Treatment of generalized granuloma annulare – a systematic review

Granuloma annulare (GA) is a benign inflammatory skin disease. Localized GA is likely to resolve spontaneously, while generalized GA (GGA) is rare and may persist for decades. GGA usually is resistant to a variety of therapeutic modalities and takes a chronic course. The objective of this study was to summarize all reported treatments of generalized granuloma annulare. This is a systematic review based on MEDLINE, Embase and Cochrane Central Register search of articles in English and German and a manual search, between 1980 and 2013, to summarize the treatment of generalized granuloma annulare. Most medical literature on treatment of GGA is limited to individual case reports and small series of patients treated without a control group. Randomized controlled clinical studies are missing. Multiple treatment modalities for GGA were reported including topical and systemic steroids, PUVA, isotretinoin, dapsone, pentoxifylline, hydroxychloroquine, cyclosporine, IFN‐γ, potassium iodide, nicotinamide, niacinamide, salicylic acid, dipyridamole, PDT, fumaric acid ester, etanercept, infliximab, adalimumab. While there are numerous case reports of successful treatments in the literature including surgical, medical and phototherapy options, well‐designed, randomized, controlled clinical trials are required for an evidence‐based treatment of GGA.

[1]  A. Baibergenova,et al.  Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. , 2013, Journal of the American Academy of Dermatology.

[2]  M. Goebeler,et al.  Treatment of Disseminated Granuloma Annulare with Oral Vitamin E: ‘Primum Nil Nocere' , 2013, Dermatology.

[3]  S. Dahan,et al.  Treatment of granuloma annulare with the 595‐nm pulsed dye laser, a multicentre retrospective study with long‐term follow‐up , 2013, Journal of the European Academy of Dermatology and Venereology : JEADV.

[4]  S. Garg,et al.  Generalized Granuloma Annulare Treated with Monthly Rifampicin, Ofloxacin, and Minocycline Combination Therapy , 2013, Indian journal of dermatology.

[5]  C. Georgescu,et al.  Disseminated granuloma annulare: study on eight cases. , 2013, Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie.

[6]  S. Milgraum,et al.  Granuloma annulare treated with excimer laser. , 2012, The Journal of clinical and aesthetic dermatology.

[7]  J. López-Estebaranz,et al.  Long lasting interstitial generalized granuloma annulare on sun‐exposed areas , 2012, Photodermatology, photoimmunology & photomedicine.

[8]  T. Torres,et al.  Treatment of recalcitrant generalized granuloma annulare with adalimumab. , 2011, Journal of drugs in dermatology : JDD.

[9]  Y. Narisawa,et al.  Generalized granuloma annulare following BCG vaccination, mimicking papular tuberculid. , 2011, European journal of dermatology : EJD.

[10]  You Chan Kim,et al.  Generalized granuloma annulare possibly associated with acute Epstein-Barr virus infection. , 2011, European journal of dermatology : EJD.

[11]  R. Yadav,et al.  Generalized granuloma annulare with open comedones in photoexposed areas , 2011, Clinical and experimental dermatology.

[12]  D. Turner,et al.  Psoralen and ultraviolet A in the treatment of granuloma annulare , 2011, Photodermatology, photoimmunology & photomedicine.

[13]  Claudia Schermann Poziomczyk,et al.  Generalized perforating granuloma annulare. , 2011, Anais brasileiros de dermatologia.

[14]  A. Enk,et al.  Generalized interstitial granuloma annulare – response to adalimumab , 2010, International journal of dermatology.

[15]  K. Kabashima,et al.  Eruptive generalized granuloma annulare presenting with numerous micropapules , 2010, International journal of dermatology.

[16]  C. Mazzatenta,et al.  Treatment of disseminated granuloma annulare with allopurinol: case report , 2010, Dermatologic therapy.

[17]  S. Mitrovic,et al.  Generalized granuloma annulare presenting as arcuate dermal erythema. , 2010, Acta dermatovenerologica Alpina, Pannonica, et Adriatica.

[18]  E. Rytina,et al.  Generalized granuloma annulare in a photosensitive distribution resolving with scarring and milia formation , 2009, Clinical and experimental dermatology.

[19]  I. Hamzavi,et al.  Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. , 2009, Archives of dermatology.

[20]  K. A. Knoell Efficacy of adalimumab in the treatment of generalized granuloma annulare in monozygotic twins carrying the 8.1 ancestral haplotype. , 2009, Archives of dermatology.

[21]  E. Şenel,et al.  Generalized granuloma annulare in a patient with myelocytic leukemia and chronic hepatitis B virus infection. , 2009, Indian journal of dermatology, venereology and leprology.

[22]  Won-Soo Lee,et al.  Clinical and pathological features of generalized granuloma annulare with their correlation: a retrospective multicenter study in Korea. , 2009, Annals of dermatology.

[23]  D. Linder,et al.  Generalized Granuloma Annulare Treated with Methylaminolevulinate Photodynamic Therapy , 2009, Dermatology.

[24]  A. Mota,et al.  Generalized granuloma annulare – response to doxycycline , 2009, Journal of the European Academy of Dermatology and Venereology : JEADV.

[25]  M. Schaller,et al.  Treatment of disseminated granuloma annulare with low-dose fumaric acid. , 2009, Acta dermato-venereologica.

[26]  U. Wollina Granuloma annulare disseminatum responding to fumaric acid esters. , 2008, Dermatology online journal.

[27]  M. Tang,et al.  Generalized granuloma annulare associated with gastrointestinal stromal tumour: case report and review of clinical features and management , 2008, Clinical and experimental dermatology.

[28]  C. Raulin,et al.  Fractional photothermolysis for the treatment of granuloma annulare: A case report , 2008, Lasers in surgery and medicine.

[29]  G. Yosipovitch,et al.  Generalized granuloma annulare as an initial manifestation of chronic myelomonocytic leukemia: a report of 2 cases. , 2008, The American Journal of dermatopathology.

[30]  J. Zone,et al.  Treatment of recalcitrant disseminated granuloma annulare with hydroxyurea. , 2008, Journal of the American Academy of Dermatology.

[31]  P. Friedman,et al.  Fractional photothermolysis: a novel treatment for disseminated superficial actinic porokeratosis. , 2007, Archives of dermatology.

[32]  R. Caputo,et al.  Generalized granuloma annulare and eruptive folliculitis in an HIV‐positive man: resolution after antiretroviral therapy , 2007, Journal of the European Academy of Dermatology and Venereology : JEADV.

[33]  P. Friedman,et al.  Fractional Photothermolysis for the Treatment of Postinflammatory Erythema Resulting from Acne Vulgaris , 2007, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[34]  A. Turan,et al.  A case of generalized granuloma annulare with myelodysplastic syndrome: successful treatment with systemic isotretinoin and topical pimecrolimus 1% cream combination , 2007, Journal of the European Academy of Dermatology and Venereology : JEADV.

[35]  D. Marra,et al.  Fractional photothermolysis for the treatment of adult colloid milium. , 2007, Archives of dermatology.

[36]  C. Demirkesen,et al.  Generalized granuloma annulare resolving to anetoderma. , 2006, Dermatology online journal.

[37]  P. Cyr Diagnosis and management of granuloma annulare. , 2006, American family physician.

[38]  N. Kluger,et al.  Generalized Interstitial Granuloma Annulare Induced by Pegylated Interferon-Alpha , 2006, Dermatology.

[39]  S. Shimizu,et al.  Atypical generalized granuloma annulare associated with two visceral cancers. , 2006, Journal of the American Academy of Dermatology.

[40]  Y. Asano,et al.  Generalized granuloma annulare treated with short-term administration of etretinate. , 2006, Journal of the American Academy of Dermatology.

[41]  Hj Ma,et al.  Generalized granuloma annulare associated with chronic hepatitis B virus infection , 2006, Journal of the European Academy of Dermatology and Venereology : JEADV.

[42]  H. Laubach,et al.  Skin responses to fractional photothermolysis , 2006, Lasers in surgery and medicine.

[43]  S. Clark,et al.  Clearance of Generalized Papular Umbilicated Granuloma Annulare in a Child with Bath PUVA Therapy , 2006, Pediatric dermatology.

[44]  S. Öztürkcan,et al.  Generalized granuloma annulare in a patient with type II diabetes mellitus: successful treatment with isotretinoin , 2006, Journal of the European Academy of Dermatology and Venereology : JEADV.

[45]  Olympia Kovich,et al.  Generalized granuloma annulare. , 2005, Dermatology online journal.

[46]  M. Falchi,et al.  Treatment of Generalized Granuloma annulare with Hydroxychloroquine , 2005, Dermatology.

[47]  A. Katsambas,et al.  Pimecrolimus 1% cream in the treatment of disseminated granuloma annulare , 2005, The British journal of dermatology.

[48]  K. Schulmeister,et al.  UVA1 phototherapy for disseminated granuloma annulare , 2005, Photodermatology, photoimmunology & photomedicine.

[49]  G. Schuler,et al.  Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with the tumour necrosis factor‐α inhibitor, infliximab , 2005, The British journal of dermatology.

[50]  J. Ring,et al.  Disseminated Granuloma Annulare – Treatment with Fumaric Acid Esters , 2005, Dermatology.

[51]  S. Georgiou,et al.  Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy , 2004, International journal of dermatology.

[52]  B. Cribier [Granuloma annulare]. , 2005, Annales de dermatologie et de venereologie.

[53]  B. Goffe Disseminated granuloma annulare resolved with the T-cell modulator efalizumab. , 2004, Archives of dermatology.

[54]  C. Stephens,et al.  Successful treatment of disseminated granuloma annulare with topical tacrolimus , 2004, The British journal of dermatology.

[55]  Kelly M. Smith,et al.  Isotretinoin in the Treatment of Granuloma Annulare , 2004, The Annals of pharmacotherapy.

[56]  B. Gicquel,et al.  TNF-alpha is a critical negative regulator of type 1 immune activation during intracellular bacterial infection. , 2004, The Journal of clinical investigation.

[57]  T. Darling,et al.  Generalized granuloma annulare in a patient with adult onset diabetes mellitus. , 2003, Journal of drugs in dermatology : JDD.

[58]  P. Rubegni,et al.  A case of disseminated granuloma annulare treated with defibrotide: complete clinical remission and progressive hair darkening , 2003, The British journal of dermatology.

[59]  A. Buendía-Eisman,et al.  Generalized annular granuloma: response to isotretinoin , 2003, International journal of dermatology.

[60]  Soyun Cho,et al.  Generalized Perforating Granuloma Annulare in an Infant , 2003, Pediatric dermatology.

[61]  D. Thappa,et al.  Cutaneous variant of angiokeratoma corporis diffusum. , 2003, Dermatology online journal.

[62]  D. C. Adams,et al.  Improvement of chronic generalized granuloma annulare with isotretinoin. , 2002, Archives of dermatology.

[63]  U. Tursen,et al.  Generalized granuloma annulare associated with Plummer's disease , 2002, Journal of the European Academy of Dermatology and Venereology : JEADV.

[64]  J. Ring,et al.  T-cell receptor repertoire and cytokine pattern in granuloma annulare: defining a particular type of cutaneous granulomatous inflammation. , 2002, The Journal of investigative dermatology.

[65]  H. Skelton,et al.  Treatment of disseminated granuloma annulare with a 5‐lipoxygenase inhibitor and vitamin E , 2002, The British journal of dermatology.

[66]  C. Holden,et al.  Sweet's syndrome in association with generalized granuloma annulare in a patient with previous breast carcinoma , 2001, Clinical and experimental dermatology.

[67]  D. Petzold,et al.  Granuloma anulare disseminatum – erfolgreiche Therapie mit Fumarsäureester , 2001, Der Hautarzt.

[68]  A. Karaduman,et al.  An unusual form of generalized granuloma annulare in a patient with insulin-dependent diabetes mellitus. , 2001, Acta dermato-venereologica.

[69]  A. Schulze-Dirks,et al.  [Granuloma annulare disseminatum: successful therapy with fumaric acid ester]. , 2001, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[70]  L. Dubertret,et al.  The use of tetracyclines for the treatment of sarcoidosis. , 2001, Archives of dermatology.

[71]  B. A.,et al.  Chronic hepatitis C virus infection associated with a generalized granuloma annulare. , 2000 .

[72]  A. Fayyazi,et al.  Expression of IFNγ, coexpression of TNFα and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare , 2000, Archives of Dermatological Research.

[73]  A. Fayyazi,et al.  Expression of IFNgamma, coexpression of TNFalpha and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare. , 2000, Archives of dermatological research.

[74]  J. Serratrice,et al.  Chronic hepatitis C virus infection associated with a generalized granuloma annulare. , 2000, Journal of the American Academy of Dermatology.

[75]  Black,et al.  Generalised granuloma annulare successfully treated with PUVA , 1999, Clinical and experimental dermatology.

[76]  J. Toro,et al.  Granuloma annulare and human immunodeficiency virus infection. , 1999, Archives of Dermatology.

[77]  S. Devaraj,et al.  α-Tocopherol Decreases Interleukin-1β Release From Activated Human Monocytes by Inhibition of 5-Lipoxygenase , 1999 .

[78]  S. Devaraj,et al.  Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[79]  G. Plewig,et al.  [Bath-PUVA therapy of granuloma annulare]. , 1999, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[80]  D. Godar UVA1 radiation triggers two different final apoptotic pathways. , 1999, The Journal of investigative dermatology.

[81]  Ockenfels,et al.  The antipsoriatic agent dimethylfumarate immunomodulates T‐cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network , 1998, The British journal of dermatology.

[82]  F. Bérard,et al.  Generalized granuloma annulare and hepatitis B vaccination. , 1998, European journal of dermatology : EJD.

[83]  W. Schill,et al.  Balneophotochemo- therapie bei disseminiertem Granuloma anulare , 1998, Der Hautarzt.

[84]  P. Altmeyer,et al.  Fumaric Acid Esters Suppress Peripheral CD4- and CD8-Positive Lymphocytes in Psoriasis , 1998, Dermatology.

[85]  L. Mazzanti,et al.  Successful Treatment of Generalized Granuloma Annulare with Polyethylene Sheet Bath PUVA , 1998 .

[86]  J. Simon,et al.  Phototherapy with UV-A-I for generalized granuloma annulare. , 1997, Archives of dermatology.

[87]  L. Klotz,et al.  Evidence that Singlet Oxygen-induced Human T Helper Cell Apoptosis Is the Basic Mechanism of Ultraviolet-A Radiation Phototherapy , 1997, The Journal of experimental medicine.

[88]  T. Ottenhoff,et al.  Selective stimulation of T helper 2 cytokine responses by the anti‐psoriasis agent monomethylfumarate , 1996, European journal of immunology.

[89]  L. Chong,et al.  Resolution of Generalized Granuloma Annulare with Isotretinoin Therapy , 1996, International journal of dermatology.

[90]  F. Di Virgilio,et al.  The purinergic P2Z receptor of human macrophage cells. Characterization and possible physiological role. , 1995, The Journal of clinical investigation.

[91]  V. Ho Cyclosporine in the treatment of generalized granuloma annulare. , 1995, Journal of the American Academy of Dermatology.

[92]  P. von den Driesch,et al.  Antimalarials for control of disseminated granuloma annulare in children. , 1994, Journal of the American Academy of Dermatology.

[93]  A. Nagler,et al.  Generalized granuloma annulare post autologous bone marrow transplantation in a Hodgkin's disease patient. , 1994, Bone marrow transplantation.

[94]  G. Angelini,et al.  Cyclosporine in the treatment of generalized granuloma annulare. , 1994, Journal of the American Academy of Dermatology.

[95]  D. Margolis,et al.  Ulcerated necrobiosis lipoidica diabeticorum in a patient with a history of generalized granuloma annulare. , 1994, Cutis.

[96]  D. Rubel,et al.  GENERALISED GRANULOMA ANNULARE SUCCESSFULLY TREATED WITH PENTOXIFYLLINE , 1993, The Australasian journal of dermatology.

[97]  G. Richard,et al.  [Retinoids in therapy of granuloma anulare disseminatum]. , 1993, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[98]  B. Vermeer,et al.  Minimising the Risks of PUVA Treatment , 1993, Drug safety.

[99]  B. J. Hiskes Generalized granuloma annulare in a diabetic patient. A case report. , 1993, Journal of the American Podiatric Medical Association.

[100]  N. Tsankov,et al.  Widespread Granuloma Annulare and Cervical Adenocarcinoma , 1992, International journal of dermatology.

[101]  R. Botella-Estrada,et al.  Disseminated granuloma annulare: resolution with etretinate therapy. , 1992, Journal of the American Academy of Dermatology.

[102]  J. McGregor,et al.  Disseminated granuloma annulare as a presentation of acquired immunodeficiency syndrome (AIDS) , 1992, Clinical and experimental dermatology.

[103]  G. Burg Disseminated granuloma anulare: therapy with vitamin E topically. , 1992, Dermatology.

[104]  W. Morison,et al.  Photochemotherapy of generalized granuloma annulare. , 1990, Archives of dermatology.

[105]  G. Plewig,et al.  Remission of human immunodeficiency virus-associated generalized granuloma annulare under zidovudine therapy. , 1988, Journal of the American Academy of Dermatology.

[106]  L. Ashamalla,et al.  Topical Vitamin E in Granuloma Annulare , 1988, International journal of dermatology.

[107]  Guillermo Planas,et al.  Familial Generalized Perforating Granuloma Annulare , 1988, International journal of dermatology.

[108]  A. Lorincz,et al.  A case of generalized granuloma annulare responding to hydroxychloroquine. , 1988, Cleveland Clinic journal of medicine.

[109]  T. Hindson,et al.  PUVA therapy of diffuse granuloma annulare , 1988, Clinical and experimental dermatology.

[110]  M. Jonckheer,et al.  Autoimmune thyroiditis and generalized granuloma annulare: remission of the skin lesions after thyroxine therapy. , 1987, Dermatologica.

[111]  D. Czarnecki,et al.  The response of generalized granuloma annulare to dapsone. , 1986, Acta dermato-venereologica.

[112]  A. Steiner,et al.  Sulfone treatment of granuloma annulare. , 1985, Journal of the American Academy of Dermatology.

[113]  Schleicher Sm,et al.  Resolution of disseminated granuloma annulare following isotretinoin therapy. , 1985 .

[114]  S. Schleicher,et al.  Resolution of disseminated granuloma annulare following isotretinoin therapy. , 1985, Cutis.

[115]  J. Dimitrowa,et al.  [Follicular lichenoid generalized granuloma annulare]. , 1984, Zeitschrift fur Hautkrankheiten.

[116]  M. Medenica,et al.  Response of generalized granuloma annulare to high-dose niacinamide. , 1983, Archives of dermatology.

[117]  S. Talhari,et al.  [Perforating granuloma annulare]. , 1981, Medicina cutanea ibero-latino-americana.

[118]  R. Schwartz,et al.  Treatment of generalized granuloma annulare with dapsone. , 1980, Archives of dermatology.

[119]  P. G. Lang,et al.  Sulfones and sulfonamides in dermatology today. , 1979, Journal of the American Academy of Dermatology.

[120]  T. Dormandy,et al.  FREE-RADICAL OXIDATION AND ANTIOXIDANTS , 1978, The Lancet.

[121]  A. Lewis,et al.  Studies on the anti-inflammatory properties of dapsone in a variety of animal models [proceedings]. , 1977, British journal of pharmacology.

[122]  David Bruce Lewis,et al.  Anti‐inflammatory actions of dapsone and its related biochemistry , 1976, The Journal of pharmacy and pharmacology.

[123]  D. Lewis,et al.  Proceedings: Anti-inflammatory properties of dapsone. , 1975, The Journal of pharmacy and pharmacology.

[124]  J. Smith,et al.  Generalized perforating granuloma annulare. , 1973, Archives of dermatology.

[125]  M. Kamimura Antiinflammatory activity of vitamin E. , 1972, The Journal of vitaminology.

[126]  R. Davis,et al.  Familial granuloma annulare; report of two cases, with observations on the incidence of the disease in Britain. , 1957, Acta dermato-venereologica.

[127]  N. Epstein,et al.  Generalized granuloma annulare. , 1950, Archives of dermatology and syphilology.