Chronic Pruritus in the Absence of Skin Disease

In This Article

Abstract and Introduction

Abstract

Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed.

Introduction

Causing an intense need to scratch, pruritus (itch) is described as an unpleasant sensation that has a large impact on patients' quality of life. Pruritus is considered to be the most frequent symptom in dermatology. It is important to differentiate between the acute induction of pruritus, such as through histamine release following contact with certain plants or animals, or an allergic reaction after application of a drug or stimuli in an experimental model, and chronic forms of pruritus (CP; pruritus lasting for >6 weeks), which can be caused by many clinical conditions.^[1,2] Peripheral and central sensitization processes are examples of complex mechanisms that take place in chronic pruritus.^[2] Of note, up to half of patients with CP have presented lacking primary skin lesions but suffering mainly from pruritus of extracutaneous origins, such as that found in lymphoproliferative or neurological disorders.^[3,4] Many of these patients presented to the dermatologist with secondary skin symptoms ranging from dry, irritated skin to severe scratch lesions. It is therefore essential for dermatologists to be familiar with the most important underlying diseases and drugs that can cause chronic pruritus.

Table 1. Presumed mechanisms underlying drug-induced pruritus in undamaged skin (examples) Modified from Reich et al. [27]
Mechanism	Drug class
Cholestatic pruritus	Antihypertensives
	Antiarrythmics
	Anticoagulants
	Antidiabetics
	Antithyroid agents
	Antibiotics (carbapenems, trimethoprim/sulfamethoxazole)
	Corticosteroids
	Psychotropic drugs
Increased bradykinin levels	Agiotensin-converting enzyme inhibitors
Activation of peripheral serotonin receptors	Selective serotonin re-uptake inhibitors
Sebostasis	Tamoxifen
Pruritogenic effect of IL-2	IL-2
Deposition of HES in peripheral nerves	HES
Increased synthesis of leukotrienes	Nonsteroidal anti-inflammatory drugs
Mast cell degranulation	Antibody against CTLA4 (e.g., ipilimumab)
	Opioids
Impact on skin differentiation (can evolve with xerosis, acneiform rash)	EGFR inhibitors (e.g., erlotinib)
Central modulation of μ-opioid-receptors	Opioids

EGFR epidermal growth factor receptor, HES hydroxyethyl starch, IL-2 interleukin 2

Table 2. Medical history: key questions in chronic pruritus ^a
Question	Interpretation
1) How long has the itch been present?	Question regarding duration (≤12 months: lymphoma or liver tumor possible. If so, please consider also Q.11)
2) Did it develop shortly after or together with a new illness identified/surgery performed/new medication?	Question regarding an easily recognizable connection. Women: please consider also pregnancy. Medications can also cause pruritus months after its initiation
3) Did the itch appear together with any skin changes?	Yes: Dermatoses or scratch lesions No: Pruritus in systemic, neurological, psychiatric diseases
4) Where is the itch located?	Localized (e.g., neuropathic causes such as notalgia paresthetica)
	Generalized
	Daily varying localizations (e.g., as described in prostate cancer)
5) Are family members also affected?	Consider infestations such as scabies
6) Does contact with water cause the itch?	Aquagenic pruritus, can also occur in connection with polycythemia vera
7) Does scratching, rubbing or pressure cause the itch?	Mechanically induced pruritus occurs in atopic dermatitis (so-called alloknesis), urticaria facticia, mastocytosis, hydroxyethyl starch-induced pruritus, cholestatic pruritus
8) Previous therapies?	Important for planning future therapies
9) Do you experience a reduced quality of life?	Simple question for assessing the burden induced by pruritus. Alternatively, patients can receive the questionnaire 'ItchyQol'
10) What is the current intensity on a numerical rating scale (NRS) from 0 (no pruritus) to 10 (severe pruritus)?	Important for documenting progress. Always ask Q.9 and Q.10 during follow-up visits
11) Do you have night sweats, lymph node swelling, or unwanted weight loss?	Symptoms associated with malignant underlying diseases

^aIn addition to general medical history questions regarding underlying diseases, allergies, atopic disposition, current medications, etc

Table 3. Basic examinations for generalized chronic pruritus on ordinary skin (follow-up laboratory test: 1x/year). Modified from the European Guideline [42]
Basic examinations
Initial laboratory tests	Blood count with differential, ferritin
	Erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP)
	Creatinine, urea, calculated glomerular filtration rate (GFR), K+, urine (stick test)
	Bilirubin, transaminases (GPT/ALAT and GOT/ASAT), gammaglutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH)
	Thyroid-stimulating hormone (TSH)
	Fasting blood glucose
Supplementary examinations
For pathological values in the initial examination	Further laboratory and radiological diagnostics of the disease
Localization and clinical history adapted diagnostics (examples)	For anal pruritus: parasites, worm eggs, digital examination of the rectum, prostate-specific antigen (PSA)
	For aquagenic and genital pruritus, pruritus of unknown origin: lactose and sorbitol intolerance test
	Pruritus during pregnancy:
	For ordinary skin findings: dermatological examination to exclude polymorphic eruption of pregnancy (PEP), gestational pemphigoid
	For abnormal skin findings: ALAT, bile acid (fasting)