity: the 72-hour fecal fat test sess and compare the beneficial effect scleroderma. Curr Opin Rheumatol 1996; 8: meets the criteria for face validity. The of therapeutic interventions in SSC 569-75. test was performed in SSc patients on clinical studies. 3. LOCK G, HOLSTEGE A, LANG B, SCHOLM- ERICH J: Gastrointestinal manifestations of a 100 g fat diet and revealed a 100% The present review is the first study to progressive systemic sclerosis. Am J Gastro- abnormality among the patients with carefully examine the validation of the enterol 1997; 92: 763-71. x-ray abnormalities (32). procedures for the assessment of SIBO 4. IOVINO P, VALENTINI G, CIACCI C et al.: Proximal stomach function in systemic scle- Content validity: the test was per- in SSc, according to the OMERACT rosis. Relationship with autonomic nerve formed in SSc patients with diffuse and criteria. function. Dig Dis Sci 2001; 46: 723-30. limited disease and various disease du- Only one out of the five tests examined, 5. COHEN S, RISHER R, LIPSHUTZ W, TURNER ration (32, 39), thus meeting the crite- is fully validated in SSc-glucose hydro- R, MYERS A, SCHUMACHER R: The patho- genesis of esophageal dysfunction in sclero- ria for content validity. gen and methane breath tests. The test derma and Raynaud’s disease. J Clin Invest Construct validity: there are no studies is non- invasive, feasible, but the main 1972; 51: 2663-8. assessing construct validity in SSc. limitations are lack of standardisation, 6. GOLDBLATT F, GORDON TP, WATERMAN SA: Criterion validity: the test is the gold false negative results and inability to Antibody-mediated gastrointestinal dysmo- tility in scleroderma. Gastroenterol 2002; standard to diagnose steatorrhoea, thus evaluate bacterial overgrowth-related 123: 1144-50. by definition meets criterion validity. antibiotic sensitivity/resistance. Jeju- 7. KHANNA D, HAYS RD, MARANIAN P et al.: Sensitivity to change/discrimination. nal cultures are only partially validated Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Sensitivity to change was assessed in in SSc with poor feasibility and no data Trial Consortium Gastrointestinal Tract In- SSc patients with malabsorption and documenting sensitivity to change or strument. Arthritis Rheum 2009; 61: 1257-63. bacterial overgrowth. Treatment with discrimination. The lactulose breath 8. JAOVISIDHA K, CSUKA ME, ALMAGRO UA, antibiotics significantly reduced the test is partially validated in SSc as SOERGEL KH: Severe gastrointestinal in- volvement in systemic sclerosis: report of amount of fecal fat in these patients neither criterion validity nor construct five cases and review of the literature. Semin (39). Both sensitivity to change and validity have been found. The 72-hour Arthritis Rheum 2008; 34: 689-702. discrimination criteria are met. fecal fat test is partially validated in 9. COBDEN I, AXON AT, GHONEIM AT, McGOL- SSc for face, content, criterion validity DRICK J, ROWELL NR: Small intestinal bac- terial growth in systemic sclerosis. Clin Exp Reliability and sensitivity to change, but construct Dermatol 1980; 5: 37-42. Reliability has not been tested. validity and reliability have not been 10. KAYE SA, LIM SG, TAYLOR M, PATEL S, examined and feasibility is low. The GILLESPIE S, BLACK CM: Small bowel bac- terial overgrowth in systemic sclerosis: de- Feasibility D-xylose test is essentially unvalidated tection using direct and indirect methods and The test is time consuming and logis- in SSC as it does not meet construct, treatment outcome. Br J Rheumatol 1995; tically difficult as it requires three day criterion validity, is not reliable, is not 34: 265-9.

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