Interstitial Granulomatous Drug Reaction Possibly Induced by Abiraterone Acetate

Reactive granulomatous dermatitis: A useful and encompassing term

Cutaneous Granulomatous Reaction After Herpes Zoster in Drug-Induced Hypersensitivity Syndrome

Sir, Interstitial granulomatous drug reaction (IGDR) is a rare entity presenting as erythematous to violaceous plaques or generalized pruritic scaly eruptions resembling cutaneous T-cell lymphoma or pigmentary purpura (1, 2). The implicated drug classes include calcium-channel blockers, lipid-lowering agents, antihistamines, anticonvulsants and antidepressants. Histopathologically , IGDR shows an interstitial granulomatous dermatitis pattern with or without an interface change and lymphoid atypia. The lack of degenerated collagen and the presence of ` granulomatous rosettes’ ’ can be subtle clues supporting interstitial granulomatous dermatitis triggered by a drug (2). We describe a case of IGDR presenting as multiple erythema nodosum-like lesions on the legs, which histopathologically showed the changes of interstitial granulomatous dermatitis.

A 61-year-old Asian woman presented with acute onset of a widespread rash and 3–4-cm infiltrated erythematous plaques in the arms, legs and torso, with a few showing an annular configuration soon after he had taken naproxen for rheumatoid arthritis. After 48 h the plaques had developed into purpura and petechiae. Past medical history also included diabetes mellitus type 2, hypertension, left knee replacement, cauda equina syndrome and asthma. Her medications comprised losartan, atorvastatin, metformin, amlodipine and naproxen. The differential diagnosis included sarcoidosis, Wells syndrome, panniculitis and vasculitis. Histopathology of the 4-mm punch biopsy from the right flank showed mild spongiosis, focal lymphocyte exocytosis, focal basal vacuolar degeneration, superficial dermal oedema, mild superficial and deep dermal perivascular and perisudoral lymphocytic infiltrate with neutrophilic microabscesses, and leucocytoclasia associated with small histiocytic aggregates. Focal involvement of the subcutis was also present. No obvious collagen necrobiosis with histiocyte palisading, flame figures or increased eosinophils were seen. No medium vessel vasculitis was identified. Periodic acid–Schiff stain was negative for fungi, and Ziehl–Neelsen stain did not reveal acid-fast bacilli. Both vasculitis and viral screens were normal apart from elevated D-dimers, serum ferritin and positive Epstein–Barr virus DNA. Our working diagnosis was a neutrophilic and histiocytic dermatosis with leucocytoclastic vasculitis. Given the history of rheumatoid arthritis, a palisading neutrophilic granulomatous dermatitis was also considered, as the findings may vary according to the age of the lesion. However, the findings were best fitted to a vasculitic granulomatous drug reaction as there were focal vacuolar interface changes and obvious lymphocyte epidermotropism involving the entire epidermal thickness. There was no resemblance to other conditions like rheumatoid nodule, interstitial granuloma annulare or infective necrotizing granulomas. In their recent review, Shah et al. identified five patterns of drug-induced granulomatous dermatosis (Shah N, Shah M, Drucker AM et al. Granulomatous cutaneous drug eruptions: a systematic review. Am J Clin Dermatol 2021; 22: 39–53). They included (i) interstitial granulomatous drug reaction, (ii) drug-induced accelerated rheumatoid nodulosis, (iii) drug-induced granuloma annulare, (iv) drug-induced sarcoidosis and (v) miscellaneous presentations. The authors also concluded that polypharmacy and a prolonged lag period from drug intake to lesion onset would result in diagnostic challenges, as in our case. On suspension of naproxen, the rash had subsided and it resolved 2 weeks later. We have presented the case of a 60-year-old patient with an unusual granulomatous neutrophilic dermatitis associated with leucocytoclastic vasculitis that did not fit with the usual patterns described in association with rheumatoid arthritis. The final diagnosis was a vasculitic granulomatous drug reaction, secondary to naproxen, as suggested by the presence of epidermal changes and absence of significant systemic symptoms. Knowledge of this entity is helpful to distinguish these lesions from palisading neutrophilic granulomatous dermatitis and from other similar dermatosis. The lesions should resolve with discontinuation of the causative drug.

Granulomatous Drug Eruptions.

A 74 year old woman presented with a 1‐month history of symmetrical erythematous annular plaques involving her groin and medial thigh 3 to 4 years post commencing simvastatin. Initial histology was consistent with the diagnosis of interstitial granulomatous drug reaction (IGDR), however 11 months post cessation of Simvastatin the plaques were expanding in size. Repeat biopsy demonstrated features of interstitial mycosis fungoides (IMF).IMF is a rare variant of mycosis fungoides. It has been reported to resemble granuloma annulare, inflammatory morphoea and IGDR with an interstitial lymphocytic infiltrate. IGDR presents most commonly with a history of asymptomatic, erythematous to violaceous plaques in an annular pattern, mainly involving the intertriginous areas, medial thighs and inner aspects of the arms. There is a temporal association between the initiation of drug therapy and lesional onset and resolution after cessation of the drug. It has clinical and histological features that overlap with IMF. This case of a rare variant of mycosis fungoides initially diagnosed as interstitial granulomatous drug reaction is presented to highlight the importance of recognising this differential diagnosis when presumed IGDR fails to resolve.

Bosutinib is a BCR-ABL tyrosine kinase inhibitor approved for the treatment of Philadelphia chromosome–positive chronic myelogenous leukemia. We report a case of bosutinib-induced interstitial granulomatous drug reaction in a 50-year-old Caucasian female with chronic myelogenous leukemia. Histologic analysis of a punch biopsy showed diffuse interstitial granulomatous infiltrates consisting of histiocytes amid thickened collagen accompanied by eosinophils. Her lesions improved with clobetasol 0.05% cream. No cases describing BCR-ABL tyrosine kinase inhibitor–associated interstitial granulomatous drug reaction were found in a search of the literature. It is important for physicians to be aware of the risk of interstitial granulomatous drug reaction associated with bosutinib treatment.

To the Editor: We read the case reported by Suran and Christopher1 with great interest because we recently treated a similar case of drug rash with eosinophilia and systemic symptoms (DRESS syndrome) with a histologic pattern consistent with an interstitial granulomatous drug reaction (IGDR). A 45-year-old man was admitted to our department with a pruritic rash and facial edema present for 3 days. The medical history included hyperuricemia; the patient was treated with allopurinol for 2 months. The physical examination demonstrated marked generalized erythema with multiple overlying papules and plaques over the entire body and cervical lymphadenopathy (Figs. 1, 2). The patient had a fever for 2 weeks; the temperature was 39.5°C on admission. Laboratory studies showed a leukocytosis 14.9 (4.0–10.0 × 109/L) with an eosinophil count of 0.81 (0–0.5 × 109/L). The alanine aminotransferase 92 (5–40 IU/L), aspartate aminotransferase 74 (0–40 IU/L), and erythrocyte sedimentation rate 75 (0–10 mm/h) were also elevated. The kidney function testing showed significant abnormalities with a raised blood urea nitrogen 43.5 (7.8–22.0 mg/dL) and creatinine 3.5 (0.6–1.2 mg/dL). The kidney biopsy was consistent with an interstitial nephritis. The skin biopsy specimen taken from a papular lesion on the abdomen revealed a dense, diffuse interstitial, perivascular, and perifollicular infiltrate (Fig. 3A) composed of histiocytes, lymphocytes, eosinophils, and multinucleated giant cells (Figs. 3B, C). Piecemeal fragmentation of collagen and elastic fibers were revealed by Masson-trichrome and Verhoeff–van Gieson stains. There were few mucin deposits noted. Focal vacuolar interface dermatitis was also observed (Fig. 3B). The skin lesions subsided and the liver and kidney function returned to normal after withdrawal of the offending medication, hemodialysis, and steroid therapy.FIGURE 1: Facial edema and erythematous papules.FIGURE 2: Generalized, symmetrical erythema with overlying papules, and plaques on the whole body.FIGURE 3: Histologic findings. A, Dense, diffuse interstitial, perivascular, and perifollicular infiltrates (hematoxylin–eosin, ×12.5). B, Interface dermatitis with basal vacuolopathy (hematoxylin–eosin, ×100). C, Granulomatous infiltrate composed of histiocytes, lymphocytes, eosinophils, and multinucleated giant cells (hematoxylin–eosin, ×200).Allopurinol-induced DRESS syndrome is characterized by hematologic abnormalities, especially eosinophilia and atypical lymphocytosis, skin rash, fever, lymph node enlargement, and single or multiple organ involvement, which starts within 8 weeks after the start of treatment with the offending drug.2,3 Our patient was diagnosed with DRESS syndrome based on fever, lymphadenopathy, cutaneous eruption, eosinophila, and interstitial nephritis developing 8 weeks after starting allopurinol. Histologically, a dense lymphocytic infiltrate in the superficial dermis with eosinophils is frequently observed in patients with DRESS syndrome.2 Diffuse interstitial granulomatous infiltrates with DRESS syndrome, as seen in our patient, were reported by Suran and Christopher.1 IGDR is a rare drug associated entity, initially described in 1998.4 This reaction has been reported in response to calcium channel blockers, angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering agents, antihistamines, anticonvulsants, antidepressants, diuretics, sennoside, herbal medications, strontium ranelate, ganciclovir, and anakinra.4–11 Most patients present with erythematous to violaceous plaques with a predilection for the skin fold areas. Lesions are usually caused by drug exposure over a long period of time, and resolve soon after discontinuation of the offending drug. Histopathologically, IGDR is characterized by diffuse interstitial infiltration of lymphocytes and histiocytes, with piecemeal fragmentation of collagen and elastic fibers. Interface dermatitis is usually noted, and affected hair follicles and acrosyringia have also been reported.4,10 Given the appearance of multiple erythematous papules and plaques in association with allopurinol treatment, the histology, and the resolution within 4 weeks after cessation of the drug, were consistent with the diagnosis of IGDR. Chen et al7 reported a case of IGDR that shared some of the features of DRESS, including erythroderma, eosinophilia, and abnormal lymphocytes. However, the patient did not have constitutional symptoms or internal organ involvement. Interestingly, our case and the case reported by Suran and Christopher1 were similar, both cases appeared to have DRESS syndrome and IGDR. Although the pathogenic mechanisms of allopurinol-induced DRESS syndrome have not been fully elucidated, immunologic, genetic, and other factors associated with drug and metabolite accumulation have been proposed to be correlated with the pathophysiology.12 In addition, the mechanisms underlying IGDR are unknown; however, type IV hypersensitivity has been postulated to play a role.7 Suran and Christopher1 proposed that herpes virus-stimulated T cells may cross-react to drug-derived hapten–protein conjugates. However, our patient did not show reactivation of herpes viruses. In conclusion, allopurinol is widely used for the treatment of hyperuricemia; some patients develop the allopurinol-induced DRESS syndrome. We report an extremely rare case of allopurinol-induced DRESS syndrome that was confirmed histologically to be present with IGDR.

Dear Editor: Interstitial granulomatous dermatitis (IGD) is a rare and peculiar disorder with cutaneous and joint manifestations1. IGD may be associated with rheumatologic and hematologic disorders of underlying malignancies2,3. Herein, we report a case of IGD associated with rheumatoid arthritis (RA). A 59-year-old Korean woman presented with multiple erythematous plaques on both extremities for 10 days (Fig. 1A). Upon physical examination, the plaques were linear shaped, non-tender, and palpable. She had been diagnosed with RA 17 years earlier. She had taken prednisolone, nonsteroidal anti-inflammatory drugs, and methotrexate to treat RA for 7 years. One month earlier, her arthritis symptoms had stabilized and the rheumatologist withdrew methotrexate. Laboratory test findings were non-specific except for an elevated C-reactive protein (CRP) level (7.12 mg/dl; normal range, 0.01~0.47 mg/dl) and erythrocyte sedimentation rate (ESR) (81 mm/h; normal range, 0~15 mm/h). Histopathologic findings indicated perivascular and interstitial lymphohistiocytic infiltration through the dermis and chronic granulomatous inflammation with collagen degeneration in the upper dermis. Immunohistochemically, most of the infiltrating inflammatory cells were CD 68-positive. Alcian blue staining revealed no mucin deposition in the areas of granulomatous inflammation (Fig. 2). Based on clinical and histological findings, she was diagnosed with IGD. A 7.5-mg methotrexate dose was given weekly and the daily prednisolone dose was increased from 5 mg to 15 mg. A topical 0.1% tacrolimus ointment and methylprednisolone cream were also applied daily for 2 months. The lesions were nearly cleared and ESR and CRP were found to be within normal limits after 2-month follow-up (Fig. 1B). Fig. 1 (A) Multiple, erythematous, palpable, and linear shaped plaques on both extremities. (B) Nearly clearing of lesions after a 2-month follow-up. Fig. 2 (A) A perivascular and interstitial lymphohistiocyte infiltration in the entire dermis (HE B: ×100, C: ×400). ... The most common clinical findings of IGD are asymptomatic multiple papules and plaques (70%~90% of cases)2. The rope sign was named for the linear prominent cutaneous cord-like lesions, considered pathognomic for IGD1. However, these lesions are not an essential feature, and are reported in only 9% of cases3. The histopathologic findings show interstitial CD 68-positive histiocyte infiltration around focally degenerated collagen2,4. Epidermal changes, mucin deposition, neutrophil and/or eosinophil infiltration, and vasculitis are usually absent 2. Differential diagnoses include interstitial granuloma annulare (IGA), interstitial granulomatous drug reaction (IGDR), and palisaded neutrophilic and granulomatous dermatitis (PNGD)1,2,4. In IGA, prominent mucin deposition and only focal interstitial infiltration could be found. Recent change of medication is present in IGDR, and IGDR presents with basal cell vacuolization and lichenoid changes with eosinophils2. Leukocytoclastic vasculitis and pandermal infiltration of neutrophil frequently present in early lesion of PNGD, and palisading granulomatous inflammation is the typical feature of fully developed one1. The pathogenesis of IGD may be associated with immune complex deposition caused by immune reactants of systemic inflammatory diseases5. Interestingly, IGD lesions in our case began to occur in association with the flare-up of RA after methotrexate withdrawal, although the causal relationship remains unknown. From our case we suggest that IGD should be considered among the differential diagnoses for patients with rheumatologic disease and cord-like skin lesions.

Granulomatous drug eruptions are rare entities, where granuloma formation occurs as an attempt to contain an exogenous or endogenous inciting agent. Granulomatous drug eruptions may be localized to the skin or may include major systemic involvement, and their characteristics depend both on the properties of the causative irritant and host factors. Because of the overlapping features amongst noninfectious granulomatous diseases, granulomatous drug eruptions are challenging to diagnose and distinguish both histologically and clinically. The objective of this article is to provide a review and summary of the current literature on the five major types of cutaneous granulomatous drug eruptions: interstitial granulomatous drug reaction, drug-induced accelerated rheumatoid nodulosis, drug-induced granuloma annulare, drug-induced sarcoidosis, andmiscellaneous presentations. A systematic review was conducted through PubMed using the search terms "granulomatous drug eruption" and "cutaneous" or "skin". English full-text studies that included human subjects experiencing a cutaneous reaction comprising granulomatous inflammation as the direct result of a drug were included. Of 205 studies identified, 48 articles were selected after a full-text review. Evidence was evaluated using the Tool for evaluating the methodological quality of case reports and case series. Polypharmacy and a prolonged lag period from drug ingestion to rash onset may create diagnostic challenges. Ruling out tuberculosis is imperative in the endemic setting, particularly where anti-tumor necrosis factor therapy is the presumed cause. Interstitial granulomatous drug reactions and granuloma annulare are often localized to the skin whereas accelerated rheumatoid nodulosis and sarcoidosis may sometimes be associated with systemic features as well. Granulomatous drug eruptions typically resolve on discontinuing the offending medication; however, the decision for drug cessation is dependent on a risk-benefit assessment. In some situations, supplementation of an additional agent to suppress the reaction may resolve symptoms. In some cases, granulomatous drug eruptions may be pivotal in the successful outcome of the drug, as in cases of melanoma treatment. In all situations, the decision to continue or withdraw the drug should be carefully based on the severity of the eruption, necessity of continuing the drug, and availability of a suitable alternative. Granulomatous drug eruptions should always be considered in the differential diagnosis of noninfectious granulomatous diseases of the skin. Further research examining dose-response relationships and the recurrence of granulomatous drug eruptions on the rechallenge of offending agents is required. Increased awareness of granulomatous drug eruption types is important, especially with continuous development of new anti-cancer agents that may induce these reactions. PROSPERO registration number CRD42020157009.

Interstitial granulomatous drug reaction is a rare condition presenting as erythematous-to-violaceous plaques on the lateral trunk, axillae, buttocks, and thighs. Calcium-channel blockers, angiotensin converting enzyme inhibitors, beta-blockers, and statins have been described as drugs that can trigger interstitial granulomatous drug reaction. We present a case of interstitial granulomatous drug reaction related to hydrochlorothiazide and our approach to management of this condition. The diagnosis was confirmed with a skin biopsy and a rechallenge of hydrochlorothiazide, which exacerbated the patient's symptoms. The patient improved significantly with rigorous photoprotection, combination dapsone-alitretinoin therapy, and discontinuation of hydrochlorothiazide.

217 Background: Androgen deprivation is associated with cognitive decline and mood changes. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are oral hormonal agents for the treatment of metastatic castration resistant prostate cancer (mCPRC); both target the androgen signaling pathway. Meta-analysis for individual neuropsychiatric adverse effects (NAEs) associated with these drugs has not been available in the literature. Methods: Following the methodology presented by Ruiz et al. a further meta-analysis was performed to estimate the pooled Relative Risk (RR) of NAEs for AAP and ENZ. A complementary analysis of the EudraVigilance database was performed to explore the consistency of the real world adverse drug reactions (ADR) reporting pattern with the meta-analysis. Results: The meta-analysis results indicate that patients treated with ENZ had a statistically significant higher risk of restless leg syndrome (RLS), anxiety, headache and insomnia vs control. Both AAP and ENZ showed significant increased risk for falls vs control. The Proportional Reporting Ratio (PRR) of ADRs reported in Eudra is higher with ENZ than with AAP for all the variables analyzed. Conclusions: NAEs studied are more prevalent with ENZ vs placebo than AAP vs prednisone plus placebo. Reporting trend in Eudra is consistent with this results. [Table: see text]

Interstitial granulomatous drug reaction caused by Chinese herbal medication

Interstitial granulomatous drug reaction to anakinra

We present 20 patients in whom drug therapy was associated with interstitial histiocytic infiltrates with variable degeneration of collagen and elastic fibers mimicking early lesions of granuloma annulare (GA). Most patients had a reproducible clinical presentation comprising erythematous-to-violaceous, nonpruritic plaques, often with an annular pattern, predominantly involving inner aspects of the arms, medial thighs and intertriginous areas. The most frequent clinical differential diagnoses included cutaneous T cell lymphoma, erythema annulare centrifigum (EAC), GA, and lupus erythematosus. A drug reaction was suspected in only 3 cases. The implicated drug classes included calcium channel blockers, angiotensin converting enzyme inhibitors, beta-blockers, lipid-lowering agents, antihistamines, anticonvulsants and antidepressants. Patients were often on two or more of these drugs; all have been associated with pseudolymphomatous infiltrates of the skin, the presumptive basis of which is iatrogenic pertubation of immune function. The defining histomorphology was diffuse infiltration of the interstitium by lymphocytes and histiocytes with piecemeal fragmentation of collagen and elastic fibers in concert with a vacuolar interface dermatitis. Ten cases showed intermediate and transformed lymphocytes with hyperchromatic convoluted nuclei disposed interstitially within the dermis or along the dermoepiderma junction with variable epidermotropism. In the 15 patients who discontinued the implicated drug, lesional resolution occurred. We propose the designations interstitial granulomatous drug reaction for this novel cutaneous reaction pattern.