Granulomatous dermatitis (GD) comprises a group of reactive skin diseases characterized by distinct histopathological patterns, clinical manifestations, and associated diseases. Clinical and histologic subtypes included in GD include palisade neutrophilic and granulomatous dermatitis (PNGD) and interstitial granulomatous dermatitis (IGD).1 The etiology of these subtypes is poorly understood. Both disorders are often associated with systemic inflammation and are therefore thought to be the result of immune dysregulation or dysfunction. Deposition of immune complexes in small dermal blood vessels in the setting of systemic disease or by external exposure such as medication can lead to inflammation, collagen damage and granulomatous infiltration.2 This review compares and contrasts the characteristics of each rash.
Palisade neutrophilic granulomatous dermatitis (PNGD)
Clinical situation:
The first of granulomatous dermatitis includes PNGD, which may present as symmetric nodules and induration on the face and trunk and/or umbilical papules on the extensor surfaces of the extremities.2 Lesions can also occur as linear cords on the flanks, often described as ‘burning rope signs’. PNGD is thought to represent a skin reaction pattern that occurs in association with a number of systemic diseases, most commonly rheumatic diseases such as connective tissue disease, inflammatory arthritis, and lymphoproliferative disease.2 Others include inflammatory bowel disease, myeloma, systemic lupus erythematosus, malignancies, infections, and certain drugs.3-5
Epidemiology:
Due to its rarity, little is known about the epidemiology of PNGD. PNGD can occur at any age, but the disease is rare in children. It affects women more than men in a ratio of approximately 3:1. This may reflect the distribution of associated systemic diseases. Regarding his PNGD associated with malignancy, cutaneous manifestations may precede the diagnosis of malignancy by up to 5 years.2
diagnose:
A diagnosis of PNGD is confirmed by a skin biopsy. Histologic examination may vary based on age of lesion, underlying etiology, and associated disease. Early lesions may reveal small-vessel leukocytoclastic vasculitis with neutrophil infiltration, whereas older lesions may show collagen degeneration and fibrosis. The palisade granulomas characteristic of PNGD are also called ‘Churg Strauss granulomas’ or ‘flames’. In particular, the absence of mucin helps distinguish PNGD from granuloma annulare.1-3,6 Recently, a unique histologic variant of PGND was identified in patients with chronic myelomonocytic leukemia. Wedge-shaped cutaneous infiltrates with foamy multinucleated histiocytes and foci of necrotic collagen may be observed in this variant.7
Although the symptoms are benign, the diagnosis of PNGD is important. This is because the disease is often a cutaneous manifestation of a more serious general condition or underlying infection.
management:
Patients presenting with subtypes of GD, including PGND, require evaluation for potential triggers and associated systemic disease. The most common drugs that cause PGND include calcium channel blockers, beta-blockers, angiotensin-converting enzyme inhibitors, and statins.6 A recent case report also highlights PGND suspected to be triggered by tocilizumab.8 Laboratory evaluation for potential autoimmune etiology includes measurement of antinuclear antibodies, antinucleocytoplasmic antigens, rheumatoid factor, and citrullinated proteins. Patients should also undergo age-appropriate cancer screening for PGND associated malignancies.6
About 20% of patients show spontaneous resolution of PGND-associated skin lesions, usually within a few weeks to a month.3
For the remaining 80%, treatment of PGND is primarily directed at addressing the underlying disease or removing irritating factors (such as medication). Treatment includes topical corticosteroids, nonsteroidal anti-inflammatory drugs, dapsone, colchicine, prednisone, oral tacrolimus, tumor necrosis factor (TNF) inhibitors, and baricitinib.8
Interstitial granulomatous dermatitis (IGD) and interstitial granulomatous drug reaction (IGDR)
Interstitial granulomatous dermatitis (IGD) is another granulomatous dermatitis characterized by various forms of erythematous plaques and patches on the inner arms, thighs, trunk, and interbruised areas. Other symptoms include macular erythema, subcutaneous nodules, and elbow papules. The presence of hardened ‘rope-like’ lesions supporting the outer trunk and skin folds, seen in only 10% of patients, is a hallmark of IGD.1
Like PGND, IGD often occurs in the setting of numerous systemic diseases, including rheumatic diseases, hematologic diseases, malignancies, and infectious diseases. Case reports of myelofibrosis- and lymphoma-induced IGD show mixed associations.9 IGD can also be induced by drugs. This condition is called interstitial granulomatous drug reaction (IGDR) and is considered to be a distinct histopathological entity.Ten The clinical appearance of IGDR is similar to IGD, with ring-shaped erythema on the proximal medial thigh, trunk, and interbruised areas.3
Epidemiology:
As with PGND, the rarity of IGD/IGDR makes epidemiological studies difficult. Like PGND, IGD occurs at all ages, but mostly occurs in adults between the ages of 40 and 50 and is less common in children. IGD also tends to favor females over males with a 3:1 ratio. For IGDR, the onset of skin lesions usually occurs months to years after starting the causative medication.Ten
diagnose:
IGD and IGDR are diagnosed by skin biopsy histology. Histopathologic findings of IGD include palisade granulomas composed of histiocytes surrounding degenerated collagen foci and cutaneous interstitial lymphocytic infiltrates composed of neutrophils. Other distinct features include lack of mucin and, unlike PNGD, lack of vasculitis.6 Some of the histopathological findings of IGDR overlap with IGD, such as interstitial histiocytes surrounding denatured collagen. Unique features of IGDR include lymphoid atypia, vacuolar interfacial dermatitis with dyskeratosis, and marked eosinophilia.2,6,10
management:
Similar to PGND, patients with IGD require evaluation for potential triggers and associated systemic disease. Drugs associated with IGDR include beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, statins, furosemide, antidepressants, and anticonvulsants. Case reports have also implicated hydrochlorothiazide, ustekinumab, and tocilizumab.Four Interestingly, TNF-α inhibitors and ustekinumab paradoxically also cause IGDR, despite being used to treat IGD.12,13
Treatment of IGD includes discontinuing provoking agents and/or addressing underlying related health conditions. Topical corticosteroids, intralesional corticosteroids, dapsone, hydroxychloroquine, and ustekinumab have been shown to improve cutaneous symptoms.13
Update on granulomatous dermatitis:
As noted above, there is considerable overlap in the clinical manifestations and contexts of PNGD and IGDR. There are various different histological and clinical patterns that appear to distinguish the two, but this distinction may not be significant. A number of recent reports on reactions further blur the distinction between PNGD and IGDR. Because of the similarities in clinical manifestations, treatment, and overall clinical course, recent literature suggests grouping PNGD and IGDR under the umbrella term “reactive granulomatous dermatitis.” It has been.6
References
1. Rodríguez-Garijo N, Bielsa I, Mascaró Jr J m., et al. Reactions as a histologic pattern involving symptoms of interstitial granulomatous dermatitis and palisade neutrophilic and granulomatous dermatitis. Granulomatous Dermatitis: A 52 Patient Study. European Journal of Dermatology2021;35(4):988-994.doi:10.1111/jdv.17010
2. Imadojemu S, Rosenbach M. Advances in inflammatory granulomatous skin disease. dermatology clinic2019;37(1):49-64. doi:10.1016/j.det.2018.08.001
3. Stiff KM, Cohen PR. Granulomatous dermatitis palisade associated with ulcerative colitis: A comprehensive literature review. cyreus9(1):e958. doi:10.7759/cureus.958
4. Zabihi-pour D, Bahrani B, Assaad D, Yeung J. Palisade neutrophilic and granulomatous dermatitis following long-standing monoclonal immunoglobulinemia: a case report. SAGE Open Med Case Rep. 2021;9:2050313X20979560. doi:10.1177/2050313X20979560
5. Akagawa M, Hattori Y, Mizutani Y, Shu E, Miyazaki T, Seishima M. Palisal neutrophilic and granulomatous dermatitis in patients with granulomatous polyangiitis. CDEs2020;12(1):52-56. Doi:10.1159/000506670
6. Wanat KA, Caplan A, Messenger E, English JC, Rosenbach M. Reactive granulomatous dermatitis: a useful and comprehensive term. JAAD Int. 2022; 7:126-128. doi:10.1016/j.jdin.2022.03.004
7. Enescu CD, Patel A, Friedman BJ. A unique and recognizable histopathologic variant in palisade neutrophilic and granulomatous dermatitis associated with SRSF2-mutant chronic myelomonocytic leukemia: a case report and review of the literature. Am J Dermatology2022;44(3):e33-e36.doi:10.1097/DAD.0000000000002085
8. Hung YT, Chung WH, Chen CB, Chan TM.Baricitinib treatment for palisade neutrophilic granulomatous dermatitis: a new paradoxical response to tocilizumab. [published online ahead of print, 2022 May 12]. Dermatitis. 2022;10.1097/DER.0000000000000879.doi:10.1097/DER.0000000000000879
9. Rose C, Hall Ulrich K. [Granulomatous reaction pattern of the skin : Interstitial granulomatous dermatitis – lymphoma – vasculitis]. Hautartz2017;68(7):553-559.doi:10.1007/s00105-017-4004-6.
10. Aldiben RT, Hausawi KA. Interstitial granulomatous drug reaction: a case report. cyreus2022;14(2). doi:10.7759/cureus.21893
11. Altemir A, Iglesias-Sancho M, Sola-Casas M de los Á, Novoa-Lamazares L, Fernández-Figueras M, Salleras-Redonnet M. Interstitial granulomatous dermatitis following tocilizumab, a paradoxical reaction? Dermatological treatment. 2020;33(6):e14207.doi:10.1111/dth.14207
12. Altemir A, Iglesias-Sancho M, Sola-Casas M de los Á, Novoa-Lamazares L, Fernández-Figueras M, Salleras-Redonnet M. Interstitial granulomatous dermatitis after tocilizumab, a paradoxical reaction? Dermatological treatment. 2020;33(6):e14207.doi:10.1111/dth.14207
13. Walker A, Westerdahl JS, Susman J, Mathis J. Interstitial granulomatous drug reactions to ustekinumab. Case Representative Dermatol Med. 2022;2022:1461145. Doi: 10.1155/2022/1461145
14. Cover image: Ahmed Z, Joad S, Singh, et al. Interstitial granulomatous dermatitis successfully treated with etanercept. Am J Case Rep, 2014; 15:94-96 DOI:10.12659/AJCR.890074
