prurigo nodularis ( pn ) of hyde , also known as nodular prurigo , is a chronic skin disease of unknown etiology . the hyperkeratotic lesions tend to be symmetrical and occur over the extensor surfaces of the extremities . pn has been associated with a range of systemic conditions such as hiv / aids , depression , gastrointestinal disorders , hypothyroidism , and hematologic malignancies . in most cases , however , the etiology is unclear [ 14 ] . first - line therapy for pn is comprised of topical antipruritics or corticosteroids , oral steroids , antihistamines , or certain antidepressants such as doxepin . recently , novel agents such as tumor necrosis factor ( tnf ) inhibitors alfacept and etanercept have also been prescribed . most of these therapies , however , are ineffective or only provide temporary relief . thus , alternative treatments are needed for refractory cases .   in 1965 , sheskin was the first to report on the use of thalidomide to treat a patient with pn . thalidomide is a drug with numerous proposed mechanisms of action and effects , ranging from acting as a prostaglandin / histamine antagonist to being an inhibitor of fibroblast growth factor and a immunomodulatory agent . as an immunomodulatory drug , tnf- induces pain by increasing the production of interleukin ( il)-1b and il-6 , which then increases the production of il-8 , a known mediator of sympathetic pain [ 810 ] . more recently , thalidomide has also been shown to inhibit the peripheral vanilloid receptor 1 ( trvp1 ) channel , which is also involved in pain sensation . thalidomide became well known for its teratogenic effects leading to severe fetal malformations when taken by pregnant women before the third trimester . this medication has other known side effects , which include peripheral neuropathy , somnolence , altered mood , thrombosis , and gastrointestinal symptoms . lenalidomide , a more potent analogue of thalidomide , has been most commonly used to treat multiple myeloma and myelodysplastic syndromes . lenalidomide s molecular structure varies by one less carbonyl group but one additional amine compared to thalidomide . this change confers a different toxicity profile and , as such , lenalidomide has a much lower frequency of peripheral neuropathy . while some studies report the use of thalidomide and lenalidomide to be beneficial for the treatment of pn , their use in the management of pn remains controversial . thus , this review aims to explore and review the efficacy and safety of thalidomide and lenalidomide for the treatment of refractory pn . a systematic literature review was performed to identify articles between january 1 , 1970 and february 15 , 2016 relevant to the treatment of prurigo nodularis with thalidomide or lenalidomide . the terms  prurigo nodularis or nodular prurigo or picker s nodules or lichen corneus obtusus or atypical nodular form of neurodermatitis circumscripta  were searched in the national library of medicine s pubmed database and returned 350 articles . exclusion criteria included articles that were not written in english and those that were not original clinical trials , case series or case reports . thirty manuscripts with relevant titles and abstracts were included for further review , based on case reports / series due to lack of controlled studies . if a study with a cohort or group did not distinguish patients with pn from other patients with different dermatological conditions within the same group , it was excluded . in addition , the scopus database was crosschecked , but no additional articles were found . as a result , a total of 18 articles were selected for inclusion in this review ( fig .  1 ) . this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.fig . in the first reported case , van de broek et al . described a 57-year - old man with refractory pn admitted for an infection superimposed on nodules that had previously failed both topical and oral steroids as well as antihistamines . thalidomide 100  mg bis in die ( bid ) was used for 3  months and discontinued after resolution of the pruritis and lesions . of these , 60% of patients showed clinical improvement , but 9.5% of patients showed no effect . the average daily dose was 100  mg , though a few patients received 50  mg due to gastrointestinal - related side effects . the mean duration of treatment was 105  weeks , and 59.5% of patients developed peripheral neuropathy ranging from 1  week to 7.5  years after initiation of treatment , prompting discontinuation of therapy at the time of symptom development . none of the subjects with neuropathy showed evidence of this adverse effect during follow - up . . started thalidomide 100  mg bid in a hepatitis b patient who developed major depressive disorder and suicidal risk following a 5-year history of pn refractory to therapy . after 3  weeks of treatment , the pruritus had mildly decreased without improvement in skin lesions . subsequently , the dose was increased to 300  mg daily . by the 8th month , the pruritus had ceased , the majority of lesions had cleared , and mild sensory loss developed . the patient was then placed on a maintenance dose of 50  mg every other day for 3  months . at the 4-month follow - up , they received thalidomide 100  mg per day and were randomized after 1  month to receive either 100 or 200  mg daily . doses were adjusted if adverse events appeared , thus daily dosing ranged from 33 to 200  mg . eight patients ( 80% ) continued the trial longer than 1  month , and all had a greater than 50% reduction in itch , while 7 ( 70% ) had a greater than 50% reduction in lesions . pruritic reduction occurred within 13  months of treatment , while decreases in erythema and nodule size occurred between 36  months . three patients ( 30% ) developed peripheral neuropathy ; however , no association with neuropathy was found between treatment duration , daily dose , or cumulative dose . also treated a case of aids - associated pn in a 35-year - old white male with a cd4 count of 8  cells / mm . following a failed trial of topical corticosteroids and antihistamines , he was placed on thalidomide 100  mg daily for 6  weeks , the patient had a relapse of tuberculosis after 1  month of discontinuing thalidomide , which was postulated to have been due to the inhibitory effect of thalidomide on tnf - a . conducted a prospective trial to evaluate combination therapy using thalidomide and ultraviolet - b ( uvb ) irradiation on four patients with pn . thalidomide was started at 100  mg daily and was discontinued once significant clinical improvement was achieved , ranging from 8 to 16  weeks . uvb phototherapy was then initiated for three sessions per week until complete clearance of the nodules was achieved , with a maximum of 70 exposures allowed . most symptoms resolved after 612 uvb treatments , at which point thalidomide was also discontinued . the follow - up period ranged from 418  months , in which one patient experienced a relapse at 5  months , which was then successfully managed with 35 treatments of uvb irradiation . she was first treated with thalidomide 200  mg daily and had a dramatic improvement , but she developed neuropathy after 18  months and treatment was stopped . after thalidomide , she also was treated with oral naltrexone , minocycline , gabapentin , alafecept , and etanercept with no sucess . thereafter , she was started on lenalidomide 5  mg a day and by the second week she noted a significant decrease in pruritus , sleep , and concentration ability . by the first month , she exhibited healing of nodules and disappearance of itching . two attempts were made to taper her dose and both resulted in disease flare - ups , thus she was maintained on 5  mg / day for a total of 24  months . she was previously treated with steroids , antihistamines , and underwent psoralen  +  uva therapy for 6  months with no relief . furthermore , the latter treatment resulted in the development of squamous cell carcinomas on her lower extremities . after discontinuation of the photochemotherapy , she was started on 100  mg of thalidomide daily . by month 3 , she developed tingling and numbness in all of her limb extremities and thalidomide was discontinued . after 1  month , she resumed thalidomide at 50  mg but her neuropathy returned and the medication was discontinued . four months later , she was started orally on lenalidomide 10  mg / day with a marked reduction in nodules and itching intensity after only 1  month . she continued taking lenalidomide and achieved almost complete clearance until right leg weakness prompted termination of the current treatment after 3  months of lenalidomide . a total of 18 studies with 106 patients treated with thalidomide or lenalidomide for pn were reviewed ( see tables  1 , 2 ) . it should be noted that these trends were based on case reports / series or retrospective literature due to lack of controlled studies , especially in regards to lenalidomide treatment , as only a few case reports exist . in the earlier studies , patients were started on higher doses of thalidomide of 200  mg or more daily [ 5 , 12 ] . in the majority of studies since then , however , patients were started on an initial dose ranging from 50 to 200  mg thalidomide per day and then tailored according to response or development of side effects . length of treatment for thalidomide ranged from 1  month to almost 12  years depending on remission of disease or discontinuation due to development of toxicity . in the study by ferrandiz et al . , patients were treated with combination therapy of thrice weekly narrow - band uvb phototherapy and thalidomide at 100  mg daily for 2.55  months . excellent responses were achieved after an average of 3  months on thalidomide and 32 uvb courses . one patient that was taking lenalidomide was kept on 5  mg for over 2  years , while the other took 10  mg daily for 3  months [ 11 , 13 ] . for lenalidomide , lenalidomide offered a relatively low toxicity treatment to patients who had toxicity to thalidomide.table  1studies utilizing thalidomide 
 for treatment of prurigo nodularisstudypatientsm : fage ( years)dose per day ( mg)duration ( months)resultsadverse effectsfollow - up ( months)van de broek 11:054200  mg3lesions gradually flattened and pruritus disappearednone  clemmensen et al . 31:22969200  mg200  mg with maintenance dose of 50  mg300  mg622two patients reported pruritus resolved and all lesions healed . one patient showed no improvement in symptomstwo developed paresthesias in hands after 1118  months , one had adverse effects persist > 1  year after discontinuation . mg then tapered to 100  mg100  mg then increased to 200  mg . after relapse , second course was maintained at 200  mg39all showed marked reduction in pruritus by 1  month and flattening of lesions by 2  months . two remained in remission at 2 and 3  years follow - up , two relapsed within 2  weeks and required a second courseno significant adverse effects . 11:049200  mg then ranged from 100 to 150  mg for 9  months14at 2  months , a dramatic decrease in number of active lesionsat 5  months , the pruritus disappearedmild peripheral neuropathy of legs that may be due to either pn or hiv medications2.75herranz et al . 11:035100  mg1.5dramatic improvement of cutaneous lesions and disappearance of the pruritusnone reported1crouch et al . 51:42371100  mg13.5three showed improvement of lesions , two had no changethree  patients ceased treatment due to adverse events , two from peripheral neurotoxicity and one from dizziness , angina , and worsening diabetes4alfadley et al . 11:037100  mg b.i.d , for 3  weeks increased to 300  mg q daily for 8  months , then tapered to maintenance of 50  mg q 48  h for 3  months19after 8  months , most of the lesions and pruritus resolvedat 8  months , developed mild sensory loss , then developed total peripheral neuropathy which prompted discontinuation . at 4-month 8100  mg then randomized to 100 or 200  mg ( range from 33 to 200  mg)123 ( avg . 8)eight had > 50% response in reduction of pruritus over 3.4  months ( average ) . seven had > 50% reduction of skin involvement over 5  months ( average ) . four patients were followed up for 1.59.5  months after treatment and three maintained a > 50% response and the last relapsedthree developed thalidomide peripheral neuropathy ( one at 1  month , two at 7  months ) . weight gain , constipation , sedation , cognitive , and mood changes were also noted1.59.5sharma et al . 11:044100  mg for 2  weeks increased to 200  mg for 2  months2.5complete resolution of lesionssedation  lan et al . 64:24086100  mg then tapered1.515all reported prominent reduction in pruritus and reduced excoriation of skin lesions . one had recurrence and was treated with a second course , which proved successfultwo had sedation , one had generalized erythema with lower leg edema that resolved without intervention after 3  weeks020doherty and hsu 12100  mg tapered to 50  mg if early clinical improvementover 1one had mild ( no worsening and < 25% ) improvement , six had moderate ( 2590% ) improvement , and one had complete ( > 90% ) improvementnumbness , constipation , and sedation  orlando et al . 10:152100  mg for 1  month , 50  mg for 2  months , then dosage increased to 100  mg for 1  month , and reduced again to maintenance of 50 or 100  mg orally alternate days6after 1 month , pruritus decreased and skin examination revealed that most lesions had disappeared or flattened . after 4  month , s dose was increased back to 100  mg and leg nodules showed significant decrease in size and numberno significant side effects reported6andersen et al . 100  mg dailyfour patients decreased to 50  mg due to gastrointestinal side effectsavg . 26.2525 patients had significant improvement , six had mild improvement , and one had complete clearing . six had no affect and four were lost to follow - up25 reported transient peripheral neuropathy ( at 89  weeks average ) , nine had sedation , seven had dizziness , and five described a rash 49.7)50100  mg for 12 patients150200  mg for 1 patient3142seven showed complete improvement after 3  months ( average ) with four on maintenance treatment at last follow - up . four showed slight improvement and treatment for two was judged to be unsuccessfulfour patients discontinued treatment due to peripheral neuropathy ) , renal toxicity , or sedation and dizziness . 10:14550  mg daily initial then increased to 100  mg and then 150  mg  significant reduction in pruritus that allowed for discontinuation of corticosteroidsexperienced peripheral neuropathy at higher doses requiring reduction to 50  mg daily 
 avg average , hx history , pts patients , y / o years old , b.i.d . bis in dietable  2studies utilizing thalidomide with uvb or lenalidomide for treatment of prurigo nodularisstudypatientsm : fage ( years)treatmentdose per day ( mg)duration ( months)resultsadverse effectsfollow - up ( months)ferrandiz et al of 3  months on thalidomide , pruritus was greatly reduced and lesions flattened . then , after an avg . of 8 uvb sessions of 32 uvb treatmentsone patient had reversible peripheral neuropathy and one had nausea418kanavy et al . 10:145lenalidomide5  mg for 4  months , decreased to every other day , then every 4th day , then increased back to 5  mg due to flare upsover 24  monthswithin 2  weeks , noticed significant reduction in pruritus and improvement in sleep , mood , and ability to concentrate . after 1  month , had near complete resolution of pruritus and visible healing of the prurigo nodules . when dose was lowered , the patient developed worsening pruritusinitially somnolence and fatigue , but this resolved after changing to bedtime dosing24liu et al . 10:164lenalidomide10  mg3  monthsafter 1  month , had significant reduction in number of nodules and pruritus , continued to improve over the next 2  months , but relapsed after discontinuationmild side effects ( nausea , vomiting , malaise , arthralgia ) , and after 3  months , weakness in right leg prompted discontinuation studies utilizing thalidomide 
 for treatment of prurigo nodularis 
 avg average , hx history , pts patients , y / o years old , b.i.d . a total of 106 patients were included in this review , 76 ( 71.7% ) of whom showed significant improvement in reduction of pruritus and disappearance of nodules [ 1 , 2 , 4 , 1428 ] . only slight or mild improvement was seen in 11 ( 10.3% ) patients [ 23 , 25 , 26 ] , while 15 ( 13.3% ) patients showed no improvement at all [ 19 , 23 , 25 , 26 , 29 ] . pruritus typically was the first to decrease with a noticeable clinical difference by 24  weeks followed by flattening of lesions and decreased excoriation which occurred at an average of 2  months . for patients who achieved complete or almost complete remission , time until that endpoint varied from as little as 1  month to as long as 8  months . overall , there were a reported 39 ( 36.8% ) cases of peripheral neuropathy [ 1 , 4 , 15 , 16 , 1820 , 2528 ] not including the additional patients affected in doherty and hsu s study , as the exact amount was unable to be obtained . thalidomide - induced neuropathy developed after 1  week to 7.5  years of treatment . in most cases , the peripheral neuropathy was reversible and took up several months to resolve . some patients with hiv / aids experienced peripheral neuropathy , but it was unclear if it was due to thalidomide or the hiv infection . had one patient who still experienced neuropathy over a year after discontinuation ; however , it should be noted that the patient used the drug for 18  months . although no studies directly or extensively addressed the subject , there appears to be increased toxicity at higher doses of thalidomide [ 14 , 20 , 22 , 26 ] . sedation , gastrointestinal symptoms , and dizziness were the other most - often reported adverse effects . lenalidomide was used in two patients after they failed thalidomide therapy [ 14 , 27 ] . the other patient also developed tingling and decreased sensation with thalidomide ; however , she eventually re - developed neuropathy after a trial of lenalidomide . more studies are needed to determine the outcomes of thalidomide compared to lenalidomide , and whether this could be a preferred treatment option with less side effects . seven patients relapsed after thalidomide - induced improvement of pn symptoms and cessation of therapy [ 14 , 15 , 17 , 22 , 27 ] . four achieved remission after a second course of completed therapy [ 15 , 17 , 22 ] , and one continued to have disease flare - ups with multiple attempts at tapering the dose , and thus was maintained on 5  mg / day of lenalidomide . the last one had to stop treatment after courses of both thalidomide and lenalidomide due to neuropathy , and relapsed without further resolution . prurigo nodularis is a severely pruritic skin disease and standard therapy often yields unsatisfactory results . thalidomide and lenalidomide can be effective alternative treatments for refractory pn , though optimal dosage and treatment time varied in the reviewed studies . clinical data compiled in this review show that individuals with severe disease experienced the most significant reduction in pruritus and improvement in the appearance of skin . historically , thalidomide has been used with reluctance due to toxicity ; however , the incidence and persistence of adverse effects including neuropathy is highly variable among patients , in the majority of whom clinical improvement preceded the development of permanent deficit . ideal treatment length and dosing regimens may help abate most side effects . to further avoid adverse effects , thalidomide could be used in sequential combination therapy with uvb or followed by its analogue lenalidomide . both options shorten the treatment length for thalidomide and may limit adverse reactions ; however , most studies are limited by virtue of being case reports and their low power . in the contemporary era of targeted therapy , an enhanced understanding of the biology and related physiology of pn additionally , understanding of the molecular mechanisms of thalidomide and lenalidomide may also further elucidate their role in the treatment of pn . given the findings in the aforementioned studies , thalidomide and its analogues should be further evaluated in a prospective manner with the aim of improving efficacy and reducing treatment - related toxicity by determining the most effective dosing and treatment time .