Thalidomide for the treatment of chronic refractory pruritus

REVIEW

Thalidomide for the treatment of chronic refractory pruritus Divya Sharma, BS,a and Shawn G. Kwatra, MDb Newark, New Jersey, and Baltimore, Maryland Pruritus is a common and often times difficult to treat symptom in many dermatologic and systemic diseases. For pruritus with an inflammatory or autoimmune origin, therapies such as topical corticosteroids and antihistamines are often initiated. However, in the case that these and additional systemic therapies are ineffective, thalidomide, an immunomodulator and neuromodulator, may be a useful alternative treatment. Considerable relief of chronic pruritus has been demonstrated with thalidomide in case reports, case series, and controlled trials. Double-blind controlled studies demonstrated thalidomide’s efficacy as an antipruritic agent in patients with uremic pruritus, primary biliary cirrhosis, and prurigo nodularis. In case reports, case series, and open-label trials, thalidomide significantly reduced pruritus associated with conditions such as actinic prurigo and paraneoplastic pruritus. Because of variations in study design and evaluation of antipruritic effect, it is difficult to fully understand thalidomide’s role based on the evidence described to date in the medical literature. In this review, we provide an overview of the reported findings and evaluate thalidomide’s utility in managing refractory pruritus in the context of its adverse risk profile. We propose that thalidomide can be an alternative or combination antipruritic treatment for patients who do not obtain enough relief from conservative therapy. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2015.09.039.) Key words: actinic prurigo; itch; prurigo nodularis; pruritus; thalidomide.

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halidomide was first synthesized and introduced in the 1950s as an over-the-counter medication.1,2 It was used as a sedative agent; touted for its rapid action, effectiveness in small doses, low addictive potential, and lack of adverse effects such as respiratory depression or motor compromise in the case of overdose.3-5 Because of its anxiolytic, mild hypnotic, antiemetic, and adjuvant analgesic properties, its use became common among pregnant women to alleviate morning sickness. By 1960, long-term thalidomide use was found to be associated with polyneuritis and its use in pregnancy was linked with phocomelia, a congenital anomaly.6 Thalidomide was withdrawn from the world market in 1961. In 1965, it was reported that when patients with leprosy were given thalidomide as a sedative to reduce suffering, they concomitantly experienced improvement in signs and symptoms of erythema nodosum leprosum.7 Since then, thalidomide has been used for many From Rutgers University, New Jersey Medical Schoola; and Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication September 16, 2015.

Abbreviations used: FDA: NCS: REMS:

Food and Drug Administration nerve conduction studies Risk Evaluation and Mitigation Strategy

refractory dermatologic conditions, most of which have an autoimmune or inflammatory origin.5,8 Its use is limited because of the side effects of teratogenesis and peripheral neuropathy; however, it may be indicated for the treatment of chronic or refractory pruritus, a symptom associated with many systemic and dermatologic diseases. Thalidomide’s efficacy as an antipruritic agent, mechanisms of action, and adverse effects are reviewed herein.

METHODS Over the course of April to July 2015, we conducted a literature search on the National

Reprint requests: Shawn G. Kwatra, MD, Cancer Research Building II, Johns Hopkins University School of Medicine, 1550 Orleans St, Baltimore, MD 21231. E-mail: [email protected]. Published online November 11, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.09.039

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Library of Medicine, Ovid MEDLINE, and OLDMEDLINE databases for word combinations of ‘‘thalidomide’’ coupled with ‘‘pruritus,’’ ‘‘itch,’’ ‘‘antipruritic,’’ and ‘‘urticaria.’’ All of the results were recursively checked for relevance and suitability. No manufacturers or authors mentioned in these reports were contacted.

myelosuppression. They are known to be effective as anticancer agents and are also approved by the Food and Drug Administration (FDA) for controlled distribution.

SIDE EFFECTS

Thalidomide is not addictive and does not have acute adverse effects if RESULTS doses as high as 14 g are CAPSULE SUMMARY Our search yielded a total ingested, except for teratogeof 208 reports (with nicity in pregnant women.1 Thalidomide has been used in the redundancy) from 1965 to Thalidomide is classified as treatment of many refractory 2014 containing the aforepregnancy category X because autoimmune and inflammatory mentioned key words. its use in pregnancy is linked dermatologic conditions. Ultimately, 33 clinical articles with deformities of the extremWe reviewed the response to were included as they ities, bones, external ear, eye, thalidomide in more than 280 patients focused on chronic refractory internal organs, and/or facial with refractory pruritus, most often pruritus. Case reports and palsy.12,13 A 100-mg dose because of prurigo nodularis. Most studies concerning thalidowithin the first 35 to 50 days experienced considerable relief. mide analogs were excluded. of pregnancy can cause In these studies, the pharabnormalities. Mortality at the Peripheral neuropathy was the most macology of thalidomide, time of delivery is 40%. common adverse event, but was neuronal mechanism, and Thalidomide’s effect on sperfrequently reversible. clinical antipruritic potency matogenesis is unknown. Thalidomide can be considered as an were often discussed. However, it can be present in option for patients with treatmentsemen, thereby necessitating resistant pruritus. the use of male condoms and PHARMACOLOGY OF advising female partners to THALIDOMIDE: use additional birth control.14 METABOLISM AND EXCRETION Thalidomide-induced teratogenicity may be a result of interference of a mesonephric signal necessary for limb Thalidomide was first synthesized in 1954 in growth or its antiangiogenic properties.15,16 West Germany and marketed in 1956. It has since been shown to have sedative, immunomodulatory, Common side effects of thalidomide are reviewed and antiangiogenic properties among others.1 in Table I and include sedation, constipation, rash, peripheral neuropathy, thromboembolism, and Thalidomide is composed of a left-sided phthalimide dizziness.1 Uncommon side effects include amenorring and a right-sided glutarimide ring.9,10 Its function as a central depressant has been attributed to its rhea, edema, neutropenia, bradycardia, dry mouth glutarimide ring, which is a moiety common in and skin, pruritus, headache, hypotension, increased several hypnosedative drugs and may be implicated appetite, mood changes, male sexual dysfunction, in the activation of a sleep center within the nausea, tachycardia, weight gain, and dermatologic forebrain. It has high oral bioavailability and requires changes. 2.9 to 5.7 hours to reach maximum plasma concenSedation is the most common side effect, and it tration.11 Thalidomide is metabolized through decreases with continued use of thalidomide. Another common, but more serious adverse effect spontaneous, nonenzymatic hydrolysis in blood is peripheral neuropathy, which may occur with and tissue, and minimally by the hepatic cytochrome more than 1 month of thalidomide use at a dosage P450 system. Its half-life to elimination is 5.5 to greater than 25 mg daily and increases in frequency 7.3 hours, and 92% is excreted in the urine, with less with long-term use ([6 months of therapy).19,20 than 1% is in its original form. Thalidomide is distributed under a special program, the Incidence rate of peripheral neuropathy is the great‘‘Thalomid’’ Risk Evaluation and Mitigation Strategy est, approximately 20%, in the first year of treatment. (REMS), which requires prescribers, patients, and Affected patients typically report bilateral distal limb pharmacies to be certified with the program. paresthesias or dysesthesias and sensory loss. Thalidomide analogs, namely lenalidomide and Afterward, they may experience muscle weakness, pomalidomide, are more potent and have fewer side hypotonia, cramps, tendon reflex decline, or a comeffects; however, they are associated with greater bination of these. Early changes in nerve conduction d

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Table I. Thalidomide side effects by organ system17,18 Neurologic Neuromuscular and musculoskeletal Respiratory Cardiovascular Gastrointestinal and hepatic Hematologic Renal Reproductive Dermatologic Endocrine and metabolic

Fatigue, somnolence, dizziness, sensory neuropathy, confusion, mood change, fever, motor neuropathy, headache Muscle weakness, tremor, weakness, myalgia, paresthesia, arthralgia Dyspnea Edema, thromboembolism (greater risk in individuals with multiple myeloma), orthostatic hypotension Constipation, nausea, anorexia, increase in aspartate aminotransferase, weight change, diarrhea, increase in bilirubin, oral candidiasis Bone-marrow suppression; leukopenia, neutropenia, anemia; lymphadenopathy Hematuria Embryo-fetal toxicity, teratogenicity Rash/desquamation, xerosis, acne Hypocalcemia, diaphoresis

can be detected by electromyography or nerve conduction studies (NCS). Further investigation is still needed to clarify the relationship between peripheral neuropathy and total cumulative dose of thalidomide.1,13,21,22 Risk of peripheral neuropathy, however, is related to daily dose regardless of duration of therapy; and it was noted that patients who receive 25 mg of thalidomide or less per day do not typically experience neuropathy.1,10,19,23-25 The majority of patients who are able to tolerate doses above 50 mg daily without detectable clinical or electrophysiologic alterations may have polymorphisms that aid in thalidomide metabolism.26 Bastuji-Garin et al19 found that the relative risk of neuropathy is 0 at 25 mg of thalidomide or less per day, increases to 8.2 at doses of 50 to 75 mg per day, and is even greater at 20.2 when taken at doses of 75 mg or higher daily.26 Therefore, a low-dose regimen that is implemented for a longer duration may be safer than a higher dose regimen given in a shorter time frame. In most cases, neuropathy is reversible, but may be slow to resolve or only partially improved with discontinuing treatment.10,27 Prescribing the lowest effective dose and frequent monitoring for neuropathic changes by clinical examination or electrophysiologic testing is recommended.17,18,21

CONTRAINDICATIONS TO THALIDOMIDE THERAPY Thalidomide has been labeled pregnancy category X because of teratogenicity.8 One dose can cause birth defects; therefore prescribing physicians must adhere to the Thalomid REMS program.1 Thalidomide prescriptions are valid for 1 week, only 28 days’ worth may be prescribed at a given time without refills, and monthly pregnancy tests

must be performed.9 Thalidomide should not be used for toxic epidermal necrolysis. In a doubleblind, randomized, controlled study thalidomide was used to treat toxic epidermal necrolysis, but 10 of the 12 patients receiving thalidomide died compared with only 3 of the 10 who received placebo.28 It was thought that toxic epidermal necrolysis associated with increased tumor necrosis factor-alpha (TNF-a) activity would respond to the anti-TNF-a activity of thalidomide, however, this study showed significant mortality and was discontinued. It is unclear if a direct correlation exists between neuropathy occurrence and total thalidomide dosage.13,21 If neuropathy does occur, terminating use should be considered in the context of severity and the patient’s underlying condition. Thromboembolic events have been reported with thalidomide use in patients with cancer, sarcoidosis, systemic lupus erythematosus, atopic dermatitis, and those taking chemotherapeutics or corticosteroids.29 These patients may be evaluated for hypercoagulability before considering thalidomide treatment.

MECHANISM OF THE ANTIPRURITIC EFFECT The antipruritic mechanism of action of thalidomide is likely multifactorial and may be a result of its action as a central depressant, anti-inflammatory agent, immunomodulator, and neuromodulator.1,4,30-32 Thalidomide may relieve itch through reduced perception of stimuli, decrease in the CD4:CD8 ratio, suppression of tumor necrosis factor-alpha (TNF-a) production and the nuclear factor-kB (NF-kB) cascade, and/or modulation of peripheral sensitive nerves, respectively. Its immunomodulatory action may also involve regulation or

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alteration of interleukins 8, 10, and 12; cyclooxygenase-2; and interferon-g.33-36 Thalidomide may increase keratinocyte proliferation and migration, accelerate collagen biosynthesis, increase TGFb production, and stimulate re-epithelialization, contributing to wound healing. With regard to its action as a neuromodulator, thalidomide may affect type C unmyelinated fibers, involved in the neural pathways of itch, by dysregulating wallerian degeneration.4,30 These neural damages that result may be responsible for the modulatory effects on itch, as they are often slow to resolve, which is evidenced by the reported side effect of peripheral neuropathy secondary to thalidomide use. Therefore, it is possible that the development of neuropathy may in fact contribute to the relief of pruritus. Recently, it was suggested that thalidomide may have a direct analgesic effect by reducing stimulation of the peripheral vanilloid receptor 1 channel.37 Upon further exploration of whether or not thalidomide may involve activation of opioid receptors as part of its mechanism of action, we found that the literature to date does not show evidence that endogenous opioid signaling contributes to thalidomide’s antinociceptive effect. Further, a study by Vale et al38 found that coadministration of naloxone did not reverse the analgesic effect of thalidomide. However, additional research may provide more insight into possible interactions between thalidomide and the opioid receptors mu, kappa, and delta.

CLINICAL ANTIPRURITIC EFFECT OF THALIDOMIDE There are many reports of thalidomide use for conditions associated with refractory pruritus and the first of these studies was conducted in the 1970s for patients with actinic prurigo.39 The efficacy of thalidomide was confirmed, however, the coauthors cautioned that its safe use had yet to be elucidated before it could be recommended for routine use. Additional studies substantiated the claim that thalidomide can indeed cause considerable relief of pruritus in most patients.30,31,33,40-68 There are only a few randomized controlled trials testing thalidomide’s use in patients with primary biliary cirrhosis, prurigo nodularis, and uremic pruritus.40,42,55 Single-arm trials, case series, and case reports have been conducted in patients with numerous conditions associated with refractory pruritus, most commonly in those with prurigo nodularis.30,31,33,39,41,43-54,56-68 A total of 284 patients were included in the reports reviewed herein.30,31,33,39-68

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In all studies, patients failed ‘‘conventional therapy,’’ frequently consisting of antihistamines and corticosteroids, and experienced considerable relief with thalidomide, defined as greater than 50% reduction in pruritus in a patient or more than 50% of patients relieved in a series or trial. In all reports in which patients experienced itch and skin manifestations, reduction in pruritus was associated with substantial improvement of skin lesions. Daly and Shuster41 suggest that skin lesions appear to improve as a result of thalidomide’s antipruritic action and not because of an impact on the underlying disease. Time to initial improvement ranged from as soon as 1 day to as late as 64 days (mean 17.75, median 17.5). Thalidomide was given within a range of 2 days to 5 years in these reports, but in 45% of studies the coauthors reported that adverse effects did lead to premature discontinuation of thalidomide, either temporarily or permanently, impacting 17% of all patients. Neuropathy was the identified side effect in 63% of these cases. Of all studies reviewed, 94% specified whether or not the patients had an abnormal NCS and/or experienced the adverse side effect of peripheral neuropathy. In the NCS, surface electrodes were used to detect change in action-potential amplitude and nerve conduction velocity as reduction in either indicated axonal degeneration.5,30 To identify signs of thalidomide-induced peripheral neuropathy, nerves in the extremities were typically monitored, such as the radial and sural nerves. From the total number of patients taking thalidomide in these studies, 19.5% were reported to have peripheral neuropathy or disturbances in nerve conduction and thalidomide was discontinued or the dosage was decreased. In studies that commented on the progression or recovery of neuropathy in these patients, it was found that the neuropathy was completely reversible in 87.2%. In the rest, either neuropathy significantly improved or patients experienced stable asymptomatic changes. Hoyer et al54 remarked that patients were willing to tolerate discomfort from thalidomide to lessen the pruritus. Follow-up duration was specified in 66.7% of studies and ranged from the end of the thalidomide course to 14 years after its cessation. Upon discontinuation of thalidomide whether it was per protocol or otherwise, relapses were noted to occur in 31% of all patients on thalidomide. Reports that discussed starting another course of thalidomide, presumably in patients who had not previously experienced adverse effects, found that the recurrent pruritus resolved without issue, except in 1 study, in which adverse effects surfaced.30

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Table II. Guidelines for thalidomide therapy57,69,70 1. Document unsuccessful management of recalcitrant pruritus (corticosteroids, antihistamines, UV light therapy, and other conventional therapies). 2. Gather history and perform physical examination (determine underlying cause of pruritus, impact of pruritus on quality of life, evaluate for presence of and risk factors associated with neuropathy). Complete nerve conduction studies in all patients. Order complete blood cell count with an absolute neutrophil count, HIV testing, and pregnancy test in women of childbearing potential. With permission, photograph lesions before initiating treatment. 3. Counsel patient on benefits and risks of initiating thalidomide and discuss contraceptive methods for both male and female patients. Devise plan for regular monitoring. Follow-up on results of pregnancy test. 4. Obtain informed consent and enroll patient into Thalomid REMS program (FDA-approved). Provide patient with information sheet that contains medication information and warnings about side effects. 5. Initiate thalidomide and ask patient to call provider within 2 wk for evaluation of any improvement, drug reactions, or adverse effects. Can repeat pregnancy test at weekly intervals for the first month if indicated. 6. Have patient return monthly starting 1 Document any improvement of pruritus effects excluding subjective neurologic discontinuation of thalidomide. Perform each 10-g increment in total dose.

mo after first dose of thalidomide. Can repeat pregnancy testing monthly. and/or lesions. Assess for neurologic changes. Adjust dosage based on side changes, which would require full neurologic examination and possible nerve conduction studies monthly for 3 mo and then every 6 mo or after

7. Withhold or discontinue thalidomide if patient fails to comply with instructions, pregnancy test returns positive, patient experiences paresthesia, nerve conduction studies show abnormality, or if absolute neutrophil count is \ 750 mm3. 8. If pruritus has improved [50% and lesions have resolved [50%, consider tapering thalidomide and monitor monthly for relapse. 9. Women of childbearing potential who stop thalidomide should continue using contraception for 3 mo. All patients who discontinue treatment should return unused medication to the physician. FDA, Food and Drug Administration; REMS, Risk Evaluation and Mitigation Strategy; UV, ultraviolet.

The shared recommendations from the concluding remarks of the reviewed reports are that thalidomide is useful for patients who fail to respond to conventional therapy and have severe symptoms; benefit/risk should be assessed before initiating therapy, patient education and consistent monitoring should be provided proactively, and thalidomide’s efficacy and safety profile should be examined in larger trials. A few reports demonstrate that low-dose thalidomide or combining thalidomide with other therapies either simultaneously or sequentially may preserve efficacy while minimizing adverse effects. Also, thalidomide’s role may extend beyond alleviating pruritus from dermatoses and include pruritus associated with systemic diseases and malignancy. Thalidomide can be a precious therapy in the palliative setting or in the elderly population where improving the patient’s quality of life may easily outweigh the associated risks. Guidelines for initiating thalidomide therapy are reviewed in Table II. We caution clinicians to consider the anticipated expense of thalidomide before beginning treatment as the cost of thalidomide is variable depending on the patient’s

insurance plan. Thalidomide may range from cost-prohibitive at a few thousand dollars to manageable requiring a copay of a few hundred dollars or less, if covered through the FDA-approved Thalomid REMS program.57,69,70

CONCLUSIONS AND PERSPECTIVES Thalidomide has been used successfully to treat chronic refractory pruritus in many of the reviewed studies. These patients experienced considerable improvement in pruritus attributed to a variety of causes, most commonly prurigo nodularis. Randomized controlled trials also reviewed its efficacy in primary biliary cirrhosis and uremic pruritus. In light of its side effects of peripheral neuropathy and teratogenicity, thalidomide remains an alternative or combination antipruritic treatment for patients who are insufficiently relieved by conservative therapy. The reported studies do demonstrate that the adverse effects of peripheral neuropathy and teratogenicity can be minimized with adherence to protocol, close monitoring as per the FDA-approved Thalomid REMS program, and curtailing treatment as soon as abnormalities are

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observed subjectively or clinically by examination or NCS. Thalidomide can also be combined with other antipruritic therapies, such as ultraviolet light therapy, or followed sequentially by thalidomide analogs that are less associated with neuropathy.44,50 Thalidomide analogs have not been investigated extensively for their use in managing chronic pruritus and are associated with a greater risk of myelosuppression. However, they are more potent, effective anecdotally, and theoretically patients could receive blood testing in scheduled intervals in order for their complete blood cell counts to be closely monitored.50 Additional studies should clarify the use of thalidomide and related analogs as alternative antipruritic agents. REFERENCES 1. Wu JJ, Huang DB, Pang KR, Hsu S, Tyring SK. Thalidomide: dermatological indications, mechanisms of action and side-effects. Br J Dermatol. 2005;153(2):254-273. 2. Mellin GW, Katzenstein M. The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med. 1962;267:1184-1192. contd. 3. Stirling D, Sherman M, Strauss S. Thalidomide. A surprising recovery. J Am Pharm Assoc (Wash). 1997;NS37(3):306-313. 4. Grosshans E, Illy G. Thalidomide therapy for inflammatory dermatoses. Int J Dermatol. 1984;23(9):598-602. 5. Wines NY, Cooper AJ, Wines MP. Thalidomide in dermatology. Australas J Dermatol. 2002;43(4):229-238; quiz 239-40. 6. Mellin GW, Katzenstein M. The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med. 1962;267:1238-1244. concl. 7. Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther. 1965;6:303-306. 8. Radomsky CL, Levine N. Thalidomide. Dermatol Clin. 2001; 19(1):87-103. 9. Perri AJ III. H.S., A review of thalidomide’s history and current dermatological applications. Dermatol Online J. 2003;9(3):5. 10. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol. 1996;35(6):969-979. 11. Stirling DI. Thalidomide and its impact in dermatology. Semin Cutan Med Surg. 1998;17(4):231-242. 12. McBride WG. Thalidomide embryopathy. Teratology. 1977; 16(1):79-82. 13. Chen M, Doherty SD, Hsu S. Innovative uses of thalidomide. Dermatol Clin. 2010;28(3):577-586. 14. Teo SK, Harden JL, Burke AB, et al. Thalidomide is distributed into human semen after oral dosing. Drug Metab Dispos. 2001;29(10):1355-1357. 15. Smith DM, Torres RD, Stephens TD. Mesonephros has a role in limb development and is related to thalidomide embryopathy. Teratology. 1996;54(3):126-134. 16. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994; 91(9):4082-4085. 17. Rehman W, Arfons LM, Lazarus HM. The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Ther Adv Hematol. 2011;2(5):291-308.

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40. McCormick PA, Scott F, Epstein O, Burroughs AK, Scheuer PJ, McIntyre N. Thalidomide as therapy for primary biliary cirrhosis: a double-blind placebo controlled pilot study. J Hepatol. 1994;21(4):496-499. 41. Daly BM, Shuster S. Antipruritic action of thalidomide. Acta Derm Venereol. 2000;80(1):24-25. 42. Maurer T, Poncelet A, Berger T. Thalidomide treatment for prurigo nodularis in human immunodeficiency virus-infected subjects: efficacy and risk of neuropathy. Arch Dermatol. 2004;140(7):845-849. 43. Lan CC, Lin CL, Wu CS, Chai CY, Chen WT, Chen GS. Treatment of idiopathic prurigo nodularis in Taiwanese patients with low-dose thalidomide. J Dermatol. 2007;34(4): 237-242. 44. Ferrandiz C, Carrascosa JM, Just M, Bielsa I, Ribera M. Sequential combined therapy with thalidomide and narrow-band (TL01) UVB in the treatment of prurigo nodularis. Dermatology. 1997;195(4):359-361. 45. Winkelmann RK, Connolly SM, Doyle JA, Padilha-Goncalves A. Thalidomide treatment of prurigo nodularis. Acta Derm Venereol. 1984;64(5):412-417. 46. Johnke H, Zachariae H. [Thalidomide treatment of prurigo nodularis]. Ugeskr Laeger. 1993;155(38):3028-3030. 47. Crouch RB, Foley AP, Ng JC, Baker CS. Thalidomide experience of a major Australian teaching hospital. Australas J Dermatol. 2002;43(4):278-284. 48. Andersen TP, Fogh K. Thalidomide in 42 patients with prurigo nodularis Hyde. Dermatology. 2011;223(2):107-112. 49. Rishi R, Ringwala S, Tracy J, Fatteh S. Prurigo nodularis and Hashimoto thyroiditis. Ann Allergy Asthma Immunol. 2014; 113(6):673-674. 50. Kanavy H, Bahner J, Korman NJ. Treatment of refractory prurigo nodularis with lenalidomide. Arch Dermatol. 2012; 148(7):794-796. 51. Alfadley A, Al-Hawsawi K, Thestrup-Pedersen K, Al-Aboud K. Treatment of prurigo nodularis with thalidomide: a case report and review of the literature. Int J Dermatol. 2003;42(5): 372-375. 52. van den Broek H. Treatment of prurigo nodularis with thalidomide. Arch Dermatol. 1980;116(5):571-572. 53. Orlando A, Renna S, Cottone M. Prurigo nodularis of Hyde treated with low-dose thalidomide. Eur Rev Med Pharmacol Sci. 2009;13(2):141-145. 54. Hoyer H, Wulff CH, Asboe-Hansen G, Brodthagen H. [Treatment of prurigo nodularis Hyde with thalidomide]. Ugeskr Laeger. 1983;145(42):3243-3245. 55. Silva SR, Viana PC, Lugon NV, Hoette M, Ruzany F, Lugon JR. Thalidomide for the treatment of uremic pruritus:

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