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How To Recognize And Manage Granuloma Annulare

When a patient presents with suspected granuloma annulare, making an accurate diagnosis can facilitate an effective treatment regimen. This author provides a guide to the various forms of granuloma annulare and how to manage this dermatologic condition with the help of an illustrative case study.

Granuloma annulare typically presents as non-scaling erythematous annular plaques that are commonly localized to the hands and feet.1 Usually, it is a self-limited disorder that disappears gradually over time but certainly not soon enough for the doctor or the patient.2  

Although the classic form of granuloma annulare is characterized by ringed erythematous plaques, there are several different clinical forms or subtypes. The various clinical appearances may look different but share a common pathology of dermal lymphohistiocytic infiltration with collagen degeneration pointing to a traumatic triggering of an immune response mechanism.1

The localized form of granuloma annulare tends to affect the lateral or dorsal surfaces of the fingers, elbows, dorsal feet and ankles.1 It presents as a well-defined circular plaque with a papular border. In this localized form of granuloma annulare, there is no erythema or scaling. Localized granuloma annulare accounts for 75 percent of reported granuloma annulare cases and tends to remit within two years.1

The generalized form of granuloma annulare is more striking with its erythematous rings, also favoring the legs and feet. With the subcutaneous form, there are painless nodules on the extremities of children. The subcutaneous form of granuloma annulare favors the anterior lower legs, buttocks and scalp. The patch form tends to develop on the proximal thigh and is typically non-scaling. Both annular granuloma annulare and generalized granuloma annulare typically affect women between 30 and 70 years of age more than men.2

An interesting subcutaneous variety of granuloma annulare presents as a painless, firm nodule that is known as a pseudorheumatoid nodule, occurring exclusively on the lower limbs of children.1 In addition, a rare acral variety that affects the palms and/or the soles is characteristically painful.3

There is a perforating form of granuloma annulare with clear or white sterile fluid draining from pruritic or painful pustules. This form can occur in young adults or children from the Hawaiian Islands.4 These draining lesions can exude damaged dermal collagen. These perforating granuloma annulare lesions typically erupt on the lower legs and are more likely to leave scars.4 Granuloma annulare can also display an isomorphic or Koebner phenomenon, which is visible in psoriasis erupting in traumatized areas. Solar exposure can also trigger the lesions.2

As one can see, morphological lesion descriptions alone cannot clearly rule out all the potential differentials so the best approach in equivocal cases is to plan a diagnostic cutaneous biopsy. Strangely, there have been reports that biopsy of the lesion triggered healing.2  

Granuloma annulare histologically appears primarily as palisaded patterns of lymphohistiocytic infiltrate with collagen degeneration and mucin deposition.5 Often, there is granulomatous inflammation in a palisading pattern with a central zone of necrotic collagen surrounded by histiocytes and lymphocytes.1

In general, most granuloma annulare cases heal without scarring but in some cases, loss of elastic fibers can leave a slightly depressed atrophic plaque resembling mid-dermal elastolysis or anetoderma.2

Case Study: Recognizing The Typical Presentation Of Granuloma Annulare

Consider the following patient. A pleasant 70-year-old lady presents with several bright red circular lesions on her left lower calf just above her sock line. Her past history includes two coronary artery bypass grafts two years ago, controlled Barrett’s esophagus and type 2 diabetes. Her medications include metformin and a hydrochlorothiazide with a lisinopril combination as well as omeprazole.  

She describes experiencing multiple recurrent bouts of red skin rashes that began with a subtle, mosquito bite-like sensation in her skin. The patient reports the rashes extended to her trunk and arms each summer over the past five to six years. The current outbreak has not yet spread beyond her lower leg. She admits regularly working in her garden and specifically denies experiencing any bug bites. She notes she always wears protective clothing as a precaution against the sun and bug bites. Each episode begins as erythematous papules that enlarge into plaques that gradually clear centrally. The patient laments that the lesions typically take months to resolve and the lesions dictate her wearing clothing that covers her rashes. She currently manages the outbreaks by immediately applying a topical corticosteroid cream at the first sign of tingling sensations to control the outbreaks.

The calf lesions are broad, ring-shaped patches with central clearing. She denies any other skin lesions, joint pain, fatigue, cough, chest pain or visual field disturbances. Interestingly, the annular patches do not exhibit scaling. She brings with her pictures that depict how the rash has gradually improved over time.

What Are The Differential Diagnoses To Consider?

The key clinical feature to help recognize granuloma annulare is the presence of non-scaling plaques on the extremities. However, one may easily confuse this patient’s lesions with quite a list of differential diagnoses. Tinea corporis, lichen planus, sarcoidosis, lymphoma, Lyme disease as well as granuloma annulare all, at least in some subtypes, share similar lesion presentations.5 Let us review each of these differentials.

The periphery of tinea corporis lesions typically has scales while the lesions of granuloma annulare typically do not. A simple skin scraping and KOH wet mount prep analysis could confirm a dermatophyte infection but because of the low sensitivity of KOH, the test does not completely rule out tinea.  

Patients with annular lichen planus tend to have pruritic polygonal papules and plaques while non-pruritic papules are generally present with annular granuloma annulare. The distribution of annular lichen planus includes the scrotum and penis while the distribution of annular granuloma annulare does not include these areas.2

Annular sarcoidosis can also present as erythematous, indurated, ring-like plaques. Sarcoidosis can involve the nails, causing a wide range of nail dystrophies including onychoschizia and pterygium as well as clubbing, which helps to distinguish sarcoidosis from granuloma annulare. Respiratory symptoms of sarcoidosis include a chronic cough, dyspnea and chest pain, which should prompt a chest X-ray to look for pulmonary granulomas. A cutaneous biopsy would find the non-caseating granuloma deposits characteristic of sarcoidosis.6

T-cell lymphoma can present in the skin as non-lesional pruritus as well as erythematous patches of mycosis fungoides. This is itching without any changes in the skin, which can be quite baffling. Mycosis fungoides can present on the thighs and in a bathing trunk distribution. This cutaneous form of T-cell lymphoma often presents as erythematous, annular raised plaques that can certainly resemble certain forms of granuloma annulare. The flat patch type of mycosis fungoides generally lacks the gradual central clearing that is visible in our patient’s case.2,7

The aforementioned patient’s erythematous rings also resemble the centrally clearing pattern of erythema migrans found in disseminated Lyme disease. The erythema multiforme lesions of Lyme disease would prompt one to order serum immunoglobulin tests and anti-Borrelia burgdorferi antibodies. A traditional two-tiered testing algorithm uses a sensitive enzyme immunoassay, such as a whole cell-based enzyme-linked immunosorbent assay (ELISA) followed by more specific Western blot tests for immunoglobulin M (IgM) and immunoglobulin G (IgG).8

What Causes Granuloma Annulare?

The specific cause of granuloma annulare is still a mystery. Researchers have implicated and investigated various potential etiologies including trauma, insect bites, inoculations, vaccinations, drugs, solar exposure, immunotherapy, hepatitis, HIV and Epstein-Barr virus. However, these investigations into possible causes to various extents did not have conclusive findings.5

Infectious agents such as bacteria and fungi have been seemingly ruled out as causes. In a study by Avitan and colleagues, they obtained cultures for Borrelia from five tissue specimens and serologic tests in seven patients with granuloma annulare.9 All the cultures were negative.

Multiple reports of familial association suggest a genetic susceptibility to granuloma annulare. An interesting case report concerns identical twins who developed granuloma annulare and shared the HLA-AH8.1 genotype.10 The HLA-AH8.1 gene is responsible for the production of tumor necrosis factor alpha by peripheral mononuclear cells. The twins both responded to adalimumab (Humira, AbbVie) 40 mg weekly for three months. Although the exact etiology of granuloma annulare remains uncertain, an autoimmune cell-mediated reaction is the favored mechanism.5

When Other Conditions Are Associated With Granuloma Annulare

Both type 1 and type 2 diabetes have been associated with the localized and generalized types of granuloma annulare.11 Friedman-Birnbaum and colleagues studied 78 patients with generalized granuloma annulare and found their histocompatibility HLA-A31 and B35 antigens were increased significantly. This was not the case in patients with localized form.12

Thyroid disease has been associated with granuloma annulare. Vazquez and colleagues explored a specific association with thyroiditis.13 They found the frequency of adult thyroiditis in 24 women with biopsy-confirmed granuloma annulare was 12 percent while the incidence was only 1 in 100 of matched controls. This association certainly supports the theory that granuloma annulare is within the spectrum of autoimmune diseases. It turns out that both disorders share the histocompatibility HLA-Bw35 antigen in some patients.

Wu and coworkers have shown an association between granuloma annulare and dyslipidemia through a case-controlled study of 140 adults with idiopathic granuloma annulare.14 All 23 patients with generalized granuloma annulare had dyslipidemia and 86 percent of the patients with annular granuloma annulare had dyslipidemia. Perhaps there is an association between microvascular inflammation and lipid abnormalities that puts patients with granuloma annulare at increased risk for cardiovascular disease, just as we now know that occurs in patients with psoriasis.5

Whether granuloma annulare is associated with an increased risk of malignancy is a cautionary tale. Retrospective studies have failed to find a definitive link between granuloma annulare and malignancy, but one study reported malignancy 18 to 42 months after a diagnosis of granuloma annulare.15 Half of these associated cases were lymphoma and occurred in patients with atypical granuloma annulare so an evaluation for underlying malignancy might be prudent. The other half of the malignances were solid tumors.

Key Pearls On Managing Granuloma Annulare

In many mild cases of granuloma annulare, no treatment is required. Patients regularly report resolution of the lesions after a diagnostic biopsy.2 Physicians have tried a variety of treatments for more severe cases but there still is no treatment of choice.

Andrews recommends developing a therapeutic ladder approach to help manage both localized and generalized forms of granuloma annulare.2 Clinicians can effectively treat small localized lesions with intralesional triamcinolone suspension. For patients who can tolerate intralesional corticosteroid injection, Brodell and Stratman typically use triamcinolone acetonide in concentrations of 2.5 to 10 mg/cc administered with a 30-gauge needle.5 Inject a 0.1 cc of the mixture into the border of a lesion. If multiple injections are required, separate the injected areas by approximately 5 to 10 mm. One may repeat injections every six to eight weeks as necessary. It is important to recall the potential for cutaneous adverse reactions with corticosteroid therapy. Adverse reactions include cutaneous atrophy, striae and loss of skin pigmentation.

Beyond the use of potent topical corticosteroids, physicians have used immunomodulators, calcineurin inhibitors and phototherapy for granuloma annulare with variable success.6

A few cases reported by Jain and Stephens demonstrated accelerated improvement with twice daily application of tacrolimus 0.1% ointment for six weeks.16 This treatment led to complete clearance in two patients and marked improvement in another two patients. The authors noted fading of the lesions within the first 10 to 21 days of this treatment.

Psoralen ultraviolet-A (PUVA) photodynamic therapy may have some benefit in the treatment of localized granuloma annulare.17 Patients receive pre-treatment with psoralen, a strong photosensitizing drug, and are subsequently exposed to long wave UVA light. Some of the PUVA therapy patients in one study had a 50 percent positive response rate.17 However, authors have reported relapse following PUVA therapy in patients with non-localized forms of granuloma annulare and surprisingly, PUVA actually triggered the onset of granuloma annulare in one patient.5

Physicians have used multiple systemic drugs in the treatment of generalized granuloma annulare including hydroxychloroquine, isotretinoin or dapsone. These drugs have the potential for serious adverse effects. Brodell and Stratman prefer the anti-malarial hydroxychloroquine despite the potential agranulocytosis.5 Higher doses seem to clear better but one should balance this advantage against the risk of variable adverse reactions that range from Stevens-Johnson syndrome to diarrhea or hair loss.5,18 Hydroxychloroquine is in wide use to prevent and treat malaria.

Generalized or disseminated granuloma annulare is therapeutically challenging. Clinicians can use adalimumab, a tumor necrosis factor (TNF)-alpha antagonist, to treat granuloma annulare. Min and Lebwohl reported seven patients who experienced significant improvement with adalimumab.19 One can consider other TNF inhibitors, including etanercept and infliximab, that have good results according to small studies.5 However, there are also reports of multiple TNF inhibitors inducing generalized granuloma annulare.20

One may employ monthly administration of antibiotics such as doxycycline, rifampin (Rifadin, Sanofi) and minocycline to treat generalized granuloma annulare.5 Cyclosporine and other immunosuppressants have been effective but the potential toxicities limit their use to patients with significant cases.

The prognosis of granuloma annulare is still highly variable. It typically takes between three and seven months of treatment to clear granuloma annulare, and half of localized granuloma annulare cases take two years to resolve.5 Generalized granuloma annulare may clear either spontaneously or become persistent for ten years.5 In lesions that are resolving, the peripheral papules fade first. Blanchable erythema often lasts for months. Thankfully, lesions typically heal without a scar.

In Conclusion

In short, how does our patient’s case fit with the typical characteristics of granuloma annulare? The presence of non-scaling annular lesions is the key finding. Our patient’s recurrent episodes, lesion distribution and morphology along with her history of concurrent cardiovascular disease and diabetes mellitus as well as the duration of her rashes along with a good response to topical corticosteroids are all consistent with a diagnosis of episodic generalized granuloma annulare.

Dr. Bodman is a retired Associate Professor with the Kent State University College of Podiatric Medicine. He is board-certified by the American Board of Podiatric Medicine.

References

1.     Piette EW, Rosenbach M. Granuloma annulare: Clinical and histologic variants, epidemiology, and genetics. J Am Acad Dermatol. 2016;75(3):457-65.
2.     James WD, Elston DM, Berger TG, Andrews GC. Andrews’ Diseases of the Skin: Clinical Dermatology. Chapter 31, Macrophage/Monocyte Disorders. Saunders/Elsevier, London, 2011, pp. 694-695.
3.     Brey NV, Malone J, Callen JP. Acute-onset, painful acral granuloma annulare: a report of 4 cases and a discussion of the clinical and histologic spectrum of the disease. Arch Dermatol. 2006; 142(1):49-54.
4.     Samlaska CP, Sandberg GD, Maggio KL, Sakas EL. Generalized perforating granuloma annulare. J Am Acad Dermatol. 1992;27(2 Pt 2):319.
5.     Brodell RT, Stratman E. Granuloma annulare. UpToDate. Available at https://www.uptodate.com/contents/granuloma-annulare . Published July 17, 2017.
6.     Prystowsky S, Sanchez M. Cutaneous manifestations of sarcoidosis. UpToDate. Available at https://www.uptodate.com/contents/cutaneous-manifestations-of-sarcoidosis. Published July 20, 2017.
7.     Hoppe RT, Kim YH. Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides. UpToDate. Available at https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-mycosis-fungoides . Published Oct. 3, 2016.
8.     Hu L. Lyme disease symptoms and diagnosis. UpToDate. Available at https://www.uptodate.com/contents/lyme-disease-symptoms-and-diagnosis-beyond-the-basics . Published May 6, 2018.
9.     Avitan-Hersh E, Sprecher H, Ramon M, Bergman R. Does infection play a role in the pathogenesis of granuloma annulare? J Am Acad Dermatol. 2013;68(2):342-3
10.     Knoell KA. Efficacy of adalimumab in the treatment of generalized granuloma annulare in monozygotic twins carrying the 8.1 ancestral haplotype. Arch Dermatol. 2009; 145(5):610-611.
11.     Studer EM, Calza AM, Saurat JH. Precipitating factors and associated diseases in 84 patients with granuloma annulare: a retrospective study. Dermatology. 1996;193(4):364.
12.     Friedman-Birnbaum R, Gideoni O, Bergman R, Pollack S. A study of HLA antigen association in localized and generalized granuloma annulare. Br J Dermatol. 1986;115(3):329
13.     Vazquez-Lopez F, Pereiro M Jr, Manjon Haces JA, et al. Localized granuloma annulare and autoimmune thyroiditis in adult women: a case-control study. J Am Acad Dermatol. 2003;48(4):517-520.
14.     Wu W, Robinson-Bostom L, Kokkotou E, Jung HY, Kroumpouzos G. Dyslipidemia in granuloma annulare: a case-control study. Arch Dermatol. 2012;148(10):1131.
15.     Li A, Hogan DJ, Sanusi ID, Smoller BR. Granuloma annulare and malignant neoplasms. Am J Dermatopathol. 2003;25(2):113.
16.     Jain S, Stephens CJ. Successful treatment of disseminated granuloma annulare with topical tacrolimus. Br J Dermatol. 2004;150(5):1042.
17.     Do TT, Bailey EC, Wang F, Smith N, Lee W, Fisher GJ, Voorhees JJ, Kang S. Targeted broadband ultraviolet B phototherapy improves disorders characterized by increased dermal matrix. Br J Dermatol. 2009;161(6):1405.
18.     Grewal SK, Rubin C, Rosenbach M. Antimalarial therapy for granuloma annulare: Results of a retrospective analysis. J Am Acad Dermatol. 2017;76(4):765.
19.     Min MS, Lebwohl M. Treatment of recalcitrant granuloma annulare (GA) with adalimumab: A single-center, observational study. J Am Acad Dermatol. 2016;74(1):127.
20.     Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA. Granuloma annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008;67(4):567-70.
21.     Naka F, Strober BE. Methotrexate treatment of generalized granuloma annulare: a retrospective case series. J Dermatol Treat. 2018;29(7):720–724.

For further reading, see “How To Detect And Treat Granuloma Annulare” in the December 2004 issue of Podiatry Today. To access the archives, visit www.podiatrytoday.com.

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By Myron Bodman, DPM
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