Long-term clinical safety of clindamycin and rifampicin combination for the treatment of hidradenitis suppurativa. A Critically Appraised Topic.

CLINICAL QUESTION/SCENARIO: Can therapy with clindamycin and rifampicin be safely continued long term beyond the recommended 10-week course? BACKGROUND: Clindamycin and rifampicin are used in combination to treat hidradenitis suppurativa (HS). There is no data on the efficacy and safety of clindamycin/rifampicin combination therapy for HS beyond 10 weeks. METHODS: We identified the following major concerns that still lack a proper evidenced-based analysis: for rifampicin, drug-induced liver injury, interstitial nephritis, drug interaction and hepatic p450 3A4 enzyme induction; for clindamycin, the concern was community-acquired Clostridium difficile infection (CA-CDI); and experience with long-term treatment. Data sources were used as appropriate to answer the question. Systematic searches were used to assess the risk of CA-CDI and experience with long-term treatment with clindamycin. RESULTS/IDENTIFIED EVIDENCE: The risk for rifampicin-induced liver injury is highest in the first 6 weeks of treatment, whereas interstitial nephritis is primarily observed during intermittent treatment. Enzyme induction due to rifampicin is usually complete after about 2 weeks of treatment and reduces clindamycin blood levels by about 90%. Three meta-analyses identified antibiotic use as a risk factor for CA-CDI. Two of them assigned the highest risk to clindamycin. None of them stratified by length of treatment. There is extensive experience with rifampicin, primarily for the treatment of tuberculosis. Long-term experience with clindamycin is limited. DISCUSSION AND RECOMMENDATION FOR CLINICAL CARE: The analysed risks associated with a combination of clindamycin and rifampicin for hidradenitis suppurative cluster within the first 10 weeks. Treatment can be continued beyond 10 weeks, if clinically necessary.

Not every patient needs a triglyceride check, but all can get pancreatitis: a systematic review and clinical characterization of isotretinoin-associated pancreatitis.

Monitoring of triglycerides for patients on isotretinoin is practised primarily to avoid hypertriglyceridaemia-associated pancreatitis. The aim of this study was to describe clinically the published cases of hypertriglyceride-associated pancreatitis. A comprehensive search strategy using MEDLINE, Embase and grey literature was conducted (1960 to January 2016) to identify all case reports of isotretinoin-associated pancreatitis and all relevant studies of isotretinoin and triglycerides for any indication (≥ 20 patients). Terms related to isotretinoin, triglycerides and pancreatitis were searched with all available synonyms. Any studies that used isotretinoin and mentioned triglycerides or pancreatitis were searched in full text, where available, for cases of pancreatitis. Studies from all countries and published in any language were included, but Korean and Turkish studies could not be analysed. Two authors independently reviewed the publications to determine eligibility, and for data extraction. In total, 125 papers fulfilled the inclusion criteria and were searched for cases of pancreatitis. Eleven papers with 25 cases of pancreatitis associated with isotretinoin were identified; four of these cases were likely due to hypertriglyceridaemia. Three patients had elevated baseline triglycerides, but no monitoring. Pancreatitis occurred 6 and 7 weeks, and 6 months after initiation of therapy. For the fourth patient who was treated for glioblastoma and died, no detailed clinical information was available. Idiosyncratic pancreatitis associated with isotretinoin is the most frequent pancreatitis on isotretinoin, and patients should be warned about it. Hypertriglyceride-associated pancreatitis is an exceedingly rare adverse event of isotretinoin therapy. Our data cannot give a frequency or risk for either adverse event. Based on the clinical information of the patients available, we conclude that for patients without elevated baseline triglycerides, or risk thereof, monitoring of triglycerides during therapy is of little value.

No survival benefit for patients with melanoma undergoing sentinel lymph node biopsy: critical appraisal of the Multicenter Selective Lymphadenectomy Trial-I final report.

BACKGROUND: Sentinel lymph node biopsy (SLNB) was developed in the hope that it would improve outcomes for patients with melanoma. SLNB is an area of discussion and controversy in melanoma medicine. The final trial results of the Multicenter Selective Lymphadenectomy Trial (MSLT-I) have now been published and the authors suggest their long-term results 'clearly validate the use of sentinel-node biopsy in patients with intermediate-thickness or thick primary melanomas'. An accompanying editorial states that MSLT-I is a practice-changing trial. CONCLUSIONS: However, critical appraisal of MSLT-I data does not support the claims of the final report. On the contrary, MSLT-I failed to demonstrate that there is a significant treatment-related difference in the 10-year melanoma-specific survival rate in the overall study population. Furthermore, there was no improvement in overall or melanoma-specific survival of the intermediate-thickness group (1·2-3·5 mm). Completion lymphadenectomy can result in complications in about a third of patients, with a rate of clinically significant lymphoedema following axillary or groin dissection of 5-10%. Unnecessary lymphadenectomy can therefore have a major effect on patient quality of life. The evidence provided by Morton et al. does not support the claim that sentinel lymph node biopsy followed by lymphadenectomy in patients with positive sentinel nodes should be the standard of care in patients with melanoma. Readers are encouraged to check with registration sites to make sure declared primary outcomes are fairly reported. Post-hoc analyses are at best exploratory and cannot be used to form the principal conclusions of a trial.

Interventions for mycosis fungoides: critical commentary on a Cochrane Systematic Review.

BACKGROUND: The authors performed a systematic review of randomized controlled trials (RCTs) on interventions for any stage of typical mycosis fungoides (MF). They searched electronic databases including the Cochrane Central Register of Controlled Trials, Medline, Embase, and the Latin American and Caribbean Health Science Information database, and included reports from conference proceedings and unpublished data without language restrictions. The authors also searched trial registries affiliated with the U.S.A., Australia, the World Health Organization and the European Organisation of Research and Treatment of Cancer for studies on 'mycosis fungoides' or 'cutaneous T-cell lymphoma'. These searches were supplemented by correspondence with the groups or individuals who conducted the RCTs. METHODS: The authors included RCTs with participants who were 18 years of age or older, that had staging information, and in which > 90% of patients had biopsy-proven typical CD4+ MF. Data on treatment and outcome of participants, including information on stage of MF, therapy, quality of life, remission or improvement, duration of remission, survival, adverse effects and toxicity were obtained from included studies. Primary outcomes were adverse effects and quality of life. Secondary outcomes were clearance of at least 90% of surface area involvement, improvement of at least 50% of surface area involvement, survival rate, relapse rate and disease-free interval. The authors also recorded potentially significant participant-related prognostic factors, such as age and sex, and tumour-related prognostic factors, such as histological subtype and systemic involvement. FINDINGS: From 407 unique references, 14 RCTs were included with a total of 675 patients. These trials included skin-directed therapies [topical peldesine, topical imiquimod, topical hypericin, intralesional interferon (IFN)-α, psoralen ultraviolet A (PUVA) therapy, electron-beam therapy (EBT) and local radiation], systemic therapies [extracorporeal photopheresis (ECP), denileukin diftitox, bexarotene] and combination therapies (injected transfer factor with concomitant topical nitrogen mustard use). Only one meta-analysis of two studies comparing PUVA with IFN-α vs. PUVA alone could be performed, and no significant differences between the two therapies were found. Two studies on intralesional IFN-α vs. placebo were included in the review and provided opposing results, but were not examined by meta-analysis due to differences in their study design. The remainder of the Cochrane analysis reviewed outcomes of individual RCTs. There were statistically significant differences in improvement or clearance for five therapeutic regimens. One trial of topical hypericin vs. placebo found a relative benefit of hypericin, risk ratio (RR) for improvement 7·00, 95% confidence interval (CI) 1·01-48·54, P ≤ 0·028. A trial comparing ECP with PUVA demonstrated significantly better improvement in the PUVA group (RR 0·07, 95% CI 0·00-1·00, P ≤ 0·002). An RCT examining 'conservative', stepwise escalation from topical nitrogen mustard to 'combination therapy' with EBT and cyclophosphamide, doxorubicin, etoposide and vincristine chemotherapy found that combination therapy was superior in clearance (RR 2·18, 95% CI 1·10-4·33, P ≤ 0·03) and improvement (RR 1·40, 95% CI 1·12-1·74, P ≤ 0·003). However, there were no statistically significant differences in survival rates at a median follow-up of 75 months. A comparison of subcutaneously injected IFN-α and acitretin vs. subcutaneously injected IFN-α and PUVA found increased clearance with IFN-α and PUVA (RR 0·54, 95% CI 0·35-0·84, P ≤ 0·005). There were also significant reductions in grade III, severe adverse events on the World Health Organization scale; events requiring discontinuation; and neurological disorders in the IFN-α plus PUVA group. Finally, a trial comparing active vs. inactivated transfer factor found significant differences between the groups, favouring inactivated transfer factor (Fisher's exact test, P ≤ 0·03, RR 0·09, 95% CI 0-0·61). The original study authors speculated that their results reflected a better initial prognosis for the group receiving inactivated transfer factor. None of the interventions assessed showed significant long-term benefit. Despite significantly superior clearance rates in four trials, participants in those studies had high relapse rates. INTERPRETATION: This review of RCTs for MF interventions led to more questions than answers due to a dearth of adequately powered RCTs. Only one meta-analysis could be performed. The remaining review was based on single trials, many of which assessed infrequently used treatments or regimens and are not reflective of current clinical practices. Only two of the 14 RCTs assessed patient health-related quality-of-life outcomes.

Urban legends series: lichen planus.

Oral Diseases (2012) Lichen planus (LP) is a common disorder affecting the oral cavity (OLP) and skin. Despite intensive research, LP/OLP etiology and treatment remain controversial. We investigated four controversial topics: (i) Is hepatitis C virus (HCV) infection associated with LP and involved in its pathogenesis? (ii) Should all patients with LP be screened for HCV? (iii) Should patients with OLP have all their amalgam restorations removed? (iv) Are there any new treatments for OLP? Results from extensive literature searches suggested that: (i) Robust evidence from three meta-analyses indicate that HCV is associated with LP and might be involved in OLP pathogenesis (ii) It would be prudent to screen patients with LP/OLP at significant risk with an ELISA for HCV antibodies using country-specific screening strategies (iii) There is no evidence that either OLP or oral lichenoid lesions patients would routinely benefit from having all their amalgam restorations replaced. Weak evidence from potentially very biased, small, non-randomized, unblinded studies suggests that a small fraction of patients may benefit from targeted amalgam replacement. (iv) There is weak evidence that, among new OLP treatments, topical pimecrolimus, aloe vera, and oral curcuminoids may be useful. The development of specific formulations for oral delivery of topical medications is a promising field.

The pathogenesis of oral lichen planus.

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta 1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.

Rates of cutaneous reactions to drugs.

OBJECTIVE: To determine the validity, magnitude, precision, and applicability of data on the rates at which drugs cause adverse cutaneous reactions. DESIGN: Systematic review of the medical literature. DATA SOURCE: The MEDLINE database was searched (1966-August 2000) for studies that contain information on the rates of cutaneous reactions to drugs. The bibliographies of retrieved articles and review articles were also examined to find relevant studies. MAIN OUTCOME MEASURES: Studies that included primary data on cutaneous reaction rates to drugs were evaluated for their validity, magnitude, precision, and applicability, using guidelines derived from existing guidelines for the evaluation of articles about harm and prognosis. RESULTS: Nine studies met the study criteria. Five of the studies were based on prospectively collected data on medical inpatients, 2 were retrospective studies based on chart or computerized medical record review, and 2 were based on spontaneous reports and consumption data. The morbilliform drug exanthem and urticaria were the most common cutaneous reactions to drugs. Reaction rates varied from 0% to 8% and were highest for antibiotics (in the range of 1% to 8% for several classes of antibiotics). CONCLUSIONS: Despite differences in the methods of the studies reviewed and their time of execution, there is remarkable agreement in the results. Reaction rates (and 95% confidence intervals) are available for many commonly used drugs.

A meta-analysis of reverse transcriptase-polymerase chain reaction for tyrosinase mRNA as a marker for circulating tumor cells in cutaneous melanoma.

OBJECTIVE: To systematically review the use of reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosinase messenger RNA as a molecular serum marker for metastatic melanoma. DATA SOURCES: Computerized searches (1966-1999) of the PubMed and MDConsult databases and a manual search of retrieved article references. STUDY SELECTION: Cohort studies containing test subjects and negative controls were reviewed. DATA EXTRACTION: Three investigators independently screened abstracts for relevant studies and 2 investigators independently reviewed all eligible studies. DATA SYNTHESIS: Of 127 identified studies, 50 were reviewed in detail and 23 met all inclusion criteria. From these 23 studies, the PCR methods, the total number of patients, the number of control subjects, and the number of RT-PCR-positive patients per stage were analyzed. Results of RT-PCR for tyrosinase messenger RNA were positive in 18% (95% confidence interval [CI], 3%-22%) patients for stage I disease, 28% (95% CI, 23%-34%) for stage II disease, 19% (95% CI, 16%-21%) for stage I/II localized disease, 30% (95% CI, 26%-34%) for stage III disease, and 45% (95% CI, 41%-50%) for stage IV disease. Specificities were 100% in all but 1 study. Results of RT-PCR were positive in only 0.4% of healthy controls and patients with nonmelanoma cancer. CONCLUSIONS: The lack of data on the outcome of stage I, II, and III patients who were RT-PCR positive and the low prevalence of RT-PCR positivity in patients with known stage IV disease limit the applicability of this test at this time. Ongoing and future studies on a quantitative RT-PCR, amplification of multiple melanoma-associated antigens, and use of the test as a prognostic indicator might improve the utility of this molecular serologic tool.