Mycophenolate mofetil for patients with autoimmune hepatitis and overlap syndromes
Bibliographic record
Abstract
Sirs, When standard treatment of autoimmune hepatitis (AIH) with prednisone and azathioprine (AZA) fails, or drug intolerance occurs, alternative therapies such as mycophenolate mofetil (MMF) can be considered.1–12 Mycophenolate mofetil is the morpholinoethyl ester of mycophenolic acid, a fermentation product of several penicillium species discovered 50 years ago. MMF is rapidly converted into mycophenolic acid after oral absorption and acts as a noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase. Its mechanism of action is similar to AZA, as it blocks de novo purine synthesis, leading to inhibition of both T- and B-cell lymphocyte proliferation. This inhibitory effect makes MMF a potent immunosuppressive agent. In the last decade, MMF has replaced AZA in many transplant centres because of its effectiveness in preventing allograft rejection. Mycophenolate mofetil has also been reported to show efficacy in the treatment of autoimmune diseases. It has an acceptable side-effect profile, is better tolerated than AZA, and it is independent from the thiopurine methyltransferase pathway of catabolism. MMF has disadvantages: it is an expensive drug, is contraindicated in pregnancy, and long-term side effects are unknown. To date, there have been no controlled clinical trials evaluating MMF in AIH/overlap syndromes. In a pilot study, seven patients with AIH type 1, who did not tolerate AZA or did not respond to standard therapy with complete normalisation of aminotransferase levels, were treated with MMF added to steroids; in five of the seven patients, remission was achieved within 3 months. These preliminary data suggested that MMF may represent another promising treatment strategy for AIH.2 In the last decade, there have been 11 case series (Table 1) describing the efficacy of MMF in patients intolerant to AZA or with insufficient response to the drug.1–11 In addition, MMF in combination with prednisolone has been evaluated as an alternative to AZA in the first-line treatment of AIH.12 This study represents the first prospective larger series of patients in whom MMF constituted an alternative to AZA as first-line treatment for AIH. Recently, the role of MMF as second line treatment after AZA – intolerance to AZA – nonresponse in the management of AIH and overlap syndromes has been evaluated.1 Forty-five patients from the Dutch Autoimmune Hepatitis Group cohort were included in this retrospective multicenter observational study, 15 of them diagnosed with overlap syndromes: four with PSC-AIH and 11 with PBC-AIH. All of them were treated with prednisone and AZA before starting MMF. The study shows that 67% patients with AIH and AZA intolerance achieved remission with MMF in comparison with 13% of patients in the AZA-nonresponse group; in overlap-syndromes remission was reached in 57% of AZA-nonresponse group and 63% of AZA-intolerance group. Overall 21 of 45 (47%) achieved a remission while using MMF. Decompensated liver cirrhosis, liver transplantations and death were only seen in the AZA-nonresponse group.1 In a previous study, 12 of 27 patients intolerant to AZA entered remission with MMF, in contrast to only two of nine patients with prior insufficient response to AZA.8 Similar data were obtained in another study where none of the 12 patients with AZA nonresponse entered in remission under MMF, compared with eight of nine patients with prior AZA intolerance.11 Considering all these data together, and according to our unpublished clinical experience, it can be concluded that MMF can be an effective therapeutic option for patients with AIH, but mainly in those who do not tolerate AZA, and for patients with AIH-overlap syndromes. However, in patients with prior insufficient response to AZA more potent immunosuppressive drugs, preferably with an alternative mechanism of action, must be used. Declaration of personal and funding interests: None.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".