Pruritus — Pathophysiology & Approach

• Pruritus = an unpleasant sensation that elicits a desire to scratch
• Presumed biologic purpose: provoke scratching to remove a parasite or other harmful pruritogen
• Most common skin-related symptom
• In 15%–50% of affected individuals, pruritus reflects an underlying SYSTEMIC disease — especially when generalized

IFSI Classification (International Forum for the Study of Itch, 2007) — Three Groups

1. Chronic pruritus of lesional (inflamed) skin
2. Chronic pruritus of non-lesional (non-inflamed) skin
3. Chronic pruritus presenting with secondary scratch-induced lesions (prurigo nodularis, lichen simplex chronicus)

Six Etiologic Categories (assigned after initial evaluation)

Dermatologic · Systemic · Neurologic · Psychogenic · Mixed · Other/unknown

• "Chronic" pruritus is defined as lasting ≥6 weeks

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Prevalence of Pruritus in Selected Conditions (core exam table)

• German population data: chronic pruritus point prevalence 13.5%, 12-month 16%, lifetime 22%
• Women have a higher lifetime prevalence than men; older adults more frequently affected

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A. Core Principle

• Pruritus is subjective — its presence or severity CANNOT be assessed objectively
• Longitudinal evaluation is essential: a pruritic condition with nonspecific findings initially may develop diagnostic features over time

B. History — the "WHEN/WHERE/HOW/WHAT" framework

• WHEN did it start (duration)
• WHERE did it start and where is it now (localized vs generalized; lesional vs non-lesional)
• HOW did it develop (abrupt, gradual, progressive)
• HOW does it feel (prickling, crawling, burning, stinging)
• HOW intense (numerical rating scale 1–10; interference with sleep/activities)
• HOW often (intermittent, continuous, cyclical, nocturnal)
• WHAT makes it worse/better
• WHAT does the patient think causes it
• Standardized instruments: numerical rating scale for intensity; ItchyQol for quality of life
• Key caveat: NO particular clinical characteristics reliably predict the likelihood of a systemic etiology

C. Examination — high-yield signs

• Examine skin, nails, scalp, hair, mucous membranes (oral/conjunctival), and anogenital area
• Assess for xerosis and dermographism (should be tested in ALL pruritus patients)
• THE "BUTTERFLY SIGN" (classic): lesions ON the mid upper back suggest a PRIMARY skin disease, because this difficult-to-reach area is typically SPARED when lesions are secondary to scratching
• Caveat: the region can be reached with "back-scratching" devices
• Palpate major peripheral lymph node groups (cervical, supraclavicular, axillary, inguinal) — especially without obvious primary skin disease, to detect lymphoma

D. Laboratory Evaluation

Basic initial evaluation:

• CBC with differential and platelets
• ESR, CRP
• Creatinine, BUN
• Liver transaminases, alkaline phosphatase, bilirubin
• LDH
• TSH
• Fasting plasma glucose
• Serum ferritin, iron, TIBC

Possible additional testing:

• Skin biopsy (routine histology; DIF — perilesional skin for bullous pemphigoid, normal-appearing skin near lesions for dermatitis herpetiformis)
• Serum IgE; serum protein electrophoresis/immunofixation; hepatitis B/C and HIV; parathyroid function (Ca, phosphate, PTH); serum tryptase; anti-BP180/BP230; anti-tissue transglutaminase IgA; anti-mitochondrial and anti-smooth muscle antibodies; stool for ova/parasites
• Imaging: chest X-ray/CT; abdominal-pelvic ultrasound/CT; lymph node ultrasound; spinal X-ray or MRI (for REGIONAL pruritus)
• Patch testing; prick testing; age-appropriate cancer screening
• If hydroxyethyl starch (HES)-induced pruritus suspected → ELECTRON MICROSCOPY of normal-appearing skin

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A. Urticaria

• Often intensely pruritic; may also produce stinging or prickling
• Early lesions and small superficial wheals are particularly symptomatic
• Histamine plays a PRIMARY role — H1-antagonists usually decrease/eliminate both itch and wheals
• IL-31 levels correlate with itch intensity
• Refractory: omalizumab, cyclosporine

B. Atopic Dermatitis

• "The diagnosis of active atopic dermatitis cannot be made if there is no history of pruritus" — a formal diagnostic criterion
• Itch comes in "attacks"; pruritus is often the FIRST indication of a flare
• Pruritus may PERSIST after resolution of inflammatory skin lesions
• Triggers: aeroallergens, sensitized foods; non-immunologic — emotional stress, overheating, perspiration, rough fabrics, or even AIR (atmokinesis)
• Most children worsen in winter; others primarily in summer
• Antihistamines are minimally effective → histamine is probably NOT the predominant mediator; their benefit is mostly SEDATIVE
• Key cytokines: IL-4, IL-13, IL-31, TSLP → hence efficacy of dupilumab/tralokinumab/lebrikizumab (IL-4/-13), nemolizumab (IL-31), JAK1/2 inhibitors
• Other mediators: substance P, CGRP, NGF, artemin (causes WARMTH-provoked itching), epidermal opioid receptors (downregulated), endothelin-1, kallikrein-related peptidase and mast cell tryptase → PAR-2
• Morphologic alterations of cutaneous nerves and neuronal sensitization may cause even painful stimuli to be perceived as itch

C. Psoriasis

• Not traditionally regarded as pruritic, but 60%–95% of patients itch
• Exacerbating factors: xerosis, heat, sweating, emotional stress
• Most often pruritic sites: scalp, back, legs; generalized itch can occur in plaque, erythrodermic, and pustular forms
• Described as tickling, crawling, burning; antihistamines rarely help
• Implicated mediators: substance P, NGF, protein gene product 9.5, CGRP, neuropeptide Y, IL-2, opioid receptors
• Drug association: coadministration of β-blockers, ACE inhibitors, or antacids may be associated with development of psoriatic itch

D. Infestations

Scabies

• Localized or generalized, may have a burning component; more intense at NIGHT; typically SPARES the head
• Onset 3–6 weeks after a FIRST-TIME infestation, but within a few days in SUBSEQUENT infestations (classic immunologic timing point)
• Multiple family members often affected
• Itch reflects immune response against mites, eggs, and scybala

Pediculosis

• Pruritus at primary sites (scalp, groin) = clue to head/pubic lice
• Generalized pruritus is characteristic of BODY lice

E. Cutaneous T Cell Lymphoma

• Affects >60% of CTCL patients; increases with stage — >90% in Sézary syndrome; also prominent in folliculotropic MF
• A Sézary variant presenting with generalized pruritus and MINIMAL/NO clinically evident skin disease exists
• Pruritus is associated with increased risk of disease progression and death
• IL-31 is a putative mediator; lower IL-31 correlates with reduced itch after histone deacetylase inhibitors and mogamulizumab (anti-CCR4)
• Treatment for refractory itch: gabapentin (900–2400 mg daily divided), mirtazapine (7.5–15 mg nightly), naltrexone (50–150 mg daily)
• Aprepitant: initially reported to relieve intractable itch, but a recent RCT FAILED to show benefit over placebo in Sézary syndrome

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A. Scalp Pruritus

• Causes: seborrheic dermatitis, psoriasis, folliculitis, lichen planopilaris, dermatomyositis
• But also occurs with NO objective changes — neuropathic (small-fiber neuropathy, postherpetic neuralgia) or psychogenic
• Topical corticosteroids/antipruritics have inconsistent efficacy

B. Pruritus Ani

• Occurs in 1%–5% of the general population; male : female ≈ 4 : 1
• Insidious onset — symptoms present weeks to years before presentation
• Primary (idiopathic) = 25%–95% of cases (definition: no apparent cutaneous, anorectal, or colonic disorder)
• Secondary causes: chronic diarrhea, fecal incontinence/seepage, hemorrhoids, fissures/fistulas, rectal prolapse, primary dermatoses (psoriasis, lichen sclerosus, seborrheic dermatitis, ACD), STDs, infections, pinworms, prior radiation/trauma, anal cancer
• Can be NEUROPATHIC — compression/irritation of lumbosacral nerves from prolapsed discs, vertebral fractures, or osteophytes
• Evaluate: history, full skin/physical exam, psychiatric screening (anxiety/depression aggravate), patch testing, and rectosigmoidoscopy/colonoscopy in recalcitrant cases
• If on chronic antibiotics with liquid stools at pH 8–10 → Lactobacillus replacement therapy recommended
• Management: eliminate irritants, sitz baths (e.g. black tea astringent), cool compresses, water-moistened fragrance-free toilet paper or bidet, dry by blotting or fan (avoid rubbing and alkaline soaps), zinc oxide paste
• Mild (class 6 or 7) corticosteroid cream often sufficient; more potent steroids raise atrophy risk → topical calcineurin inhibitors, possibly rotational with steroids

C. Pruritus Vulvae and Scroti

• Solely psychogenic in only 1%–10% of patients
• Symptoms worse at night; rubbing/scratching → lichenification
• Acute: candidiasis, scabies, allergic/irritant contact dermatitis
• Chronic: psoriasis, atopic dermatitis, lichen sclerosus, lichen planus, LSC, malignancy (extramammary Paget disease, SCC), atrophic vulvovaginitis
• Scrotal pruritus secondary to lumbosacral radiculopathy is described

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A. Aquagenic Pruritus

• Usually SECONDARY to systemic disease (polycythemia vera) or another skin disorder (urticaria, dermographism); primary/idiopathic form is relatively uncommon
• Symptoms: prickling, tingling, burning, stinging within 30 MINUTES of water contact, irrespective of temperature or salinity, lasting up to 2 hours
• Typically begins on lower extremities then generalizes, with sparing of head, palms, soles, and mucosae
• NO specific skin lesions on examination
• Elevated dermal/epidermal acetylcholine, histamine, serotonin, PGE2 described
• Treatment: aspirin 300–500 mg daily (benefit in one RCT); NB-UVB/BB-UVB or PUVA; alkalinization of bath water with baking soda; capsaicin; β-blockers (propranolol, atenolol), clonidine, ibuprofen before bathing, pregabalin, H2-blockers, opioid antagonists, antidepressants, interferon-α

Differential Diagnosis of Water-Provoked Pruritus (high-yield triage table)

B. Pruritus in Scars

• Scar remodeling lasts 6 months to 2 years
• Mechanisms: physical (mechanical stimulation of nerve endings during remodeling), chemogenic (histamine, kinins, PGE1/E2), and nerve regeneration (disproportionate thinly myelinated and unmyelinated C-fibers)
• Small nerve fiber neuropathy proposed within keloids
• Oral antihistamines do NOT significantly help
• Treatment: emollients, topical/intralesional corticosteroids, cryotherapy, brachytherapy, silicone gel sheets; oral pentoxifylline 400 mg 2–3× daily relieved pain/pruritus in giant keloids

C. Post-Thermal Burn Pruritus

• ~85% of burn patients experience pruritus during the healing phase — particularly with limb burns
• Usually gradually decreases but may persist for years
• Predictors: deep dermal burn injury, female sex, psychological distress; morphine therapy may contribute
• Treatment: emollients, topical anesthetics (lidocaine/prilocaine) or doxepin, massage, oiled/colloidal oatmeal baths, extracorporeal shockwave therapy, botulinum toxin
• RCT: oral gabapentin MORE effective than cetirizine for postburn pruritus

D. Fiberglass Dermatitis

• Common in manufacturing/construction workers
• Severe pruritus sometimes with NO visible skin lesions
• Involves hands and other non-covered sites (arms, face, upper trunk)
• May resemble scabies, eczematous dermatitis, folliculitis, or urticaria
• Tolerance often develops with prolonged exposure

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A. Chronic Kidney Disease-Associated Pruritus (CKD-aP)

• Terminology pearl: "uremic pruritus" is a MISNOMER — it incorrectly implies causation by elevated urea; CKD-aP is the preferred term
• Occurs in advanced CHRONIC (not acute) kidney disease, especially on dialysis; 25%–45% of hemodialysis patients
• An INDEPENDENT PREDICTOR OF MORTALITY in dialysis patients; associated with sleep disturbance, depression, impaired QoL
• NOT associated with sex, race, dialysis duration, or etiology of kidney disease; rare in children but otherwise no age correlation
• Peritoneal dialysis patients slightly less or equally affected vs hemodialysis
• Temporal pattern: peaks in the evening after 2 days without dialysis, relatively high during dialysis, lowest the following day

Pathogenesis — mostly negative findings (high-yield):

• NO relationship between plasma histamine levels and severity (supported by antihistamine failure)
• NO correlation between degree of pruritus and PTH levels; PTH is NOT found in skin, does NOT cause itch when injected intradermally, and itch is not always present in hyperparathyroidism — despite dramatic relief after subtotal parathyroidectomy in some
• Pruritus does NOT correlate with xerosis, stratum corneum hydration, or sweat secretion
• Peripheral neuropathy affects up to 65% of dialysis patients → possible neuropathic contribution
• Loss of itch-INHIBITING CGRP-expressing neurons in the papillary dermis
• Decrease of κ-opioid receptors in skin of hemodialysis patients with pruritus
• Elevated serum IL-31; higher serum aluminum associated

Therapeutic ladder:

• Also: assess Kt/V ≥1.2 (dialysis adequacy), assess and treat hyperparathyroidism
• KEY PEARL: even in intractable CKD-aP, RENAL TRANSPLANTATION generally leads to RESOLUTION of itch

B. Cholestatic Pruritus

• Nearly any liver disease can present with pruritus; most common: primary biliary cholangitis, primary sclerosing cholangitis, obstructive choledocholithiasis, bile duct carcinoma, cholestasis (incl. drug-induced), chronic hepatitis C
• Character: generalized, migratory, NOT relieved by scratching; worse at night; typically worse on hands and feet (especially palms and soles) and areas constricted by clothing
• Can precede other manifestations of liver disease by YEARS

Pathogenesis:

• MRGPRX4 — a bile acid receptor on sensory neurons; potential therapeutic target
• Elevated serum bile acids are NOT always associated with pruritus; in severe cholestasis, development of hepatocellular FAILURE tends to cause SPONTANEOUS CESSATION of pruritus
• Increased opioidergic neurotransmission in the CNS
• Autotaxin (ATX) and lysophosphatidic acid (LPA): UNLIKE other putative mediators, ATX levels CORRELATE with itch intensity

Treatment ladder:

• Monitoring caution: rifampin can cause hepatitis, hemolytic anemia, renal failure; bezafibrate can cause hepatic toxicity, rhabdomyolysis, osteoporosis
• Gabapentin did NOT show advantage over placebo in a controlled study for cholestatic itch
• Liver transplantation ultimately improves symptoms in end-stage disease

C. Hematologic Pruritus

Iron deficiency

• Generalized or localized (especially perianal or vulvar) itch improving with iron supplementation
• Critical caveat: iron deficiency can itself be a SIGN of polycythemia vera or other malignancy — always determine the cause, including exclusion of GI blood loss

Polycythemia vera

• Aquagenic pruritus may PRECEDE polycythemia vera by SEVERAL YEARS; eventually affects ~30%–50%
• Consider PV in ALL patients with aquagenic pruritus
• Other findings: ruddy facial complexion, erythema of hands/feet, conjunctival injection
• ~97% have the somatic JAK2 V617F mutation → constitutive activation and agonist hypersensitivity in basophils
• Ruxolitinib (JAK1/2 inhibitor) led to rapid improvement in RCTs
• Others: hydroxyurea, aspirin 300 mg daily, UVB/PUVA, SSRIs, interferon-α-2b (approved, good efficacy), H1/H2 antagonists (variable)

D. Pruritus and Malignancy

• "Paraneoplastic itch" (IFSI 2014 definition) = "a systemic reaction to the presence of a tumor or hematologic malignancy, neither induced by the local presence of cancer cells nor by tumor therapy"
• Disappears with remission, returns with relapse
• Most frequent with: myeloproliferative neoplasms (polycythemia vera > essential thrombocythemia), lymphoma (Hodgkin > non-Hodgkin), and liver/biliary cancers
• Cohort data: chronic pruritus without skin findings → 2-fold increased risk of hematologic malignancy and 3.7-fold increased risk of bile duct malignancy; 1-year absolute cancer risk 1.6%
• In pediatric patients, itch is most often associated with HEMATOLOGIC malignancies
• Intensity and extent of pruritus do NOT generally correlate with extent of tumor involvement
• Mechanisms proposed: toxic products from necrotic tumor cells, tumor-produced mediators, allergic reaction to tumor antigens, increased proteolytic activity; also biliary obstruction or brain involvement ("central" pruritus)
• Treatment: treat the malignancy; refractory → antidepressants (paroxetine, mirtazapine), gabapentinoids, opioid modulators, NK1 receptor antagonists, histone deacetylase inhibitors

Hodgkin lymphoma specifically:

• Up to 30%; usually generalized, classically at NIGHT with chills and sweating
• Severe persistent pruritus predicts a POOR PROGNOSIS; return may portend recurrence
• It has been proposed that pruritus be added to the "B symptoms"
• Mechanisms: eosinophilia, histamine from basophils, leukopeptidases, bradykinin; IL-5 from Reed–Sternberg cells → eosinophilia
• Reported treatments: phototherapy, cimetidine, carbamazepine, mirtazapine, oral corticosteroids, NK1 antagonists

Leukemia

• Not common; when present usually generalized; most often CLL and hypereosinophilic syndromes
• CLL patients can develop exaggerated reactions to insect bites

E. Endocrine Pruritus

• Hyperthyroidism: severe generalized pruritus may be a PRESENTING symptom; postulated direct thyroid hormone effect on skin
• Hypothyroidism: less frequent; dry skin → asteatotic eczema with pruritus
• Diabetes mellitus: generalized pruritus often first develops on the BACK; diabetic polyneuropathy causes pain/burning/prickling but can present with pruritus starting on the feet and lower legs

F. Pruritus in HIV Infection

• Severe, treatment-resistant pruritus; possible correlation with increased HIV viral load
• Immunologic: markedly elevated IgE, peripheral hypereosinophilia, Th2-type cytokine profile
• Associated dermatoses: pruritic papular eruption, eosinophilic folliculitis, severe seborrheic dermatitis, psoriasis, scabies, insect bite reactions, drug eruptions, xerosis, acquired ichthyosis; Kaposi sarcoma occasionally pruritic
• Antihistamines with anti-eosinophilic potential (e.g. cetirizine) may be more effective
• UVB is considered SAFE in HIV-infected individuals
• Caution: skin conditions may FLARE when ART is started (immune reconstitution inflammatory syndrome)
• Thalidomide 100–300 mg daily used for pruritus and prurigo nodularis in HIV/AIDS — advantage: it is NOT an immunosuppressant

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• Some drug effects (e.g. hepatotoxicity) have a relatively LONG LATENCY period before pruritus appears
• Morphine also causes NON-IMMUNOLOGIC histamine release from mast cells

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• Purely sensory complaint WITHOUT a delusional component, primary skin disease, or underlying medical condition
• Rare; must be separated from excoriation (skin-picking) disorder, in which lesions are created WITHOUT pre-existing pruritus
• Intensity parallels the emotional state and is often exaggerated
• No primary lesions; secondary lesions range from lichenification to excoriations
• Sleep pattern is usually UNINTERRUPTED (useful discriminating feature)
• Sedative antipruritics (doxepin) used since topicals alone are rarely effective; psychiatric consultation recommended

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A. Overarching Principle

> "No antipruritic drug is indicated for relief of itch irrespective of its origin" — individualized management is mandatory.

B. General Measures

• Patient education and elimination of provocative factors
• Soft breathable clothing (no wool or rough fabrics)
• Avoid excessive bathing; lukewarm baths/showers with mild synthetic detergents (syndets)
• Daily emollients, applied immediately after bathing
• Manage dermographism if present
• Teach methods to interrupt the itch–scratch cycle (cold washcloth, gentle pressure)
• Controlled exercise, relaxation therapy, minimize heat exposure, reduce stress/anxiety
• IMPORTANT COUNSELING PEARL: AVOID telling patients "don't scratch" — it is extremely difficult advice to follow

C. Topical Treatment

• Corticosteroids; anesthetics (pramoxine, polidocanol); counterirritants (menthol, camphor)
• Topical anesthetics (lidocaine/prilocaine): decrease pain and pruritus; may relieve tingling and dysesthesias
• Topical doxepin: effective in atopic dermatitis, LSC, nummular eczema, contact dermatitis
• Cautions: drowsiness when applied over large areas or in young children; allergic contact dermatitis; risk of SYSTEMIC contact dermatitis with subsequent oral doxepin
• Compounded cromolyn sodium: relieves allergen-/histamine-induced pruritus without blocking wheal formation → suggests a mechanism other than prevention of mast cell degranulation
• Capsaicin: alkaloid from Solanaceae (chili peppers)
• Mechanism: enhances release then secondarily inhibits re-accumulation of neuropeptides (substance P); transiently destroys intraepidermal nerve fibers
• 0.025%–0.1%, applied 3–6× daily for maximal effect
• Safe on large areas; side effects (stinging, burning, pain, erythema) decrease with continued use
• NOT beneficial in atopic dermatitis (important negative)
• Tacrolimus/pimecrolimus: anti-inflammatory + antipruritic; burning and erythema most common adverse events
• Topical ruxolitinib: rapid improvement of pruritus in atopic dermatitis

• Chronic pruritus (CP) = 'an unpleasant sensation leading to the desire to scratch', lasting ≥6 weeks; a symptom of dermatological, systemic, neurological or psychiatric disease.
• Classification terms: pruritus on inflamed skin (e.g. atopic eczema); pruritus on non-inflamed skin (replaces "pruritus sine materia"); pruritus along with chronic scratch lesions (secondary excoriations/erosions/ulcers/crusting/lichenification/dyspigmentation forming typical pictures such as lichen simplex or prurigo nodularis (PN)).
• Specific terms: aquagenic pruritus (after water contact), premonitory pruritus (precedes a disease), paraneoplastic pruritus (with malignancy).

• CP may be generalised or localised; most frequent underlying diseases: atopic eczema, chronic urticaria, psoriasis vulgaris, xerosis, chronic kidney disease (CKD) ± dialysis, hepatobiliary/cholestatic liver disorders, haematological disease. Significant proportion unexplained.
• High symptom burden, impaired QoL, sleep disturbance, reactive depression. In atopic eczema, DLQI correlates with pruritus, xerosis, disturbed sleep; in psoriasis, pruritus significantly impacts QoL (DLQI≥10); in systemic sclerosis, pruritus severity independently associates with severe sleep disturbance; PV-associated aquagenic pruritus → reduced health status, higher fatigue; CKD-associated CP → poor sleep, depression, 17% higher mortality risk. Women experience higher negative QoL impact than men, regardless of CP origin.

• Incidence in general population: 7% (German study, 1190 participants); similar point prevalence 8.4% (Oslo, 18 747 participants).
• Prevalence range: 13.5% (point) to 25.5% (lifetime) (4500 participants); working-age population point prevalence 16.8% (11 730 participants).
• Prevalence increases with age: 12.3% (ages 16–30) → 20.3% (ages 61–70).
• Dermatological patient retrospective studies: pruritus in 2.5% (Copenhagen), 8.2% (London), 42% (France).
• Age: no age limit; can occur in newborns (atopic eczema, ichthyosis). Frequency increases with age.
• Sex: nearly equal (women 54.8%, men 45.2%); men significantly older at onset (mean +3 years), more cardiovascular/uro-genital comorbidities and co-medications; women have more neuropathic/psychosomatic disease and report more emotional/psychosomatic negative influence on CP. PN more common in women, with higher itch intensity and QoL impact.
• Ethnicity: prevalence varies; darker skin types thought more affected. European study: healthy male immigrants from East Asia/Middle East/North Africa had more frequent acute pruritus than Norwegians/Western immigrants. Capsaicin studies: African Americans had lower pain hypersensitivity than East Asians/Hispanics/white people. US studies: African Americans have more severe pruritus than white people — suggests neurobiological ethnic differences.

Examples of diseases inducing CP (% of patients affected, selected)

• Dermatological: atopic eczema 100%; chronic urticaria (all forms) 100%; bullous pemphigoid 100%; erythroderma 97%; post-burn scars 87%; psoriasis 67–84%; systemic sclerosis 42.6%; pruritic papular eruption in HIV 11–46%; elderly skin 20–46%.
• Metabolic/endocrine: hepatobiliary disease with/without cholestasis 80–100%; primary biliary cholangitis 25–70%; CKD 10–77%; anorexia 58%; diabetes mellitus 2.7–49%; hyperthyroidism 4–7.5%.
• Infective: HIV/AIDS 13%; hepatitis C 15%; varicella 17% (during shingles), 4.5% (CP after healing).
• Haematological/neoplastic: myelofibrosis 69%; Hodgkin lymphoma 30%; polycythaemia vera 28–42.2%; non-Hodgkin lymphoma 10%; iron deficiency anaemia 7.4–13.6%; essential thrombocytosis 7.1–9.1%; leukaemia 5%; solid tumours 3%.
• Drug-induced: all targeted cancer therapies 17.4% (14–47%); imatinib 10.2%; infliximab 8%; rituximab 20%.
• Neurological: brachioradial pruritus 100%; notalgia paraesthetica 100%; postherpetic neuralgia 58%.
• Psychiatric/psychosomatic: depression 17.5%; fibromyalgia 60%; stress and anxiety 56–72%.

• More than one disease often responsible; sometimes none found. Systemic disease presence in CP patients varied 13–50% across small studies. Analysis of 3700 CP patients: dermatological disease 31.6%; systemic disease 8.6%; neurological disease 10.2%; psychiatric disease 1.5%; multiple aetiologies 41.3%; unknown origin 6.8%.
• Malignancy is a rare but important association: large cohorts (n=8744, n=12 813) of CP on non-lesional skin identified haematological diseases and bile duct malignancies, particularly within the first year after onset.

Cutaneous induction of itch

• Cutaneous sensory C and Aδ nerve fibres involved. 1997: unmyelinated, mechano-insensitive C fibres specialised for histamine-induced itch (not pain) identified. TRPV1-equipped nociceptors transmit histamine-induced itch via phospholipase Cβ3 (PLCβ3).
• Most CP types (except urticaria, several drug-related forms) are non-histaminergic: mechano-sensitive C and Aδ nociceptors (2007) require TRPA1 and TRPV1 channels. Cowhage (Mucuna pruriens) activates mechano-sensitive non-histaminergic C and Aδ fibres. C fibres transmit slow burning, Aδ fibres transmit faster pricking itch qualities.
• Spontaneous C-fibre activity found in symptomatic CP skin areas. Atopic eczema, PN, psoriasis show decreased epidermal nerve fibre number and increased substance P (SP)-positive dermal nerve fibres.

Central transmission of itch

• Peripheral afferents synapse in dorsal horn (laminae I–II); itch-specific spinal neurons express GRPR and NPPB (natriuretic polypeptide B). GRP (gastrin-releasing peptide) also acts peripherally — induces scratching via mast cell degranulation in animal models.
• Spinal circuits form gates controlling itch transmission (e.g. via scratching counter-stimuli); dynorphin release activates κ receptors, decreasing spinal neuronal activity; spinal interneurons expressing Bhlhb5 inhibit dorsal horn itch pathways (under control of pain neurons) — identified novel antipruritic drug targets.
• Secondary itch neuron crosses to contralateral spino-thalamic tract, ascends to prefrontal areas, SMA, premotor cortex, anterior insular cortex, anterior midcingulate cortex, S1/S2, thalamus, basal ganglia, cerebellum. No specific 'itch matrix' — broad overlap with pain activation maps on fMRI.

Important mediators and receptors for itch (selected)

• Acetylcholine — muscarinic ACh receptor — atopic eczema (cutaneous/spinal neurotransmitter).
• GRP — GRP receptor — mast cell degranulation.
• IL-31 — IL-31RA/OSMR — atopic eczema, familial primary cutaneous amyloidosis, PN, bullous pemphigoid.
• IL-4, IL-13 — IL-4R — atopic eczema.
• Periostin — integrin αVβ3 — atopic eczema, PN, stasis dermatitis, bullous pemphigoid.
• Histamine — H1, H4 receptor — urticaria, insect bite reactions, cutaneous mastocytosis.
• Endothelin 1 — endothelin A receptor — NO release, vasodilatation.
• NGF — TrkA — atopic eczema, psoriasis.
• Endorphins — μ opioid receptor — cholestatic pruritus.
• Dynorphin — κ opioid receptor — uraemic pruritus.
• Tryptase, mucunain — PAR-2, PAR-4 — atopic eczema, cutaneous mastocytosis.
• Cathepsin S — PAR-2, PAR-4, MrgprC11; MrgprA3, TRPA1 for chloroquine — chloroquine-induced pruritus.
• Bilirubin — MrgprX4 — hepatic pruritus.
• Autotaxin — LPA — hepatic pruritus.
• Substance P — neurokinin 1 receptor (NK1R) — atopic eczema, PN, psoriasis.

Scratching

• Reflex functioning at spinal level, modified by higher centres; may be habitual/triggered by boredom or emotion. Relieves itching for several minutes (temporary suppression of relay-synapse facilitating circuits via fast-conducting myelinated afferent stimulation — transepidermal electrical nerve stimulation, vibration, or scratching itself); alternatively may simply damage sensory nerve endings (repair takes minutes). Why some itches evoke scratching (scabies) vs rubbing (lichen planus, urticaria) is unknown. Scratching used as objective quantification method for itch.

Peripheral and central neuronal sensitisation

• Sensitisation = increased primary sensory neuron responses to itch/pain mediators. Clinical pointers: ongoing spontaneous neuronal activity, alloknesis (non-pruritogenic stimuli, e.g. light touch, eliciting itch), hyperknesis (enhanced itch response to a normal itch stimulus). Mediated by bradykinin, NGF. Central sensitisation: spontaneous superficial dorsal horn neuron activity, enhanced mechanically-evoked responses; brain areas (parabrachial nucleus, periaqueductal gray, prefrontal cortex, anterior cingulate cortex, amygdala) show excitability changes.

Mediators of itching in skin diseases

• Concept pioneered by Lewis ('H substances'). Measured via intradermal injection + NRS/VAS, mouse scratching assays, or skin perfusion/microdialysis.
• Histamine: archetypal acute itch mediator; itch if injected upper dermis, pain if deeper; tachyphylaxis with repeat injection. H1 receptors traditionally responsible (via TRPV1 opening through PLCβ3); H4 receptors act directly on mast cells and Th2 lymphocytes in atopic eczema; H2 receptors not involved. Main source = dermal mast cells (± basophils), released via FcεR1 cross-linking (specific antigen, or autoantibody in chronic urticaria). Elevated tissue histamine demonstrated in chronic urticaria lesional skin. H1 antihistamines have been used (often inappropriately) for pruritus generally, based on urticaria efficacy.
• Acetylcholine: causes pain in healthy subjects but itch in atopics on intradermal injection; tissue levels elevated in atopic eczema. Botulinum toxin A inhibits ACh release, suppresses experimental histamine-induced pruritus and notalgia paraesthetica.
• Tachykinins (Substance P): 11-amino-acid neuropeptide binding NK1R (widely expressed CNS, dorsal horn, skin including keratinocytes/mast cells); synthesised in C-fibre cell bodies, released with depolarisation; induces neurogenic inflammation (redness, wealing, itching) partly via mast cell degranulation; SP mediates TNF-α release from mast cells → afferent nociceptive sensitisation. Aprepitant (selective NK1R antagonist) effective in case series for Sézary syndrome, PN, targeted-cancer-therapy drug-induced pruritus — but phase II (aprepitant) and phase III (serlopitant) trials failed to show meaningful itch reduction in PN and chronic itch of unknown origin.
• Opioid peptides: 3 groups (endorphins, enkephalins, dynorphins), 3 receptor types (μ, δ, κ). μ receptor mediates morphine/opioid pruritus (antagonised by naloxone/naltrexone); κ receptor ligation is antipruritic. Skin expresses μ and κ receptors. Elevated tissue/plasma opioid peptides in cholestasis; cholestatic pruritus ameliorated by μ antagonist naloxone. Nalfurafine (κ agonist) reduces end-stage CKD itch — licensed in Japan 2009. Difelikefalin (κ agonist) — significant phase III antipruritic effect, approved for CKD pruritus. Nalbuphine also under testing.
• Proteases, Mrgpr agonists, endothelin 1: cowhage spicules contain mucunain (cysteine protease, more pruritic than histamine when injected) acting via PAR-2/PAR-4 on mechano-sensitive C fibres; natural counterpart = mast cell tryptase, causes SP release from C neurons. PAR-2 overexpressed in atopic eczema skin, tryptase levels increased (microdialysis). SLIGRL-NH2 (histamine-independent pruritogen) acts via MrgprC11 rather than PAR-2. Mrgpr family: >20 members in mice, single human analogues (MrgprX1, MrgprX4). Chloroquine induces itch via MrgprA3. Netherton syndrome (SPINK5 mutation → lack of LEKTI protease inhibitor) itch speculated due to increased protease activity. Cathepsin E = endogenous itch inducer via epidermal endothelin 1 production (produced by mast cells, endothelial cells, keratinocytes). MrgprX2 on skin mast cells — activation triggers degranulation/mediator release/itch; plays a role in chronic spontaneous urticaria, atopic dermatitis, psoriatic itch.
• Neurotrophins: NGF and neurotrophin 4 regulate neuron growth/function; NGF (from keratinocytes/mast cells) binds TrkA, causes nerve fibre sprouting, upregulates SP. Atopic eczema skin shows elevated keratinocyte NGF and increased epidermal/dermal TrkA.
• Cytokines (IL-2, 4, 13, 31): IL-2 (from activated T cells) injected intradermally causes intense pruritus in atopic and non-atopic volunteers; ciclosporin (IL-2 suppressor) is antipruritic in atopic eczema. IL-4 and IL-13: receptors on sensory neurons signal via JAK pathway and TRPA1/TRPV1; IL-4Rα activation sensitises sensory neurons to other pruritogens; released by Th2 cells/mast cells/basophils in acute inflammation; act on keratinocytes/fibroblasts/eosinophils/monocytes/B cells, enhancing epidermal CXCL9/10/11 and thymic stromal lymphopoietin expression. IL-31: Th2 cytokine (CLA subtype), elevated in atopic eczema skin/serum; heterodimeric receptor IL-31RA + OSMR on keratinocytes/monocytes and dorsal root ganglia neurons; induces itch/scratching in mouse models; anti-IL-31R antibody ameliorates scratching. Highly associated with itch in PN, lichen amyloidosis, cutaneous T-cell lymphoma, stasis dermatitis, CKD-pruritus, dermatomyositis. Periostin (extracellular matrix/matricellular protein): binds integrins, directly stimulates nerve fibres, interacts with immune/non-immune cells → Th2 response; contributes to itch in atopic eczema, PN, pemphigoid, stasis dermatitis, scabies.

History

• Standardised questionnaires recommended. Important to address psychological impairment — adjustment disorder, social/professional withdrawal, reactive depression. Assessment tools: PHQ-15, PHQ-2, PHQ-9, HADS.

Important history-taking details in CP

• Pruritus-specific: start/duration; localisation (start, spread); quality (burning [classic in dermatitis herpetiformis/lupus], pricking, tingling, formication, presence of pain); intensity (VAS/NRS, past 24h average/worst); course (diurnal variation — scabies typically worse at night; situational/continuous/attacks; spontaneous change); triggering/ameliorating factors, role of emotions pre-scratching; behavioural response (scratch/rub, conscious vs subconscious); temporal association with illness/surgery/medication; occupational/social exposure (fibreglass, birds, dogs, cats, rats, farm animals); travel history (onchocerciasis, gnathostomiasis, giardiasis); other affected family members (suggests scabies); previous therapies; self-treatment/over-bathing; patient's own theory of cause; psychogenic stress factors; QoL impairments, sleep disturbance.
• General: previous illnesses/dermatoses; drug intake (prescribed/OTC/recreational), infusions, transfusions; previous surgeries; allergies (type I/IV); atopic predisposition; malignancy signs (weight loss, fever, night sweats); pregnancy; systems review.

Presentation

• May occur on non-diseased skin or with dermatosis; scratching alters the clinical picture — excoriations, erosions, papules, nodules, lichenification, scars, hyper-/hypopigmentation. If predominant, may conceal the initial dermatosis. Distinguish primary dermatosis from secondary scratch lesions; ask about relief methods.
• Specific reaction patterns: lichen simplex, prurigo nodularis.
• 'Butterfly sign': sparing of the interscapular back (acnestis) unreachable by the patient — common finding in generalised pruritus with scratch lesions.

Clinical variants

Pruritus in inflamed skin (dermatoses)

• All patients: atopic eczema, urticaria, bullous pemphigoid report itch; only a subset: pityriasis rubra pilaris, lichen planus. Intense widespread pruritus: Sézary syndrome; cutaneous mastocytosis (with rubbing/Darier sign). Mycosis fungoides: pruritus may precede skin signs ('invisible mycosis fungoides'), mainly late-stage and follicular variant. Subclinical urticaria: invisible dermographism.

Pruritus of atopic eczema

• Aggravated by scratch damage (itch–scratch cycle), worse at night, aggravated by wool contact, sweating, spicy food, alcohol. Multifactorial: dryness, inflammation, peripheral/central neural sensitisation. Alloknesis is a major component — explains paroxysms from scratching, sweating, temperature change, dressing/undressing. Histamine iontophoresis studies show decreased afferent response to high doses but increased sensitivity to low concentrations (possibly increased permeability of normal-looking atopic skin).
• Distinguish inflammation/lichenification-driven itch from dry-skin-driven itch — emollients alone insufficient if inflammation drives it. Lowering skin pH + soothing emollients (oatmeal extracts, pramoxine, polidocanol) reduce itch. Mediators beyond histamine: IL-4, -13, -31, thymic stromal lymphopoietin. H1 antihistamines of little proven value (Cochrane review), though widely used (sedative type) for presumed central sedative effect — some evidence sedation is a required component of successful systemic itch treatment in atopics, though data conflicting.
• Systemic antibiotics may modulate pruritus: microbiome dysbiosis → S. aureus colonisation (superantigen, T-cell activation, nerve activation via serine proteases, mast cell activation via TLRs, promotes IL-31).
• Topical corticosteroids effective (suppress inflammation, indirectly reduce itch) — especially with 'wet wrap' technique in pruritic children. Topical calcineurin inhibitors (tacrolimus, pimecrolimus) effective via T-cell downregulation. Crisaborole (topical PDE4 inhibitor) shows rapid antipruritic effect. Systemic ciclosporin, methotrexate, azathioprine highly effective (pan T-cell inhibition) but safety limits prolonged use.
• Dupilumab (anti-IL-4Rα): significant antipruritic effect, meaningful improvement after first dose. In trials: JAK inhibitors (baricitinib, abrocitinib, upadacitinib), IL-13/IL-31 receptor antagonists (tralokinumab, nemolizumab) — very potent antipruritic effects.
• Broad-band/narrow-band UVB effective (narrow-band superior/safer). Oral naltrexone (μ-opioid antagonist) if UVB ineffective.

Pruritus of psoriasis vulgaris

• Generalised pruritus in 80–89%; National Psoriasis Foundation (>5600 patients, 2003–2011): pruritus most common symptom (93%). Not dependent on age, gender, psoriasis type, disease duration, or last flare. ~80% have daily pruritus, usually confined to lesions, moderate intensity, but significantly affects QoL, causes stigmatisation and depressive symptoms. Higher embarrassment reported vs atopic eczema. Exacerbating factors: ambient heat (81%), skin dryness (80%), sweating (65%), stress (55%). Psoriasis Symptom Inventory (PSI): 8 items (itch, redness, scaling, burning, cracking, stinging, flaking, pain).
• Likely mediators: inflammatory T cells, neutrophils, IL-17; IL-31 initially thought uninvolved but recent studies show correlation with itch intensity. Neuropeptides from nerve fibres contribute — correlation between pruritus intensity and PGP 9.5-positive intraepidermal nerve fibres, NGF-positive keratinocytes, TrkA expression; increased perivascular SP-containing fibres, decreased neutral endopeptidase (SP-degrading enzyme); increased mast cell numbers/degranulation in papillary dermis.
• Unresponsive to most antipruritics including phototherapy, but declines with effective plaque clearance. Apremilast (PDE4 inhibitor) and biologics (IL-17, IL-23 inhibitors) reduce psoriatic itch.

Itching in systemic disease

CKD-associated pruritus (nephrogenic/uraemic pruritus)

• Occurs in ~10–77%; rare in children/acute renal failure; more common with haemodialysis than CAPD. Skin may be normal-appearing; can be persistent/extensive/refractory or transitory/localised. Secondary changes: pigmentation, PN (often secondarily infected). Histology: normal-appearing skin may show sweat/sebaceous gland attenuation, increased mast cells (no correlation with pruritus established).
• Multifactorial pathophysiology: μ opioid receptor overexpression/κ downregulation imbalance, Th1 cytokine upregulation, elevated IL-31, abnormal neuron-specific-enolase-positive unmyelinated nerve fibre sprouting. Raised PTH (secondary hyperparathyroidism) suggested (PTH increases tissue mast cells) but no convincing PTH-pruritus correlation. Aluminium overload proposed but unconfirmed. Histamine unlikely (antihistamines ineffective). DOPPS (29 000 patients): risk factors = male sex, pre-existing lung/heart/liver disease, elevated serum calcium/phosphorus — NOT uraemia — hence term "CKD pruritus" now preferred over "uraemic pruritus."
• Management: urea-based topical humectants may help; topical tacrolimus 0.1% ineffective in RCT. Elevated plasma met-enkephalin reported but uncorrelated. κ opioid agonists promising — nalfurafine (Japan only) and difelikefalin (significant phase III effect, approved US/Europe). Dialysis itself has little benefit (though improved with better-biocompatible membranes). Renal transplantation = only curative/reliable treatment. Parathyroidectomy may relieve pruritus in secondary hyperparathyroidism. UVB phototherapy frequently effective (meta-analysis support); combined UVA/UVB depletes skin vitamin A (proposed mechanism). Only UVB and activated charcoal have established track records. Heparin, mexiletine, ion-exchange resin, IV lignocaine of uncertain effectiveness. Naltrexone some efficacy but unconfirmed by controlled studies. Antihistamines/topical steroids generally unhelpful; emollients help dry skin. Topical capsaicin 0.025% effective for localised CKD pruritus.

Hepatobiliary diseases and cholestasis (cholestatic pruritus)

• May be generalised or localised (hands/feet); early symptom of hepatobiliary disease; associated with rubbing rather than scratching (less secondary excoriation/infection than renal pruritus). ~70% of cholestasis patients report pruritus. Commonest causes: intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hereditary paediatric cholestatic disorders. Hepatitis C: intense cholestatic pruritus in 15% of infected patients.
• Bile salt levels correlate poorly with pruritus (except ICP); bile salts applied to blister bases cause pruritus only at supra-physiological concentrations. Autotaxin (ATX) and its product lysophosphatidic acid (LPA) implicated as mediators — serum ATX levels specific for cholestatic pruritus. Colesevelam (bile salt sequestrant) reduces serum bile salts but only marginally alters pruritus/ATX. Rifampicin significantly reduces itch intensity and ATX activity in bile-salt-sequestrant-refractory patients (caution: hepatotoxicity). Cholestyramine (ion-exchange resin) similar results. Ursodeoxycholic acid disappointing in meta-analysis. Bilirubin elicits itch via MrgprX4 on peripheral nerve fibres.
• Elevated plasma opioid peptides in cholestasis (human and rat); cholestatic plasma induces facial scratching in monkeys, reversed by naloxone. Parenteral/oral opioid antagonists (naloxone, naltrexone) effective — response can trigger opioid withdrawal symptoms. Cholestatic pruritus can also occur in pregnancy and premenstrually.

Polycythaemia vera (PV)

• ~50% of untreated JAK2V617-mutated PV patients develop severe prickly discomfort within minutes of water contact, lasting 15–60 min ('bath itch'/aquagenic pruritus). No visible skin change; associated with elevated serum/urinary histamine; platelet aggregation suggested mechanism. May precede PV diagnosis by years. Regional sponge-bathing may mitigate. Treating underlying PV may not relieve itch; correcting venesection-induced iron deficiency may help but risks worsening PV. Antihistamines effective in ~30% (JAK2V617 → increased mast cell activation). PUVA, narrow-band UVB, interferon-α2b, paroxetine, pregabalin, aspirin all reported successful in some patients. JAK2 inhibitors may reduce PV itch.

Thyrotoxicosis

• Intractable itch with warm moist skin, may be presenting symptom; cause uncertain — cutaneous vasodilatation increases skin temperature, lowering itch threshold.

Diabetes (diabetogenic pruritus)

• Contrary to past assumptions, generalised pruritus IS a diabetic manifestation. Large survey (2656 diabetic, 499 non-diabetic): 26.3% vs 14.6% with CP (P<0.001); truncal pruritus 11.3% vs 2.9% (P=0.0001). Abnormal sensation and Achilles areflexia = independent risk factors → associated with diabetic polyneuropathy. Another study: 27.5% of 385 type 2 diabetics had itching, positively associated with postprandial blood glucose. Scalp itch without rash in elderly highly associated with diabetes (neuropathic cause suggested).

Malignancy (paraneoplastic pruritus)

• Haematological malignancies and hepatobiliary neoplasms associated with pruritus in large cohorts. Premonitory pruritus: Hodgkin disease (up to 5 years documented), PV (up to 13 years documented). Other candidates: Sézary syndrome, myelodysplastic syndrome, myelofibrosis; rarely non-Hodgkin lymphoma (incl. children), multiple myeloma, CLL, chronic myelomonocytic leukaemia. ~30% of Hodgkin disease patients have pruritus — one study linked to shorter life expectancy (not confirmed in recent studies).
• Rare localised paraneoplastic pruritus: unilateral facial pruritus (brainstem glioma); nasal pruritus (cerebral tumour); abdominal itching (astrocytoma in NF1). Other solid tumours (liver, breast, lung, gastric, laryngeal, prostate, cervical) anecdotally reported.
• Treatment: SSRIs (paroxetine), combined κ agonist/μ antagonist, pregabalin, gabapentin, thalidomide (haematological malignancies), short-course oral corticosteroids.

Drug-induced pruritus

• ~5% of all adverse skin reactions after drug intake. Two groups: (i) known drug/mechanism, clear temporal relationship (e.g. morphine, chloroquine, hydroxyethyl starch); (ii) unclear role, long latency. Hydroxyethyl starch: generalised pruritus in 15–42% of patients, from cutaneous nerve deposits, severe long-lasting mechanically-inducible itch, poorly responsive to antihistamines, may respond to topical capsaicin, systemic gabapentin or naltrexone.
• Second group: ACE inhibitors (captopril, enalapril), calcium channel blockers (amlodipine), β-blockers (atenolol, metoprolol), antidiabetics (glimepiride, metformin), diuretics (hydrochlorothiazide), hormones, statins, allopurinol. Recently: targeted/immunotherapeutic anticancer agents — EGFR inhibitors, tyrosine kinase inhibitors, BRAF/MEK inhibitors, PD1/PD-L1/CTLA-4 inhibitors.

Pruritus in pregnancy

• Occurs in ~20% of pregnant women; majority linked to pre-existing dermatoses (psoriasis, atopic eczema). Atopic eruption of pregnancy (AEP): early pregnancy, no fetal risk. Polymorphic eruption of pregnancy (PEP, formerly PUPPP): ~21.6% of itchy pregnant women, no fetal risk. Pemphigoid gestationis: rare (4.2%), may cause small-for-date babies. ICP: generalised pruritus without skin lesions initially, elevated bile acids, jaundice may follow onset; MDR3 gene splicing mutations linked, associated with stillbirth/cholelithiasis risk.
• No absolutely safe treatment, but persistent intense pruritus itself is prejudicial to healthy pregnancy. Loratadine used in >5000 pregnancies with no increased fetal risk (all trimesters). First-generation antihistamines (chlorpheniramine, hydroxyzine, dexchlorpheniramine) also considered safe (unlicensed). Topical corticosteroids as needed; UV therapy possible late pregnancy.

Pruritus of senescence

• Persistent widespread itching in ≥50% of people age ≥70. May be postmenopausal manifestation in women; may reflect subtle skin disease (scabies, especially institutionalised), systemic disorder (stroke, dementia, Parkinson disease, renal/hepatic/malignant disease), adverse drug reaction, or depression/loneliness (often multifactorial). Commonly from xerosis — reduced sebum production/altered composition (not major factor), impaired water retention (worse in winter). Water-induced itch in elderly is a variant, especially in institutionalised/overheated-dry environments. Senescent stratum corneum shows greatly reduced water content. Dystrophic afferent nerve terminal changes may contribute; immunosenescence (Th2 cytokine skew) causes eczematous itchy rash. Bullous pemphigoid, stasis dermatitis, PN, cutaneous T-cell lymphoma more common in elderly.
• Management: multiple emollients trialled; white soft paraffin cheap/occlusive, accelerates barrier recovery; 10% urea lotion effective; encourage ≥twice-daily application; modify ambient temperature/humidity. Mirtazapine at night useful with depression/sleep disturbance. Corticosteroids/antihistamines/cooling lotions NOT indicated for xerosis-driven itch. For inflammatory/eczematous cases, methotrexate and dupilumab seem safer than ciclosporin/systemic corticosteroids in the elderly.

Neurological diseases (neuropathic pruritus)

• From peripheral/central nerve fibre injury; overlapping itch/pain = 'pruralgia' (stinging, burning, wet sensation, electric shock, pins and needles, mechanical dynamic allodynia). Cannot be clearly differentiated from neuropathic pain; may co-occur. Arises from local nerve compression (brachioradial pruritus, notalgia paraesthetica — dermatomal distribution) or nerve fibre degeneration (small fibre neuropathy — localised or generalised). Standard oral antipruritics (antihistamines, doxepin, chlorpromazine, diphenylhydantoin) and topical/intralesional corticosteroids are ineffective; gabapentinoids effective.

Notalgia paraesthetica: common localised persistent pruritus — persistent burning pruritus in the mid-scapular area, may spread more widely including scalp. Mild lichenification/pigmentation ± macular amyloidosis (from rubbing — amyloid from necrotic keratinocyte material) but little else visible. Linked to nerve root entrapment/sensory neuropathy of primary dorsal rami T2–T6; more common in females. Capsaicin cream/patch can help. Other localised neuropathic itch types: cheiralgia paraesthetica (radial nerve), meralgia paraesthetica (lateral femoral cutaneous nerve), gonyalgia paraesthetica (infrapatellar saphenous nerve branch).

Brachioradial pruritus (BRP): elbow/adjacent arm region, C5/C6 dermatome, may involve shoulder/neck; worsened by sunlight, improved by cold ('ice pack sign'); more females, mostly age >60. Caused by cervical spinal cord/nerve root compression (disc herniation, osteophytes, cervical rib, cervical ependymomas) — MRI cervical spine strongly recommended. Topical local anaesthetics/cooling compounds help; gabapentin or pregabalin most effective; anecdotal: topical capsaicin, ketamine–lidocaine, amitriptyline, oral carbamazepine, botulinum toxin injections.

• Localised pruritus also common in genito-anal area (pruritus ani, pruritus vulvae, trichodynia).

Psychiatric and psychosomatic diseases (psychogenic pruritus)

• No satisfactory "rule in/rule out" paradigm — diagnosed by exclusion. Psychiatric comorbidities (stress, depression, anxiety) common regardless of underlying cause; severe persistent pruritus → secondary depression → lowers itch threshold → vicious circle. Diagnostic criteria proposed for functional itch disorder. High CP prevalence in psychiatric inpatients (up to 32%). Fibromyalgia often has significant chronic itch component.
• Widespread psychogenic pruritus can cause extensive disfiguring excoriation/scarring/self-mutilation. Delusions of infestation: rare, recognisable by description (formication) and "the specimen sign" (patient brings particulate material believed to be insects/products). Refer to psychiatry, ideally joint dermatology/psychiatry clinic; consider risperidone.

• VAS (100 mm line, 0=none to 100=worst); NRS (0–10); VRS (graduated adjectives, 0=none to 4=very severe) — all show high reliability/correlation, good test-retest reproducibility.
• VAS severity bands: 0 = none; >0–<30 = mild; ≥30–<70 = moderate; ≥70–<90 = severe; ≥90 = very severe.
• No diagnostic serum biomarker for CP exists. Symptom diary useful for severe/unclear cases.

• Thorough exam: entire skin, scalp, hair, nails, ano-genital region, mucous membranes; general exam including lymph node palpation.
• Follow the European Guideline Expert Panel diagnostic algorithm, balancing clinical need vs exhaustive rule-out.

Laboratory and radiological diagnostics in CP

• First-step screening: non-specific inflammatory markers (plasma viscosity, ESR, CRP); differential blood count; blood urea nitrogen, creatinine; alkaline phosphatase, γ-GT, AST, ALT, bilirubin; TSH; glucose; ferritin; LDH; age >40: stool occult blood; ano-genital pruritus: stool parasite testing; urine dipstick for microscopic haematuria; chest X-ray; abdominal ultrasound.
• Further investigations: biopsy with routine histology and DIF (mastocytosis, pemphigoid, etc.); immunoelectrophoresis; hepatitis B/C antibodies; antimitochondrial antibodies; HIV antibodies; ANA; PTH, calcium; erythrocyte fluorescence (erythropoietic protoporphyria screen); PSA; tryptase; bile acid (if ICP suspected); Candida swab (mucocutaneous pruritus); further imaging/bone marrow per symptoms (e.g. MRI thoracic/cervical spine for neuropathic pruritus); skin biopsy with electron microscopy for hydroxyethyl starch.
• CP can be prodromal (e.g. before Hodgkin lymphoma) — annual physical exam recommended for unclear-origin CP; encourage patient self-examination/re-presentation with new symptoms.

• No general recommendation — individualised based on age, comorbidities, medications, itch quality/intensity. Elderly, pregnant women, children need special attention.
• General measures instituted in every patient; careful diagnostic evaluation and treatment of underlying disease before further therapy; stepwise symptomatic treatment if pruritus persists.

General measures for treating CP

• Avoid: dry skin; factors worsening dry skin (heat, frequent washing/bathing); irritant contact (poison ivy/oak, stinging nettle); hot/spicy food, large amounts of hot drinks and alcohol; stress.
• Apply: non-alkaline soaps, synthetic detergents, moisturising bath/shower oils; luke-warm bath water (≤20 min) ± colloidal oatmeal; short luke-warm showers; soft air-permeable clothing (cotton); daily skin moisturisation (especially post-shower/bath); topicals for night-time symptomatic relief (5–10% urea, 0.5–5% menthol in aqueous cream, tannin, calamine oily lotion, crotamiton cream, doxepin cream); emollients with urea, ceramide, nicotinamide, lactic acid, glycerol, lauromacrogols, soya oil; wet cooling wraps (moisturiser, black tea); 20% zinc oxide ointment-impregnated rayon stockings (limbs with chronic scratch lesions); habit reversal training.

Symptomatic therapy guideline

• Step 1: general measures + basic moisturiser therapy + initial symptomatic therapy (systemic non-sedative H1 antihistamines, topical corticosteroids).
• Step 2: if CP origin known — symptomatic causative-adapted therapy.
• Step 3: unknown origin or step-2-refractory — topical/systemic options: pramoxine, capsaicin, calcineurin inhibitors, topical polidocanol, ketamine–lidocaine and amitriptyline, systemic naltrexone, gabapentin, pregabalin, butorphanol, UV phototherapy, immunosuppressants (ciclosporin, methotrexate).
• Concomitant at every step: diagnostics/treatment of underlying disease; general measures; sedative H1 antihistamines/tricyclic antidepressants/neuroleptics for sleep disorders; psychosomatic care, habit reversal therapy; disinfecting measures + topical corticosteroids for erosive scratch lesions.

• Pruritus (itching) is a sensation EXCLUSIVE TO THE SKIN, defined as the sensation that produces the desire to scratch.
• Pruritogenic stimuli are FIRST responded to by KERATINOCYTES, which release a variety of mediators, and by fine intraepidermal C-neuron filaments.
• Approximately 5% of the afferent UNMYELINATED C NEURONS, as well as a population of thinly myelinated type A γ nerve fibers, respond to pruritogenic stimuli.
• Itch sensations are also influenced by pruritogens released by lymphocytes, mast cells, eosinophils, and macrophages.

• Histamine and the H4 receptor
• Tryptase and its proteinase-activated receptor type 2
• Opioid peptides and the mu (µ) and kappa (κ) opioid receptors
• Leukotriene B4
• Prostaglandins such as PGE
• Thymic stromal lymphopoietin
• Acetylcholine
• Cytokines such as interleukin-31 (IL-31)
• Neuropeptides and vasoactive peptides (e.g., nerve growth factor, substance P) and their receptors (e.g., TRPV1)

• Via signaling involving BOTH histaminergic AND nonhistaminergic pathways, itch sensations are transmitted by the LATERAL SPINOTHALAMIC TRACT to the brain, where a variety of foci generate BOTH stimulatory AND inhibitory responses.
• The SUM of this complicated set of interactions appears to determine the QUALITY and INTENSITY of itch.
• Investigation is ongoing into downstream mediators such as the intracellular JANUS KINASE signaling pathways.

• Itching may be elicited by many normally occurring stimuli: light touch, temperature change, and emotional stress.
• Also chemical, mechanical, and electrical stimuli.
• Affected more commonly and to a more significant degree: OLDER patients, WOMEN, and BLACK persons.
• The brain may REINTERPRET such sensations as being PAINFUL or causative of BURNING or STINGING sensations.

1. Pruritoceptive itch — initiated by SKIN disorders.
2. Neurogenic itch — generated in the CENTRAL NERVOUS SYSTEM and caused by SYSTEMIC disorders.
3. Neuropathic itch — caused by ANATOMIC LESIONS of the central or peripheral nervous system.
4. Psychogenic itch — the type observed in PARASITOPHOBIA.

• An OVERLAP or MIXTURE of these types may be causative in any individual patient.

• There are wide variations from person to person, and a person may have a variation in reactions to the SAME stimulus.
• HEAT will usually AGGRAVATE preexisting pruritus.
• Stress, absence of distractions, anxiety, and fear may all ENHANCE itching.
• Itching tends to be MOST SEVERE during UNDRESSING FOR BED.
• PAROXYSMAL pruritus: severe pruritus, with or without prior skin lesions, may be paroxysmal with SUDDEN onset, often severe enough to AWAKEN the patient.
• May STOP INSTANTLY and COMPLETELY as soon as PAIN is induced by scratching.
• However, the PLEASURE of scratching is so intense that the patient, despite realizing they are damaging the skin, is often unable to stop short of inflicting such damage.

• Lichen simplex chronicus
• Atopic dermatitis
• Nummular eczema
• Dermatitis herpetiformis
• Neurotic excoriations
• Eosinophilic folliculitis
• Uremic pruritus
• Prurigo simplex
• Paraneoplastic itch (usually secondary to LYMPHOMA)
• Prurigo nodularis
• In general, ONLY these disorders produce such intense pruritus and scratching as to INDUCE BLEEDING. In individual cases, other diseases may manifest such severe symptoms.

• Keep COOL; avoid HOT baths or showers and WOOL clothing (a nonspecific irritant, as is xerosis).
• Many patients note itching INCREASES after showers when they wash with soap and then dry roughly.
• Using soap ONLY in the axilla and inguinal area, PATTING dry, and applying a MOISTURIZER can often prevent such exacerbations.
• If itching is severe, a trial of "SOAKING AND SMEARING" may provide significant relief.
• Patients often use an ice bag or hot water; however, HOT WATER can IRRITATE the skin, is effective only for SHORT periods, and OVER TIME EXACERBATES the condition.

• Topical anesthetics:
• Many contain BENZOCAINE, which may produce CONTACT SENSITIZATION.
• PREFERRED anesthetics (beneficial in localized conditions): pramoxine in a variety of vehicles, lidocaine 5% ointment, eutectic mixture of lidocaine and prilocaine (EMLA) ointment, and lidocaine gel.
• EMLA and lidocaine may be TOXIC if applied to LARGE areas.
• Topical antihistamines are generally NOT recommended, although doxepin cream may be effective for MILD pruritus when used alone.
• Doxepin cream may cause CONTACT ALLERGY or a BURNING sensation, and SOMNOLENCE may occur when used over LARGE areas.
• Menthol- or camphor-containing lotions feel cool and improve pruritus.
• May be kept in the REFRIGERATOR to enhance this soothing effect.
• Other lotions have specific CERAMIDE content designed to mimic that of the normal epidermal barrier.
• Capsaicin — effective by DEPLETING SUBSTANCE P, but the BURNING sensation present during INITIAL use frequently causes patients to DISCONTINUE.
• Topical steroids, ruxolitinib, and calcineurin inhibitors decrease itching through antiinflammatory action — therefore of LIMITED efficacy in NEUROGENIC, PSYCHOGENIC, or SYSTEMIC disease–related pruritus.
• Crisaborole inhibits phosphodiesterase 4; helpful for atopic itch, but may produce a transient burning on application — as can the topical cannabinoid N-palmitoylethanolamine.

• Phototherapy with UVB, UVA, and PUVA may be useful.
• UVB is FAVORED because of PUVA's LONG-TERM INDUCTION OF SKIN CANCERS.
• Botulinum neurotoxin — helps neuropathic itch and lichen simplex chronicus.
• Intralesional corticosteroids — help inflammatory itch.

• Antihistamines (most frequently used by nondermatologists):
• First-generation H1 antihistamines (hydroxyzine, diphenhydramine) may be helpful for NOCTURNAL itching, but their efficacy as antipruritics is DISAPPOINTING in many disorders — EXCEPT for URTICARIA and MASTOCYTOSIS.
• DOXEPIN is an EXCEPTION: it can reduce anxiety and depression and is useful for several pruritic disorders.
• Sedating antihistamines should be prescribed CAUTIOUSLY, especially in ELDERLY patients, because they may induce IMPAIRED COGNITIVE FUNCTION.
• Nonsedating antihistamines and H2 blockers are effective ONLY for URTICARIA and MAST CELL DISEASE.
• Opioids:
• In general, activation of µ-OPIOID receptors STIMULATES itch, whereas κ-OPIOID receptor stimulation INHIBITS itch perception; however, the interaction is COMPLEX.
• Opioid-altering agents — naltrexone, naloxone, nalfurafine, butorphanol — have significant side effects and varying modes of delivery (intravenous, intranasal, oral).
• Initial reports of benefit in one condition are often followed by CONFLICTING reports on further study.
• These agents and prednisone are MOST USEFUL as RESCUE THERAPY for INTRACTABLE pruritus.
• Central reduction of itch perception:
• Anticonvulsants — gabapentin and pregabalin
• Antidepressants — mirtazapine and the SSRIs
• These take 8–12 WEEKS to attain FULL onset of action.
• Thalidomide — through direct neural effects, immunomodulatory actions, and hypnosedative effects; useful in select patients.
• Nonsteroidal immunosuppressants — methotrexate, mycophenolate, cyclosporine, and azathioprine — help itch from cutaneous and systemic inflammatory processes, especially those with heightened EOSINOPHILS and histologic SPONGIOSIS.
• Biologic/small-molecule agents — dupilumab, tofacitinib, abrocitinib, and upadacitinib.
• Tralokinumab — a human monoclonal antibody targeting the IL-13 receptor; helps inflammatory-mediated itch.
• Many more medications are in phase II and III trials, so the future is bright for improved therapeutics.

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• Itching may be present as a symptom in a number of internal disorders; intensity and duration vary from one disease to another.

• Liver disease — especially OBSTRUCTIVE and HEPATITIS C (with or without evidence of jaundice or liver failure)
• Renal failure
• Diabetes mellitus
• Hypothyroidism AND hyperthyroidism
• Hematopoietic diseases — e.g., iron deficiency anemia, polycythemia vera
• Neoplastic diseases — e.g., lymphoma (especially HODGKIN DISEASE and CUTANEOUS T-CELL LYMPHOMA), leukemia, myeloma
• Internal solid-tissue malignancies
• Intestinal parasites
• Carcinoid
• Multiple sclerosis
• AIDS
• Connective tissue disease — particularly DERMATOMYOSITIS
• Neuropsychiatric diseases — especially ANOREXIA NERVOSA

• Hodgkin disease: pruritus is usually CONTINUOUS and at times accompanied by SEVERE BURNING.
• Incidence of pruritus is 10–30%.
• It is the FIRST symptom of this disease in 7% of patients.
• Leukemia: pruritus — EXCEPT for chronic lymphocytic leukemia — tends to be LESS SEVERE than in Hodgkin disease.

• Internal organ cancer may be found in patients with generalized pruritus unexplained by skin lesions.
• RISK FACTORS FOR MALIGNANCY:
• Duration of LESS THAN 12 MONTHS
• Age OVER 60 YEARS
• A history of SMOKING or LIVER DISEASE

Suggested Workup for Chronic, Generalized Pruritus Without Primary Skin Findings

• Complete history
• Thorough physical examination
• Laboratory tests:
• Complete blood count (CBC) and differential
• Thyroid, liver, and renal panels
• Fasting blood glucose
• Hepatitis C serology
• HIV antibody (if risk factors are present)
• Urinalysis
• Stool for occult blood
• Serum protein electrophoresis
• Chest x-ray evaluation
• EOSINOPHILIA on the CBC is a GOOD SCREEN for PARASITIC diseases.
• BUT if the patient has been receiving SYSTEMIC CORTICOSTEROIDS, blood eosinophilia may NOT be a reliable screen, and STOOL SAMPLES for ova and parasites should be submitted.
• Additional radiologic studies or specialized tests are performed as indicated by age, history, and physical findings.
• Ethnic difference: BLACK patients may have a GREATER tendency to HEMATOLOGIC malignancies, whereas WHITE patients may be at increased risk of SKIN or LIVER cancers.
• A biopsy for DIRECT IMMUNOFLUORESCENCE is occasionally helpful to detect DERMATITIS HERPETIFORMIS or PEMPHIGOID.

• In many conditions, treatment of the UNDERLYING disease state (e.g., treating the cancer, replacing thyroid hormone in hypothyroidism) causes relief of the pruritus.
• A CLUE TO TREATMENT RESPONSE in chronic pruritus of unknown origin is the presence of EOSINOPHILIA:
• If PRESENT — as it is in approximately 40% — patients are MORE LIKELY to respond to ANTIINFLAMMATORY agents such as dupilumab, methotrexate, or UVB.
• Those who LACK this marker of TH2 differentiation may respond more to interventions targeting NEUROGENIC disorders, such as gabapentin or pregabalin.
• BE AWARE that disease-specific therapies can EXACERBATE itching during treatment — for example, in cancer patients treated with biologic agents such as the anti-EGFR monoclonal antibodies.

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• CKD is the MOST COMMON SYSTEMIC CAUSE of pruritus.
• 20–80% of patients with chronic renal failure have itching.
• The pruritus is often generalized, intractable, and severe; however, dialysis-associated pruritus may be EPISODIC, MILD, or LOCALIZED to the dialysis catheter site, face, or legs.

Mechanism (Multifactorial)

• Xerosis
• Secondary hyperparathyroidism
• Increased serum histamine levels
• Hypervitaminosis A
• Iron deficiency anemia
• Neuropathy

Complications That Contribute to Severity

• Acquired perforating disease (Fig. 4.2A and B — acquired perforating dermatosis of uremia)
• Lichen simplex chronicus
• Prurigo nodularis

Treatment

• Many patients have concomitant xerosis — aggressive use of emollients, including "soaking and smearing," may help.
• A trial of γ-linolenic acid cream twice daily was effective, as was one using baby oil.
• Gabapentin or pregabalin given THREE TIMES WEEKLY at the END of hemodialysis sessions can be effective.
• Renal excretion is DECREASED in CKD, so a LOW INITIAL DOSE of 100 mg of gabapentin or 25 mg of pregabalin after EACH session with SLOW UPWARD TITRATION is recommended.
• If a patient is intolerant of one, they may tolerate the other.
• A MAINSTAY of CKD-associated pruritus has been NARROW-BAND UVB therapy, which may be combined with gabapentin or pregabalin.
• Naltrexone, topical tacrolimus, and ondansetron were reported useful in initial trials, but SUBSEQUENT studies did NOT support the initial observations.
• Nalfurafine, 2.5 to 5 µg once daily after supper — demonstrated improvement and was relatively well tolerated over a 1-YEAR study.
• Other options: thalidomide, difelikefalin, dupilumab, and sodium thiosulfate.
• Patients on PERITONEAL dialysis have a LOWER severity of pruritus than those on HEMODIALYSIS.
• RENAL TRANSPLANTATION WILL ELIMINATE PRURITUS.

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• Chronic liver disease with obstructive jaundice may cause severe generalized pruritus.
• 20–50% of patients with jaundice have pruritus.
• KEY DISTINGUISHING FEATURE: as opposed to other causes of pruritus, ITCHING OF THE PALMS AND SOLES may be PRESENT BEFORE the generalized sensation.
• Conditions sharing pruritus: intrahepatic cholestasis of pregnancy, primary sclerosing cholangitis, and hereditary cholestatic diseases such as ALAGILLE SYNDROME.
• Hepatitis C may be associated with pruritus as well.

Pathophysiology

• Itching of biliary disease is probably caused by CENTRAL mechanisms.
• Not well understood, but it appears that LYSOPHOSPHATIDIC ACID — formed by the action of the enzyme AUTOTAXIN on lysophosphatidylcholine — is central.
• It is now known that BILIRUBIN activates Mas-related G protein–coupled receptor member X4 (MRGPRX4) receptors on SENSORY NEURONS and likely contributes to the pruritus of chronic liver disease.

Treatment

• FIRST-LINE: CHOLESTYRAMINE, 4–16 g daily.
• Rifampin, 150–300 mg/day — may be effective but should be used with CAUTION because it may cause HEPATITIS.
• Naltrexone, up to 50 mg/day — useful but has significant side effects.
• If used, START at 1/4 tablet (12.5 mg) and INCREASE by 1/4 tablet every 3–7 days until pruritus improves.
• Sertraline, 75–100 mg/day — another option.
• UVB phototherapy — effective in a small case series.
• Ursodeoxycholic acid — effective for the pruritus in INTRAHEPATIC CHOLESTASIS OF PREGNANCY, but NOT for the itching from OTHER causes.
• Albumin dialysis via the molecular absorbent recycling system — effective but of limited availability and costly.
• Plasmapheresis may cause transient relief.
• LIVER TRANSPLANTATION is the DEFINITIVE treatment for end-stage disease and provides dramatic relief from the severe pruritus.

Primary Biliary Cholangitis

• Old term: "primary biliary cirrhosis."
• Occurs almost EXCLUSIVELY in WOMEN OLDER THAN 30.
• Itching often begins INSIDIOUSLY and may be the PRESENTING symptom in a QUARTER TO HALF of patients.
• With time, EXTREME pruritus develops in ALMOST 80% of patients.
• This almost intolerable itching is accompanied by JAUNDICE and a striking MELANOTIC HYPERPIGMENTATION of the ENTIRE skin.
• The patient may turn ALMOST BLACK, EXCEPT for a HYPOPIGMENTED "BUTTERFLY" AREA IN THE UPPER BACK.
• Xanthomas: eruptive xanthomas, planar xanthomas of the palms, xanthelasma, and tuberous xanthomas over the joints may be seen.
• Other features: dark urine, steatorrhea, and osteoporosis occur frequently.
• Laboratory: serum bilirubin, alkaline phosphatase, serum ceruloplasmin, serum hyaluronate, and cholesterol values are INCREASED.
• The ANTIMITOCHONDRIAL ANTIBODY test is POSITIVE.
• The disease is usually RELENTLESSLY PROGRESSIVE with the development of HEPATIC FAILURE.
• Several cases have been accompanied by SCLERODERMA.
• Treatment of the itch is as with other causes of biliary pruritus.

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• 40% to 50% of patients with polycythemia vera report pruritus.
• Usually induced by TEMPERATURE CHANGES or SEVERAL MINUTES AFTER BATHING.
• The cause is UNKNOWN.

Treatment

• ASPIRIN — shown to provide IMMEDIATE relief from itching; however, there is a RISK OF HEMORRHAGIC COMPLICATIONS.
• PUVA and NB UVB are also effective.
• Marked improvement after an average of SIX treatments, with complete remission often occurring in 2–10 WEEKS.
• Paroxetine, 20 mg/day — produced clearing or near-complete clearing in a series of NINE patients.
• Interferon (IFN) α2 — effective for treating BOTH the underlying disease AND associated pruritus.
• Ruxolitinib is becoming a common therapy of polycythemia; it is hoped this will also quell the aquagenic pruritus.

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• Other names: asteatotic eczema, eczema craquelé, and xerotic eczema.
• Characterized by pruritus that usually FIRST manifests and is MOST SEVERE on the LEGS and ARMS.
• Extension to the body is common; HOWEVER, the FACE, SCALP, GROIN, AXILLAE, PALMS, and SOLES are SPARED.
• The skin is DRY with FINE FLAKES.
• The PRETIBIAL regions are PARTICULARLY susceptible and may develop FINE CRACKS in the eczematous area.

• Frequent and lengthy bathing with plenty of soap during the winter is the MOST FREQUENT cause.
• Especially prevalent in ELDERLY persons, whose skin has a DECREASED rate of repair of the epidermal water barrier and whose sebaceous glands are LESS PRODUCTIVE.
• LOW HUMIDITY in overheated rooms during cold weather contributes.
• In a study of 584 elderly individuals, the prevalence of asteatosis (28.9%) was SECOND ONLY to SEBORRHEIC DERMATITIS as the most common finding.

• Educate the patient: use soap ONLY in the axillae and inguinal area, and lubricate the skin with emollients IMMEDIATELY after showering.
• Preparations containing LACTIC ACID or UREA applied after bathing are helpful for some patients but may cause IRRITATION and may WORSEN ITCHING for patients with erythema and eczema.

The "Soaking and Smearing" Regimen

• For those with MORE SEVERE symptoms, LONG-STANDING disease, or a SIGNIFICANT INFLAMMATORY component — DRAMATICALLY effective.
• The patient SOAKS in a tub of PLAIN WATER at a COMFORTABLE TEMPERATURE for 20 MINUTES BEFORE BEDTIME.
• IMMEDIATELY on exiting the tub, WITHOUT DRYING, TRIAMCINOLONE 0.025–0.1% OINTMENT is applied to the WET skin.
• This will TRAP THE MOISTURE, LUBRICATE the skin, and allow for EXCELLENT PENETRATION of the steroid component.
• An OLD PAIR OF PAJAMAS is then donned, and the patient will note relief EVEN ON THE FIRST NIGHT.
• Nighttime soaks are repeated for SEVERAL NIGHTS, after which the ointment alone suffices, with maintenance therapy of limiting soap use to the axillae and groin, and moisturization after showering.
• PLAIN PETROLATUM may be used as the lubricant after soaking if SIMPLE DRYNESS WITHOUT INFLAMMATION is present.
• FOLLICULITIS may COMPLICATE this therapy.

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• Pruritus is often centered on the anal or genital area (LESS FREQUENTLY in BOTH), with minimal or no pruritus elsewhere.
• Anal neurodermatitis is characterized by PAROXYSMS OF VIOLENT ITCHING when the patient may tear at the affected area until BLEEDING is induced.
• Manifestations are IDENTICAL to lichen simplex chronicus elsewhere on the body.
• Specific etiologic factors should ALWAYS be sought — generally classified as dermatologic disease, local irritants (which may coexist with colorectal and anal causes), and infectious agents.

• Allergic contact dermatitis is a COMMON dermatologic cause or SECONDARY COMPLICATION.
• From various medicaments, FRAGRANCE IN TOILET TISSUE, or PRESERVATIVES IN MOIST TOILET TISSUE.
• One study reported 18 OF 40 consecutive patients having POSITIVE PATCH TEST results.
• Seborrheic dermatitis, psoriasis, lichen planus, lichen sclerosis, and atopic dermatitis may all cause perianal itching — examine other classic sites of involvement carefully.
• Extramammary Paget disease and Bowen disease — although NOT OFTEN ITCHY — may be present and WILL NOT IMPROVE WITH THERAPY.
• BIOPSY of resistant dermatitic-appearing skin should be done in NONRESPONSIVE pruritus ani.

• Irritant contact dermatitis from GASTROINTESTINAL CONTENTS, such as hot spices or cathartics, or failure to cleanse the area adequately after bowel movements.
• Anatomic factors may lead to leakage of rectal mucus onto perianal skin, promoting irritation.
• Physical changes — hemorrhoids, anal tags, fissures, and fistulas — may aggravate or produce pruritus.

• MYCOTIC pruritus ani — characterized by FISSURES and a WHITE, SODDEN EPIDERMIS.
• Scrapings examined directly with KOH mounts; cultures will usually reveal Candida albicans, Epidermophyton floccosum, or Trichophyton rubrum.
• Other sites of fungal infection — groin, toes, and nails — should also be investigated.
• ERYTHRASMA in the groin and perianal regions may occasionally produce pruritus.
• Diagnosis established by CORAL RED FLUORESCENCE under the Wood's light.
• β-Hemolytic streptococcal infections have been implicated, especially in YOUNG CHILDREN.
• The use of TETRACYCLINES may cause pruritus ani, MOST OFTEN IN WOMEN, by inducing CANDIDIASIS.
• DIABETIC patients are susceptible to PERIANAL CANDIDIASIS.

• PINWORM infestations — especially in children and sometimes in their PARENTS; NOCTURNAL pruritus is most prevalent.
• Other intestinal parasites: Taenia solium, Taenia saginata, amebiasis, and Strongyloides stercoralis.
• Pediculosis pubis may cause anal itching; however, attention is focused by the patient on the PUBIC area, where itching is most severe.
• Scabies may be causative but often will also involve the FINGER WEBS, WRISTS, AXILLAE, AREOLAE, and GENITALIA.

• LUMBOSACRAL RADICULOPATHY also may be present with pruritus ani, as assessed by radiographs and nerve conduction studies; PARAVERTEBRAL BLOCKADE may help these patients.

• Meticulous toilet care should be followed, NO MATTER WHAT the cause of the itching.
• After defecation, the anal area should be cleansed whenever possible, washed with mild soap and water.
• Cleansing with WET TOILET TISSUE is advisable in ALL cases.
• Medicated cleansing pads (Tucks) should be used regularly.
• A variety of moist toilet tissue products are available — CONTACT ALLERGY TO PRESERVATIVES in these products is occasionally a problem.
• An emollient lotion (Balneol) is helpful for cleansing without producing irritation.
• Once the etiologic agent is identified, a rational and effective treatment regimen may be started.
• Topical corticosteroids are effective for most noninfectious types; however, topical TACROLIMUS ointment will frequently suffice and is SAFER.
• Pramoxine, a nonsteroidal topical anesthetic, is also often effective, especially in a lotion form combined with hydrocortisone.
• In pruritus ani, as well as in pruritus scroti and vulvae, it is sometimes BEST to DISCONTINUE ALL topical medications and treat with PLAIN WATER SITZ BATHS AT NIGHT, followed IMMEDIATELY by PLAIN PETROLATUM applied OVER WET SKIN.
• This soothes the area, provides a barrier, and eliminates contact with potential allergens and irritants.
• If an oral agent is needed, DUPILUMAB has given salutary results.

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• The scrotum of an adult is a SUSCEPTIBLE site for CIRCUMSCRIBED NEURODERMATITIS (lichen simplex chronicus).
• PSYCHOGENIC pruritus is probably the MOST FREQUENT type of itching seen.
• Why it PREFERENTIALLY affects the scrotum — or in women the vulva — is UNCLEAR.
• Lichenification may result, can be EXTREME, and may PERSIST FOR MANY YEARS despite intensive therapy.

• Infectious conditions may complicate or cause pruritus but are LESS COMMON than idiopathic scrotal pruritus.
• FUNGAL infections, EXCEPT CANDIDIASIS, usually SPARE the scrotum.
• When CANDIDAL infection affects the scrotum, BURNING RATHER THAN PRURITUS is frequently the PRIMARY symptom — the scrotum is eroded, weepy, or crusted.
• KEY DISTRIBUTION CONTRAST: the scrotum may be affected to a lesser degree in pruritus ani, but this pruritus usually affects the MIDLINE, extending from the anus along the midline to the BASE of the scrotum — rather than the DEPENDENT SURFACES of the scrotum, where PRURITUS SCROTI usually occurs.
• Scrotal pruritus may be associated with ALLERGIC CONTACT DERMATITIS from topical medications, INCLUDING STEROIDAL AGENTS.

• Topical tacrolimus, pramoxine, doxepin, and simple petrolatum applied after a sitz bath (as described for pruritus ani) are all useful and AVOID use of topical corticosteroids.
• Effective topical steroids should be used with CAUTION.
• As with FACIAL skin, after attempts to WEAN patients off the steroid, SEVERE BURNING and REDNESS may occur.
• Although usually seen after CHRONIC use, this may occur EVEN WITH SHORT-TERM HIGH-POTENCY steroids.

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• The vulva is a common site for pruritus of different causes; pruritus vulvae is the COUNTERPART of pruritus scroti (lichen simplex chronicus of the vulva).

• Unspecified dermatitis — 54%
• Lichen sclerosus — 13%
• Chronic vulvovaginal candidiasis — 10%
• Dysesthetic vulvodynia — 9%
• Psoriasis — 5%
• In PREPUBERTAL children, such itching is MOST FREQUENTLY IRRITANT in nature, and girls generally benefit from EDUCATION about improved hygienic measures.

• VAGINAL CANDIDIASIS is a FREQUENT cause — especially during PREGNANCY and when ORAL ANTIBIOTICS are taken.
• The inguinal, perineal, and perianal areas may be affected.
• Microscopic examination for Candida albicans and cultures for fungus should be performed.
• Trichomonas vaginalis infection may cause vulvar pruritus.
• Examination of VAGINAL SECRETIONS is often diagnostic.
• The organism is recognized by its MOTILITY, SIZE (somewhat LARGER than a leukocyte), and PIRIFORM SHAPE.

• PATCH TESTING will discover a RELEVANT ALLERGEN in MANY cases of otherwise nonspecific itchy genital dermatitis.
• Common causes of vulvar pruritus: contact dermatitis from topical medications (especially LOCAL ANESTHETICS and CORTICOSTEROIDS), sanitary pads, contraceptives, douche solutions, fragrance, preservatives, and a partner's condoms.
• URINARY INCONTINENCE should also be considered.
• LICHEN SCLEROSUS — another frequent cause of pruritus in the genital area of MIDDLE-AGED and ELDERLY women.
• LICHEN PLANUS may involve the vulva → pruritus and mucosal changes, including EROSIONS and ULCERATIONS, RESORPTION OF THE LABIA MINORA, and ATROPHY.
• Other causes: atopic dermatitis, lichen simplex chronicus, and plasma cell vulvitis.
• WHEN BURNING RATHER THAN ITCHING PREDOMINATES, the patient should be EVALUATED FOR SIGNS OF SENSORY NEUROPATHY.

• Candidiasis and Trichomonas treatments are discussed in Chapters 13 and 15, respectively.
• Lichen sclerosus responds BEST to PULSED DOSING of HIGH-POTENCY topical steroids or to topical tacrolimus or pimecrolimus.
• Topical steroidal agents and topical tacrolimus may be used to treat psychogenic pruritus or irritant or allergic reactions.
• The use of SILK FABRIC UNDERWEAR may limit irritation.
• PATCH TESTING will assist in identifying the inciting allergen.
• High-potency topical steroids are effective in treating lichen planus (other options in Chapter 10).
• Topical lidocaine, topical pramoxine, or oral agents such as dupilumab or tricyclic antidepressants (TCA) may be helpful in select cases.
• ANY chronic genital skin disease that does NOT respond to therapy should prompt a BIOPSY to investigate for BOWEN DISEASE or EXTRAMAMMARY PAGET DISEASE.

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• Aquagenic pruritus = itching evoked by CONTACT WITH WATER OF ANY TEMPERATURE.
• Most patients experience severe, PRICKLING discomfort WITHIN MINUTES of exposure to water or ON CESSATION of exposure.

• About ONE-THIRD: an OLDER, primarily MALE population who have polycythemia vera, essential thrombocytopenia, hypereosinophilic syndrome, or myelodysplastic syndrome.
• TWO-THIRDS: YOUNGER WOMEN who develop aquagenic pruritus as young adults, have NO known underlying disease, and may have a FAMILY HISTORY of similar symptoms.
• A specific mutation in JAK2 V617F causes polycythemia vera — this test should be ordered for patients with aquagenic pruritus AND a RAISED HEMOGLOBIN or HEMATOCRIT.

• MUST be distinguished from XEROSIS, as water may be perceived as an irritant in severely dry skin — in these cases an initial trial of "soaking and smearing" is recommended.
• Treatment options: antihistamines, SODIUM BICARBONATE dissolved in bath water, propranolol, atenolol, SSRIs, acetylsalicylic acid (aspirin), pregabalin, β-ALANINE (2 g twice daily), montelukast, omalizumab, and NB UVB or PUVA phototherapy.
• One patient found TIGHT-FITTING CLOTHING settled the symptoms after only 5 MINUTES.

• Shelley et al reported two patients with WIDESPREAD BURNING PAIN lasting 15–45 MINUTES after water exposure, calling this "AQUADYNIA" and considering it a VARIANT of aquagenic pruritus.
• CLONIDINE and PROPRANOLOL seemed to provide some relief.

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• Rather common, especially in ELDERLY persons.
• BLACK patients also experience MORE scalp pruritus, DYSESTHESIA (tingling, pain, burning), and HAIR LOSS than White persons.
• LACK of excoriations, scaling, or erythema EXCLUDES inflammatory causes of scalp pruritus such as seborrheic dermatitis, psoriasis, dermatomyositis, or lichen simplex chronicus.
• Most such remaining cases are NEUROPATHIC or PSYCHOGENIC, but SOME represent CHRONIC FOLLICULITIS.

• Topical tar shampoos, salicylic acid shampoos, corticosteroid topical gels, mousse, shampoos, and liquids can be helpful.
• In patients with severe scalp pruritus with LOCALIZED itch, an intralesional injection of corticosteroid suspension may provide relief.
• Oral TETRACYCLINES or oral ANTIHISTAMINES may be helpful.
• In other patients, LOW doses of antidepressants such as DOXEPIN are useful.
• At times, FULL antidepressant doses will be effective, with monitoring for TROUGH LEVELS and ELECTROCARDIOGRAMS (EKGs) recommended.

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• Medications should be considered a possible cause of pruritus WITH OR WITHOUT a skin eruption.
• Pruritus is frequently present after OPIOID use.
• CHLOROQUINE and, to a lesser degree, other antimalarials produce pruritus in many patients, ESPECIALLY BLACK PATIENTS, treated for MALARIA.
• Other frequent causes: SSRIs, NSAIDs, cardiovascular medications including CALCIUM CHANNEL BLOCKERS and DIURETICS, heparin, trimethoprim-sulfamethoxazole, hormonal agents, bleomycin, rifampin, β-lactam antibiotics, and drugs causing CHOLESTATIC LIVER DISEASE.

• Used as a VOLUME EXPANDER, a substitute for human plasma.
• ONE-THIRD of ALL patients treated will develop SEVERE PRURITUS with a LONG LATENCY OF ONSET (3–15 WEEKS) and PERSISTENCE.
• Up to 30% of patients have LOCALIZED symptoms.
• ANTIHISTAMINES ARE INEFFECTIVE.

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• The PREFERRED term for the chronic itchy idiopathic dermatosis described here.
• Likely variations of prurigo simplex: papular dermatitis, subacute prurigo, "ITCHY RED BUMP" DISEASE, urticarial dermatitis, and the ERUPTION OF SENESCENCE OF BERGER.
• The term "prurigo" continues to LACK NOSOLOGIC PRECISION.

Clinical Features

• Characterized by the PRURIGO PAPULE: DOME SHAPED and TOPPED WITH A SMALL VESICLE.
• The VESICLE is usually present ONLY TRANSIENTLY because of its IMMEDIATE REMOVAL BY SCRATCHING, so a CRUSTED PAPULE is more frequently seen.
• Prurigo papules are present in VARIOUS STAGES of development.
• Seen mostly in MIDDLE-AGE or ELDERLY persons of BOTH SEXES.
• Common sites: trunk and EXTENSOR surfaces of the extremities, SYMMETRICALLY distributed.
• Other areas: face, neck, lower trunk, and buttocks.
• Lesions usually appear in CROPS, so papulovesicles AND the late stages of SCARRING may be seen AT THE SAME TIME.
• At times, ECZEMATOUS morphology may be intermixed.

Histopathology

• NONSPECIFIC but often SUGGESTS AN ARTHROPOD REACTION.
• Often a PERIVASCULAR MONONUCLEAR infiltrate with SOME EOSINOPHILS and OCCASIONALLY SPONGIOSIS.

Differential Diagnosis

• Scabies, atopic dermatitis, insect bite reactions, papular urticaria, dermatitis herpetiformis, contact dermatitis, PLEVA (pityriasis lichenoides et varioliformis acuta), transient acantholytic dermatosis (TAD), papuloerythroderma of Ofuji, dermatographism, and physical urticarias.
• BIOPSY may be helpful in differentiating DERMATITIS HERPETIFORMIS, PLEVA, TAD, and, on occasion, UNSUSPECTED SCABIES.

Treatment

• Initial: topical corticosteroids and oral antihistamines.
• Early in the disease process, MODERATE-strength steroids should be used; if unresponsive, change to HIGH-POTENCY forms.
• "Soaking and smearing" may be necessary.
• Intralesional injection of triamcinolone will eradicate individual lesions.
• For more recalcitrant disease: UVB or PUVA therapy may be beneficial.
• If such interventions do not provide relief: dupilumab, JAK inhibitors, mycophenolate, methotrexate, or LOW-DOSE azathioprine may be needed.

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• A RARE dermatosis of UNKNOWN cause.
• Characterized by the SUDDEN onset of erythematous PAPULES or VESICLES that leave RETICULATED HYPERPIGMENTATION when they heal.
• Mainly affects JAPANESE people, although numerous cases have been reported in WHITE patients.
• WOMEN outnumber MEN 2:1.
• The MEAN AGE OF ONSET is 25 YEARS.

Associations and Triggers

• Associated with: WEIGHT LOSS, DIETING, ANOREXIA, POST–BARIATRIC SURGERY, PREGNANCY, DIABETES, and KETONURIA.
• EXACERBATED by HEAT, SWEATING, and FRICTION — and thus occurs MOST OFTEN in the WINTER and SPRING.

Distribution and Histology

• Areas most frequently involved: UPPER BACK, NAPE, CLAVICULAR REGION, and CHEST.
• MUCOUS MEMBRANES ARE SPARED.
• Histology of EARLY lesions: NEUTROPHILS in the DERMAL PAPILLAE and EPIDERMIS.
• Following this: a LICHENOID DERMATITIS with VARIABLE PSORIASIFORM HYPERPLASIA occurs.
• DIRECT IMMUNOFLUORESCENCE yields NEGATIVE findings.

Treatment

• MINOCYCLINE, 100–200 mg/day, is the TREATMENT OF CHOICE.
• Also effective: dapsone, colchicine, topical crisaborole, and ALTERATION OF THE DIET.
• TOPICAL STEROIDS ARE NOT EFFECTIVE.
• RECURRENCE and EXACERBATIONS ARE COMMON.

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• A RARE disorder MOST OFTEN found in JAPAN.
• Characterized by FLAT-TOPPED, RED-TO-BROWN PRURITIC PAPULES that SPARE the SKINFOLDS, producing BANDS OF UNINVOLVED CUTIS — the so-called DECK-CHAIR SIGN.
• ALMOST ALL patients are OVER AGE 55, with CLEAR MALE PREDOMINANCE.
• Frequently, there is associated BLOOD EOSINOPHILIA.

Histology

• A DENSE LYMPHOHISTIOCYTIC infiltrate
• EOSINOPHILS in the PAPILLARY DERMIS
• INCREASED LANGERHANS CELLS

Malignancy Association

• Malignancies have occurred in 21% of reported cases, but the TIMING and COURSE do NOT always correlate with PEO.
• Reported malignancies: T-cell lymphomas, B-cell lymphomas, Sézary syndrome, myelodysplastic syndrome, and visceral carcinomas.

Other Inducers and Mimics

• Drugs (e.g., aspirin, ranitidine, furosemide) and infections (e.g., HIV, hepatitis C) may induce the condition.
• Severe ATOPIC DERMATITIS and CUTANEOUS T-CELL LYMPHOMA may present with IDENTICAL morphologic findings of PEO.
• HISTORY will assist in making the diagnosis of ATOPIC DERMATITIS, whereas BIOPSY may reveal findings diagnostic of other eruptions.

Treatment

• PUVA in combination with ORAL RETINOIDS or ORAL STEROIDS has HISTORICALLY produced the BEST results.
• DUPILUMAB has proven effective in some cases.
• Other effective treatments: tar derivatives, emollients, and cyclosporine; UVB, PUVA, and oral retinoids ALONE may also be therapeutic.

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