HistoryThis section has been translated automatically.
The disease was first described by Haraway in the USA in 1880. Subsequently, in France, Lailler, Brocq, de Beurmann, Hallopeau described the disease casuistically. Brocq describes it under the title Lichen corneus obtusus. In the German literature Fabry, Kreibich Hübner and Brill are listed among the authors. Hyde & Montgomery proposed the name prurigo nodularis in 1909, which later became accepted.
DefinitionThis section has been translated automatically.
Very rare, chronic, polyetiologic systemic disease characterized by numerous, large, intensely pruritic (or also painful) plaques and nodules, which is regarded as the maximum form of prurigo simplex subacuta (or nodular variant of lichen simplex chronicus) (remark: many authors emphasize the etiogenetic independence of prurigo nodularis).
Characteristic for this disease is an almost unbreakable cycle of itching/pain, uncontrollable scratching. From lesional scratching effects with reactive skin changes (inflammation, acanthosis, fibrosis, increased density of substance P-positive nerves) and a again flaring itching/pain (Tsianakas A et al. 2016).
Clinically, malignant tumor diseases (e.g., lymphogranulomatosis of the skin; cutaneous T-cell lymphoma) should be excluded. Renal and hepatic insufficiency, diabetes mellitus and gluten sensitivity should be clarified (Suárez C et al. 1984).
A highly chronic course over several years (decades) is predictable and must be taken into account when planning therapy.
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EtiopathogenesisThis section has been translated automatically.
A sensorimotor peripheral polyneuropathy induced by multiple factors, often subclinical, is discussed (Hughes JM et al. 2020). It has been shown that reduced intraepidermal nerve fiber density (IENFD) is present in the skin lesions of prurigo nodularis (see also small fiber neuropathy). To date, the effects and associations of gluten sensitivity on this disorder have received little attention or research.
In the pathogenesis of prurigo nodularis, a form of "neuronal sensitization" is also present, whereby the itch/pain-processing neurons are triggered and activated, thereby maintaining an "itch-scratch cycle".
An inflammatory response in the skin and neuronal plasticity also play a role. Histopathologically, there are changes in the nerve fibers in the skin as well as inflammatory cells in the dermis. The itch/pain in this disease may be triggered by release of tryptase, interleukin 31 (IL-31), prostaglandins, eosinophil cationic protein (ECP), and neuropeptides by inflammatory cells, mast cells, and nerve fibers.
Recent studies show that up to 50-fold increased production of interleukin-31 mRNA is detectable in prurigo nodes. The studies in patients with atopic dermatitis and prurigo nodularis, suggest that interleukin-31 released by activated CD4-positive T cells is a major trigger of itch/pain in these diseases. Thus, interleukin-31 is already referred to as the "itch cytokine."
IL-31 receptor A is most highly expressed in the sensory neurons of the spinal ganglia of the spinal cord. Similarly, interleukin-31 activates signal transducers of the JAK-STAT pathway (JAK1 and JAK2), which in turn can re-induce itch.
ManifestationThis section has been translated automatically.
LocalizationThis section has been translated automatically.
Sacral area (50%), abdomen (40%), extremity extensor sides bilaterally, soles and palms always remain free. Face is rarely affected. The mucous membranes close to the skin are never affected. Nail lesions are absent.
Clinical featuresThis section has been translated automatically.
Disseminated, usually symmetrically arranged, dome-shaped, 0.3-2.0 cm in size, coarse, initially slightly or more reddened with prolonged persistence, reddish-brown to dirty-gray, excruciatingly burning-itching (itching is described as burning pain ) roundish, firm papules and nodules. The itchy burning pain persists continuously or alternates with periods of relative calm with periods of unbearable itching.
The papules and nodules are usually sharply demarcated. They maintain a defined distance from each other and do not confluence. The interlesional skin remains intact. A Köbner phenomenon cannot be observed. However, there is a certain linearity in the distribution pattern.
This results in a conspicuously ordered, topographic pattern showing nodular or papular efflorescences in an otherwise unchanged skin. The papules/nodules are often excoriated or exulcerated by purposefully placed sharp scooping (linear scratch marks indicating uncoordinated scratching, as in atopic dermatitis, do not exist), whereby the lesions are levered out to the deep corium with the fingernails or suitable objects. This provides patients with significant relief. Any wound pain that develops later is reported to be more tolerable.
In older nodules, there is a tendency to keratotic or verruciform, even bifurcated surface structures. Other signs of underlying skin disease (e.g., evidence of atopic, psoriatic, or lichen planus diathesis) are absent.
HistologyThis section has been translated automatically.
Pronounced, plump acanthosis with irregular elongation of the mostly colbulous distended rectal ridges. Marked proliferation of the adnexal epithelia. There is overall aspect of pseudoepitheliomatous hyperplasia. Vigorous orthohyperkeratosis with focal parahyperkeratosis. Widespread capillaries are evident in the stratum papillare as well as in the upper dermis. In addition, there are predominantly vascular, but also diffuse, rather sparse lymphohistiocytic infiltrates, occasionally intermixed with eosinophilic leukocytes. In erosions, plasma cells and neutrophilic leukocytes are also found. There is usually marked fibrosis of the dermis, with collagen bundles running perpendicular to the epidermis. Repeated evidence of schwannoma-like neural hyperplasias(Pautrier's neuromas).
Differential diagnosisThis section has been translated automatically.
Prurigo simplex subacuta (no nodule formation, only nodules, identical itching)
Prurigo form of atopic eczema (detectable signs of atopic eczema)
Lichen planus verrucosus (to be verified histologically, mostly lower leg; look for other lichen planus lesions!)
Prurigoform of bullous pemphigoid (DIF to be clarified, flat nodule formation, possibly blistering)
Multiple eruptive keratoacanthomas (eruptive onset, itching absent, typical clinic of keratoacanthoma with central honey plug)
General therapyThis section has been translated automatically.
Therapeutic results of all known therapeutic measures are unsatisfactory. In almost all patients, topical cortisone preparations fail after initial slight success, and antihistamines are also ineffective.
Cooperation with a psychologist or a psychiatrist is necessary to improve the (reactively) depressive attitude of the patient. Especially in prurigo nodularis patients suffer more from anxiety, depression and have more suicidal thoughts.
A therapeutic approach with tricyclic antidepressants can be helpful in coping with the disease.
A new approach is the treatment with nemolizumab, which showed good results in a phase II trial at Münster University Hospital in 2020 as part of the drug approval process. The compound has recently been approved (Williams KA et al. 2021).
External therapyThis section has been translated automatically.
Short-term highly potent external glucocorticoids such as 0.1% mometasone ointment (e.g. Ecural) or 0.05% clobetasone cream (e.g. Dermoxin) under occlusion.
If without effect, multiple, potwise, intralesional application of triamcinolone (draw up 10 mg Volon A together with 1-2 ml 1% scandicaine, take your time when injecting, use a thin needle).
Sublesional application is easier but useless. In addition, there is a risk of fat tissue atrophy in women!
There have been reports of success with ablative laser systems, see below. Here, the principle of "eradication" of the lesion with subsequent scar healing is effective.
Radiation therapyThis section has been translated automatically.
In case of atopically superimposed clinical picture try phototherapy (UVB or UVA1), balneophototherapy, PUVA therapy, systemic or local (as balneophotochemotherapy).
Internal therapyThis section has been translated automatically.
Sedating antihistamines such as hydroxyzine (e.g. Atarax) with 1-3 tablets/day p.o. Dimetinden (e.g. Fenistil) 2 times/day 1 tablet p.o. or Clemastin (e.g. Tavegil) 2 times/day 1 tablet p.o. are therapeutics of first choice.
In case of therapy resistance: therapy with methotrexate - 15-20mg/week s.c. ( off-label use)
Alternative: Ciclosporin A (3.0-5.0 mg/kg bw/day).
Alternative: Trial of thalidomide 200 mg/day ( off-label use).
Alternative: Further therapeutic options are amitriptyline or gabapentin (= anticonvulsant; e.g. Gabapentin STADA) initially 1 time/day 300 mg, increase to 3 times/day 300 mg p.o.; further dose increase if necessary, with intact renal function (control of renal parameters!), by 300 mg/day each time up to a maximum dose of 3600 mg/day in 3 ED.
Alternative: pregabalin (Lyrica®) and the neurokinin-1 receptor antagonist aprepitant.
Alternative: Dupilumab; in case of absolute resistance to therapy, a curative trial with Dupilumab is warranted. Very good success has been described with this therapy (Calugareanu A et al. 2019). (According to our own findings, this therapeutic approach is superior to any previously applied therapeutic measure!)
Experimental: Nemolizumab: In clinical trials, the interleukin31 receptor blocker nemolizumab, a first-in-class humanized monoclonal antibody, has achieved good clinical success. Nemolizumab targets the IL-31 receptor alpha, which blocks IL-31 signaling (Ständer S et al 2020) .
Experimental: Tofacitinib: a clinical trial is available on the Janus kinase inhib itor (JAK inhibitor) tofacitinib (Molloy OE et al 2020). Tofacitinib has an immunomodulatory/immunosuppressive effect and was primarily developed for the treatment of moderate to severe active rheumatoid arthritis.
Operative therapieThis section has been translated automatically.
Cryosurgery (2-fold cryocycle in open spray procedure), electrocoagulation or laser therapy( dye laser).
Note: Surgical measures lead tolocal destruction with consecutive scarring (including destruction of dermal nerve structures). Such eradications remain (in a systemic disease) always only localized measures.
In this respect, reports on a general healing of prurigo nodularis after surgical measures are to be evaluated with scepticism!
Progression/forecastThis section has been translated automatically.
Highly chronic course characterized by considerable resistance to therapy. Spontaneous healing is very rare. The single-cell florescence heals with shallow scarring.
Note(s)This section has been translated automatically.
Although the clinical picture of the (very rare) nodular Prurigo can be well differentiated from the nodular Prurigo simplex subacuta, this differentiation is often not made in international literature. However, our own experience confirms the entity of the clinical picture in several cases.
LiteratureThis section has been translated automatically.
- Ahmed E et al (1997) Cyclosporine treatment of nodular prurigo in a dialysis patient. Br J Dermatol 136: 805-806.
- Calugareanu A et al (2019) Dramatic improvement of generalized prurigo nodularis with dupilumab. J Eur Acad Dermatol Venereo 33:e303-e304.
- Fostini AC et al (2013) Prurigo nodularis: an update on etiopathogenesis and therapy. J Dermatolog Treat 24:458-462.
- Hughes JM et al (2020) Association between Prurigo Nodularis and Etiologies of Peripheral
- Neuropathy: Suggesting a Role for Neural Dysregulation in Pathogenesis.
- Medicines (Basel) 7:4.
- Hyde JN, Montgomery FH (1909) A practical treatise on disease of the skin for the use of students and practitioners. Lea & Febiger, Philadelphia, pp. 174-175.
Kwon CD et al (2019) Diagnostic workup and evaluation of patients with prurigo nodularis. Medicines (Basel) 6:97.
- Lotti T et al (2008) Prurigo nodularis and lichen simplex chronicus. Dermatol Ther 21:42-46
- Molloy OE et al (2020) Successful treatment of recalcitrant nodular prurigo with tofacitinib. Clin Exp Dermatol 45: 918-920.
- Ruzicka T et al: Anti-interleukin-31 receptor A antibody for atopic . N Engl J Med 376: 826-35.
- Siepmann D (2008) Antipruritic effect of cyclosporine microemulsion in prurigo nodularis: results of a case series. JDDG 6: 941-946
- Spring P et al (2014) Prurigo nodularis: retrospective study of 13 cases managed with methotrexate. Clin Exp Dermatol 39:468-473
- Ständer S et al (2020) Trial of nemolizumab in moderate-to-severe prurigo nodularis. N Engl J Med 382:706-716.
- Stefanini G et al (1999) Prurigo nodularis (Hyde's prurigo) disclosing celiac disease. Hepatogastroenterology 46:2281-2284.
- Suárez C et al (1989) Prurigo nodularis associated with malabsorption. Dermatologica 169:211-214 .
Szymanski K et al (2022) Case Report: Pemphigoid Nodularis-Five Patients With Many Years of Follow-Up and Review of the Literature. Front Immunol 13:885023.
- Tanis R et al (2019) Dupilumab Treatment for Prurigo Nodularis and Pruritis. J Drugs Dermatol 18:940-942.
Theodoridis A et al (2013) Malignant atrophic papulosis (Köhlmeier-Degos disease) - a review. Orphanet J Rare Dis 8:10.
- Tsianakas A et al (2016) Prurigo nodularis management. Curr Probl Dermatol 50:94-101.
- Vaidya DC et al (2008) Prurigo nodularis: a benign dermatosis derived from a persistent pruritus. Acta Dermatovenerol Croat 16:38-44.
- Wieser JK et al (2020) Resolution of Treatment-Refractory Prurigo Nodularis With Dupilumab: A Case Series. Cureus 12:e8737
- Williams KA et al.(2021) Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis. Expert Rev Clin Pharmacol 14:67-77.
- Woo PN et al (2000) Nodular prurigo successfully treated with the pulsed dye laser. Br J Dermatol 143: 215-216.
- Zeidler C et al (2021) Chronic prurigo: Similar Clinical Profile and Burden Across Clinical Phenotypes. Front Med (Lausanne) 8:649332.
Incoming links (32)Aprepitant; Chronic lymphocytic leukemia; Collagenosis reactive perforating; Diabetic pruritus; Dupilumab; Dystrophic epidermolysis bullosa pruriginosa recessive; Gabapentin; Granulocyte eosinophile; Hodgkin's lymphoma, skin manifestations; Hyde, james nevin; ... Show all
Outgoing links (38)Amitriptyline; Antihistamines, systemic; Aprepitant; Atopic dermatitis (overview); Ciclosporin a; Clemastine; Cryosurgery; Dimetinden; Dupilumab; Dye laser; ... Show all
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