Venous thromboembolism prophylaxis in patients with multiple myeloma: where are we and where are we going?

Venous thromboembolism is a common complication of patients with hematologic malignancies, due both to release of procoagulant factors by tumor cells and to external factors, such us drugs. In multiple myeloma patients, the risk is increased by use of immunomodulants, especially when associated to multidrug therapy, during the induction phase. Prevention of venous thromboembolism in myeloma patients is highly recommended but specific guidelines are still lacking. The most common approach is to stratify the thrombotic risk according to individual, myeloma-related and therapy-related risk factors and to use aspirin for all patients, except those with two or more thrombotic risk factors who should be treated with traditional oral or parenteral anticoagulant. A more controversial approach indicates for prophylaxis either anticoagulant or aspirin, regardless of risk stratification. Recent trials investigate prophylaxis in myeloma patients with direct oral anticoagulants, based on studies showing efficacy and safety of this new class of drugs in the treatment and prophylaxis of thrombosis in patients with any malignancy. The results of these trials are encouraging but they need to be confirmed by larger studies. An international consensus about best prophylaxis to prevent venous thromboembolism in patients with multiple myeloma on treatment is still missing. Therefore, thrombosis in multiple myeloma remains an ongoing issue.

[Diverticulitis--conservative therapy]. / Divertikulitis--Konservative Therapie.

BACKGROUND: Diverticulitis due to diverticulosis of the colon is a common clinical problem with a high morbidity and socio-economic consequences. Frequent clinical signs are flatulence, abdominal pain, stool problems which may often be misinterpreted as the symptoms of an irritable bowel or a colitis. Accordingly, the diagnostic work-up must be adequate to allow for the stage-adapted planning and performance of the therapy. MATERIAL AND METHODS: The following questions will be addressed in this review: What do we need to clarify diagnosis? Which antibiotics should be used? What is the best conservative approach for treatment? RESULTS AND CONCLUSIONS: Basic conservative therapy consists of systemic antibiosis which can be extended by a topical antibiosis, and administration of aspirin as well as probiotics. The indications for a specific therapy is made on an individual basis according to stage (Hansen and Stock). Above all, a "team approach" and close communication between gastroenterologists and surgeons are mandatory for adequate treatment of these patients.

Interventions for erythema nodosum leprosum.

BACKGROUND: Erythema nodosum leprosum (ENL) is a serious immunological complication of leprosy, causing inflammation of skin, nerves, other organs, and general malaise. Many different therapies exist for ENL, but it is unclear if they work or which therapy is optimal. OBJECTIVES: To assess the effects of interventions for erythema nodosum leprosum. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1, 2009), MEDLINE (from 2003), EMBASE (from 2005), LILACS and AMED (from inception), CINAHL (from 1981), and databases of ongoing trials, all in March 2009. We checked reference lists of articles and contacted the American Leprosy Missions in Brazil to locate studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for ENL in people with leprosy. DATA COLLECTION AND ANALYSIS: Two authors performed study selection, assessed trial quality, and extracted data. MAIN RESULTS: We included 13 studies with a total of 445 participants. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant remission of skin lesions compared to acetylsalicylic acid (aspirin) (RR 2.43; 95% CI 1.28 to 4.59) (1 trial, 92 participants). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 1.36 to 9.91) (1 trial, 24 participants), and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01 to 0.56) (1 trial, 72 participants). We did not find any significant benefit for intravenous betamethasone compared to dextrose (1 trial, 10 participants), pentoxifylline compared to thalidomide (1 trial, 44 participants), indomethacin compared to prednisolone, aspirin or chloroquine treatments (2 trials, 80 participants), or levamisole compared to placebo (1 trial, 12 participants). Mild to moderate adverse events were significantly lower in participants taking 100 mg thalidomide compared to 300 mg thalidomide daily (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes. AUTHORS' CONCLUSIONS: There is some evidence of benefit for thalidomide and clofazimine, but generally we did not find clear evidence of benefit for interventions in the management of ENL. However, this does not mean they do not work, because the studies were small and poorly reported. Larger studies using clearly defined participants, outcome measures, and internationally recognised scales are urgently required.

Interventions for erythema nodosum leprosum. A Cochrane review.

INTRODUCTION: Treatment for erythema nodosum leprosum (ENL), an immunological complication of leprosy, is diverse. We undertook a systematic review as it was not clear which treatments were most beneficial. METHODS: We did a systematic search to identify randomised controlled trials (RCTs) comparing treatment with placebo, no treatment or another therapy. Two authors assessed quality and checked data. RESULTS: We included 13 studies involving 445 participants. These trials assessed: betamethasone, thalidomide, pentoxifylline, clofazimine, indomethacin and levamisole. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant benefit compared to aspirin (RR 2.43; 95% CI 1.28 to 4.59). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 136 to 9.91) and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01, 0-56). Minor adverse events were significantly lower in participants on a low dose thalidomide regimen compared to a high dose thalidomide regimen (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes. CONCLUSION: There is some evidence of benefit for thalidomide and clofazimine, but generally we did not find clear benefits for interventions in the management of ENL. This does not mean they do not work because the studies were small and poorly reported. Larger studies using clear definitions and internationally recognised scales are urgently required.

[Sensory-motor neuropathy: a slow and misleading case of leprosy]. / Neuropathie périphérique sensitivomotrice : une forme lente et trompeuse de maladie de Hansen.

The diagnostic process of sensory-motor neuropathies is difficult. Atypical variants and rare etiologies also contribute to delay the diagnosis. We report the case of a 70-year-old woman with slowly progressive asymmetric axonal sensory-motor neuropathy. Leprosy was identified after an eight-year delay. Nerve biopsy was required to establish the diagnosis: electron microscopy revealed debris of Hansen's bacillus in the nerve. Treatment was fully curative after several months. Leprosy is a rare cause of neuropathy in Europeans. Systematic inquiry about travel to endemic areas would be helpful in establishing the diagnosis. In such cases, nerve biopsy is crucial.

The role of thalidomide in the management of erythema nodosum leprosum.

Erythema nodosum leprosum (ENL, Type 2 reactions) complicates lepromatous and borderline lepromatous leprosy and can affect many organ systems, often with irreversible damage. The reactions commonly occur in the 2 years after starting treatment and often run a recurrent or chronic course, sometimes for many years. Even with WHO multi-drug therapy about 30% of LL patients experience ENL. We review drug management of ENL focussing on data from controlled trials and other studies. The treatment of ENL is difficult because high doses of steroids may be required for prolonged periods and do not always control the inflammation. The paradox of ENL is that it can be a life-threatening disorder and requires control with immunosuppression which may itself pose life-threatening risks for patients. Treatment with thalidomide provides an effective alternative to steroid therapy, gives better long-term control and avoids the adverse effects of prolonged steroid therapy. Controlled clinical trials have demonstrated that thalidomide rapidly controls ENL and is superior to aspirin and pentoxifylline. However, thalidomide is teratogenic when taken in early pregnancy and is unavailable in many leprosy endemic countries. We discuss the role of thalidomide in treating ENL, the complications encountered and risk reduction strategies that can be used. These include good patient selection and counselling, close supervision and adequate access to appropriate contraception. Further research is needed to improve the understanding and treatment of this severe and debilitating complication of leprosy. Topics for research include: i. The development of validated tools to measure the severity and/or activity of ENL. ii. A detailed assessment of the neurotoxic effects of thalidomide when used to treat ENL. iii. A well designed trial comparing thalidomide with prednisolone. iv. The development of a safe and effective alternative to both steroids and thalidomide.

Reiter's disease in a six-year-old girl.

Reiter's syndrome has characteristically been described in young males and presents with a triad of urethritis, conjunctivitis and arthritis. Reiter's syndrome has been known to affect children, although they usually do not manifest with the typical triad. Only a few such cases have been reported and these have described males predominantly. A case of a six-year-old girl who presented with watery diarrhea, redness of eyes and joint pains followed by skin involvement is reported. She was managed with topical salicylic acid and hydrocortisone, and oral aspirin and showed complete resolution of her clinical features in three weeks.

[Novel potential uses of thalidomide in the management of pain? A review of the literature]. / Neue Indikation für Thalidomid in der Schmerztherapie. Eine Literaturübersicht.

Thalidomide was introduced as a sedative and antiemetic agent to the European market in the late 1950s. However, it soon became clear that a hitherto unheard-of incidence of severe birth defects was due to the maternal use of thalidomide and the drug was withdrawn from the market. Despite its teratogenesis, thalidomide is currently being rediscovered because of its known spectrum of anticachectic, antiemetic, mildly hypnotic, anxiolytic, anti-inflammatory, antiangiogenic, and analgesic properties. The mechanism of action of thalidomide is probably based on its immunomodulatory effect, namely the suppression of production of tumor necrosis factor alpha and the modulation of interleukins. A striking but not well-known finding is the effectiveness of thalidomide as an analgesic or analgesic adjuvant. During the early era of thalidomide use, the drug was shown to enhance the analgesic efficacy of a combined treatment with acetylsalicylic acid, phenacetin, and caffeine (APC) by testing "normal volunteers, using electrical stimulation of teeth." The combination of thalidomide and APC was superior to other combinations (APC alone, APC and codeine) with respect to both the total analgesic effect and the duration of this analgesic effect. In 1965 thalidomide was found to be effective in treating the painful subcutaneous manifestations of the leprosy-associated erythema nodosum leprosum, a condition for which it eventually was approved by the United States Food and Drug Administration in 1998. In an animal model of neuropathic pain (chronic constriction injury), thalidomide was shown to reduce both mechanical allodynia and thermal hyperalgesia. Recent studies documented the analgesic efficacy of thalidomide in treating painful mucocutaneous aphthous ulcers associated with HIV syndrome and Behcet's disease.However, to date there are no recent clinical trials that are specifically designed to explore the analgesic potential of thalidomide. In view of the current basic research and clinical findings,we suggest to investigate the potential benefits of thalidomide in severe pain conditions that respond poorly to common pain management approaches such as neuropathic pain, postherpetic neuralgia, or central pain phenomena. Because its mechanism of action is distinct from that of other drugs such as steroids, thalidomide offers the possibility of a combined treatment with other agents with nonoverlapping toxicities. We conclude that thalidomide, when used properly,may enrich the therapeutic regimen in the management of some pain-related conditions.

Comentários acerca do tratamento da hanseníase / Annotations on the therapy of leprosy

É importante na terapêutica da hanseníase näo serem olvidados certos princípios básicos de bioquímica e farmacologia que näo obedecidos, implicaräo em prejuízos para o tratamento. O presente trabalho focaliza três desses princípios: 1§ a sulfona e os corpos férricos têm açöes antagônicas frente ao M leprae e näo devem ser associados no tratamento da hanseníase; 2§ a DDS, como todo composto sulfamídico, tem açäo antivitamina B e seu uso, indiscriminado agrava os sintomas neurológicos da hanseníase; 3§ deve-se associar alcalino no tratamento da reaçäo hansênica, tendo em vista que este estado agudo favorece a acidose

Prostaglandins and leprosy. A role for aspirin?

Prostaglandins not only have a role in inflammation, but may also be involved as mediators in the immune response. Drugs which affect prostaglandin synthesis may therefore be potential tools with which to modulate disturbed immunity. These possibilities are discussed with reference to immunity in leprosy, and in particular reversal reactions.

The management of reaction in leprosy.

Reaction and the subsequent development of neuritis is the basis for the majority of the disabilities and deformities that occur in leprosy. All possible means to prevent, to treat, and to reverse every reaction should be employed in all-out effort to ultimately effect as ideal a functional status for the patient as can be attained.

Analgesic use by leprosy patients.

We questioned 235 subjects with leprosy regarding the consumption of analgesic preparations, and 46 subjects (19.5%) admitted to having consumed more than 2 kg of analgesics; the main reason for consumption was neuritic pain. The commonly consumed analgesics are paracetamol (acetaminophen) and local proprietary compound analgesics containing aspirin, phenacetin, and caffeine. Intravenous urograms were done on 28 of the 46 subjects, but none showed evidence of renal papillary necrosis. The reasons for this lack of renal papillary necrosis are postulated. Excessive ingestion of analgesics may be a contributory factor in the development of interstitial nephritis in patients with leprosy.