Risk of skin cancer in kidney, liver and heart recipients: A nationwide population-based study in Taiwan.

Background Previous population-based studies in western countries had revealed increased skin cancer risk among transplant recipients compared to the general population. However, population-based studies in Asia on skin cancer among recipients of different transplanted organs were lacking in the literature. Aims This study aims to estimate skin cancer risk among recipients in Taiwan, examine the association between each specific type of skin cancer and each type of transplanted organ, and compare skin cancer risk between different immunosuppressive regimens. Methods This population-based retrospective cohort study identified 7550 patients with heart, lung, kidney or liver transplantation and 30,200 controls matched for gender, age and comorbidity index from the National Health Insurance Research Database in Taiwan between 2000 and 2015. Using multivariable Cox proportional hazard models, we estimated the hazard ratios and 95% confidence intervals for the correlation of skin cancer with organ transplantation as well as immunosuppressive regimen. Results Organ transplant recipients in Taiwan had an increased risk of skin cancer with adjusted hazard ratios of 4.327 (95% confidence intervals 2.740-6.837, P < 0.001), with the greatest risk, observed among heart recipients (adjusted hazard ratios 6.348, 95% confidence intervals 3.080-13.088, P < 0.001). The risk of non-melanoma skin cancer and melanoma was 4.473 (95% confidence intervals 2.568-7.783, P < 0.001) and 3.324 (95% confidence intervals 1.300-8.172, P < 0.001), respectively. When comparing immunosuppressants, those with calcineurin inhibitors carried the highest risk of skin cancer (adjusted hazard ratios 4.789, 95% confidence intervals 3.033-7.569, P < 0.001), followed by those with antimetabolites (adjusted hazard ratios 4.771, 95% confidence intervals 3.025-7.541, P < 0.001). Limitations We could not evaluate confounding behavioural risk factors of skin cancers that were not documented in the database, nor could we recognize patients' compliance with immunosuppressants. Conclusion Organ recipients have a greater risk of skin cancer. Clinicians should inform recipients of the importance of photoprotection and regular dermatologic follow-up.

Leprosy detection rate in patients under immunosuppression for the treatment of dermatological, rheumatological, and gastroenterological diseases: a systematic review of the literature and meta-analysis.

BACKGROUND: Recently developed immunosuppressive drugs, especially TNF antagonists, may enhance the risk of granulomatous infections, including leprosy. We aimed to evaluate the leprosy detection rate in patients under immunosuppression due to rheumatological, dermatological and gastroenterological diseases. METHODS: We performed a systematic review of the literature by searching the PubMed, EMBASE, LILACS, Web of Science and Scielo databases through 2018. No date or language restrictions were applied. We included all articles that reported the occurrence of leprosy in patients under medication-induced immunosuppression. RESULTS: The search strategy resulted in 15,103 articles; finally, 20 articles were included, with 4 reporting longitudinal designs. The detection rate of leprosy ranged from 0.13 to 116.18 per 100,000 patients/year in the USA and Brazil, respectively. In the meta-analysis, the detection rate of cases of leprosy per 100,000 immunosuppressed patients with rheumatic diseases was 84 (detection rate = 0.00084; 95% CI = 0.0000-0.00266; I2 = 0%, p = 0.55). CONCLUSION: Our analysis showed that leprosy was relatively frequently detected in medication-induced immunosuppressed patients suffering from rheumatological diseases, and further studies are needed. The lack of an active search for leprosy in the included articles precluded more precise conclusions. TRIAL REGISTRATION: This review is registered in PROSPERO with the registry number CRD42018116275 .

Safety of important dermatological drugs (retinoids, immune suppressants, anti androgens and thalidomide) in reproductively active males with respect to pregnancy outcome: A brief review of literature.

Paternally transmitted damage to offspring is recognized as a complex issue. Each parent contributes 23 chromosomes to a child; hence, it is necessary to know the effects of both maternal and paternal pre-and peri-conceptional exposure to drugs on pregnancy outcome. While there are many studies on the effects of maternal drug exposure on pregnancy outcome, literature on paternal exposure is scarce. Of late however, paternal exposure has been receiving increasing attention. We present a brief review on the safety of commonly used drugs in dermatology, focused on retinoids, immune suppressants, anti androgens and thalidomide.

Clinical, immunological profile and follow up of patients with pemphigus: A study from India.

BACKGROUND: Pemphigus has a protracted course and multiple factors influence its prognosis. The objective of this study was to describe the epidemiology and clinical profile of pemphigus patients and to study its influence on treatment end points. METHODS: : This was a retrospective chart review done in an Indian tertiary care hospital from December 1991 to December 2013. Patients with less than 3 months' follow up and those who had paraneoplastic pemphigus were excluded. RESULTS: : There were 132 patients with pemphigus, of which 118 (89.4%) had pemphigus vulgaris and 14 (10.6%) had pemphigus foliaceous. The time to disease control (TDC) was available for 100 patients (n = 100, 75.7%); patients with a minimum follow up of 3 months (n = 80) were included for studying the end points like time to first disease remission (TDR) and time to first disease relapse (TDRe). The median period of follow up was 23 months (range 3-245). Out of the 100 patients, 61.9% were on oral steroids with adjuvant therapy. The steroid dose required for disease control for n = 100, ranged from 0.2 to 1.5 mg/kg body weight. Of these, 60% were treated with steroid dose of 1 mg/kg, 22% with >1 mg/kg, and 18% with <1 mg/kg. The mean time to disease control (in months) in the group which received <1 mg/kg steroid was 1.02 ± 0.68, 1 mg/kg was 0.72 ± 0.51, and >1 mg/kg was 1.02 ± 0.62 (P = 0.017); with a significant difference between the groups 2 and 3 (P = 0.007), implying a faster disease control in those who received 1 mg/kg dose. This difference was significant after adjusting for the steroid sparing drugs taken at baseline (P = 0.009, C.I. - 1.44-13.59). The mean time to first disease remission (TDR) was 11.46 ± 2.06 months. Out of the 80 patients with a minimum follow up of 3 months, 75% had achieved either partial or complete remission. None of the other epidemiological, clinical or immunological parameters had an impact on the TDC or TDR. CONCLUSIONS: The epidemiological, clinical or immunological parameters had no impact on the treatment end points like time to disease control and time to first disease remission. The dose of steroids required for disease control higher than 1 mg/kg offered no advantage in the time to disease control as compared to 1 mg/kg. LIMITATIONS: The study was retrospective and disease severity scores were not applied. In view of the shorter follow up period, long term prognostic end points and mortality could not be well represented. The median period of follow up was 23 months. The serum anti- desmoglein antibody titres were not available at various treatment end points for correlation at different time intervals.

Urocytological evaluation of pemphigus patients on long term cyclophosphamide therapy: A cross sectional study.

BACKGROUND: Cyclophosphamide therapy is associated with several urological complications including urinary bladder malignancy. Data on urologic complications of chronic cyclophosphamide therapy for dermatologic conditions is not available. OBJECTIVES: To study the urocytological profile of pemphigus patients on long-term cyclophosphamide therapy. MATERIALS AND METHODS: In a cross-sectional study, consecutive patients who had received cyclophosphamide therapy for pemphigus for more than 12 months were included. All patients were subjected to urinalysis including microscopy, culture, and urine cytology. Immunocytochemical staining for cytokeratin 20 (CK-20) on urine sediments and ELISA (enzyme-linked immunosorbent assay) for nuclear membrane protein-22 (NMP-22) were performed in all cases. In patients with urinary symptoms, microscopic hematuria, or those detected with abnormal urine sediment cytology, NMP-22, and CK-20 positivity, cystoscopy, and other relevant investigations were also done. RESULTS: A total of 44 patients (43 of pemphigus vulgaris and one of pemphigus foliaceus) were recruited. Mean duration of cyclophosphamide intake was 2.9 ± 1.7 years (range 1-8 years) with a mean cumulative dose of 53 ± 28.4 g (range 6.5-141 g). Twenty-one cases (47.7%) each were asymptomatic and symptomatic with episodic urinary symptoms [of which two had urinary tract infection (UTI)] and two patients had gross hematuria. Urine cytology revealed mild urothelial nucleomegaly with hyperchromasia in four patients. However, CK-20 and NMP-22 were negative in all samples. Cystoscopy was performed in 21 cases and did not reveal any sign of bladder malignancy. LIMITATIONS: A relatively small sample size and lack of long-term follow-up were limitations. CONCLUSIONS: In our study, no serious urologic complications were found in pemphigus cases on chronic cyclophosphamide therapy.

"The legacy of thalidomide" - A multidisciplinary meeting held at the University of York, United Kingdom, on September 30, 2016.

BACKGROUND: Between 1957 and 1962 thalidomide was used as a nonaddictive, nonbarbiturate sedative that also was successful in relieving the symptoms of morning sickness in early pregnancy. Infamously, thousands of babies were subsequently born with severe birth defects. The drug is used again, today, to successfully treat leprosy, and tragically, there is a new generation of thalidomide damaged children in Brazil. While the outward damage in babies has been documented, the effects of the damage upon the survivors as they grow up, the lifestyle changes and adaptations required to be made, as well as studies into ageing in survivors, has received little attention and remains understudied. METHODS: A unique multidisciplinary meeting was organized at the University of York bringing together thalidomide survivors, clinicians, scientists, historians, and social scientists to discuss the past, the current and the future implications of thalidomide. RESULTS: There is still much to learn from thalidomide, from its complex history and ongoing impact on peoples' lives today, to understanding its mechanism/s to aid future drug safety, to help identify new drugs retaining clinical benefit without the risk of causing embryopathy. CONCLUSION: For thalidomide survivors, the original impairments caused by the drug are compounded by the consequences of a lifetime of living with a rare disability, and early onset age-related health problems. This has profound implications for their quality of life and need for health and social care services. It is vital that these issues are addressed in research, and in clinical practice if thalidomide survivors are to "age well". Birth Defects Research 109:296-299, 2017. © 2017 Wiley Periodicals, Inc.

Erythema Nodosum Leprosum-Like Lesions Are a Histopathologic Pattern in Whipple's Disease and a Sign of the Immune Reconstitution Inflammatory Syndrome: A Case Series and Review of the Literature.

Inflammatory and subcutaneous nodules can arise in treated and untreated cases of Whipple disease (WD). The inflammatory immune reconstitution syndrome describes paradoxical clinical inflammatory worsening of a preexisting condition because of a return of immune function. Clinicopathologic examination of 4 patients with WD who presented with erythema nodosum leprosum (ENL)-like lesions and the findings of a systematic review of this phenomenon revealed that ENL-like lesions occurred in predominantly middle-aged male patients who suffered from WD, mostly on the legs. Patients showed a nonvasculitic, mostly septal panniculits with neutrophils, macrophages, and lymphocytes. Numerous bacteria-laden periodic acid-Schiff + macrophages and free bacilli were detected in the dermis, as well as subcutaneous septae and adipose lobules. These lesions occurred in both untreated and treated patients as part of inflammatory immune reconstitution syndrome. In conclusion, ENL-like lesions represent a characteristic histopathologic pattern associated with WD, which can occur in different contexts whenever there is a change in the immunological status of the patient. This change can be triggered by antimicrobial treatment, immunomodulatory and immunosuppressant therapy, or occur spontaneously, rarely.

A Randomized Controlled Double Blind Trial of Ciclosporin versus Prednisolone in the Management of Leprosy Patients with New Type 1 Reaction, in Ethiopia.

BACKGROUND: Leprosy Type 1 (T1R) reactions are immune-mediated events leading to nerve damage and preventable disability affecting hands, feet and eyes. Type 1 Reactions are treated with oral corticosteroids. There is little evidence on alternative treatments for patients who do not respond to steroids or experience steroid adverse effects. We report the results of a randomized controlled trial testing the efficacy and adverse effect profile of ciclosporin and prednisolone (CnP) in comparison to prednisolone only (P) in patients with new T1R in Ethiopia. Ciclosporin is a potent immunosuppressant. Outcomes were measured using a clinical severity score, recurrence rate, adverse events and quality of life. RESULTS: Seventy three patients with new T1R were randomized to receive CnP or P for 20 weeks. Recovery rates in skin signs was similar in both groups (91% vs 88%). Improvements in nerve function both, new and old, sensory (66% vs 49%) and motor (75% vs 74%) loss were higher (but not significantly so) in the patients on CnP. Recurrences rates of T1R (85%) were high in both groups, and recurrences occurred significantly earlier (8 weeks) in patients CnP, who needed 10% more additional prednisolone. Serious major and minor adverse events rates were similar in patients in the two treatment arms of the study. Both groups had a significant improvement in their quality of life after the study, measured by the SF-36. CONCLUSIONS: This is the first double-blind RCT assessing ciclosporin, in the management of T1R in Africa. Ciclosporin could be a safe alternative second-line drug for patients with T1R who are not improving with prednisolone or are experiencing adverse events related to prednisolone. This study illustrates the difficulty in switching off leprosy inflammation. Better treatment agents for leprosy patients with reactions and nerve damage are needed.

Successful long-term thalidomide therapy for discoid lupus erythematosus-lichen planus overlap syndrome.

Although thalidomide is a U.S. Food and Drug Admistration (FDA) approved medication for erythema nodosum leprosum and multiple myeloma, it has many off-label uses, including for discoid lupus erythematosus (DLE), Behçet's disease, apththous ulcers in HIV patients, and prurigo nodularis. Herein, we present a patient with an overlap of discoid lupus erythematosus and lichen planus who was successfully treated with thalidomide for over 19 years without significant side effects. We propose that some of the most common side effects, including peripheral neuropathy, numbness, parasthesias, sedation, and constipation, can be avoided at lower doses, typically less than 100mg/day.

The mortality associated with erythema nodosum leprosum in Ethiopia: a retrospective hospital-based study.

BACKGROUND: Erythema nodosum leprosum (ENL) is a debilitating multisystem disorder which complicates leprosy. It is characterised by fever, malaise and painful erythematous cutaneous nodules. ENL is often recurrent or chronic in nature and frequently severe. Patients often require prolonged treatment with high doses of oral corticosteroids. There are no data on the mortality associated with treated ENL. METHODOLOGY: The notes of patients who were admitted, discharged, transferred to another facility or died with a diagnosis of leprosy or a leprosy-related complication for a five year period were reviewed. RESULT/DISCUSSION: 414 individuals were identified from the ward database. 312 (75.4%) patient records were located and reviewed. Ninety-nine individuals had ENL and 145 had a Type 1 reaction. The median age of individuals with ENLwas 25 years. Eight patients with erythema nodosum leprosum died compared with two diagnosed with Type 1 reaction. This difference is statistically significant (p = 0.0168, Fisher's Exact Test). There is a significant mortality and morbidity associated with ENL in this Ethiopian cohort. The adverse outcomes seen are largely attributable to the chronic administration of oral corticosteroids used to control the inflammatory and debilitating symptoms of the condition.

Left thigh phlegmon caused by Nocardia farcinica identified by 16S rRNA sequencing in a patient with leprosy: a case report.

BACKGROUND: In recent years, Nocardia farcinica has been reported to be an increasingly frequent cause of localized and disseminated infections in the immunocompromised patient. However, recent literature is limited. We report a case of left thigh phlegmon caused by N. farcinica that occurred in a patient with leprosy undergoing treatment with prednisone for leprosy reaction. CASE PRESENTATION: We describe the case of left thigh phlegmon caused by Nocardia farcinica in a 54-year-old Italian man affected by multi-bacillary leprosy. The patient had worked in South America for 11 years. Seven months after his return to Italy, he was diagnosed with leprosy and started multi-drug antibiotic therapy plus thalidomide and steroids. Then, during therapy with rifampicin monthly, minocycline 100 mg daily, moxifloxacin 400 mg daily, and prednisone (the latter to treat type 2 leprosy reaction), the patient complained of high fever associated with erythema, swelling, and pain in the left thigh. Therefore, he was admitted to our hospital with the clinical suspicion of cellulitis. Ultrasound examination and Magnetic Resonance Imaging showed left thigh phlegmon. He was treated with drainage and antibiotic therapy (meropenem and vancomycin replaced by daptomycin). The responsible organism, Nocardia farcinica, was identified by 16S rRNA sequencing in the purulent fluid taken out by aspiration. The patient continued treatment with intravenous trimethoprim/sulfamethoxazole and imipenem followed by oral trimethoprim/sulfamethoxazole and moxifloxacin. A whole-body computed tomography did not reveal dissemination to other organs like the lung or brain.The patient was discharged after complete remission. Oral therapy with trimethoprim/sulfamethoxazole, moxifloxacin, rifampicin monthly, clofazimine and thalidomide was prescribed to be taken at home. One month after discharge from the hospital the patient is in good clinical condition with complete resolution of the phlegmon. CONCLUSION: N. farcinica is a rare infectious agent that mainly affects immunocompromised patients. Presentation of phlegmon only without disseminated infection is unusual, even in these kinds of patients. In any case, a higher index of suspicion is needed, as diagnosis can easily be missed due to the absence of characteristic symptoms and the several difficulties usually encountered in identifying the pathogen.

Topical photodynamic therapy with methylaminolevulinate for the treatment of actinic keratosis and reduction of photodamage in organ transplant recipients: a case-series of 16 patients.

BACKGROUND: Organ transplant recipients (OTR) are at high risk of developing cutaneous neoplasms. Topical photodynamic therapy (PDT) has been used for the treatment of actinic keratosis (AK) in OTR. AIMS: The objective was to evaluate the efficacy of PDT with methylaminolevulinate (MAL) in the treatment of facial AK in OTR. As a secondary objective, we wanted to evaluate the usefulness of topical PDT in the reduction of photodamage in OTR. METHODS: A prospective, single center, single arm study was made. 16 OTR were included. Topical PDT was applied for 1 or 2 cycles depending on the patient's characteristics. An evaluation of AK was made at visits pre-treatment, at 12 weeks and at 24 weeks. Photodamage was measured with multispectral image technique (SkinCare). RESULTS: A complete response rate of 100% was achieved for AK in all patients; it persisted without change at 12 and 24 weeks of follow-up. 62.5% of patients improved their photodamage as measured by SkinCare®, but this result was not statistically significant (P = 0.12). All patients had high level of satisfaction at the end of the therapy. CONCLUSIONS: MAL-PDT is an effective therapy for the treatment of AK in OTRs. It can reduce photodamage in this group of patients, but these results were not statistically significant.

Development of lepromatous leprosy following etanercept treatment for arthritis.

We present a case of a patient treated with etanercept (TNF-a antagonist) for psoriatic arthritis, who then developed clinical symptoms of lepromatous leprosy. She presented with multiple erythematous plaques on trunk, face and extremities, saddle nose deformity, alopecia, articular deformities of the feet and peroneal neuropathy. The clinical suspicion of Hansen's Disase was confirmed by the biopsy findings (lepromatous leprosy). On further questioning, the patient stated that her father was diagnosed with leprosy 70 years ago and had spent some years in a leper colony in Spinalonga island in Southern Greece in the 1940s. This first report of Hansen's disease after administration of etanercept highlights the need of careful risk assessment of patients for whom antiTNF treatment is planned.

Secondary leprosy infection in a patient with psoriasis during treatment with infliximab.

Tumor necrosis factor α antagonists are proven to be effective for the treatment of chronic inflammatory conditions, such as psoriasis. A major concern for patients is the risk of acquiring granulomatous infectious diseases caused by the immunosuppressive effects of the drugs. We report a 60-year-old man with psoriasis who underwent infliximab treatment for 2 years and developed secondary leprosy, presenting extensive erythematous and infiltrated plaques on the trunk and limbs with loss of sensitivity (thermal, pain and tactile). The skin lesion biopsy showed perivascular epithelioid granulomas, nodular dermal aggregates of foamy macrophages and bundles of acid-fast bacilli. The clinical picture associated with histopathologic evaluation suggested borderline lepromatous leprosy. Before infliximab treatment, the patient had a positive tuberculin skin test and underwent chemoprophylaxis treatment for latent tuberculosis. Although the tuberculin reactivity suggests a strong correlation with a latent Mycobacterium tuberculosis infection, the possibility of infections by other mycobacteria, such as Mycobacterium leprae, should not be discarded.

Lepromatous leprosy in a kidney transplant recipient: a case report.

Leprosy is a chronic granulomatous disease of the skin and peripheral nerves caused by Mycobacterium leprae. Among mycobacterial infections, leprosy is rare in renal transplant recipients. Here, we report the manifestations of lepromatous leprosy in a 41-year-old renal transplant recipient. Before the renal transplant, the patient had recurrent bullous lesions on his extremities with no systemic complaints. He was on an immunosuppressive regimen that included prednisolone (1 mg/kg/d), cyclosporine (6 mg/kg), and mycophenolate mofetil (2000 mg/d), and had 2 serologically confirmed acute episodes of cytomegalovirus infection that responded favorably to intravenous ganciclovir. The density of his bullous skin lesions decreased after renal transplant. During his regular posttransplant visits, we noticed a decrease in his eyebrow hairs on their lateral margins bilaterally. Later, he developed generalized, symmetric, erythematous papules. With a positive acid-fast bacilli with Fite staining, the results of a skin biopsy showed diffuse foamy histiocyte infiltration in the dermis. These findings are compatible with lepromatous leprosy. After antileprosy therapy, no deterioration of renal allograft function or lepra reactions was noted in a 4-month follow-up. Clinicians should consider leprosy in the differential diagnosis of skin lesions in immunocompromised hosts, and in particular, solid organ transplant recipients in endemic areas.