sign in sign up
<<
Home , Systemic scleroderma, Uremic pruritus

Continuing

Pruritus in Connective Tissue and Other Common Systemic Disease States

Alison Galatian, MD; Gillian Stearns, MD; Renee Grau, MD

RELEASE DATE: October 2009 TERMINATION DATE: October 2010 The estimated time to complete this activity is 1 hour. Goal To understand pruritus to better manage patients with conditions presenting with this symptom

Learning Objectives Upon completion of this activity, you will be able to: 1. Discuss the neuropathophysiologic classifications of pruritus. 2. Recognize the characteristic skin lesions that induce pruritus in patients with connective tissue or systemic disease. 3. Differentiate for pruritus based on disease state.

Intended Audience This CME activity is designed for dermatologists and general practitioners.

CME Test and Instructions on page 221.

This article has been peer reviewed and approved by College of is accredited by the ACCME to provide Michael Fisher, MD, Professor of Medicine, Albert Einstein continuing medical education for . College of Medicine. Review date: September 2009. Albert Einstein College of Medicine designates this edu- This activity has been planned and implemented in cational activity for a maximum of 1 AMA PRA Category 1 accordance with the Essential Areas and Policies of the Credit TM. Physicians should only claim credit commensurate Accreditation Council for Continuing Medical Education with the extent of their participation in the activity. through the sponsorship of Albert Einstein College of This activity has been planned and produced in accor- Medicine and Quadrant HealthCom, Inc. Albert Einstein dance with ACCME Essentials.

Drs. Galatian, Stearns, and Grau report no conflict of interest. The authors discuss off-label use of active charcoal, choles- tyramine, dronabinol, etanercept, gabapentin, mirtazapine, nalmefene hydrochloride, naloxone hydrochloride, naltrexone hydrochloride, paroxetine hydrochloride, rifampicin, sertraline hydrochloride, tacrolimus ointment, thalidomide, ursodeoxycholic acid, UVA1 , and UVB phototherapy for pruritus. Dr. Fisher reports no conflict of interest. The staff of CCME of Albert Einstein College of Medicine and Cutis® have no conflicts of interest with commercial interest related directly or indirectly to this educational activity.

Pruritus is a common symptom reported in connec- states. Unfortunately, the unique pathophysi- tive tissue and other common systemic disease ologic etiology of the often chronic and severe pruritus that is a debilitating component of many Dr. Galatian was a student, Dr. Stearns was an intern, and Dr. Grau was Assistant Clinical Professor, all from the Department connective tissue disorders makes treatment with of , The University of Oklahoma, Oklahoma City. conventional anti- agents difficult. As the Dr. Galatian currently is a resident, The University of Oklahoma. underlying mechanisms of pruritus have been Dr. Stearns currently is a resident, State University of New York, identified, treatment strategies have evolved. Syracuse. Dr. Grau currently is a dermatologist, Saints Dermatology, Considering the diversity of available antipru- Oklahoma City, and Volunteer Assistant Clinical Professor, The University of Oklahoma. ritic therapies and the variability of underlying Correspondence: Renee Grau, MD, Saints Dermatology, 608 NE factors specific to disease states, individual- 9th St, Ste 3206, Oklahoma City, OK 73102 ([email protected]). ized therapy recommendations are necessary.

VOLUME 84, OCTOBER 2009 207 Pruritus in Common Disease States

Important new areas of treatment target the cen- syndromes, such as notalgia paresthetica, brachiora- tral and peripheral mechanisms of pruritus and dial pruritus, and meralgia paresthetica.7 include anticonvulsants, antidepressants, opioid Neurogenic itch is pruritus of a central origin antagonists, and phototherapy. Further research with no neural damage. It often includes itch is necessary to quantify the role of new and novel associated with systemic diseases in which neuro- therapies. peptides and opiates are responsible for induction of Cutis. 2009;84:207-214. pruritus. Examples include chronic liver disease and uremia due to renal failure.3 Pathophysiology and Classification Psychogenic itch is associated with psychological of Pruritus abnormalities and primary skin lesions, which helps Pruritus (or itch), once considered to be low-intensity support the idea of a central origin of itch.1 pain, is now known to be neurologically distinct from Alternately, itch can be classified based on nociperception. Once stimulated by a pruritogen, a the clinical presentation and symptom complex. specialized subset of C fibers within the skin sends While the clinical classification of pruritus may be signals to the dorsal horn of the spinal cord that diagnostically helpful, it generally does not aid in are transmitted by the spinothalamic tract to the determining antipruritic therapy.8 Although cuta- thalamus and on to the somatosensory cortex.1 These neous neurobiology appears to be similar for acute C fibers, also called pruriceptors, are distinguished and chronic itch, chronic itch is thought to develop from the most common type of C fibers by sensitiv- when central mechanisms undergo neuroplasticity ity to histamine and unresponsiveness to mechani- and are sensitized toward itch9; therefore, when cal stimulation, whereas classical nociceptors are treating chronic pruritus, it is important to target mechano-heat sensitive, have little response to hista- cutaneous, peripheral, and central mechanisms. mine, and are responsible for transmitting pain. Pru- riceptors also are known to have half the conduction Pruritus as a Manifestation of the Disease velocities of nociceptors and receptor fields that are —Dermatomyositis is a chronic auto- approximately 3 times larger.2 immune inflammatory with characteristic Although pain and itch are now accepted as skin involvement.10 Patients generally present with distinct entities, there are certainly interactions insidious onset of proximal muscle weakness and pain between the 2 systems.3,4 Scratching to the point with pathognomonic skin changes of Gottron papules of pain commonly relieves itch. It also has been and Gottron sign.11 Frequently, the initial cutaneous shown that other painful stimuli, such as heat and manifestation is the heliotrope rash, which consists electric stimulation, can reduce histamine-induced of highly pruritic, confluent, macular, violaceous ery- itch for several hours. On the contrary, adminis- thema of the periorbital region.10,12 Other character- tration of opioids, specifically μ-opioid receptor istic skin lesions associated with the disease include agonists, for analgesia causes a common side effect photodistributed violaceous erythema of the upper of pruritus. The administration of μ-opioid receptor chest as well as the neck and upper back (shawl sign), antagonists such as naloxone and naltrexone has poikiloderma, and .10 an antipruritic effect and can be a useful treat- Skin manifestations of dermatomyositis often are ment in patients with uremic or cholestatic itch in symptomatic and cause the patients much discomfort which an upregulation of endogenous opioids is the with pruritus and skin burning.12 A survey of patients suspected mechanism.3,4 with controlled muscle disease but unknown control Itch can be neurophysiologically classified based of skin manifestations showed that the majority on mechanism into cutaneous or pruritoceptive, continue to experience moderate pruritus despite neuropathic, neurogenic, psychogenic, or mixed.1,5 inactive muscle disease.13 In fact, of 26 respondents, Itch that originates in the skin is pruritoceptive 18 reported that they continued to experience pru- and is stimulated by a variety of pruritogens, includ- ritus. The authors suggest 2 etiologies for their itch- ing histamine and other amines, proteases, growth ing: the inflammatory component of the disease and factors, neuropeptides, opioids, prostaglandin, and the side effect of disease treatment.13 For example, . Some pruritogens appear to work by one study found that hydroxychloroquine was linked direct stimulation of itch-specific C fibers, while to a highly pruritic eruption in nearly one-third others cause histamine release from local mast cells of patients with dermatomyositis (12/39), a much that sensitize the C fibers.1-3,6 higher prevalence than in patients with .14 Neuropathic itch usually is attributed to damage The pruritus associated with dermatomyositis can or disruption along the afferent neuronal pathway. be severe. Another study evaluating the effect of It includes postherpetic itch and nerve entrapment pruritus on quality of life found that compared to

208 CUTIS® Pruritus in Common Disease States

psoriasis and atopic , pruritus in dermato- Treatment of the underlying disease with nonsteroi- caused a greater impairment.15 Furthermore, dal anti-inflammatory and immunosuppressive drugs treatment response of cutaneous and muscular dis- typically does not alleviate pruritus, though it may ease can be discordant.16 Treatment of cutaneous lessen the disease course and aid in softening of the manifestations includes aggressive sun protection and skin. While low-dose systemic have topical corticosteroids, sodium,17 anti- been effective for severe cases of pruritus, topical malarial agents,18,19 topical tacrolimus,20,21 tamoxifen steroids rarely have been of benefit.33 Tacrolimus and anastrozole,22 dapsone,23 and intravenous immu- ointment 0.1% applied twice daily under occlusion noglobulin.24 Pruritus often is improved by treating appears to allow faster resolution of the inflamma- cutaneous dermatomyositis but may be seen as a side tory phase and aids in skin softening in prelimi- effect of treatment, as nonallergic pruritic eruptions nary reports, though antipruritic effects were not have been reported in patients on methotrexate, mentioned.36 Another relatively new treatment is antimalarial agents, and tamoxifen. While systemic UVA1 therapy. The antipruritic action of UVA1 is therapies that treat the underlying disease generally thought to be due to inhibitory effects on histamine are beneficial, specific antipruritic treatments used in release from basophils and mast cells.37,38 Studies have dermatomyositis include antihistamines (hydroxyzine shown that UVA1 therapy can improve pruritus and hydrochloride, doxepin hydrochloride) and class 1 reduce skin stiffness and thickness; furthermore, it (superpotent) or class 2 (potent) topical cortico- is generally well tolerated.39,40 UVA1 therapy along steroids.25,26 Tacrolimus ointment 0.1% has been with antihistamines and lubricants appear to be reported to be effective in resistant cutaneous dermat- the most effective and safest antipruritic agents in omyositis and associated pruritus.27,28 the treatment of . Scleroderma—Scleroderma is a spectrum of related Lupus Erythematosus—Lupus erythematosus is a disorders; the majority share the feature of skin disease that can have a wide range of systemic and thickening secondary to excess fibers. The cutaneous manifestations. Pruritus in systemic lupus exact etiology and pathogenesis are unknown, but erythematosus (SLE) occurs in roughly 2.8% to 45% of the activation of the immune system, particularly patients, according to various reports.41,42 It is unclear , T and B lymphocytes, and endothelial if the itching is due to the disease process or if it is an cells, are indicated as key factors of excess collagen adverse drug reaction seen especially with antima- production.29 Scleroderma is first classified into local- larial drugs such as chloroquine phosphate. Hoffman ized or systemic disease. (SSc) and Gray43 reported a case of aseptic meningitis is further broken down on the basis of internal upon administration of ibuprofen to a patient with involvement and extent of skin involvement. SLE and suggested that the pruritus experienced by Certain currently are being researched the patient may have been secondary to a hypersen- to discover their involvement in the excess collagen sitivity reaction. In a study on pimecrolimus, pruritus production associated with scleroderma. Transform- was observed in 40% (4/10) of patients after initia- ing growth factor b (TGF-b) also is thought to be tion of therapy and was considered to be an adverse involved because most patients with SSc show ele- drug reaction.44 vated levels of the receptor for TGF-b. Pannu et al30 Therapy must be adjusted to the subtype of demonstrated that aberrantly expressed TGF-b cutaneous involvement as well as signs of systemic receptor type 1 may instigate an autocrine loop that disease. In the absence of systemic disease, focus can upregulates collagen-producing fibroblasts. Eight of be placed on cutaneous manifestations. Mainstays 9 SSc strains exhibited increased levels of this pro- of therapy for cutaneous disease include topical or tein, which was associated with increased collagen intralesional corticosteroids.45 Severe widespread or synthesis.30 as well as human b-defensins unresponsive lesions may require more aggressive are being investigated for potential involvement.31,32 therapy with oral corticosteroids, antimalarial agents, Skin thickening, Raynaud phenomenon, calcinosis, or azathioprine.45,46 Unfortunately, the response of and are common skin manifestations cutaneous disease to the immunosuppressive drugs of both localized scleroderma and SSc. used to treat SLE to control organ involvement Pruritus is associated with the inflammatory state often is disappointing.42 Etanercept was reported to of the skin in the earliest stages of diffuse cutaneous be successful for intractable pruritus in one patient SSc.33,34 It typically is associated with nonpitting with subacute cutaneous lupus erythematosus47; oth- edema of the extremities that takes place prior to erwise, specific therapy for pruritus in the context of collagen deposition.35 There have been few treat- lupus has not been described. ment modalities that immediately alleviate pruritus Sjögren Syndrome—Sjögren syndrome is an besides antihistamines and adequate lubrication. characterized by glandular

VOLUME 84, OCTOBER 2009 209 Pruritus in Common Disease States

dysfunction that leads to desiccation of the skin and results in continuous activation of the C fibers, mucous membranes.48 It has a primary and second- perhaps by pruritogens retained because of cholesta- ary form that often occurs in conjunction with other sis.56 Some studies have associated pruritus with collagen vascular diseases such as lupus. The eti- a single nucleotide alteration, which leads to a sub- ology and pathogenesis of Sjögren syndrome are stitution of valine for glutamate in the multidrug unclear but could be due to immunoregulatory prop- resistance 2 gene, MRP2. This gene makes erties of sex hormones because most patients with the multidrug resistance–associated protein 2 (mrp2) Sjögren syndrome are female. Glandular destruction that regulates the transport of organic compounds, appears to be mediated by CD41 lymphocytes.48 including bile salts.56,57 Bile acids produce a local Xerosis in primary Sjögren syndrome also has been pruritic response when intracutaneously injected found to be highly associated with anti–SS-A in healthy participants, but bile acids most likely (Sjögren syndrome antigen A) and anti–SS-B are not the cause of pruritus in the cholestasis of (Sjögren syndrome antigen B) antibodies.49 PBC because results show that pruritus is not always The primary cutaneous lesions involved in directly related to the level of bile acids present in Sjögren syndrome are xerosis and angular cheilitis, the afflicted patient. Some patients experience itch- which affect roughly 50% of individuals, followed ing with no concomitant increase in serum by , cutaneous , and ery- levels, while others experience frank hepatic failure thema annulare.48 Xerosis and erythema annulare with maximum levels of bile acids and no pruritus.56 are found more frequently in patients with primary Thus, bile acids are not considered to be the primary versus secondary Sjögren syndrome.49 pruritogens associated with cholestasis. Skin and vaginal involvement are secondary to Evidence suggests that pruritus is related to xerosis. If the pruritus is intense, dermatitis herpeti- increased neurotransmission mediated by endog- formis should be considered in the differential diag- enous opioids, particularly methionine and leucine nosis. The 2 diseases share a common genetic link enkephalins.55,56 This theory of increased opioid- of HLA-DR3.12,50 Xerosis and pruritus associated ergic tone is due to the observation that the pru- with Sjögren syndrome can be managed with use of ritus of cholestasis can be relieved by naloxone humidifiers and moisturizers. Treatment of Sjögren hydrochloride, and administration of morphine syndrome typically revolves around managing the can induce opiate antagonist–reversible pruritus.57 ocular and oral manifestations, with systemic ther- μ-Opioid receptor antagonists such as naloxone apy reserved for refractory or severe cases.51 It is not hydrochloride and naltrexone hydrochloride have described in the literature if patients treated with been widely studied with good results.58-63 Opiate systemic immunosuppressive therapy experience withdrawal syndrome is a potential side effect of relief of xerosis. the opioid antagonists and naloxone is hepatotoxic, Primary Biliary —Primary biliary which may limit its use in some patients. Nalmefene cirrhosis (PBC) is a progressive chronic disease hydrochloride has been successful as an antipruritic leading to cholestasis and is typically described in treatment but was dismissed in initial studies for long- middle-aged women. It is categorized as an autoim- term therapy because of poor oral bioavailability.55,64 mune condition, though some lines of study on the Despite good efficacy, opioid antagonists generally etiology have shown both the environment and are not recommended as first-line agents because as probable factors.52 Dermatologic of unfavorable side effects and high cost. The anti- manifestations include dermographism, melanosis, depressants sertraline hydrochloride,65,66 paroxetine xerosis, and xanthomatous lesions. Dermatologic hydochloride,67 and mirtazapine68 all have been manifestations were the presenting symptom of PBC studied with success and generally are well tolerated. in more than one-third (19/49) of participants in Sertraline hydrochloride has been recommended as a study by Koulentaki et al.53 Some patients have a potential first-line therapy.66 Cholestyramine is a been reported to present with symptoms that indi- bile acid–binding resin that is widely used, has low cated connective tissue disease, such as , toxicity, and appears to have an antipruritic effect fatigue, and morbilous or urticarial skin lesions.54 despite the lack of rigorous clinical trials.69,70 Urso- Pruritus is a common side effect of PBC that deoxycholic acid, a choleretic agent, may decrease occurred in 70% (34/49) of participants in one cholestasis but has not been consistently shown study and had a substantial impact on quality to relieve pruritus.71 The antibiotic rifampicin has of life.53 It is hypothesized that patients with been evaluated in several well-designed studies and cholestasis might undergo central sensitiza- meta-analyses and has been shown to effectively tion for itch to the point that noxious stimuli relieve pruritus, though patients must be monitored are perceived as pruritus by the patient, which for hepatotoxicity.70,72 Dronabinol also has been

210 CUTIS® Pruritus in Common Disease States

studied and found to improve intractable cholestatic endings. Cho et al79 proposed that uremic pruritus pruritus in a small group of patients73 as well as aid may be mediated by the release of substance P and in sleep. While it may prove to be a novel approach other neuropeptides from the cutaneous sensory to antipruritic therapy in the future, it is not neurons in response to the toxin. currently recommended. Phototherapy and plasma- A correlation between higher Kt/V values, a measure pheresis74 generally also are thought to be successful of the clearance of small molecules such as urea, and but require fairly extensive treatment regimens and increased pruritus has been described.81 The work of recurrence tends to be a problem. Treatment gener- Dimkovi´c et al82 suggests that larger-sized toxins that ally is initiated with cholestyramine and advanced are not accounted for in the Kt/V value also may be to naltrexone hydrochloride or rifampicin in the responsible for uremic pruritus. event of continued pruritus.69,70 Uremic pruritus has been palliated with hydra- End-stage Renal Disease—Patients with end-stage tion, topical lubricants, keratolytics, antihista- renal disease are afflicted with multiple cutaneous mines, and many new novel agents. The current manifestations of the disease, including pruritus, gold standard of therapy for this condition is pallor, sallow yellowish skin tones, hyperpigmenta- UVB phototherapy.84 According to Ada et al,85 tion, and elastosis. Pruritus (uremic pruritus) is the UVB phototherapy works by inducing apopto- most frequently occurring symptom of end-stage sis of dermal mast cells and reducing the release renal disease, affecting 58% to 90% of patients on of substance P by decreasing epidermal nerve dialysis. The prevalence is similar among patients on fibers. This therapy is effective, but recurrence either or peritoneal dialysis.75 Okada is a problem. Maintenance therapy may prevent and Matsumoto76 found that the prevalence was relapse.84 Novel treatments that have been uti- higher in men and postulated that this increased lized include gabapentin, UVA, μ-opioid receptor prevalence in men may be due to women using antagonists, cholestyramine, active charcoal, and emollients more frequently. thalidomide. Conflicted studies on the utility of Zucker et al77 defines uremic pruritus as pruritus the opioid antagonist naltrexone hydrochloride that appears shortly before the onset of dialysis or at have been reported, but it may be useful in a sub- any time after dialysis without any other explana- set of patients.86-88 , a relatively new tion. The following criteria must be met: (1) at least k-opioid receptor agonist, also has been found 3 episodes of itch during a period of 2 weeks or less, to be effective in preliminary reports, but further or (2) the appearance of an itch in a regular pattern studies are necessary.89 Among second-line agents, during a period of 6 months. gabapentin usually is preferred in the treatment Patients with uremic pruritus present with fre- of uremic pruritus because of safety and effi- quent paroxysmal episodes of severe itch that occur cacy.90,91 The definitive cure for uremic pruritus is most commonly at night (possible relation to diurnal renal transplantation.75 rhythms) and adversely affect sleep.78 Pruritus can be generalized or localized, with most episodes located Comment on the back (70%) and abdomen (46%).77 Patients Pruritus is a common symptom of connective tissue also can develop complications from scratching, and other common systemic disease states that often including excoriations, , proves to be the most bothersome symptom for many and nodularis.75 Furthermore, the presence of patients. A search of the literature using PubMed and pruritus appears to be associated with poor outcomes the terms pruritus and itching did not reveal reports in patients undergoing chronic hemodialysis.78 of an association between the heritable connective The exact mechanism of uremic pruritus is tissue diseases and Ehlers-Danlos unknown, but the pathogenesis is thought to be syndrome, or rheumatoid and pruritus, aside multifactorial. Numerous theories have been pro- from pruritus reported as an adverse drug reaction. posed, including uremic skin developing xerosis; To discuss each potential drug of interest is beyond secondary hyperparathyroidism78 (refuted by Cho the scope of this article. While it can be difficult to et al79); divalent ion abnormalities, particularly cal- identify the cause of pruritus in many of the diseases cium80,81; iron deficiency anemia; increased levels of discussed, medications are important sources and mast cells in the skin leading to increased histamine should be considered in the etiology. The conven- release82; angiotensin-converting enzyme inhibi- tional mainstays in the treatment of pruritus include tor use; neuropathy and neurologic changes83; and topical agents and antihistamines, which often are retention of urochrome and other toxins in the skin. ineffective. The widespread use of novel agents has Retained toxins in the skin have been proposed great potential for patients, and treatment now can be to cause pruritus by stimulating cutaneous nerve directed at both central and peripheral mechanisms

VOLUME 84, OCTOBER 2009 211 Pruritus in Common Disease States

of pruritus. Further study of the pathophysiology of 19. Ang GC, Werth VP. Combination antimalarials in the pruritus has great promise to produce new targeted treatment of cutaneous dermatomyositis: a retrospective antipruritic therapies. study. Arch Dermatol. 2005;141:855-859. 20. Ueda M, Makinodan R, Matsumura M, et al. Successful References treatment of amyopathic dermatomyositis with topical 1. Twycross R, Greaves MW, Handwerker H, et al. Itch: tacrolimus. Br J Dermatol. 2003;148:595-596. scratching more than the surface. QJM. 2003;96:7-26. 21. Jorizzo JL. Dermatomyositis: practical aspects. Arch 2. Paus R, Schmelz M, Bíró T, et al. Frontiers in pruritus Dermatol. 2002;138:114-116. research: scratching the brain for more effective itch 22. Sereda D, Werth VP. Improvement in dermatomyositis therapy. J Clin Invest. 2006;116:1174-1186. rash associated with the use of antiestrogen medication. 3. Ikoma A, Steinhoff M, Ständer S, et al. The neurobiology Arch Dermatol. 2006;142:70-72. of itch. Nat Rev Neurosci. 2006;7:535-547. 23. Cohen JB. Cutaneous involvement of dermatomyosi- 4. Schmelz M. Itch and pain. Dermatol Ther. 2005;18: tis can respond to Dapsone therapy. Int J Dermatol. 304-307. 2002;41:182-184. 5. Greaves MW. Itch in systemic disease: therapeutic options. 24. Kikuchi-Numagami K, Sato M, Tagami H. Success- Dermatol Ther. 2005;18:323-327. ful treatment of a therapy-resistant severely pruritic 6. Greaves MW, Wall PD. Pathophysiology of itching. skin eruption of malignancy-associated dermatomyositis Lancet. 1997;349:133. with high-dose intravenous immunoglobulin. J Dermatol. 7. Yosipovitch G, Fleischer A. Itch associated with skin 1996;23:340-343. disease: advances in pathophysiology and emerging thera- 25. Kovacs SO, Kovacs SC. Dermatomyositis. J Am Acad pies. Am J Clin Dermatol. 2003;4:617-622. Dermatol. 1998;39:899-920. 8. Ständer S, Weisshaar E, Mettang T, et al. Clinical clas- 26. Sontheimer RD. The management of dermatomyositis: sification of itch: a position paper of the International current treatment options. Expert Opin Pharmacother. Forum for the Study of Itch. Acta Derm Venereol. 2007;87: 2004;5:1083-1099. 291-294. 27. Lampropoulos CE, D’Cruz DP. Topical tacrolimus treat- 9. Ständer S, Schmelz M. Chronic itch and pain— ment in a patient with dermatomyositis. Ann Rheum Dis. similarities and differences. Eur J Pain. 2006;10:473-478. 2005;64:1376-1377. 10. Levin J, Werth VP. Skin disorders with arthritis. Best Pract 28. Hollar CB, Jorizzo JL. Topical tacrolimus 0.1% ointment Res Clin Rheumatol. 2006;20:809-826. for refractory skin disease in dermatomyositis: a pilot 11. Dinh HV, McCormack C, Hall S, et al. Rituximab for the study. J Dermatolog Treat. 2004;15:35-39. treatment of the skin manifestations of dermatomyositis: a 29. Zuber J, Spertini F. Immunological basis of systemic scle- report of 3 cases. J Am Acad Dermatol. 2007;56:148-153. rosis. . 2006;45(suppl 3):iii23-iii25. 12. Sontheimer RD. Skin manifestations of systemic auto- 30. Pannu J, Gardner H, Shearstone JR, et al. Increased immune connective tissue disease: diagnostics and thera- levels of transforming growth factor beta receptor peutics. Best Pract Clin Rheumatol. 2004;18:429-462. type I and up-regulation of matrix gene program: a 13. Shirani Z, Kucenic MJ, Carroll CL, et al. Pruritus in adult model of scleroderma. Arthritis Rheum. 2006;54: dermatomyositis. Clin Exp Dermatol. 2004;29:273-276. 3011-3021. 14. Pelle MT, Callen JP. Adverse cutaneous reactions to 31. Lemaire R, Korn JH, Shipley JM, et al. Increased hydroxychloroquine are more common in patients with expression of type I collagen induced by microfibril- dermatomyositis than in patients with cutaneous lupus associated glycoprotein 2: novel mechanistic insights erythematosus. Arch Dermatol. 2002;138:1231-1233. into the molecular basis of dermal in scleroderma. 15. Hundley JL, Carroll CL, Lang W, et al. Cutaneous symp- Arthritis Rheum. 2005;52:1812-1823. toms of dermatomyositis significantly impact patients’ 32. Kreuter A, Hyun J, Skrygan M, et al. Ultraviolet A1- quality of life. J Am Acad Dermatol. 2006;54:217-220. induced downregulation of human B-defensins and 16. Iorizzo LJ 3rd, Jorizzo JL. The treatment and prognosis of interleukin-6 and interleukin-8 correlates with clinical dermatomyositis: an updated review. J Am Acad Dermatol. improvement in localized scleroderma. Br J Dermatol. 2008;59:99-112. 2006;155:600-607. 17. Kasteler JS, Callen JP. Low-dose methotrexate 33. Denton CP. Overview of the treatment and prognosis administered weekly is an effective corticosteroid- of systemic sclerosis (scleroderma) in adults. UpToDate. sparing agent for the treatment of the cutaneous manifes- http://www.uptodate.com/online/content/topic tations of dermatomyositis. J Am Acad Dermatol. 1997;36: .do?topicKey5sclerode/2411&selectedTitle=1~150 67-71. &source5search_result. Updated June 17, 2009. Accessed 18. Dawkins MA, Jorizzo JL, Walker FO, et al. Dermatomyo- September 20, 2009. sitis: a dermatology-based case series. J Am Acad Dermatol. 34. Frieri M. Systemic sclerosis. the role of the mast cell and 1998;38:397-404. cytokines. Ann . 1992;69:385-392, 395-396.

212 CUTIS® Pruritus in Common Disease States

35. Moses S. Pruritus. Am Fam . 2003;68: 52. Oo YH, Neuberger J. Options for the treatment of primary 1135-1142. biliary cirrhosis. Drugs. 2004;64:2261-2271. 36. Mancuso G, Berdondini RM. Localized scleroderma: 53. Koulentaki M, Ioannidou D, Stefanidou M, et al. Der- response to occlusive treatment with tacrolimus ointment. matological manifestations in primary biliary cirrho- Br J Dermatol. 2005;152:180-182. sis patients: a case control study. Am J Gastroenterol. 37. Rombold S, Lobisch K, Katzer K, et al. Efficacy of 2006;101:541-546. UVA1 phototherapy in 230 patients with various skin 54. Covelli M, Favia I, Marrone M, et al. Cutaneous lesions diseases. Photodermatol Photoimmunol Photomed. 2008;24: as presenting symptoms of primary biliary cirrhosis: an 19-23. undifferentiated connective tissue disease-like onset. Clin 38. Stege H, Berneburg M, Humke S, et al. High-dose UVA1 Rheumatol. 2006;25:919-922. for localized scleroderma. J Am Acad 55. Bergasa NV, Alling DW, Talbot TL, et al. Oral nalmefene Dermatol. 1997;36(6, pt 1):938-944. therapy reduces scratching activity due to the pruritus 39. Dawe RS. Ultraviolet A1 phototherapy. Br J Dermatol. of cholestasis: a controlled study. J Am Acad Dermatol. 2003;148:626-637. 1999;41(3, pt 1):431-434. 40. Krönauer C, Eberlein-König B, Ring J, et al. Influence of 56. Bergasa NV. The pruritus of cholestasis. J Hepatol. UVB, UVA and UVA1 irradiation on histamine release 2005;43:1078-1088. from human basophils and mast cells in vitro in the pres- 57. Floreani A, Carderi I, Variola A, et al. A novel multidrug- ence and absence of antioxidants. Photochem Photobiol. resistance protein 2 gene mutation identifies a subgroup 2003;77:531-534. of patients with primary biliary cirrhosis and pruritus. 41. Bhalla R, Ajamani HS, Kim WW, et al. Systemic lupus . 2006;43:1152-1154. erythematosus and Hodgkin’s lymphoma. J Rheumatol. 58. Bergasa NV, Talbot TL, Alling DW, et al. A controlled 1993;20:1316-1320. trial of naloxone infusions for the pruritus of chronic cho- 42. Sticherling M, Bonsmann G, Kuhn A. Diagnostic lestasis. . 1992;102:544-549. approach and treatment of cutaneous lupus erythemato- 59. Bergasa NV, Alling DW, Talbot TL, et al. Effects of nalox- sus [in English, German]. J Dtsch Dermatol Ges. 2008;6: one infusions in patients with the pruritus of cholestasis. 48-59. a double-blind, randomized, controlled trial. Ann Intern 43. Hoffman M, Gray RG. Ibuprofen-induced meningi- Med. 1995;123:161-167. tis in mixed connective tissue disease. Clin Rheumatol. 60. Carson KL, Tran TT, Cotton P, et al. Pilot study of the use 1982;1:128-130. of naltrexone to treat the severe pruritus of cholestatic 44. Tlacuilo-Parra A, Guevara-Gutiérrez E, Gutiérrez-Murillo liver disease. Am J Gastroenterol. 1996;91:1022-1023. F, et al. Pimecrolimus 1% cream for the treatment 61. Mansour-Ghanaei F, Taheri A, Froutan H, et al. Effect of of discoid lupus erythematosus. Rheumatology (Oxford). oral naltrexone on pruritus in cholestatic patients. World J 2005;44:1564-1568. Gastroenterol. 2006;12:1125-1128. 45. Callen JP. Update on the management of cutane- 62. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrex- ous lupus erythematosus. Br J Dermatol. 2004;151: one treatment for : a double-blind, 731-736. placebo-controlled study. Gastroenterology. 1997;113: 46. Jessop S, Whitelaw D, Jordaan F. Drugs for discoid lupus 1264-1269. erythematosus. Cochrane Database Syst Rev. 2001;(1): 63. Terg R, Coronel E, Sordá J, et al. Efficacy and safety of oral CD002954. naltrexone treatment for pruritus of cholestasis, a cross- 47. Norman R, Greenberg RG, Jackson JM. Case reports over, double blind, placebo-controlled study. J Hepatol. of etanercept in inflammatory dermatoses. J Am Acad 2002;37:717-722. Dermatol. 2006;54(suppl 2):S139-S142. 64. Bergasa NV, Schmitt JM, Talbot TL, et al. Open-label trial 48. Soy M, Piskin S. Cutaneous findings in patients with of oral nalmefene therapy for the pruritus of cholestasis. primary Sjogren’s syndrome. Clin Rheumatol. 2007;26: Hepatology. 1998;27:679-684. 1350-1352. 65. Browning J, Combes B, Mayo MJ. Long-term efficacy 49. Bernacchi E, Amato L, Parodi A, et al. Sjögren’s of sertraline as a treatment for cholestatic pruritus in syndrome: a retrospective review of the cutaneous features patients with primary biliary cirrhosis. Am J Gastroenterol. of 93 patients by the Italian Group of Immunodermatology. 2003;98:2736-2741. Clin Exp Rheumatol. 2004;22:55-62. 66. Mayo MJ, Handem I, Saldana S, et al. Sertraline as a 50. Sontheimer RD, Provost TT, eds. Cutaneous Manifestations first-line treatment for cholestatic pruritus. Hepatology. of Rheumatic Diseases. Baltimore, MD: Wilkins & 2007;45:666-674. Wilkins; 1996. 67. Zylicz Z, Krajnik M, Sorge AA, et al. Paroxetine in 51. Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. the treatment of severe non-dermatological pruritus: a The management of Sjögren’s syndrome. Nat Clin Pract randomized, controlled trial. J Pain Symptom Manage. Rheumatol. 2006;2:252-261. 2003;26:1105-1112.

VOLUME 84, OCTOBER 2009 213 Pruritus in Common Disease States

68. Davis MP, Frandsen JL, Walsh D, et al. Mirtazapine for 80. Blachley JD, Blankenship DM, Menter A, et al. Uremic pruritus. J Pain Symptom Manage. 2003;25:288-291. pruritus: skin divalent ion content and response to ultra- 69. Bergasa NV. Update on the treatment of the pruritus of violet phototherapy. Am J Dis. 1985;5:237-241. cholestasis. Clin Liver Dis. 2008;12:219-234. 81. Duque MI, Thevarajah S, Chan YH, et al. Uremic 70. Tandon P, Rowe BH, Vandermeer B, et al. The efficacy pruritus is associated with higher kt/V and serum and safety of bile acid binding agents, opioid antagonists, calcium concentration. Clin Nephrol. 2006;66: or rifampin in the treatment of cholestasis-associated pru- 184-191. ritus. Am J Gastroenterol. 2007;102:1528-1536. 82. Dimkovi´c N, Djukanovi´c L, Radmilovi´c A, et al. Uremic 71. Gong Y, Huang Z, Christensen E, et al. Ursodeoxycholic pruritus and skin mast cells. Nephron. 1992;61:5-9. acid for patients with primary biliary cirrhosis: an updated 83. Zakrzewska-Pniewska B, Jedras M. Is pruritus in chronic systematic review and meta-analysis of randomized clini- uremic patients related to peripheral somatic and auto- cal trials using Bayesian approach as sensitivity analyses. nomic neuropathy? study by R-R interval variation Am J Gastroenterol. 2007;102:1799-1807. test (RRIV) and by sympathetic skin response (SSR). 72. Khurana S, Singh P. Rifampin is safe for treatment Neurophysiol Clin. 2001;31:181-193. of pruritus due to chronic cholestasis: a meta-analysis 84. Seckin D, Demircay Z, Akin O. Generalized pruri- of prospective randomized-controlled trials. Liver Int. tus treated with narrowband UVB. Int J Dermatol. 2006;26:943-948. 2007;46:367-370. 73. Neff GW, O’Brien CB, Reddy KR, et al. Preliminary 85. Ada S, Seçkin D, Budakoğlu I, et al. Treatment of uremic observation with dronabinol in patients with intrac- pruritus with narrowband ultraviolet B phototherapy: an table pruritus secondary to cholestatic liver disease. Am J open pilot study. J Am Acad Dermatol. 2005;53:149-151. Gastroenterol. 2002;97:2117-2119. 86. Peer G, Kivity S, Agami O, et al. Randomised cross- 74. Cohen LB, Ambinder EP, Wolke AM, et al. Role of over trial of naltrexone in uraemic pruritus. Lancet. in primary biliary cirrhosis. Gut. 1985;26: 1996;348:1552-1554. 291-294. 87. Legroux-Crespel E, Clèdes J, Misery L. A comparative 75. Robinson-Bostom L, DiGiovanna JJ. Cutaneous manifes- study on the effects of naltrexone and loratadine on ure- tations of end-stage renal disease. J Am Acad Dermatol. mic pruritus. Dermatology. 2004;208:326-330. 2000;43:975-986. 88. Pauli-Magnus C, Mikus G, Alscher DM, et al. Naltrexone 76. Okada K, Matsumoto K. Effect of skin care with an emol- does not relieve uremic pruritus: results of a randomized, lient containing a high water content on mild uremic double-blind, placebo-controlled crossover study. J Am pruritus. Ther Apher Dial. 2004;8:419-422. Soc Nephrol. 2000;11:514-519. 77. Zucker I, Yosipovitch G, David M, et al. Prevalence and 89. Wikström B, Gellert R, Ladefoged SD, et al. Kappa- characterization of uremic pruritus in patients undergo- opioid system in uremic pruritus: multicenter, random- ing hemodialysis: uremic pruritus is still a major problem ized, double-blind, placebo-controlled clinical studies. J for patients with end-stage renal disease. J Am Acad Am Soc Nephrol. 2005;16:3742-3747. Dermatol. 2003;49:842-846. 90. Manenti L, Vaglio A, Costantino E, et al. Gabapentin in 78. Narita I, Alchi B, Omori K, et al. Etiology and prognostic the treatment of uremic itch: an index case and a pilot significance of severe uremic pruritus in chronic hemodi- evaluation. J Nephrol. 2005;18:86-91. alysis patients. Kidney Int. 2006;69:1626-1632. 91. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin 79. Cho YL, Liu HN, Huang TP, et al. Uremic pruritus: roles therapy for pruritus in haemodialysis patients: a random- of parathyroid hormone and substance P. J Am Acad ized, placebo-controlled, double-blind trial. Nephrol Dial Dermatol. 1997;36:538-543. Transplant. 2004;19:3137-3139.

DISCLAIMER The opinions expressed herein are those of the authors and do not necessarily represent the views of the sponsor or its publisher. Please review complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients.

CONFLICT OF INTEREST STATEMENT The Conflict of Interest Disclosure Policy of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to present. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States.

214 CUTIS®