Letter: retrospective reviews of liver‐related case reports allegedly associated with Herbalife present insufficient and inaccurate data

Abstract

First, our conclusions were misinterpreted. We did not conclude that combination therapy did not add a benefit in achieving clinical remission, but led to a reduction of flares in the long-term and short-term. The timing of the combination therapy was a key point in our results. We concluded that the combination of an immunossuppressive drug (IS) and adalimumab (ADA) reduced the semesters with flares when the IS was given during the first 6 months of ADA treatment and then continued in the long-term, compared with semesters with ADA monotherapy.The analysis of the type of flare showed that this benefit was mainly from a lower need to dose escalate with the combination therapy compared with monotherapy, but not the risk of surgery or perianal complications. We also showed that the first 6 months of combotherapy with ADA + IS, whether the IS was continued or not, decreased the risk of ADA interruption due to future treatment failure.As explained in the discussion, we agree that the retrospective character of the study is a limitation. A prospective controlled study is indeed required to give definitive conclusions. However, we think that interesting data can be extracted from good quality retrospective studies that reflect real-life clinical practice. We do not see how a retrospective study can be randomised. The patients were followed in tertiary centres by specialists who follow the ECCO guidelines. The differences in the clinical practice according to the country have been discussed.We studied separately IS-naive patients and IS-failure patients among patients on IS at ADA start and no difference was observed (P = 0.86). We also studied separately the effect of the type of IS (thiopurine versus methotrexate), and no difference was observed between the 2 drugs (P = 0.08).The author compares his own experience (24 patients on ADA) with our study (207 patients on ADA) and reports high rates of remission after ADA induction. We also report high rates of successful induction, although slightly lower compared with our Italian colleague (85% vs. 92%), and no difference was demonstrated between ADA monotherapy and ADA + IS combotherapy in our study.Looking at our results, we suggest starting ADA in combination with an IS for at least 6 months to reduce the risk of further ADA failure. Nevertheless, we think that this could be discussed on a case-by-case basis with the patients, balancing benefit/risk, as the treatment failure was only 10% in ADA monotherapy, as compared with 5% in the ADA/IS combination therapy. Continuing ADA for more than 6 months will reduce the need for ADA dose escalation. Here again, the choice between ADA monotherapy and combination therapy after 6 months should be discussed, taking into account, on the one hand, the potential risks and the problems of adherence with long-term combination therapy and, on the other hand, the cost of an increased frequency of weekly ADA. ACKNOWLEDGEMENTThe authors' declarations of personal and financial interests are unchanged from those in the original article.

Herbal and Dietary Supplement–Induced Liver Injury

“…Since then, several reports have shown similar associations of HILI with Herbalife products, also suggesting contamination with Bacillus subtilis as a potential cause for its hepatotoxicity profile. (39, 72) Employees of Herbalife have aggressively criticized reports of Herbalife-associated hepatotoxicity (73, 74), but their criticisms have been effectively rebutted. (75)…”

Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

“…Possible or likely alternative diagnoses were evident in 278/573 cases (48.5%) of suspected HILI cases; causality assessment was impeded in 165/573 patients (29.0%), resulting in diagnostic problems in 77.5% of all cases [30] . Given these limitations, actual discussions of suspected Herbalife hepatotoxicity are understandable regarding case data quality and the preferred tool to assess causality [69,70] , issues also recognized before [16,30,34] and in the present study (Tables 1, 2, 4 and 5). In reference to three case series of suspected Herbalife hepatotoxicity from Israel [2] , Switzerland [3] , and Spain [5] , the opinion has been expressed that these series have utilized generally accepted causality assessment for herbal hepatotoxicity [70] .…”

Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

“…Possible or likely alternative diagnoses were evident in 278/573 cases (48.5%) of suspected HILI cases; causality assessment was impeded in 165/573 patients (29.0%) due to missing case data or lack of a temporal association, resulting in diagnostic problems in 77.5% of all cases [82] . Given these limitations, actual discussions of validity of reported HILI cases are understandable [82,90,91,94,[98][99][100] , and uncertainty also extends to the validity of the type of liver injury reported for some cases lacking a probable or highly probable causality. Considering these restrictions, the hepatocellular type of injury was described for Indian Ayurvedic herbs [72,98] , Chaparral (Larrea tridentata) [40,98] , Dai Saiko To [47,98] , Germander [98] , Green Tea extract [98] , Greater Celandine [37] , Hydroxycut ® [98] , Jin Bu Huan (Lycopodium serratum) [45,98] , Kava [13] ; the cholestatic or mixed type for Chaparral [98] , Germander [98] , Green Tea extract [98] , Greater Celandine [98] , Hydroxycut ® [98] ; and the veno-occlusive disease for plants containing pyrrolizidine alkaloids such as Senecio, Heliotropium, Crotalaria, and Symphytum species [98] .…”