Aiming to hit the target in cutaneous granulomatous diseases

By Heidi Splete, Contributing Writer, February 1, 2026

Approved treatments for granulomatous skin diseases are lacking, but a growing number of case series and early research suggest new opportunities for managing these conditions with targeted therapies.

Treatment trends involve leveraging new medications such as biologics and Janus kinase (JAK) inhibitors for more targeted therapies that may help reduce patients’ long-term reliance on broad-acting immunosuppressants.

Granulomas, localized collections of immune cells that form in response to a variety of stimuli, are a defining feature in a range of skin diseases, some benign and some severe. The lesions themselves are not universal across conditions, and may appear as small bumps, or as with granuloma annulare, a distinctive raised, ring-shaped rash with a clear center.

The primary challenge in managing granulomatous skin diseases is the broad differential diagnosis that surrounds granulomatous inflammation, and that treatment choices for many inflammatory granulomatous conditions are often based on limited data, said Avrom S. Caplan, MD, FAAD, assistant professor of dermatology at NYU Langone in New York.

Granulomas can form in response to an infection or sometimes in response to an overreaction of the immune system, such as in patients with sarcoidosis or Crohn disease, according to the Cleveland Clinic. Other potential causes include medications and environmental exposures. The infectious and non-infectious causes of granulomas can be tricky at times to tease apart, Dr. Caplan added.

“Consider granulomas in tattoos; these can result from infection, sarcoid, foreign body reactions, or hypersensitivity reactions, and the workup and treatment will vary based on the diagnosis,” he said. “We have tools we can use to help differentiate these, including biopsies and tissue cultures, and sometimes we need to take additional steps including advanced testing for infections,” Dr. Caplan said. However, it is important to link a patient’s presentation to pathology, which can be challenging, he added.

Precision is key to approaching the diagnosis of granulomatous skin diseases, as granulomas on the skin can be a sign of systemic disease from infectious or non-infectious causes, Dr. Caplan said.

Since granulomatous conditions can look like anything, accurate diagnosis depends on understanding how these eruptions may manifest, Dr. Caplan said. Dermatologists should be sensitive to describing morphology across the full spectrum of skin tones, he noted. In addition, certain granulomatous conditions, including sarcoidosis, may lead to chronic and systemic disease, with granulomatous lesions that may be difficult to treat, he said.

Off-label opportunities

Many off-label treatments continue to have been reported across the spectrum of skin granulomas, but data for most of these medications, until recently, have been limited to case reports and case series, Dr. Caplan told DermWorld. This is especially true of granuloma annulare, as its waxing and waning nature makes interpretation of individual case reports difficult, he said.

However, recent translational research in granulomas is helping us better understand these diseases and expand treatment options, said Dr. Caplan.

The JAK inhibitors, as in other dermatologic conditions, have been increasingly reported and researched for granulomatous skin disorders as well as other dermatologic conditions, and this work has been important to the understanding of disease pathogenesis, as well as for identifying potential treatment targets, Dr. Caplan said.

In a 2023 review published in the Journal of Investigative Dermatology: Innovations, researchers at Yale University in the Damsky Lab reviewed the latest evidence for molecularly targeted treatments and recent updates in disease immunopathogenesis. The precise place for JAK inhibitors in the treatment stepladder for various granulomatous disorders remains to be determined, Dr. Caplan added. “Some patients with mild disease may not need systemic medications, especially with the potential side effects of these medications, whereas other patients may benefit from these medications over others that have been used previously,” he said. These situations are nuanced, and require discussions not only with patients, but with other clinicians who may be managing potential side effects and comorbidities, Dr. Caplan noted.

“We don’t have many FDA-approved therapies in this area of dermatology; prednisone and corticotropin gel, for example, are the only FDA-approved therapies in sarcoidosis, so patient discussions must be prefaced by stating that this use is off-label,” Dr. Caplan said. Importantly, the off-label use of immunologically targeted therapies is limited to non-infectious granulomas; infectious granulomas, such as cutaneous tuberculosis, should be managed in conjunction with, or primarily by, experts in these areas, he added.

Granuloma annulare activity

Granuloma annulare (GA) is considered the most common non-infectious granulomatous skin disease. While generally benign, GA is concerning to patients, and clinicians have identified a range of strategies, although many cases, especially localized cases, clear up on their own.

In the absence of any medication approved by the FDA, research has shown some effectiveness with topical treatments including topical or intralesional corticosteroids, topical immunomodulators, and phototherapy. Other options with varying degrees of success include antibiotics and antimalarials. Although localized granuloma annulare lesions often resolve on their own, patients experiencing generalized, persistent GA may be more amenable to aggressive treatments, including lasers.

In a 2022 review published in the American Journal of Clinical Dermatology, Tejas P. Joshi, MD, of Baylor College of Medicine, and Madeleine Duvic, MD, of MD Anderson Cancer Center, both in Houston, recommended starting treatment with intralesional or topical corticosteroids, but acknowledged that these treatments often fail patients with generalized disease.

However, evolving research shows the potential game-changing impact of JAK-inhibitors for GA patients. In a 2024 case report published in JAAD Case Reports, a 51-year-old female with recalcitrant, generalized GA achieved total clearance after 12 weeks of treatment with ruxolitinib 1.5% cream.

Other case reports have described successful treatment of localized and generalized GA with abrocitinib and upadacitinib, respectively. Additionally, both dupilumab and ustekinumab have shown effectiveness in improving GA in some case reports.

In GA, there has been increasing recognition of the negative impact of the condition on patients’ quality of life, said William Damsky, MD, FAAD. “Although considered benign, GA is not always just a cosmetic disease,” he said. This attitude shift, especially in patients with generalized disease, has led clinicians to use more aggressive therapies when appropriate, including TNF inhibitors and JAK inhibitors, said Dr. Damsky, a physician-scientist at Yale Medicine in New Haven, Connecticut, who specializes in the mechanisms of inflammatory skin diseases.

“Unfortunately, even with molecularly targeted therapies for sarcoidosis and GA, we do not have evidence that disease natural history is altered, or that these medications ‘cure’ patients,” Dr. Damsky noted. “Generally, even with these molecularly targeted therapies, treatment should be considered long-term in most instances, and this is an important point to discuss with patients considering these therapies,” he said. “We do tend to think, however, that molecularly targeted therapies have fewer adverse effects, and possibly increased efficacy, when comparing to conventional medications, such as prednisone for sarcoidosis,” he added.

For GA patients with moderate-to-severe disease, Dr. Damsky favors including discussion of TNF inhibition or JAK inhibition. “Given that some patients with certain medical comorbidities, or those with concerns about potential adverse effects may not be candidates for these therapies, we also discuss hydroxychloroquine, apremilast, and sometimes phototherapy,” he said.

“Ask the patient how their skin disease is affecting their quality of life,” said Dr. Damsky. In the case of GA, “If a patient is motivated to treat, we should be motivated to help them, including if this means discussing stronger medications such as TNF inhibitors and JAK inhibitors,” he emphasized. Dr. Damsky said that, following discussion with patients, he is less likely to choose TNF inhibitors for patients with a history of recent or active malignancy, multiple sclerosis, or a history of serious infections. Regarding JAK inhibitors, Dr. Damsky said he is less likely to prescribe them for patients who are older than 65 years, or who have a significant smoking history, history of serious infections, history of recent or active malignancy, significant cardiovascular disease, history of deep vein thrombosis/pulmonary embolism, or morbid obesity.

Further considerations for GA assessment

Granulomatous diseases, while having some classic morphologic appearances, can also be subtle or nonspecific, said Juliana Berk-Krauss, MD, FAAD, assistant clinical professor of dermatology at the University of Southern California.

GA classically presents as distinctive pink or skin-colored annular plaques with raised borders or clusters of papules, Dr. Berk-Krauss said. “A biopsy of GA lesions will show interstitial or palisading histiocytes around degenerated collagen, and these clinical and histologic findings distinguish it from more serious granulomatous disorders,” she explained. However, GA can also be associated with a range of underlying disorders including diabetes, thyroid disease, dyslipidemia, and, rarely, malignancy, she said. “Atypical or recalcitrant presentations, especially in older patients, will prompt me to do a more thorough malignancy workup,” she added.

For GA patients with localized disease, Dr. Berk-Krauss said she opts for topical and/or intralesional steroids. “For generalized GA, I typically start with hydroxychloroquine, plus or minus doxycycline or pentoxifylline, and about half of patients will respond to this,” she said. “In the right patient, I will escalate to a TNF-alpha inhibitor or JAK inhibitor if there is little-to-no improvement,” she added.

Phototherapy for sun-protected lesions can be a helpful adjunct for some cases, but overall treatment approaches for GA depend on the extent of disease, how bothersome it is to the patient, and the patient’s comorbidities, Dr. Berk-Krauss said. “If a patient opts for no treatment of GA, that is fine, too; about half of GA cases resolve spontaneously within two years. Generalized GA, however, tends to be more persistent,” she said.

Several important studies on the pathophysiology of GA have been published in recent years suggesting that GA may exist on a spectrum with different triggers and inflammatory profiles, which adds to the challenges of treatment, said Dr. Berk-Krauss.

“Further research linking the presence of certain markers in the skin to the success of specific treatment modalities would be very helpful,” she added.

A 2024 review published in Current Dermatology Reports is a step in the right direction and outlines several studies of Th1, Th2, and JAK-STAT targeting therapies.

Necrobiosis lepoidica lessons

Necrobiosis lepoidica (NL) is most often associated with diabetes and may be associated with autoimmune disorders. NL is characterized by a granulomatous response associated with collagen degeneration.

Although not life-threatening itself, this chronic condition can significantly impact quality of life. Patients may experience complications including chronic and painful ulceration, secondary infections, and rare cases of squamous cell carcinoma, according to data from the National Institutes of Health.

Currently, no FDA-approved treatments are available for NL, and many patients fail to respond to common off-label therapies including topical glucocorticoids and/or tacrolimus, phototherapy, and antimalarials. A 2024 update on treatments published in the International Journal of Molecular Sciences concluded that biologics, notably ustekinumab and secukinumab, can be effective in patients with recalcitrant NL. Tapinarof, an aryl hydrocarbon receptor agonist, is on the radar, but more research is needed.

An investigational drug known as PCS499 (a metabolite of pentoxifylline) met safety and tolerability criteria in an open-label phase 2 study, and a phase 3 study is in the works to assess its ability to completely close NL patients’ ulcers, according to manufacturer Processa Pharmaceuticals.

Other more invasive treatment options include surgical resection of lesions with a skin autograft or the use of sequential punch grafting technique as an adjunctive therapy. NL patients also have been treated with hyperbaric oxygen therapy and platelet-rich plasma injections.

Cutaneous sarcoidosis challenge

Sarcoidosis, a condition in which immune cells also form granulomatous aggregates, occurs most often in the lungs and lymph nodes, but may also present as a granulomatous skin disease in about one-third of patients.

Cutaneous sarcoidosis triggers have been proposed to include bacteria and viruses, and some medications, but the true cause remains unknown. A skin biopsy is needed to confirm the diagnosis, but mild cases may resolve on their own, although this process may take anywhere from months to years. Patients with more severe presentations characterized by numerous papules, plaques, and/or nodules that may lead to scarring and pigmentary changes generally need treatment.

In many instances of cutaneous sarcoidosis, clinicians are moving away from conventional immunosuppressants and toward molecularly targeted therapies, such as TNF inhibitors, and in some cases JAK inhibitors, especially in patients with severe disease, Dr. Damsky said.

In the clinic, Dr. Damsky explained that treatment discussions for patients with moderate-to-severe cutaneous sarcoidosis most often involve TNF inhibition or JAK inhibition. “For patients with medical comorbidities, or concerns about potential adverse effects from these therapies, we will also discuss hydroxychloroquine and methotrexate,” he added. However, care for these patients involves coordination with other specialists, but should always include weighing how patients feel the skin manifestations of their sarcoidosis are impacting their quality of life, he said.

Distinguishing reactions

Reactive granulomas are the subset of granulomatous skin reactions that are thought to be triggered by medication or underlying autoimmune disease or sometimes malignancy.

In 2022, a group of experts recommended the adoption of Reactive Granulosis Dermatitis (RGD) as an umbrella term to provide a framework for evaluation, diagnosis, and treatment of patients with reactive granulomas. In a research letter published in JAAD International, authors noted the expanded definitions of conditions including palisaded and neutrophilic granulomatous dermatitis (PNGD), interstitial granulomatous dermatitis (IGD), and interstitial granulomatous drug reactions (IGDR).

A 2025 report published in JAAD described 65 patients with RGD. In the report, the condition was most common among white female adults, but was associated with diverse clinical and histopathologic features, as well as a range of comorbidities. Some patients experienced spontaneous resolution, but most were treated with various therapies with varying degrees of success.

The overall prevalence of malignancies and autoimmune/inflammatory comorbidities was 34% and 74%, respectively. Most of the patients (80%) pursued treatment; approximately half of these (48%) experienced improvement, while 14% experienced no improvement. Patients for whom a drug reaction has been ruled out may be treated with topical corticosteroids, but the benefits are controversial.

Other treatment options include systemic corticosteroids, non-steroidal anti-inflammatory drugs, hydroxychloroquine, methotrexate, and TNF-alpha inhibitors, among others. Other emerging therapies may include JAK inhibitors like topical ruxolitinib and abrocitinib, and as well as deucravacitinib, a TYK2 inhibitor that resulted in rapid relief for a patient with RGD as a result of myelodysplastic syndrome, described in a recent case report.

Rubella association

The reach of granulomas extends to rubella, as multiple studies have detected rubella in immunocompromised patients.

Additionally, a recent case series published in JAMA Dermatology demonstrated both vaccine-derived (three patients) and wild-type rubella (one patient) in immunocompetent patients with atypical cutaneous granulomas. The results suggest that rubella virus can persist for years in cutaneous granulomas in immunocompetent adults and should be considered in the workup of atypical granulomatous dermatitis, the researchers said. The potential for virus transmission in these patients remains unclear, they added.

Rubella in association with granulomatous dermatitis may not top the list of differential diagnoses for infectious granulomatous dermatitis, according to Karolyn Wanat, MD, FAAD, professor and chair of dermatology at the Medical College of Wisconsin in Milwaukee.

“The ability to diagnose rubella granulomas can be difficult,” noted Dr. Wanat, who has co-authored several papers on rubella granulomas, including a 2025 clinical review in JAAD. Previous options for testing involved immunohistochemical staining that was only available in a research setting, she said. “There is now a clinically validated immunostain that can be performed and is currently available at the Medical College of Wisconsin, although specific testing characteristics are being determined,” Dr. Wanat said. Other clinical clues to rubella granulomas include indurated papules, plaques, and nodules with histopathology characterized by suppurative granulomatous inflammation or granulomatous inflammation with brisk lymphocytic infiltrate in absence of other infections, she said.

Clinicians are working to understand the possible association between rubella virus and a subset of granulomatous dermatitis, said Dr. Wanat.

“Although rubella has been essentially eliminated from the United States because of widespread vaccination, the presence of the virus in granulomas suggests it may be persisting,” she said. However, evidence to date shows no transmission of the virus to other individuals beyond the patient, she added.

Management of patients with rubella granulomas is an evolving process that likely involves a combination of anti-virals and anti-inflammatory agents, and many avenues are open for additional research, said Dr. Wanat. “We are investigating the extent of rubella associated with granulomas, driving factors leading to the granulomas, and use of new and evolving treatments,” she said.

Research gaps, translational and clinical

Looking ahead, research that continues to shed light on treatment response, treatment choice, and disease pathogenesis continues to be needed, said Dr. Caplan. Ongoing research includes determining the duration of treatment and when and how to use newer, targeted therapies for patients with granulomatous skin conditions, he said.

Overall, higher quality evidence is needed to support treatment decisions for granulomatous skin diseases, Dr. Damsky said. This evidence will come from randomized, blinded, controlled trials, of which there is a paucity in these diseases, he noted. However, researchers continue to explore options, and a randomized phase 2 trial, known as BEACON, is in progress to examine the safety and effectiveness of oral brepocitinib, a JAK inhibitor for adults with cutaneous sarcoidosis, he said. Ultimately, FDA approval is needed to make emerging medications more widely available to patients, Dr. Damsky said.

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