PracticalDermatology

Proton pump inhibitors (PPIs) are widely prescribed for the management of various upper gastrointestinal disorders and generally carry minor side effects such as headache, nausea, flatulence, constipation, and abdominal pain.1,2 They have been implicated in causing various skin reactions including mild to life-threatening IgE-mediated hypersensitivity reactions, occupational contact dermatitis, maculopapular eruption, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption, vasculitis, drug-induced subacute lupus erythematosus, sticky palms, and Sweet’s syndrome.3-9 Although most reports discuss lansoprazole, omeprazole, pantoprazole, and rabeprazole as the primary culprits of drug hypersensitivity reactions, no drug has been singled out as a main cause.4,10 Skin testing can be useful in confirming hypersensitivity reactions and cross-reactivities between PPIs, but it can be challenging to specifically identify PPIs as the cause of symptoms, especially in patients taking multiple maintenance drugs.6,10-12

To date, no reports have described a PPI-induced skin reaction with the clinicopathologic appearance of arthropod bite reaction lesions. Here, we report the case of a 73-year-old woman who presented with pruritic papular urticaria with compatible histologic findings suggestive of an arthropod bite reaction. After undergoing months of treatment that provided temporary improvement, it was discovered that pantoprazole was the cause of her persistent rash, as significant improvement was observed after discontinuing this drug. Our report emphasizes the importance of maintaining a high index of suspicion for PPI-induced skin rashes in patients with no suggestive history for arthropod bite reaction. Early recognition can prevent extensive workup and treatment-related costs that may arise from managing this atypical clinical situation.

CASE REPORT

A 73-year-old woman presented to the dermatology clinic with a diffusely pruritic, erythematous, papular rash that began 4 days after she underwent a colonoscopy 2 weeks earlier. Her medical history was notable for colon cancer in remission following resection and chemotherapy, hypothyroidism, asthma, depression, and isolated IgG hypogammaglobulinemia with specific antibody deficiency. She reported no exposure to pets and no recent travel. Physical examination was unremarkable except for cutaneous findings of multiple discrete, erythematous, edematous, grouped papules with overlying excoriations, which were diffusely present throughout the chest and extremities, with no involvement of the skin folds or webbed spaces (Figure 1a, b, c). The patient reported minimal improvement after using over-the-counter camphor-menthol lotion and hydroxyzine. She had completed a course of prednisone, which provided temporary improvement of symptoms and was taking azithromycin at the time of initial presentation. Other active medications included albuterol, aripiprazole, azelastine, calcium carb-cholecalciferol, clobetasol, duloxetine, fluticasone, ivermectin, levothyroxine, nitroglycerin, pantoprazole, pentoxifylline, propranolol, verapamil, cholecalciferol, zolmitriptan, and zolpidem. Allergies included nausea and vomiting from butalbital/aspirin/caffeine, nausea and dizziness from hydrocodone, and hives from milnacipran.

Figure 1a, 1b, 1c. Cutaneous findings of multiple discrete, erythematous, edematous, grouped papules with overlying excoriations diffusely present throughout the chest and extremities.

PPI-induced drug hypersensitivity reaction was suspected. The differential diagnosis at the time of presentation included an urticarial dermatitis and bullous pemphigoid. The patient was advised to follow a sensitive-skin regimen and was prescribed triamcinolone 0.1% cream, oral levocetirizine 5 mg, and oral doxepin 25 mg. During the initial visit, a punch biopsy of a single erythematous papule was also obtained, which showed histologic changes consistent with an arthropod bite reaction and revealed dense superficial to mid dermal, perivascular, and interstitial lymphoplasmacytic infiltrates with a vaguely nodular and wedge-shaped formation. Numerous scattered eosinophils were present admixed with the dermal infiltrate. In addition, the patient followed the decontamination protocol for scabies and bed bug infestation, which included covering non-washable furniture in plastic and machine washing and drying clothes, bedding, and towels in hot water and high heat. She also hired extermination services twice for her house.

One month later, the patient returned and had developed additional lesions scattered underneath the bilateral breasts, lower legs, and arms. There was a newly developed 3-millimeter edematous, erythematous papule under the right axilla, which was excised via shave biopsy. Given the patient’s history, complete blood count (CBC) and comprehensive metabolic panel (CMP) were ordered to rule out the possibility of a lymphoma and to evaluate for blood urea nitrogen (BUN), uric acid, and other electrolyte abnormalities to identify the etiology for her generalized pruritus. She was also prescribed a course of oral ivermectin and permethrin cream.

One week later, she returned for follow-up and reported overall improvement in her symptoms since her last visit, despite the development of new lesions in her groin area. The results of the shave biopsy from the antecubital fossa that was performed at the previous visit revealed superficial and deep perivascular lymphocytic and eosinophilic inflammatory infiltrate with features compatible with an arthropod attack, supporting the suspected diagnosis (Figure 2). She was advised to continue following a sensitive skin care regimen and to utilize topical medications as needed.

Figure 2. Histological image of medium magnification (10x) H&E of the biopsy from the right antecubital fossa which shows a normal basket weave keratinized cell layer and a relatively unremarkable epidermis with dense superficial and deep perivascular inflammation composed predominantly of lymphocytes.

One month later, she returned to the clinic to report that her rash had finally resolved on its own after 8 weeks, resulting in significant improvement in her symptoms. She attributed this resolution to stopping her oral pantoprazole 40 mg delayed release tablet, as recommended by a different physician. At this visit, skin examination revealed small healing excoriations along the forearms and dry skin over the arms and hands. Her face, back, chest, abdomen, and legs were clear. She was advised to see her primary care provider to discuss switching to a different medication class with to treat her abdominal pain as other PPI options may cause similar symptoms. She was also counseled on monitoring the rash until it completely disappeared and to seek follow-up as needed.

DISCUSSION

PPIs rank among the most prescribed classes of medications worldwide.13,14 They are widely used to treat multiple gastrointestinal disorders, including peptic ulcer disease, Zollinger-Ellison syndrome, eradication of Helicobacter pylori, and gastroesophageal reflux disease.15 Although generally well-tolerated, PPIs have been associated with various skin eruptions, ranging from mild, local urticarial reactions to severe and life-threatening conditions, such as toxic epidermal necrolysis (TEN) or DRESS.3-9,16

Our patient presented with clinical and histologic findings consistent with an arthropod bite reaction, despite having no history of exposure or response to treatment for this cause. Scabies was considered unlikely, as she had been quarantining at home for several months and reported no exposure or close contact with affected individuals. Arthropod bite reactions generally manifest as papular urticaria with edematous and erythematous eruptions.17,18 Histologic findings reveal eosinophilic spongiosis, which resembles a pattern shared across drug reactions, scabies, contact dermatitis, autoimmune bullous disorders, and arthropod assaults.19,20,21 Dermal edema and dense mixed inflammatory infiltrate are also characteristic histologic changes seen in arthropod assaults, which can be challenging to correlate to nonspecific clinical findings.22 In our case, this was challenging because both the punch and shave biopsy results showed a wedge-shaped superficial and deep perivascular lymphocytic and eosinophilic inflammatory infiltrate consistent with an arthropod bite reaction. Also complicating matters, our patient was taking multiple medications with no associated history of adverse cutaneous reactions, which made it difficult to pinpoint the cause of the rash to a specific medication.

In the absence of any known cause or historical factor, it was determined that pantoprazole was the cause of her rash based on the timing of the dermal hypersensitivity reaction and PPI treatment. Rapid clinical reversal of symptoms was observed after discontinuing oral pantoprazole, and the conclusion was further supported by the lack of meaningful improvement in response to multiple therapeutic agents prescribed over several months. Previous reports have primarily identified omeprazole, esomeprazole, rabeprazole, lansoprazole, and rabeprazole as the primary culprits of PPI-induced drug hypersensitivity reactions.23,24 However, these reports mainly describe severe and life-threatening manifestations of cutaneous reactions, unlike the papular urticaria observed in our patient.4 Notably, rabeprazole was associated with less than 1% of all PPI-induced dermatological adverse events and was found to have a desirable safety profile compared to other drugs in this class.4

Diagnosing a PPI-induced dermal hypersensitivity reaction can be challenging for several reasons. Initially, dermal hypersensitivity reaction may not be suspected given the nonspecific clinical pattern of symptoms and appearance of the rash, especially in patients with no history of adverse reactions to PPIs. Histologic analysis is necessary to narrow down the differential list, but it can also reveal nonspecific findings that can further lead dermatologists to consider unrelated causes such as arthropod bite reactions, contact dermatitis, or autoimmune blistering disorders. Various cross-reactivity patterns exist between PPIs, and an adverse reaction to one drug in the class does not always preclude reactivity to all other PPIs.25 Although skin testing can help to precisely identify the offending agent, confirming the adverse reaction to PPIs may be delayed, and instead, can be confirmed earlier with a clinical examination.10,11 In general, three patterns of cross-reactivity among PPIs have been observed: whole-group hypersensitivity to all drugs within the class, hypersensitivity based on structural analogs (such as omeprazole-esomeprazole-pantoprazole or lansoprazole-rabeprazole cross-reactivity), and hypersensitivity to a single PPI.26, 27 Despite these general patterns, a comprehensive allergological workup is recommended to confirm cross-reactivity in patients with adverse reactions.28

Our case illustrates the importance of considering PPIs as a cause of dermal hypersensitivity reaction in patients presenting with papular urticaria with nonspecific histologic findings characteristic of arthropod bite lesions. Pharmacovigilance reports indicate a growing number of adverse drug reactions associated with PPIs, which is attributed to their high prescription rates; however, these reactions differ in severity and presentation among patients.23 Cutaneous reactions to PPIs can lead to delayed diagnosis due to their atypical clinical manifestations, and this condition remains underreported in the literature. Early recognition of this condition improves quality of care for patients, as discontinuing the PPI will result in clearing the rash. Conversely, delayed identification will result in persistence of symptoms, unnecessary treatment with potentially harmful drugs, and invasive workup.

Conclusion

Given the growing use of PPIs, it is crucial to consider their adverse effects, which remain underrecognized and underreported in the medical literature. Several PPIs are also available over the counter and may not always be documented in the patient’s medication history. It is vital for clinicians to be aware of the diverse presentation of cutaneous reactions to PPIs and to include them in the differential diagnosis for at-risk patients. This increased awareness can expedite diagnosis, enhance clinical management, and improve patient outcomes.

The authors have received no funding for this manuscript. They report no conflicts of interest.

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