For the win! Championing the use of the term “reactive granulomatous dermatitis” in clinical practice

By David A. Wetter, MD, FAAD
March 8, 2023
Vol. 5, No. 10

Growing up in the 1980s in suburban St. Louis, Missouri, I spent many evenings listening to Cardinals’ baseball on the local AM radio station, KMOX 1120. After the final out of each Cardinals’ victory, the late Hall-of-Fame broadcaster, Jack Buck, would emphatically say, “That’s a winner!”

Similarly, when Rosenbach and English coined the term “reactive granulomatous dermatitis” (RGD) in 2015 (1), I thought that this was a “winning” concept. They proposed RGD as a unifying term to encompass interstitial granulomatous dermatitis (IGD), palisaded neutrophilic and granulomatous dermatitis (PNGD), and interstitial granulomatous drug reaction (IGDR). (1)

I wish that RGD had been part of our vernacular during my dermatology residency and early faculty years. When receiving a dermatopathology report with the diagnosis of IGD or PNGD, I recall struggling to determine the proper workup for these patients. Should the evaluation for associated systemic diseases differ depending upon whether the skin biopsy showed IGD compared to PNGD? Is a different treatment approach employed for patients with IGD compared to PNGD? Is the prognosis different for patients with IGD compared to PNGD? Even with a thorough review of the literature, those questions could not be answered using the “pre-RGD” terminology.

I will always remember a patient I encountered during my first year on faculty in 2009. He had been referred for a chronic granulomatous skin eruption that had not responded to corticosteroids (topical and systemic) or hydroxychloroquine. I was struck by how prominent his skin eruption was and the 60-pound weight loss he reported over the previous year. I was unsure what to specifically call his skin condition, but I was concerned that it represented a “reactive” process to an underlying systemic disease. Unfortunately, our workup confirmed this suspicion: the patient was found to have myelodysplastic syndrome that soon progressed to acute myeloid leukemia, leading to his death. We decided to publish this patient’s case in 2011 to alert the dermatologic community that unexplained granulomatous skin eruptions could be a sign of underlying hematologic malignancy. (2) Although we used the term “generalized granulomatous dermatitis” to describe the patient’s skin eruption, I would now use the term “RGD” to describe his condition more accurately. In retrospect, had the concept of “RGD” existed at that time, I also wonder if a more detailed search for malignancy might have been undertaken earlier during the patient’s skin disease, leading to the diagnosis of his hematologic malignancy sooner and at a more treatable stage.

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It is heartening to see the term “RGD” used more frequently in the dermatologic community in recent publications, including a case series of adult (3) and pediatric (4) patients. Wanat and colleagues encourage broad use of the term “RGD,” delineating clinical features, histopathology, associated diseases, and workup of patients with the various RGD subtypes (PNGD, IGD, IGDR — see table I). (5) Discussing a different granulomatous condition (granulomatous cheilitis) in a recent issue of Dermatology World Insights and Inquiries, Rosenbach opined within “Our expert’s viewpoint” that: “Our field should be prepared to modernize and update our thinking about different diseases — including considering when it’s appropriate to lump them together under one broader all-encompassing term. The objective is helping patients, and different names for the same disease sometimes can hinder achieving that goal.” (6)

To that end, we retrospectively studied RGD at Mayo Clinic in a large series of 65 adult patients. (7) All patients had a final diagnosis of RGD based upon Rosenbach and English’s proposed criteria. (1) A board-certified dermatologist retrospectively reviewed skin biopsy slides for all patients and classified them as having either the IGD or PNGD subtype of RGD, based upon the observed predominant inflammatory pattern. The following bulleted points are some of the clinically relevant pearls from our study:

• Median age at RGD diagnosis was 62 years; 63.1% of patients were women

• Subtypes of RGD in the 65 patients were: 37 IGD, 26 PNGD, 2 IGDR

• Skin findings were asymptomatic in 64.9% of patients

• 50 (76.9%) of 65 patients with RGD had an associated systemic condition

  • Rheumatologic conditions were most common (34 patients [52.3%]), including rheumatoid arthritis, seronegative inflammatory arthritis, systemic lupus erythematosus, and undifferentiated connective tissue disease

  • Malignancy was associated with RGD in six patients (9.2%), 5 of whom had a hematologic malignancy

  • Gastrointestinal conditions (i.e., inflammatory bowel disease) were present in 5 patients (7.7%)

• Associated systemic diseases occurred before RGD onset in 78% (39 of 50) patients

• A specific systemic condition was not significantly associated with a particular subtype of RGD (P = 0.99 for both IGD and PNGD)

• Specific histopathologic findings (inflammatory cell type; degree of dermal cellularity; inflammatory pattern; and presence of necrobiosis, mucin, vascular damage, or basophilic collagen) were not significantly associated with an underlying systemic condition (P > 0.90 for rheumatologic condition, malignancy, and gastrointestinal disease, respectively)

• Of 32 patients with available data for treatment response, 28 (87.5%) had either complete response or partial response (>50%) — this response did not differ between patients with IGD or PNGD subtype of RGD, although statistical analyses were unable to be performed due to incomplete treatment response data for 33 of the 65 patients

Given that our study did not find a statistically significant association between RGD subtypes and a specific associated systemic condition, nor were any specific histopathologic findings predictive of an associated systemic condition, we believe that RGD is a clinically relevant umbrella term that should be routinely used in dermatologic practice (in lieu of IGD, PNGD, and IGDR). We also recommend incorporating the term “RGD” into dermatopathology reports to alert the treating dermatologist to consider a review of systems and evaluation for the possible presence of an associated systemic disease.

Point to Remember: Consider using the term “reactive granulomatous dermatitis” (RGD) in your dermatologic practice, prompting search for an underlying associated systemic condition following a thorough review of systems.

Our experts’ viewpoint

Avrom S. Caplan, MD, FAAD
Assistant Professor, Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine

Karolyn A. Wanat, MD, FAAD
Associate Professor of Dermatology, Medical College of Wisconsin

Being invited to write an expert viewpoint from Dr. Heymann on one of our favorite subjects — reactive granulomatous dermatitis (RGD) — is an absolute privilege. This entity in particular highlights two important aspects of dermatology: 1) cutaneous eruptions can serve as a sign of systemic disease and 2) confusion in our field can arise when multiple and often overlapping terms are introduced in the literature to describe similar entities. Under the umbrella of RGD are multiple dermatologic diagnoses with overlapping clinicopathologic features and disease associations. From the initial reports of “subcutaneous bands in rheumatoid arthritis” in 1965 and necrotizing granulomas in association with systemic disease in 1977 and 1978, we see an expanded nomenclature of these conditions to include terms such as “linear rheumatoid nodules,” “linear granuloma annulare,” “interstitial granulomatous dermatitis with arthritis,” “interstitial granulomatous dermatitis with cutaneous cords and arthritis,” “Ackerman syndrome,” “Churg–Strauss granulomas,” “cutaneous extravascular necrotizing granulomas,” and “Winkelmann granuloma.” (8) Consensus ultimately settled on “interstitial granulomatous dermatitis” (IGD) and “palisaded neutrophilic and granulomatous dermatitis” (PNGD), with the former defined histopathologically by clefting between histiocyte rosettes and degenerated collagen, minimal mucin, absent vasculitis and the latter by leukocytoclasia, neutrophilic infiltrates, minimal mucin, and fibrosis. (8) Clinically, the classic findings of IGD and PNGD included linear bands on the trunk in the former and papules (smooth, sometimes crusted) on the extremities (particularly the elbows) in the latter, although published reports included mixed and multiple morphologic pictures for these. (1,8) “Interstitial granulomatous drug eruption” (IGDR) and “drug-induced interstitial granulomatous dermatitis” (D-IGD) were also described and separated by clinicopathologic criteria, but this was not strictly adhered to in the literature. (1,8) Within this mishmash of terms and phrases, the debate between “lumpers” and “splitters” thrived. Was this distinction without difference?

Fast forward to 2015 when Rosenbach and English reviewed these conditions in detail and introduced the term, “reactive granulomatous dermatitis,” arguing that these entities should be lumped together (including medication induced reactive granulomatous processes) and attention should be paid to the underlying medication and disease associations that have been reported with all of these disorders. (1)

How well has this term stood the test of time? Have the “lumpers” prevailed? We (and others) argue yes. (3,5,7) Recent publications call attention to the overarching similarities among these entities, further emphasizing that the distinctions between IGD and PNGD are less important than the implication of these conditions. Kumar et al reviewed 65 patients with RGD in 2022 and Rodriguez-Garijo reviewed 52 patients with RGD in 2021. In both papers RGD was highly associated with systemic diseases (77% vs 75% respectively) and subtypes of RGD did not correlate with disease association. (3,7) Thus, when we see RGD on the skin, it matters less whether it is IGD vs PNGD or IGDR vs D-IGD but matters more that this eruption is a skin sign that warrants a workup for associated conditions and medications.

The term RGD allows for unified language and a similar approach to evaluation and treatment among dermatologists and colleagues who care for these patients. Though some may consider sub-types of RGD to include IGD/PNGD/IGDR/D-IGD, we encourage the use of the term RGD. (5) We may additionally ask whether the umbrella term should include other granulomatous entities. Is granuloma annulare a “reactive granulomatous dermatitis marked by mucin?” Should we consider necrobiosis lipoidica a “reactive granulomatous dermatitis marked by necrobiosis,” or necrobiotic xanthogranuloma a “reactive granulomatous dermatitis marked by a paraprotein?” Time, and additional research, will unfold the nuances of these diseases and tell.

1. Rosenbach M, English JC 3rd. Reactive granulomatous dermatitis: A review of palisaded neutrophilic and granulomatous dermatitis, interstitial granulomatous dermatitis, interstitial granulomatous drug eruption, and a proposed reclassification. Dermatol Clin. 2015;33:373-387.

2. Balin SJ, Wetter DA, Kurtin PJ, et al. Myelodysplastic syndrome presenting as generalized granulomatous dermatitis. Arch Dermatol. 2011;147:331-335.

3. Rodríguez-Garijo N, Bielsa I, Mascaró JM Jr, et al. Reactive granulomatous dermatitis as a histological pattern including manifestations of interstitial granulomatous dermatitis and palisaded neutrophilic and granulomatous dermatitis: A study of 52 patients. J Eur Acad Dermatol Venereol. 2021;35:988-994.

4. Akinshemoyin Vaughn OL, Siegel DH, Chiu YE, et al. Clinical and histologic presentation of pediatric reactive granulomatous dermatitis. Pediatr Dermatol. 2020;37:498-503.

5. Wanat KA, Caplan A, Messenger E, et al. Reactive granulomatous dermatitis: A useful and encompassing term. JAAD Int. 2022;7:126-128.

6. Heymann WR. Granulomatous cheilitis: Back to the future. Dermatology World Insights and Inquiries. June 1, 2022.

7. Bangalore Kumar A, Lehman JS, Johnson EF, et al. Reactive granulomatous dermatitis as a clinically relevant and unifying term: A retrospective review of clinical features, associated systemic diseases, histopathology and treatment for a series of 65 patients at Mayo Clinic. J Eur Acad Dermatol Venereol. 2022 May 10. Doi:10.1111/jdv.18203. Online ahead of print.

8. Caplan A, Wanat K, English JC III, Rosenbach M. Reactive granulomatous dermatitis (interstitial granulomatous dermatitis, palisaded neutrophilic and granulomatous dermatitis, and variants). In: Rongioletti F, Smoller B, eds. New and Emerging Entities in Dermatology and Dermatopathology. 1st ed. Springer Nature; 2021:423-445.

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