|Year : 2022 | Volume
| Issue : 1 | Page : 32-37
Pentoxifylline in the treatment of generalized granuloma annulare: A report of three cases
Vidya D Kharkar, Harish Balaji Rajendran, Anmol Bhargava
Department of Dermatology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
|Date of Submission||20-Apr-2021|
|Date of Decision||12-Feb-2022|
|Date of Acceptance||21-Mar-2022|
|Date of Web Publication||11-Jun-2022|
Harish Balaji Rajendran
Department of Dermatology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Granuloma annulare (GA) is a benign self-limited granulomatous cutaneous disorder of unknown etiology. Clinical variants include localized, generalized, perforating, and subcutaneous. Generalized or disseminated GA is an uncommon variant displaying some clinical features that differentiate it from the localized form, including later age of onset, inadequate response to treatment, and less tendency to spontaneous resolution. The treatment modalities used for localized GA (topical or intralesional steroids, freezing with liquid nitrogen, or surgical excision) cannot be successfully applied to the large numbers of lesions seen in GA’s generalized form. Systemic treatments have included dapsone, chlorambucil, isotretinoin, systemic steroids, cyclosporine, salicylates, chloroquine, and PUVA. These treatments have potentially serious side effects in the long term and have not demonstrated consistent results. Literature overuse of pentoxifylline in the treatment of GA is limited. Here we report three prospective cases of generalized GA showing resolution with oral pentoxifylline.
Keywords: Generalized granuloma annulare, granuloma annulare, oral pentoxifylline
|How to cite this article:|
Kharkar VD, Rajendran HB, Bhargava A. Pentoxifylline in the treatment of generalized granuloma annulare: A report of three cases. Indian J Drugs Dermatol 2022;8:32-7
|How to cite this URL:|
Kharkar VD, Rajendran HB, Bhargava A. Pentoxifylline in the treatment of generalized granuloma annulare: A report of three cases. Indian J Drugs Dermatol [serial online] 2022 [cited 2022 Jun 26];8:32-7. Available from: https://www.ijdd.in/text.asp?2022/8/1/32/347283
| Introduction|| |
Granuloma annulare (GA) is a benign self-limited granulomatous cutaneous disorder of unknown etiology. Clinical variants include localized, generalized, perforating, and subcutaneous. Generalized or disseminated GA is an uncommon variant displaying some clinical features that differentiate it from the localized form, including later age of onset, inadequate response to treatment, and less tendency to spontaneous resolution. Literature overuse of pentoxifylline in the treatment of GA is limited. Here we report three prospective cases of generalized GA showing resolution with oral pentoxifylline.
| Case Report|| |
A 65-year-old woman came with biopsy-proven generalized GA with chief complaints of multiple red raised lesion associated with mild itching over bilateral upper extremities, dorsum of hand, neck, lower back, and left flank [Figure 1] since 2 years presented to our outpatient department for treatment after having tried methotrexate, hydroxychloroquine and oral corticosteroids along with topical steroids and topical calcineurin inhibitors over 2 years with no improvement. The patient was started on oral pentoxifylline 400 mg three times daily along with sunscreen and topical calcineurin inhibitors. Posttreatment, lesions started to resolve with no new lesions after 4 weeks of starting oral pentoxifylline, and all lesions showed complete resolutions, eventually forming post-inflammatory hyperpigmentation after 3 months [Figure 2]. The patient was later tapered to oral pentoxifylline 400 mg BD for 3 months, followed by a daily regimen for 3 months, and stopped. The patient has been following up for 1 year without any new onset of lesions.
|Figure 1: Case 1: Multiple erythematous infiltrated papules coalescing to form annular plaques over extremities and lower back|
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|Figure 2: Three months post-treatment, lesions resolving with post inflammatory hyperpigmentation (Case 1)|
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A 64-year-old woman came with complaints of asymptomatic red raised lesions over bilateral upper extremities, back, and chest [Figure 3] for 6 months and was diagnosed as GA on skin biopsy [Figure 4]. The patient was initially started on hydroxychloroquine 300 mg at night and topical tacrolimus, but the patient failed to respond with persistent new lesions after 1 month of treatment and was later shifted to oral pentoxifylline 400 mg TDS along with sunscreens. Posttreatment, the patient started showing resolution of lesions with no new lesions after 3 weeks of starting oral pentoxifylline and showed complete remission after 5 months of therapy [Figure 4]. Later oral pentoxifylline was tapered to twice a day regime for 2 months and later was tapered to once a day regime for 3 months and stopped and maintained on topical tacrolimus and sunscreen. The patient is relapse-free for 1 year now.
|Figure 3: Case 2: Multiple erythematous infiltrated papules coalescing to form annular plaques over chest and upper back|
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|Figure 4: Five months post-treatment, complete resolution of lesions with post inflammatory hyperpigmentation (Case 2)|
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A 60-year-old woman came with complaints of asymptomatic red raised lesions over the face, bilateral upper extremities and chest [Figure 5] for one and half years. The patient was diagnosed with GA on biopsy [Figure 6]. The patient was initially started on oral hydroxychloroquine 300 mg at night and topical tacrolimus and responded partially after 1 month but on consequent follow up patient complained of new lesions, and oral pentoxifylline 400 mg TDS was added to her treatment regimen. Posttreatment, patient started showing resolution after 3 weeks of starting oral pentoxifylline, and all lesions showed complete resolution leaving behind post-inflammatory hyperpigmentation after 4 months of therapy [Figure 7]. Oral hydroxychloroquine was stopped, and the patient was maintained on oral pentoxifylline 400 mg TDS with topical tacrolimus and sunscreen. During treatment, the patient stopped the medication independently and continued with topical tacrolimus—the patient-reported onset of new lesions after 1 month of stopping pentoxifylline. The patient was restarted on oral pentoxifylline 400 mg TDS, which showed signs of resolution after 3 weeks and is maintained on the same.
|Figure 5: Case 3: Multiple erythematous infiltrated papules coalescing to form annular plaques over face and chest|
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|Figure 6: H & E stain—perivascular and interstitial infiltrates over upper and mid dermis. Palisading granuloma around areas of collagen necrobiosis is seen (encircled). Note the anuclear dermis, which represents necrobiosis, along with palisading granuloma made up of lymphohistiocytic infiltrate and epithelioid histiocytes around it (magnified view)|
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|Figure 7: Four months after starting treatment, near total resolution of lesions (Case 3)|
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All three patient had no comorbidity and was not on any drug before the onset of lesions.
| Discussion|| |
GA is a benign self-limited granulomatous disorder of unknown etiology. Clinical variants include localized, generalized, perforating, and subcutaneous. Various studies showed that generalized GA represents between 2.8% and 15% of all cases and is usually unmanageable to therapy. Associations between generalize GA and diabetes mellitus, disorders of the lipid metabolism, malignant disease (Hodgkin’s and non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, lung and breast cancer), thyroid disease (autoimmune thyroiditis, toxic adenoma), infections like Hep B, Hep C, and HIV. Association of GA with necrobiosis lipoidica and sarcoidosis was reported.
Certain trigger factors include insect bites, BCG vaccination, B or C hepatitis viruses, α-interferon treatment for hepatitis C virus infection, HPV, HIV, Epstein Barr virus, Varicella–Zoster virus have been discussed. Sun exposure is controversial. However, a case of generalized GA was noted after exposure to PUVA therapy, although this represents an alternative therapy for the generalized form of GA. GA lesions have a predilection for sun-exposed areas. Drugs like Allopurinol, calcium blockers, Calcitonin, anti-TNF-α, some chemotherapeutics, Topiramate, Amlodipine are involved in GA.
Treatment for Generalized GA is not standardized, and often the disease is recalcitrant to administered therapy. Systemic treatments have included dapsone, hydroxychloroquine, chlorambucil, isotretinoin, systemic steroids, cyclosporine, salicylates, chloroquine, and PUVA.,,
The etiopathogenesis of GA is unclear. The following hypotheses have been issued: microangiopathy, autoimmune vasculitis, delayed-type hypersensitivity, fault of neutrophil migration with an accumulation of abnormal neutrophil, β-glucuronidase high serum titer, involved in the degradation of mucopolysaccharides. According to the immune-mediated vasculitis model, the immune response to the unidentified antigen results in endothelial cell swelling, perivascular inflammation, and fibrin deposition in vessel walls. Loss of plasma volume due to leaking vessels and aggregation of platelets and leukocytes leads to occlusion of the microvasculature and ensuing ischemic damage.
Pentoxifylline is a triple substituted methylxanthine chemically related to caffeine and theophylline. It is primarily metabolized in the liver and excreted in the urine. Studies of pentoxifylline have shown that it affects all the factors responsible for the viscosity of whole blood. It enhances erythrocyte flexibility and thus decreases aggregation, and Rouleaux formation increases leukocyte flexibility and mobility in response to chemotactic factors and decreases leukocyte attachment to vascular endothelium following complement activation. Pentoxifylline stimulates PGI2 (prostacyclin) release, which enhances fibrinolysis and inhibits platelet aggregation.
The exact mechanism of action of pentoxifylline in GA is not known. It has been postulated that, in GA, pentoxifylline, probably with its TNF-α blocking action, inhibits macrophage activation, and hence the granulomatous inflammation. Moreover, with its anti-inflammatory action, it may also reduce the vasculitis occurring in GA. It also decreases blood viscosity and improves tissue oxygenation.
Oral pentoxifylline is well-tolerated, and the most common side effects are nausea and vomiting. Particular caution should be taken in patients with pre-existing coagulopathy or renal impairment, and patients should also be monitored for bleeding. Pentoxifylline is a phosphodiesterase inhibitor commonly used in intermittent claudication. Its dermatological uses include Raynaud’s phenomenon, livedoid vasculopathy, necrobiosis lipoidica, and venous ulcers. Even though the drug has been in use for many decades, novel indications are emerging even recently. Pentoxifylline has been successfully used in generalized GA by Rubel et al. and Patrascu et al.
Resolution of GA after various forms of trauma, including biopsy, is a controversial phenomenon in the dermatologic literature. There is a paucity of literature on the relation between biopsy and resolution of GA. The Wells and Smith’s  study shows no difference in the rate of resolution of GA between patients who had biopsies and those who did not, implying that biopsy is not related to resolution. One case report showed resolution of biopsied lesions 2 weeks to 2 months after the procedure on two separate occasions, suggesting at least the possibility that forms of controlled injury to the skin could sufficiently alter the cellular and extracellular milieu to change the course of, and possibly to clear, an inflammatory process such as GA. Mutasim and Bridges also reported resolution of patch GA within weeks to months after biopsy in several patients, although these patients were treated with topical corticosteroids. However, it has been noted in the above reports that only specific lesions (once that were biopsied) have shown resolution post-biopsy. None of them have reported generalized resolution of all lesions as seen in our 3 cases, therefore attributing resolution to biopsy is unlikely. We believe that a possible association between biopsy of GA and subsequent rapid resolution of lesions has not been adequately addressed in the literature and warrants further investigation. The time interval between biopsy and initiation of pentoxifylline in the three cases in our report was 2 years for case 1 and 2 months for cases 2 and 3.
There are only a few reported cases of using pentoxifylline to treat GA [Table 1], but the results have been promising. With its favorable toxicity profile compared to systemic immunosuppressive therapies, pentoxifylline is worth considering in GA.
|Table 1: Documented cases of generalized GA responding to oral pentoxifylline|
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Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Burns DA Necrobiotic disorders. In: Burns T, Breathnach S, Cox NH, Griffiths C, editors. Rook’s Textbook of Dermatology. 8th ed. Oxford: Wiley-Blackwell; 2010. p. 60.1-60.12.
Pătraşcu V, Giurcă C, Ciurea RN, Georgescu CV Disseminated granuloma annulare: Study on eight cases. Rom J Morphol Embryol 2013;54:327-31.
Kerker BJ, Huang CP, Morison WL Photochemotherapy of generalized granuloma annulare. Arch Dermatol 1990;126:359-61.
Botella-Estrada R, Guillen C, Sanmartin O, Aliaga A Disseminated granuloma annulare: Resolution with etretinate therapy. J Am Acad Dermatol 1992;26:777-8.
Dahl M, Goltz W Granuloma annulare In: Fitzpatrick T, Eisen A, Wolf K, Freedberg M, Austen K, editors. Dermatology in General Medicine. 3rd ed. New York: McGraw-Hill; 1987. p. 1018.
Wong GN, Wee E, Tam M, Kelly R Pentoxifylline as a treatment for granuloma annulare. Australas J Dermatol 2019;60:328-31.
Rubel DM, Wood G, Rosen R, Jopp-McKay A Generalised granuloma annulare successfully treated with pentoxifylline. Australas J Dermatol 1993;34:103-8.
Nambiar KG, Jagadeesan S, Balasubramanian P, Thomas J Successful treatment of generalized granuloma annulare with pentoxifylline. Indian Dermatol Online J 2017;8:218-20.
Hassan I, Dorjay K, Anwar P Pentoxifylline and its applications in dermatology. Indian Dermatol Online J 2014;5:510-6.
Wells RS, Smith MA The natural history of granuloma annulare. Br J Dermatol 1963;75:199-205.
Mutasim DF, Bridges AG Patch granuloma annulare: Clinicopathologic study of 6 patients. J Am Acad Dermatol 2000;42:417-21.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]