Introduction

This case series highlights the importance of detailed evaluation of pruritus in the absence of a rash. By integrating thorough clinical examinations and a detailed medical history this series illustrates how subtle symptoms can often indicate a more complex, multisystem disorder causing the chronic itch.

Background

Chronic pruritus, as a symptom, has been shown to have a severe impact on patient well-being and quality of life, comparable to that of chronic pain. Individuals suffering from persistent pruritus report major impairments in sleep, mood, concentration, and social interactions, effects that may exacerbate mental health issues, leading to anxiety and depression.1

In many cases, chronic pruritus arises from neuropathic mechanisms, including damage to sensory fibers in the skin such as unmyelinated C-fibers and myelinated Aδ fibers, which contribute to the sensation of chronic itch. Additionally, mast cell activation can cause dermatographic urticaria and persistent pruritic symptoms. Numerous molecular and cellular pathways are involved in the persistence of this symptom, with many pathways currently under investigation for the development of targeted diagnostic and therapeutic approaches.2-4

When no visible or an atypical rash is present, the itch is often misattributed to psychological causes or incorrectly treated with standard dermatologic therapies. This misdiagnosis can delay appropriate neurological or immunologic evaluation and treatment, potentially worsening symptoms. This reality underscores the importance of clinician awareness and a comprehensive approach to the evaluation and management of patients presenting with unexplained pruritus.3

Case 1

Case 1 provides insight into the diagnostic challenges of neuropathic itch. A 48-year-old presented with severe generalized itch described as a 10/10 on the Worst Itching Intensity Numerical Rating Scale (WI-NRS). She reported 2 years of burning and electrical shock sensations throughout her entire body. These symptoms would worsen at night and interfere with her sleep. However, she exhibited no visible rash, only excoriations and scratches from the marks she made by using paperclips (Figure 1).

Her medical history included hypertension, and she took lisinopril, multivitamins, Ubrogepant, and naproxen. She had a penicillin allergy but no history of other atopic or allergic disorders. The differential diagnosis of drug-induced pruritus from lisinopril was ruled out after a 10-week trial off the medication did not improve her condition. Common systemic causes such as thyroid, liver, and kidney disease were excluded by normal laboratory results. Atopic or allergic pruritus was considered unlikely in the absence of any visible rash.

Two other possibilities that were investigated included iron deficiency anemia, suggested by microcytic indices, and small fiber polyneuropathy (SFPN). A punch biopsy of the right thigh and right foot revealed reduced intraepidermal nerve fiber (IENF) density. Confirmatory laboratory studies showed low ferritin and low iron saturation, supporting the diagnosis of SFPN associated with iron deficiency anemia. The patient was treated with iron supplementation, which improved her itch to a WI-NRS of 4/10 after 3-4 weeks. Then appropriately titrated pregabalin, from 50 mg at night, to 50 mg twice a day (BID), slowly getting to 200mg three times a day (TID), which led to a WI-NRS of 1/10 at her last visit.

This case underscores the importance of having clinical suspicion for neuropathic pruritus in instances of chronic severe itch without rash, particularly when accompanied by burning and electric shock sensations. To diagnose or exclude SFPN, IENF density biopsy and with systemic contributors such as iron deficiency, diabetes, and vitamin B12 deficiency should be considered.

Case 2

Case 2 involves a 74-year-old man with a decade-long history of very severe, progressive, and persistent itch, tingling, and burning predominantly affecting his upper body. The itch, which had a reported WI-NRS of “20/10,” worsened with sun exposure, heat, stress, and at night. Initially, the patient presented without a rash, but over time developed multiple erythematous plaques with excoriations and scarring on the arms, shoulders, neck, and upper back (Figure 2).

His past medical history included hypothyroidism, osteoarthritis, and hypertension. His current medications included levothyroxine, aspirin, metoprolol, and multivitamins. In addition to over-the-counter (OTC) emollients, ultrapotent topical steroids, antihistamines, and courses of prednisone, the patient had been undergoing narrowband ultraviolet-B (NB-UVB) phototherapy, which, in fact, worsened the itch. Differential diagnoses of chronic eczema and prurigo nodularis were considered unlikely due to a lack of typical changes such as widespread erythema, scaling, or oozing. Photodermatoses were ruled out because the lesion characteristics were not consistent with photosensitive patterns.

Two additional differential diagnoses, a neuropathic cause due to burning and tingling sensations, and cervical spine disease, were investigated. A MRI of the cervical and thoracic spine revealed narrowing of disc space C4-C5 and a disc space collapse from C5 to T1, which confirmed a diagnosis of brachioradialis pruritus (BRP), a neuropathic itch affecting the dorsolateral forearm, upper arms, and posterior shoulders, secondary to cervical spine compression. The treatment consisted of discontinuing phototherapy and initiating gabapentin at 200 mg, which was gradually titrated up to 900 mg TID. Due to patient constipation and sedation, the dose was brought down to 600 mg TID. The WI-NRS after this point was a 4/10. After this, nortriptyline, which started at 10 mg but was titrated up to 20 mg nightly, physical therapy, and a corticosteroid injection were provided. This led to the patient’s WI-NRS score improving to a 2/10 by the date of the last visit.

This case highlights the importance of considering neuropathic mechanisms when a persistent regional burning itch presents without a distinct rash, underscoring the importance of neuroimaging alongside clinical assessment in establishing a diagnosis to guide therapy. For BRP, neuromodulators such as gabapentin and spine directed therapies have demonstrated effectiveness and should be properly considered as a therapeutic avenue.5,6

Case 3

Case 3 describes a 68-year-old woman who presented with several months of severe widespread itch rated a 9/10 on the WI-NRS. She reported severe sleep deficits, increasing anxiety, and unintentional weight loss due to the itch. Physical examination revealed numerous excoriations, several lichenified nodules, and hyperpigmented plaques, some surrounded by wheals, indicating dermatographic urticaria (Figure 3).

Her medical history was relatively nonsignificant. The patient took no medications other than diphenhydramine. The patient had unsuccessfully trialed mometasone cream, hydroxyzine, permethrin, prednisone, and phototherapy.

Differential diagnoses of atopic dermatitis and chronic urticaria were considered but were deemed unlikely due to the absence of typical widespread eczematous changes and poor responses to antihistamines. Skin biopsies were taken from the patient’s back and buttocks. The back biopsy demonstrated prurigo nodules with surrounding spongiotic dermatitis, while the buttock biopsy demonstrated an urticarial hypersensitivity reaction. Laboratory testing including CBC, CMP, thyroid function, and IgE levels were all within normal limits. Imaging, including chest X-ray, and malignancy screenings were negative for any systemic diseases or malignancies.

Upon evaluation, a trial-based treatment approach was initiated. The patient underwent trials of biologics–dupilumab, nemolizumab, and upadacitinib– with symptom improvement ranging from minimal to moderate with the lowest WI-NRS rating being a 5/10 on upadacitinib. A final trial of ketotifen, a mast cell stabilizer, started at 3 mg twice daily, leading to significant improvement bringing the WI-NRS score down to 2. This supported a true diagnosis of chronic prurigo nodularis with possible mast-cell involvement. This improvement allowed the patient to sleep again and enjoy a markedly improved quality of life.

This case highlights the importance of considering a mast-cell mediated itch in patients displaying chronic pruritus. Hereditary alpha tryptasemia (extra copies of alpha tryptase gene [TPSAB1]) or mast cell instability should be considered when a chronic itch is present with refractory and dermatographic symptoms. Additionally, exclusion of Hodgkin's lymphoma is critical as this type of pruritus commonly precedes diagnosis. Hodgkins is associated with mast cell infiltrations which can promote growth by modifying the tumor microenvironment.7 Early consideration of Hodgkin’s in chronic pruritus can be lifesaving and significantly improve patient outcomes.

Conclusion

Through this case series, we see an emphasis on a comprehensive approach to chronic pruritus, especially when rashes are absent or a subtle dermatographism is present. A deep assessment of nerve health using IENF density analysis and spinal imaging is key in determining whether neuromodulators could provide relief for neuropathic itch. In cases of itch accompanied with a mild dermatographism, clinicians should consider mast-cell targeting agents and evaluate the possibility of malignancies. Effective chronic pruritus management requires a personalized treatment guided by vigilant screening to allow patients to maintain a good quality of life.