Letters to the Editor
REFERENCES 1. 2. 3. 4.
5. 6. 7.
8.
Tenenbein M. Seizures after lindane therapy. J Am Geriatr Soc 1991;39:394-5. Solomon LM, Fahrner L, West DP. Gamma benzene hexachloride toxicity: A review. Arch Dermatol 1977;113:353-7. Singal A, Thami GP. Lindane neurotoxicity in childhood. Am J Ther 2006;13:277-80. Kramer MS, Hutchinson TA, Rudnick SA, Leventhal JM, Feinstein AR. Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide. Clin Pharmacol Ther 1980;27:149-55. Sudakin DL. Fatality after a single dermal application of lindane lotion. Arch Environ Occup Health 2007;62:201-3. Daud Y, Daud-ur-Rehman, Farooq U. Lindane toxicity in a 7 year old boy. J Ayub Med Coll Abbottabad 2010;22:223. Centers for Disease Control and Prevention. Unintentional topical lindane ingestions--United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005:54:533-5. Aks SE, Krantz A, Hryhrczuk DO, Wagner S, Mock J. Acute accidental lindane ingestion in toddlers. Ann Emerg Med 1995;26:647-51.
lymphadenopathy. Application of topical steroids for several weeks induced no improvement. Skin biopsy showed a normal epidermis, mild diffuse interstitial and perivascular inflammation, with a prominent histiocytic component, spilled interstitially between the collagen bundles [Figure 2, upper left inset]. On closer view [Figure 2, upper right inset] piecemeal fragmentation of collagen and elastic fibers, small and medium sized lymphocytes, sometimes with hyperchromic nuclei, but showing no atypia and some eosinophils were also present. Immunohistochemistry confirmed the abundance of histiocytes (CD68+) and the presence of both CD4
Access this article online Quick Response Code:
Website: www.ijdvl.com DOI: 10.4103/0378-6323.129419 PMID: 129419
Interstitial granulomatous drug reaction due to febuxostat
Figure 1: Annular erythematous-edematous plaques on the posterior side of both legs tending to coalescence in polycyclic figures and showing central follicular scaling in older lesions
Sir, Febuxostat is a selective xanthine oxidase inhibitor, approved as second-line therapy in adult symptomatic hyperuricemia. Adverse effects of the drug are poorly documented. A regulatory trial reported the occurrence of a skin rash in 0.5-1.6% of patients[1] while a retrospective study on gout patients with prior documented severe allopurinol reactions noted the development of a hypersensitivity type cutaneous vasculitis in one of 13 patients.[2] We report a case in which an interstitial granulomatous drug reaction developed during febuxostat administration. A 78-year-old Caucasian man presented with a 1-month history of asymptomatic, sharply demarcated annular erythematous lesions, symmetrically distributed on the legs [Figure 1]. Older lesions merged into polycyclic patches, with rather pale and atrophic centers, covered with adherent follicular scales. There was no regional 182
Figure 2: Histology of the skin biopsy showed normal thickness epidermis, mild pervascular and interstitial lymphocytic inflammation in the underlying dermis, with a prominent histiocytes component (H and E, ×100). On higher magnification (H and E, ×400), histiocytes appeared spilled interstitially between fragmented collagen bundles, some small lymphocytes showed hyper chromic nuclei, eosinophils were also noted (right side inset); immunohistochemical stain for histiocytes (CD68) confirmed their abundance; CD3, CD4 and CD8 were normally expressed
Indian Journal of Dermatology, Venereology, and Leprology | March-April 2014 | Vol 80 | Issue 2
Letters to the Editor
and CD8 positive lymphocytes [Figure 2, bottom insets]. Medical history revealed a previous myocardial infarction and persistent atrial fibrillation treated daily for more than 5 years with hydrochlorothiazide-fosinopril 20 + 12.5 mg, torasemide 10 mg, barnidipine 10 mg, simvastatin 40 mg, metoprolol 100 mg, isosorbide mononitrate 80 mg, and acenocoumarol 4 mg. In the last 6 months, his general practitioner had prescribed febuxostat 80 mg, twice daily for asymptomatic hyperuricemia. The choice of this novel drug was made because it is not chemically related to allopurinol, which was suspected to have caused a similar skin eruption that spontaneously recovered after drug withdrawal 11 months prior to presentation in our department. On that occasion, the patient declined any investigations. No personal or family history of arthritis or autoimmune diseases was reported. Investigations were performed to exclude other etiologies or associated conditions, including autoimmune diseases, chronic infections and malignancies. The only alterations documented were a slight leukocytosis with a white blood cell count of 10600/mm3 (normal range 4000-10000/mm3) eosinophilia of 160/ μl (normal range 50-900/μl), hyperglycemia of 113 mg/ dl (normal range 74-106 mg/dl), and hyperuricemia of 9.51 mg/dl (normal range 3.5-7.2 mg/dl). Febuxostat was withdrawn and after four weeks the lesions disappeared [Figure 3a], while reintroduction caused a sudden flare [Figure 3b]. No relapses occurred in the following 6 months. Final causality assessment for adverse drug reaction following Jones algorithm was definite.[3]
a
b
Figure 3: Skin recovery after febuxostat withdrawal (a); flare-up after drug rechallenge (b)
Among the wide spectrum of cutaneous drug reactions, Magro et al. in 1998 described a rare entity with a peculiar histopathology characterized by the dermal presence of histiocytes between fragmented collagen bundles, coining the name interstitial granulomatous drug reaction.[4] The clinical presentation is variable and includes asymptomatic annular plaques with a predilection for the flexures, generalized erythematous macules and/or papules, erythroderma and DRESS.[5] Our patient had an unusual site of involvement and polycyclic plaques with central follicular scaling suggesting several differential diagnoses including mycosis fungoides. In their report, Magro et al. had pointed out the resemblance of interstitial granulomatous drug reaction to mycosis fungoides, with some cases showing atypical lymphocytes on light microscopy.[4] However, a careful examination performed by our pathologist excluded atypical lymphocytic infiltrates and epidermotropism. In addition, there were no palisading granulomas typical of granuloma annulare, no vasculitis nor septal panniculitis suggestive of erythema nodosum. Features of erythema annulare centrifugum such as papillary edema, spongiosis and parakeratosis were absent. Interstitial granulomatous drug reaction completely regresses with drug cessation and awareness of this will avoid prolonged disease and unnecessary treatments. The list of culprit drugs has increased with time and includes calcium channel blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, antihistamines, diuretics, anticonvulsants, antidepressants, allopurinol, thalidomide and anti-tumor necrosis factor (TNF) agents.[3-6] The role of TNF-alpha inhibitors in causing interstitial granulomatous drug reaction is controversial, as the drugs have been reported to cure the condition during the course of rheumatoid arthritis but have also been implicated in the onset of interstitial granulomatous reactions in other cases of psoriatic and rheumatoid arthritis.[6] The mechanisms underlying interstitial granulomatous dermatitis, associated with arthritis or drug intake, are unknown. The common histopathological hallmark is activation of histiocytes and recruitment of lymphocytes, which might be further amplified or inhibited by anti-TNF agents. Recovery without immunosuppressant treatment and the long interval between drug initiation and onset of the eruption suggests a temporary immunologic reactivity and/or restoration by spontaneous removal of the causative agent.[3-5] Previously reported allopurinol-induced interstitial granulomatous
Indian Journal of Dermatology, Venereology, and Leprology | March-April 2014 | Vol 80 | Issue 2
183
Letters to the Editor
reactions were characterized by constitutional symptoms and internal organ involvement characteristic of the DRESS syndrome,[5] in which a type IV hypersensitivity has been postulated to play a role. Our patient was taking several drugs for years without complaints until the intake of allopurinol caused a cutaneous eruption, not further investigated due to the patient’s refusal, but not suspected to be DRESS. To the best of our knowledge, febuxostat has not been associated with interstitial granulomatous drug reaction or DRESS. It is possible that xanthine oxidase inhibitors unveil a granulomatous diathesis in certain patients and hyperuricemia is the common feature connecting our case with the previous allopurinol-induced interstitial granulomatous [5] reactions. Both allopurinol and febuxostat prevent uric acid formation by blocking the conversion of xanthine precursors. However, both drugs are ineffective during an acute attack of gout and might even induce it, because the lower circulating uric acid levels favor the release of micro-crystals from the cartilage into the joint cavity triggering the synovial inflammatory cascade.[1] Dermal and subcutaneous soft tissue might react similarly to the dissolution of uric acid crystal deposits with exaggerated histiocyte activation. Drug-induced unknown dermal products and/or a disturbance in the degradation of collagen fibers might be responsible for the final interstitial granulomatous inflammation.[3-5] Further studies are necessary to confirm the role of febuxostat and predisposing individual conditions to the development of interstitial granulomatous drug reaction. ACKNOWLEDGMENTS We thank Dr. Robin Mark Weathon for the kind revision of the English text.
Atzori Laura, Pilloni Luca1, Pinna Anna Luisa Department of Medical Science, Dermatology Clinic, and 1Departments of Cyto-Morphology, Division of Pathology, University of Cagliari, Italy Address for correspondence: Dr. Laura Atzori, Clinica Dermatologica, Via Ospedale 54, 09124 Cagliari, Italy. E-mail: [email protected]
REFERENCES 1.
184
Ernst ME, Fravel MA. Febuxostat: A selective xanthine-oxidase/ xanthine-dehydrogenase inhibitor for the management of
2. 3. 4. 5.
6.
hyperuricemia in adults with gout. Clin Ther 2009;31:2503-18. Chohan S. Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions. J Rheumatol 2011;38:1957-9. Jones JK. Criteria for journal reports of suspected drug reactions. Clin Pharm 1982;1:554-5. Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: A distinctive clinical and pathological entity. J Cutan Pathol 1998;25:72-8. Kim MS, Lee JH, Park K, Son SJ. Allopurinol-induced : DRESS syndrome with a histologic pattern consistent with interstitial granulomatous drug reaction. Am J Dermatopathol 2014;36:193-6. Deng A, Harvey V, Sina B, Strobel D, Badros A, Junkins-Hopkins JM, et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol 2006;142:198-202. Access this article online Quick Response Code:
Website: www.ijdvl.com DOI: 10.4103/0378-6323.129420 PMID: 129420
Adult variant of self-healing papular mucinosis in a patient treated with interferon α2a 2a Sir Papular mucinosis (PM), also known as lichen myxedematosus (LM) is characterized by papules, plaques or subcutaneous nodules due to an idiopathic deposition of mucin in the dermis; a variable degree of fibrosis may appear and thyroid function is normal. The current classification was developed by Rongioletti and Rebora in 2001[1] dividing papular mucinosis into:scleromyxedema, a generalized scleroderma like form, accompanied by paraproteinemia and systemic involvement; localized papular forms, distributed into five subtypes: Discrete papular mucinosis, acral persistent papular mucinosis, self-healing papular mucinosis (SHPM), juvenile papular mucinosis and nodular papular mucinosis; and atypical forms: Scleromyxedema cases without monoclonal gammopathy, localized forms with monoclonal gammopathy and/or systemic symptoms, localized forms with mixed features of the five subtypes, and indeterminate cases.
Indian Journal of Dermatology, Venereology, and Leprology | March-April 2014 | Vol 80 | Issue 2
Copyright of Indian Journal of Dermatology, Venereology & Leprology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
REFERENCES 1. 2. 3. 4.
5. 6. 7.
8.
Tenenbein M. Seizures after lindane therapy. J Am Geriatr Soc 1991;39:394-5. Solomon LM, Fahrner L, West DP. Gamma benzene hexachloride toxicity: A review. Arch Dermatol 1977;113:353-7. Singal A, Thami GP. Lindane neurotoxicity in childhood. Am J Ther 2006;13:277-80. Kramer MS, Hutchinson TA, Rudnick SA, Leventhal JM, Feinstein AR. Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide. Clin Pharmacol Ther 1980;27:149-55. Sudakin DL. Fatality after a single dermal application of lindane lotion. Arch Environ Occup Health 2007;62:201-3. Daud Y, Daud-ur-Rehman, Farooq U. Lindane toxicity in a 7 year old boy. J Ayub Med Coll Abbottabad 2010;22:223. Centers for Disease Control and Prevention. Unintentional topical lindane ingestions--United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005:54:533-5. Aks SE, Krantz A, Hryhrczuk DO, Wagner S, Mock J. Acute accidental lindane ingestion in toddlers. Ann Emerg Med 1995;26:647-51.
lymphadenopathy. Application of topical steroids for several weeks induced no improvement. Skin biopsy showed a normal epidermis, mild diffuse interstitial and perivascular inflammation, with a prominent histiocytic component, spilled interstitially between the collagen bundles [Figure 2, upper left inset]. On closer view [Figure 2, upper right inset] piecemeal fragmentation of collagen and elastic fibers, small and medium sized lymphocytes, sometimes with hyperchromic nuclei, but showing no atypia and some eosinophils were also present. Immunohistochemistry confirmed the abundance of histiocytes (CD68+) and the presence of both CD4
Access this article online Quick Response Code:
Website: www.ijdvl.com DOI: 10.4103/0378-6323.129419 PMID: 129419
Interstitial granulomatous drug reaction due to febuxostat
Figure 1: Annular erythematous-edematous plaques on the posterior side of both legs tending to coalescence in polycyclic figures and showing central follicular scaling in older lesions
Sir, Febuxostat is a selective xanthine oxidase inhibitor, approved as second-line therapy in adult symptomatic hyperuricemia. Adverse effects of the drug are poorly documented. A regulatory trial reported the occurrence of a skin rash in 0.5-1.6% of patients[1] while a retrospective study on gout patients with prior documented severe allopurinol reactions noted the development of a hypersensitivity type cutaneous vasculitis in one of 13 patients.[2] We report a case in which an interstitial granulomatous drug reaction developed during febuxostat administration. A 78-year-old Caucasian man presented with a 1-month history of asymptomatic, sharply demarcated annular erythematous lesions, symmetrically distributed on the legs [Figure 1]. Older lesions merged into polycyclic patches, with rather pale and atrophic centers, covered with adherent follicular scales. There was no regional 182
Figure 2: Histology of the skin biopsy showed normal thickness epidermis, mild pervascular and interstitial lymphocytic inflammation in the underlying dermis, with a prominent histiocytes component (H and E, ×100). On higher magnification (H and E, ×400), histiocytes appeared spilled interstitially between fragmented collagen bundles, some small lymphocytes showed hyper chromic nuclei, eosinophils were also noted (right side inset); immunohistochemical stain for histiocytes (CD68) confirmed their abundance; CD3, CD4 and CD8 were normally expressed
Indian Journal of Dermatology, Venereology, and Leprology | March-April 2014 | Vol 80 | Issue 2
Letters to the Editor
and CD8 positive lymphocytes [Figure 2, bottom insets]. Medical history revealed a previous myocardial infarction and persistent atrial fibrillation treated daily for more than 5 years with hydrochlorothiazide-fosinopril 20 + 12.5 mg, torasemide 10 mg, barnidipine 10 mg, simvastatin 40 mg, metoprolol 100 mg, isosorbide mononitrate 80 mg, and acenocoumarol 4 mg. In the last 6 months, his general practitioner had prescribed febuxostat 80 mg, twice daily for asymptomatic hyperuricemia. The choice of this novel drug was made because it is not chemically related to allopurinol, which was suspected to have caused a similar skin eruption that spontaneously recovered after drug withdrawal 11 months prior to presentation in our department. On that occasion, the patient declined any investigations. No personal or family history of arthritis or autoimmune diseases was reported. Investigations were performed to exclude other etiologies or associated conditions, including autoimmune diseases, chronic infections and malignancies. The only alterations documented were a slight leukocytosis with a white blood cell count of 10600/mm3 (normal range 4000-10000/mm3) eosinophilia of 160/ μl (normal range 50-900/μl), hyperglycemia of 113 mg/ dl (normal range 74-106 mg/dl), and hyperuricemia of 9.51 mg/dl (normal range 3.5-7.2 mg/dl). Febuxostat was withdrawn and after four weeks the lesions disappeared [Figure 3a], while reintroduction caused a sudden flare [Figure 3b]. No relapses occurred in the following 6 months. Final causality assessment for adverse drug reaction following Jones algorithm was definite.[3]
a
b
Figure 3: Skin recovery after febuxostat withdrawal (a); flare-up after drug rechallenge (b)
Among the wide spectrum of cutaneous drug reactions, Magro et al. in 1998 described a rare entity with a peculiar histopathology characterized by the dermal presence of histiocytes between fragmented collagen bundles, coining the name interstitial granulomatous drug reaction.[4] The clinical presentation is variable and includes asymptomatic annular plaques with a predilection for the flexures, generalized erythematous macules and/or papules, erythroderma and DRESS.[5] Our patient had an unusual site of involvement and polycyclic plaques with central follicular scaling suggesting several differential diagnoses including mycosis fungoides. In their report, Magro et al. had pointed out the resemblance of interstitial granulomatous drug reaction to mycosis fungoides, with some cases showing atypical lymphocytes on light microscopy.[4] However, a careful examination performed by our pathologist excluded atypical lymphocytic infiltrates and epidermotropism. In addition, there were no palisading granulomas typical of granuloma annulare, no vasculitis nor septal panniculitis suggestive of erythema nodosum. Features of erythema annulare centrifugum such as papillary edema, spongiosis and parakeratosis were absent. Interstitial granulomatous drug reaction completely regresses with drug cessation and awareness of this will avoid prolonged disease and unnecessary treatments. The list of culprit drugs has increased with time and includes calcium channel blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, antihistamines, diuretics, anticonvulsants, antidepressants, allopurinol, thalidomide and anti-tumor necrosis factor (TNF) agents.[3-6] The role of TNF-alpha inhibitors in causing interstitial granulomatous drug reaction is controversial, as the drugs have been reported to cure the condition during the course of rheumatoid arthritis but have also been implicated in the onset of interstitial granulomatous reactions in other cases of psoriatic and rheumatoid arthritis.[6] The mechanisms underlying interstitial granulomatous dermatitis, associated with arthritis or drug intake, are unknown. The common histopathological hallmark is activation of histiocytes and recruitment of lymphocytes, which might be further amplified or inhibited by anti-TNF agents. Recovery without immunosuppressant treatment and the long interval between drug initiation and onset of the eruption suggests a temporary immunologic reactivity and/or restoration by spontaneous removal of the causative agent.[3-5] Previously reported allopurinol-induced interstitial granulomatous
Indian Journal of Dermatology, Venereology, and Leprology | March-April 2014 | Vol 80 | Issue 2
183
Letters to the Editor
reactions were characterized by constitutional symptoms and internal organ involvement characteristic of the DRESS syndrome,[5] in which a type IV hypersensitivity has been postulated to play a role. Our patient was taking several drugs for years without complaints until the intake of allopurinol caused a cutaneous eruption, not further investigated due to the patient’s refusal, but not suspected to be DRESS. To the best of our knowledge, febuxostat has not been associated with interstitial granulomatous drug reaction or DRESS. It is possible that xanthine oxidase inhibitors unveil a granulomatous diathesis in certain patients and hyperuricemia is the common feature connecting our case with the previous allopurinol-induced interstitial granulomatous [5] reactions. Both allopurinol and febuxostat prevent uric acid formation by blocking the conversion of xanthine precursors. However, both drugs are ineffective during an acute attack of gout and might even induce it, because the lower circulating uric acid levels favor the release of micro-crystals from the cartilage into the joint cavity triggering the synovial inflammatory cascade.[1] Dermal and subcutaneous soft tissue might react similarly to the dissolution of uric acid crystal deposits with exaggerated histiocyte activation. Drug-induced unknown dermal products and/or a disturbance in the degradation of collagen fibers might be responsible for the final interstitial granulomatous inflammation.[3-5] Further studies are necessary to confirm the role of febuxostat and predisposing individual conditions to the development of interstitial granulomatous drug reaction. ACKNOWLEDGMENTS We thank Dr. Robin Mark Weathon for the kind revision of the English text.
Atzori Laura, Pilloni Luca1, Pinna Anna Luisa Department of Medical Science, Dermatology Clinic, and 1Departments of Cyto-Morphology, Division of Pathology, University of Cagliari, Italy Address for correspondence: Dr. Laura Atzori, Clinica Dermatologica, Via Ospedale 54, 09124 Cagliari, Italy. E-mail: [email protected]
REFERENCES 1.
184
Ernst ME, Fravel MA. Febuxostat: A selective xanthine-oxidase/ xanthine-dehydrogenase inhibitor for the management of
2. 3. 4. 5.
6.
hyperuricemia in adults with gout. Clin Ther 2009;31:2503-18. Chohan S. Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions. J Rheumatol 2011;38:1957-9. Jones JK. Criteria for journal reports of suspected drug reactions. Clin Pharm 1982;1:554-5. Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: A distinctive clinical and pathological entity. J Cutan Pathol 1998;25:72-8. Kim MS, Lee JH, Park K, Son SJ. Allopurinol-induced : DRESS syndrome with a histologic pattern consistent with interstitial granulomatous drug reaction. Am J Dermatopathol 2014;36:193-6. Deng A, Harvey V, Sina B, Strobel D, Badros A, Junkins-Hopkins JM, et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol 2006;142:198-202. Access this article online Quick Response Code:
Website: www.ijdvl.com DOI: 10.4103/0378-6323.129420 PMID: 129420
Adult variant of self-healing papular mucinosis in a patient treated with interferon α2a 2a Sir Papular mucinosis (PM), also known as lichen myxedematosus (LM) is characterized by papules, plaques or subcutaneous nodules due to an idiopathic deposition of mucin in the dermis; a variable degree of fibrosis may appear and thyroid function is normal. The current classification was developed by Rongioletti and Rebora in 2001[1] dividing papular mucinosis into:scleromyxedema, a generalized scleroderma like form, accompanied by paraproteinemia and systemic involvement; localized papular forms, distributed into five subtypes: Discrete papular mucinosis, acral persistent papular mucinosis, self-healing papular mucinosis (SHPM), juvenile papular mucinosis and nodular papular mucinosis; and atypical forms: Scleromyxedema cases without monoclonal gammopathy, localized forms with monoclonal gammopathy and/or systemic symptoms, localized forms with mixed features of the five subtypes, and indeterminate cases.
Indian Journal of Dermatology, Venereology, and Leprology | March-April 2014 | Vol 80 | Issue 2
Copyright of Indian Journal of Dermatology, Venereology & Leprology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
