A 38-year-old White man presents to a primary care clinic stating that he has a bothersome rash on his torso, sacrum, and arms that began 3 days prior. He describes the inflammation as “itchy red bumps” (Figure 1).
The patient’s medical history includes anxiety, depression, bicuspid aortic valve, gallstones, kidney stones, hay fever, gastroesophageal reflux disease (GERD), and obstructive sleep apnea. His past surgical record consists of an appendectomy at age 21. A colonoscopy was performed in 2013 and an esophagogastroduodenoscopy in 2012 for GERD. A review of his family history includes depression, anxiety, diabetes, and heart disease. Laboratory tests are within normal limits other than abnormal cholesterol panel (LDL, 130 mg/dL; triglycerides, 161 mg/dL), vitamin D insufficiency (24 ng/mL), and low testosterone.
A review of systems is negative for headache, fever, chills, shortness of breath, and cough. Vital signs are within normal limits. The patient’s primary care office focuses on functional medicine; his medications consist of niacin 500 mg daily, coenzyme Q10 (CoQ10) 100 mg daily (hyperlipidemia), and vitamin D 10,000 IU daily (vitamin D insufficiency). He is also taking a combination of B vitamins and magnesium for anxiety as well as a testosterone supplement. His vaccinations are up to date.
While taking the patient’s history, he notes that his wife began washing his clothes in a new brand of laundry detergent, which he believes is the cause of the rash. The patient denies any prior dermatologic conditions. He reports a history of seasonal allergies that are successfully treated with over-the-counter antihistamines and no other food or drug allergies. In addition, he mentions that he began a keto diet 30 days ago; he has been taking ketone pills and only eating fruit, vegetables, and meat. He denies any recent illnesses or exposure to anything that could have potentiated the rash except the new detergent, new diet, and gardening hobby. The patient works as an information technology engineer, denies tobacco use, and drinks approximately 2 alcoholic beverages per day and 3 caffeinated beverages per day.
A physical examination reveals an alert male who is calm and conversant. No dyspnea, throat redness, tonsillar enlargement, or lymphadenopathy is noted. His heart sounds are normal, and no murmur is detected despite his history of bicuspid aortic valve. His lung examination is clear to auscultation. Upon assessing the integumentary system, the torso, arms, and sacrum show a pruritic eruption of inflamed erythematous crusted papules. The papules merge in some areas to form a reticulating (network-like) pattern. There is symmetrical distribution overall and no rash is noted on the face, mucous membranes, hair, or nails. Abdominal and neurologic assessments are unremarkable as well. His BMI is in normal range.
An initial diagnosis of contact dermatitis is considered based on the history of changing laundry detergent brands; a drug reaction to the ketone supplement also is considered. The patient is instructed to stop the supplement and rewash his laundry in gentle soap. He is prescribed over-the-counter antihistamines (cetirizine 10 mg in the morning, diphenhydramine 25 mg at night) in addition to a topical steroid (triamcinolone acetonide 0.1% cream) for itching. The patient is told to follow up in 1 week and to call the office if his symptoms are not improving, fever develops, or other symptoms arise.
The patient presents for follow-up 9 days later with little improvement (Figure 2). The rash showes minimal change and the patient states he unknowingly slept in sheets washed in the suspected causative laundry detergent. He also did an aggressive run the night prior, which seemed to exacerbate the dermatitis. The patient said he had been getting relief from the steroid cream, which minimized the itching. The patient’s wife also found an article about keto rash and thought that maybe the patient’s low carbohydrate, moderate protein, high-fat diet could be the cause of his symptoms. After some research, a new diagnosis of keto rash (ie, prurigo pigmentosa related to the ketogenic diet) was considered. The patient was instructed to discontinue the ketogenic diet (to stop ketosis), continue use of the steroid cream, and follow up with dermatology if no improvement is found in 1 week.
Six days later, over the phone, the patient states the rash is clearing up well and he feels that no follow-up appointment is necessary.
Prurigo pigmentosa (PP), also known as Nagashima disease, is a rare inflammatory dermatosis of unknown etiology that was first described in 1971.1 A review of prurigo pigmentosa in the literature yielded approximately 300 cases (mostly in the Japanese population), including less than 20 cases in the United States.2
The scarcity of cases in the United States could be attributed to misdiagnosis or practitioners being unaccustomed to the condition or because the condition is more prevalent in populations with larger Asian populations.3 The reported mean age at diagnosis is 24 years among women and 27 years among men.4 Prurigo pigmentosa most commonly occurs in Asian women of childbearing age.3 Mechanical stimuli, contact allergies, and climate (ie, spring and summer) may play a role in the development of PP.5,6
Prurigo pigmentosa is also associated with conditions that involve ketosis such as uncontrolled diabetes mellitus, fasting, and anorexia nervosa.7 Other systemic conditions associated with PP include diabetes mellitus, adult-onset Still disease, atopy, Helicobacter pylori infections, and Sjögren syndrome.4,6 Hormone changes during pregnancy may play a role in PP development and there are reported cases following bariatric surgery.6,8 The exact etiology of PP remains unclear and more extensive cohort studies need to be conducted to clarify the association between ketosis and PP.9
Pathophysiology of Prurigo Pigmentosa
The pathogenesis of PP is described as a ketosis-induced, neutrophil-mediated inflammation in the skin.4 The similarities seen in the immune response stimulated by ketosis and PP suggest a possible link between the two.9 Park et al presented 3 cases of PP with an elevated antinuclear antibody(ANA), which reinforces the autoimmune linkage.10 Patients with PP may also present with elevated urine/and or blood ketone levels.6 Prurigo pigmentosa has also been seen in nonketotic patients, raising suspicion that PP can develop from other causes than ketosis states.4 Although the exact mechanism of PP pathogenesis has yet to be determined, a growing body of evidence provides a connection between gut dysbiosis and host immunity.3
Keto Diet and Gut Microbiome
Descriptions of the keto diet began emerging in the 1920s.11 The keto diet has been used to treat refractory epilepsy and is currently gaining popularity as a potential treatment for neurodegenerative diseases, metabolic diseases, and obesity.11 The diet consists of very low carbohydrate consumption (<50 g/d or 5% of total daily caloric intake), which can mimic starvation metabolically.11 Ketogenic diets typically include 5% of calories from carbohydrates, 75% from fat, and 20% from protein.12 The significant decrease in carbohydrates results in insufficient glucose for fat oxidation and energy required for the central nervous system. In turn, fats become the primary fuel source.3,11
Optimal composition and quality of fats (ie, eating a diet high in unsaturated fatty acids and reducing the omega-3:omega-6 fatty acid ratio) is vital to consider when undergoing the keto diet and can improve the gut microbiota.13 It should also be noted that the Western diet is rich in saturated-trans fats and deficient in monounsaturated fatty acids (MUFAs), causing detrimental metabolites and expansion of bacteria associated with a chronic state of inflammation.13 Altering the gut microbiome through antibiotic use, diet, nutritional, or environmental factors plays a role in modifying the immune response.3 This modification can lead to the progression of various chronic diseases ranging from metabolic disease to gastrointestinal disorders.14
Several skin diseases (ie, atopic dermatitis, psoriasis, acne vulgaris, dandruff, and skin cancer) are also linked to an altered gut microbiome.15 In terms of the immune response, overexpression of interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemo-attractant protein-1 (MCP-1) triggered by ketosis could explain the inflammatory process detected on the skin in patients with PP.16 Further studies are needed to further delineate the mechanisms underlying this relationship.
Presentation, Histopathology, and Diagnosis
Prurigo pigmentosa presents as erythematous, pruritic papules that evolve into a meshwork of hyperpigmentation.4 The most prominent presentation is seen on the back, chest, and neck.14 These uncommon dermatosis features are determined based on 3 stages (early, fully developed, and late).4
The early-stage lesions present as pruritic, urticarial papules or plaques that include superficial perivascular neutrophilic infiltrate under microscopic examination.3,4 Fully developed lesions manifest as crusted erythematous papules, papulovesicles, and vesicles classically present with histology of spongiosis and necrotic keratinocytes. Late-stage lesions develop into smooth-surfaced pigmented macules; lymphocytic infiltrate and melanophages in the papillary dermis are hallmarks of this stage.3
The differentiation of PP and other pathologies is the unique reticular pattern present in all 3 stages.6 Other differential diagnoses include medication-induced responses, contact dermatitis, urticaria, erythema multiforme, and confluent and reticulated papillomatosis (CARP).16 Although CARP has a remarkably similar presentation, the intense pruritus that coincides with PP is absent in patients with CARP.3 In addition, there is no persistent dyspigmentation noted with CARP, whereas hyperpigmentation in PP can last months to years.16
A thorough history of allergies can rule out an IgE-mediated diagnosis such as atopic dermatitis. Further diagnostic criteria are shown in Table 1.3-6,17,18 The clinical and histologic differential diagnoses of prurigo pigmentosa are outlined in Table 2.4
Table 1. Diagnostic Criteria of Prurigo Pigmentosa3-6,17,18
|Etiology|| • Endogenous factors: ketosis, diet, starvation, pregnancy, diabetes, or H pylori infection|
• Exogenous factors: sweating, clothes rubbing on skin, exposure to allergens
• Growing evidence on PP related to gut dysbiosis and host immunity
|Incidence|| • PP most commonly occurs in Asian women of childbearing age |
• Observed not only in men but also in individuals of other nationalities
|Pathophysiology||• Ketosis-induced neutrophil-mediated inflammation|
|Histopathology|| • Early-stage: pruritic, urticarial papules or plaques that include superficial perivascular neutrophilic infiltrate under microscopic examination |
• Fully developed: crusted erythematous papules, papulovesicles, and vesicles classically present with histology of spongiosis and necrotic keratinocytes
• Late-stage: smooth-surfaced pigmented macules; lymphocytic infiltrate and melanophages in the papillary dermis are hallmarks of this stage
|Symptoms/ Physical Examination|| • Intense pruritus with the development of urticarial plaques, scaly papules/smooth-surfaced papulovesicles, and pigmented macules (most common on back, chest, and neck)|
• Unique reticular arrangement of the lesions allows clinicians to distinguish from similar skin conditions
|Diagnostics||• Elevated urine/and or blood ketone levels|
|Differential Diagnosis|| • Medication-induced response|
• Contact dermatitis
• Erythema multiforme
• Confluent and reticulated papillomatosis (CARP)
|Treatment|| • Antibiotics:|
– Minocycline (first line) or doxycycline 100 mg orally every 12 h x 3 weeks
– Dapsone 100 mg/d
• Topical steroid:
– Triamcinolone acetonide 0.1% cream, apply 2-4/d as needed for itching
• Cessation of ketosis
• Refer to a dietician (for patients who need to remain in ketosis)
Table 2. Clinical and Histologic Differential Diagnosis of Prurigo Pigmentosa4
|Stage||Clinical Differential Diagnosis||Histologic Differential Diagnosis|
|Early-stage||Contact dermatitis; dermatitis herpetiformis; linear IgA dermatosis; psoriasis vulgaris; systemic lupus erythematosus; urticaria||Dermatitis herpetiformis; dermatophytosis; leukocytoclastic vasculitis (early); linear IgA dermatosis; psoriasis vulgaris; systemic lupus erythematosus|
|Late-stage||Erythema multiforme; Mucha-Habermann disease (PLEVA)||Erythema multiforme; Mucha-Habermann disease (PLEVA)|
|Fully developed stage||Confluent and reticulated papillomatosis; Dowling–Degos disease; erythema ab igne; erythema dyschromicum perstans; lichen planus pigmentosus; macular amyloidosis; medication-induced pigmentation||Post-inflammatory hyperpigmentation|
Reprinted with permission from Beutler et al.