CONTINUING MEDICAL EDUCATION 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 therapies 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 Medicine is accredited by the ACCME to provide Michael Fisher, MD, Professor of Medicine, Albert Einstein continuing medical education for physicians. 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 joint 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 therapy, 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 Dermatology, The University of Oklahoma, Oklahoma City. conventional anti-itch 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- antipruritic 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—Dermatomyositis is a chronic auto- approximately 3 times larger.2 immune inflammatory myopathy 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 calcinosis cutis.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, cytokines. 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 lupus.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 dermatitis, pruritus in dermato- Treatment of the underlying disease with nonsteroi- myositis 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 glucocorticoids have topical corticosteroids, methotrexate sodium,17 anti- been effective for severe cases of pruritus, topical malarial agents,18,19 topical