Reactive Granulomatous Dermatitis: A Descriptive Study of 10 Patients

Introduction

Reactive granulomatous dermatitis (RGD) is a rare disease whose pathogenesis has not yet been fully elucidated. This entity is part of a group of non-infectious granulomatous diseases including sarcoidosis, granuloma annulare, annular elastolytic giant cell granuloma, and necrobiosis lipoidica. RGD includes interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD), in addition to interstitial granulomatous drug reaction (IGDR).^1,2 Indeed, given the significant overlap in their clinical presentations, their histological findings, and their underlying conditions, they are considered a continuum by many authors. The growing recognition that RGD is an all-encompassing term reduced previous confusion in the scientific literature surrounding this nomenclature.

RGD is found in association with various systemic diseases, such as autoimmune diseases (eg, inflammatory arthritis, connective tissue disease, vasculitis),^1-3 malignancy (especially hematologic neoplasms), ⁴ certain drugs [eg, tumor necrosis factor (TNF) inhibitors, furosemide, angiotensin-converting enzyme inhibitors],^1,5 and rare infections (coccidioidomycosis and borreliosis).^6,7 The majority of patients had a systemic association prior to diagnosis. ² However, it is unclear which investigations should be carried out and if new associations were subsequently identified. Thus, the objective of this study is to describe cases of RGD with their possible underlying associations at the time of diagnosis and within the following year. It aims to support the associations previously described in the literature and possibly enlighten physicians on the relevant investigations to perform.

Material and Methods

This study was approved by the Director of Professional Services of the Capitale-Nationale and the Ethics Committee to access patient files.

We describe confirmed cases of RGD seen between January 2000 and December 2020 in the Centre Hospitalier Universitaire de Québec—Université Laval. They were identified by the morphological codes used by the pathology department. Any histopathological diagnosis of granuloma other than RGD was excluded. All patients have confirmed clinicopathologic correlation of RGD by a qualified dermatologist who ultimately retained IGD, PNGD, and/or IGDR as the final diagnosis. Patients of all ages and genders were accepted.

The data were collected from electronic patient records. A retrospective chart review was conducted. Notably, histopathological diagnosis of RGD, demographic characteristics, clinical descriptions, identification of suspected association, and prescribed investigations were collected at the time of diagnosis. New systemic conditions identified within a 12-month period from the diagnosis were also retrieved.

Results

Among the patients, 4/10 were diagnosed with IGD, 3/10 with PNGD, and 3/10 mentioned both. A majority of patients were female (8/10). Their ages ranged from 29 to 81, with a median age of 48 years. The clinical presentations and locations were highly variable between patients. One patient had a single large lesion, while others had multiple disseminated lesions. Lesions were mainly present on the trunk and limbs (8/10). Four patients had lesions on the hands. Only 1 patient had facial involvement. Table 1 summarizes the clinical characteristics of all 10 patients.

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Table 1.

Characteristics of 10 Patients With Reactive Granulomatous Dermatitis.

Patient	Diagnosis	Sex	Age	Clinical description	Affected sites
1	IGD	H	71	8 purple firm edematous papules	Back, right arm, and right hand
2	IGD	F	63	Multiple erythematous papules	Neck and anterior chest
3	IGD	F	81	Purpuric edematous nodules and plaques	Arms and legs
4	IGD-PNGD	H	66	Infiltrated erythematous plaques; linear or arciform	Back and right thigh
5	IDG-PNGD	F	35	Erythematous nodules	Elbows and proximal interphalangeal joints
6	IGD	F	47	Erythematous nodules	Fingers
7	PNGD	F	49	20 to 30 firm pink-purple papules and nodules	Arms and thighs
8	PNGD	F	29	Purple edematous papules and plaques with pseudo vesicles	Neck, anterior chest, upper limbs, and face
9	PNGD	F	29	Pink and purpuric edematous papules	Fingers
10	IGD-PNGD	F	45	Large cyanotic erythematous plaque	Left thigh and buttocks

Abbreviations: IGD, interstitial granulomatous dermatitis; PNGD, palisaded neutrophilic and granulomatous dermatitis.

At the time of diagnosis, 7/10 patients had a known autoimmune disease: 3 patients with seronegative arthritis and 4 patients with inflammatory bowel disease (3 patients had Crohn’s disease and 1 patient had ulcerative colitis). One patient with Crohn’s disease also had concomitant spondylitis. Furthermore, in 2 of the 7 patients with autoimmune conditions, there was a clinical suspicion of a possible association with a TNF inhibitor (infliximab and etanercept, respectively). In both cases, the clinicians could not determine whether the TNF inhibitor or the associated autoimmune disease was the precipitating factor. In one of these patients, the TNF inhibitor was changed to baricitinib, a Janus kinase inhibitor, with subsequent improvement of lesions. None of the 10 patients had a known malignancy at the time of RGD diagnosis.

Two out of 10 patients were not further investigated after skin biopsy. In 8/10 patients, conducted investigations varied and included complete blood count, anti-nuclear antibody, rheumatoid factor, extractable nuclear antigen, thyroid function tests, serum protein electrophoresis with immunofixation, sedimentation rate, and C-reactive protein. Within the 12-month period, only 1 patient had a new association possibly related to RGD. An 81-year-old woman was diagnosed with a high-grade B-cell lymphoma 6 months after the diagnosis of RGD and died shortly thereafter. This patient was 1 of the 3 patients categorized as idiopathic RGD at the time of diagnosis.

Prescribed treatments aimed to treat RGD and/or its clinically suspected underlying association. The majority of patients (8/10) were treated with topical corticosteroids. Response with this treatment ranged from resolution within 1 month for 1 patient, while 3 other patients still had recurrent plaques after 12 months from diagnosis. Concomitantly or subsequently, some patients received hydroxychloroquine, methotrexate, and oral corticosteroids with varying responses. The majority of patients still had lesions despite the use of these systemic treatments. Two patients started a new TNF inhibitor (adalimumab and infliximab), a drug paradoxically associated with RGD. In these 2 cases, no clinical improvement of RGD was observed during the 12 months following diagnosis.

As previously mentioned, a patient’s TNF inhibitor (etanercept), possibly thought to be a trigger, was changed to baricitinib. With this replacement and topical corticosteroids, resolution of RGD occurred within 3 months. The second patient with a clinical suspicion of TNF inhibitor-induced RGD continued to receive infliximab. He was treated only with topical corticosteroids, and the lesions persisted within 12 months of diagnosis.

Patients had variable evolutions. In 4/10, remission was observed in a few months, while 6/10 patients had no resolution during the 12-month period with recurrence of lesions. Table 2 summarizes the associations, investigations, and treatments for all 10 patients.

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Table 2.

Associated Diseases of 10 Patients With Reactive Granulomatous Dermatitis.

Patient	Association at the moment of diagnosis			Investigation after diagnosis	New association within 1 year of diagnosis	Treatments	Time between diagnosis and resolution of lesions
	Autoimmune diseases	Drug	Malignancy
1	No	No	No	Yes	No	Topical corticosteroids	>12 months
2	Seronegative arthritis	TNF inhibitor (Etanercept)	No	No	No	Topical corticosteroids, baricitinib (for etanercept replacement)	3 months
3	No	No	No	Yes	High-grade B-cell lymphoma	No treatment	1 month
4	No	No	No	Yes	No	Topical corticosteroids	1 month
5	Seronegative arthritis	No	No	Yes	No	Topical corticosteroids, hydroxychloroquine	>12 months
6	Crohn’s-associated spondylitis	No	No	Yes	No	Topical corticosteroids, methotrexate, adalimumab	>12 months
7	Seronegative arthritis	No	No	No	No	Colchicine, hydroxychloroquine, methotrexate, oral corticosteroids	7 months
8	Crohn’s disease	No	No	Yes	No	Topical corticosteroids, hydroxychloroquine, dapsone, infliximab	>12 months
9	Ulcerative colitis	TNF inhibitor (Infliximab)	No	Yes	No	Topical corticosteroids	>12 months
10	Crohn’s disease	No	No	Yes	No	Topical and oral corticosteroids	>12 months

Abbreviation: TNF, tumor necrosis factor.

Discussion

We describe 10 cases of RGD and their suspected systemic associations. The majority of patients (70% of cases) had an autoimmune disease upon diagnosis, either inflammatory arthritis or inflammatory bowel disease. Our results mirror the cases previously described in the literature. Indeed, in the recent study by Kumar et al, 76.9% of patients had an associated systemic disease before the development of RGD. In this same study, the most common association was a rheumatologic condition (52.3% of patients). ² Besides arthritis and inflammatory bowel disease, systemic lupus erythematosus, systemic sclerosis, ANCA vasculitis, Sjogren’s syndrome, and mixed cryoglobulinemia have also been described with RGD.^1-3,8-13

Analogous to previous publications, TNF inhibitors could be a trigger for RGD. ¹⁴ Out of the 10 patients in our study, 2 cases were possibly related to this medication. However, doubts remain about whether it is related to the active disease or the prescribed medication. Other drugs often associated with RGD are calcium channel blockers, angiotensin-converting enzyme inhibitors, statins, furosemide, and beta-blockers.^1,2,5

No patient had malignancy at the time of diagnosis, but 1 patient was diagnosed with a high-grade B-cell lymphoma in the following months. The association with hematological neoplasms has also been noted in the literature, such as Hodgkin lymphomas, myelodysplastic syndromes, and acute myelocytic leukemia.^1,2,4,15

In most cases, skin involvement did not resolve within the year following the diagnosis of RGD. These findings contrast with previous studies where PNGD patients had rapid resolution and IGD patients had spontaneous remission. For instance, Aloi et al ¹⁶ reported 3 cases of RGD that resolved spontaneously over a period of 6 to 12 months. Several treatments are used to treat RGD and/or the underlying disease, the most common being topical corticosteroids.^2,17 Therapeutic alternatives described in the literature include systemic corticosteroids, hydroxychloroquine, TNF inhibitors, colchicine, methotrexate, azathioprine, dapsone, cyclosporine, doxycycline, and intralesional corticosteroids.^2,3,18 Baricitinib could be an additional therapeutic option.

Given the design of our study and our small population, we cannot recommend precise investigations in patients with RGD. Nevertheless, reported cases of RGD in patients with autoimmune diseases and hematological neoplasia should be kept in mind when considering further investigations, especially in cases where an underlying systemic disorder was not initially present at the time of diagnosis.

In conclusion, this descriptive study reflects the associations previously described with RGD, particularly autoimmune diseases, malignancy, and certain drugs (specifically inhibitors of TNF).^1,2 Most patients already had an underlying systemic disease possibly associated with RGD at the time of histopathological diagnosis. Among the 3 patients without an initial identification of association, 2 patients remained idiopathic despite further investigations and 1 patient developed a lymphoma in the following months. An interesting avenue for future studies would be to do a longer follow-up of idiopathic cases to better characterize new associations, with particular attention to malignancy.