Correspondence 423
Reference 1 Katugampola RP, Anstey AV, Finlay AY et al. A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases. Br J Dermatol 2012; 167:4. Funding sources: none. Conflicts of interest: none declared.
Thalidomide in the treatment of refractory orofacial granulomatosis Fig 2. Bulla formation with hyper- and hypopigmentation and scarring.
The patient also suffered from a congenital bone marrow fibrosis of unknown cause. This was diagnosed at the age of 12 months. He presented with persistent anaemia, with bone marrow biopsy showing fibrosis. He has been transfusion dependent since the age of 1 year, but, despite transfusions, the anaemia became more difficult to control from the age of 7 years, with the concentration of haemoglobin generally being around 62 g dL 1 over the last 18 months. The marked worsening of anaemia preceded the onset of bulla formation by 2 months. We have prescribed a visible light sunscreen (Tayside Pharmaceuticals, Dundee, U.K.) and fingerless gloves as part of a rigorous regime of photoprotection, as the patient has a mild neutropenia caused by the marrow fibrosis, which increases his risk of skin infections. CEP caused clinical problems only when his anaemia relapsed owing to an unrelated bone marrow fibrosis. Anaemia drives the production of porphyrin as part of the increased drive to synthesize haem. This is the rationale for hypertransfusion – the standard treatment for CEP1 – which controls symptoms by increasing the concentration of haemoglobin sufficiently to suppress the production of porphyrin. The absence of symptoms when his anaemia was controlled suggests that the underlying CEP is mild. Even when the CEP became manifest owing to anaemia, the absence of porphyrin-induced haemolysis indicates mild disease. The early onset of symptoms and haemolytic anaemia are the two main predictors of poor prognosis in CEP. It is fortunate that the anaemia-related expression of CEP in this patient has not induced haemolysis, which would have made the marrow fibrosis-related anaemia even more difficult to control than it currently is. 1
Photodermatology Unit, St John’s Institute of Dermatology, London SE1 7EH, U.K. 2 Paediatric Dermatology Department, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, U.K. E-mail: [email protected] © 2014 British Association of Dermatologists
A. VERMA1 E. RASHIDGHAMAT1 A. MARTINEZ2 H. FASSIHI1 R. SARKANY1
DOI: 10.1111/bjd.12944 DEAR EDITOR, The treatment of orofacial granulomatosis (OFG) remains challenging, and spontaneous remission is rare. We report the case of a 43-year-old man with a 15-year history of swollen and cracked lips who initially presented to dermatology in 2007 following referral from oral medicine. Examination revealed thickened, indurated and fissured lips, cobblestoning of the buccal mucosa and lower labial mucosa, and angular cheilitis. A clinical diagnosis of OFG was made, and histology showed noncaseating granulomas. He was systemically well. Thorough radiological and endoscopic investigations revealed no evidence of inflammatory bowel disease, tuberculosis or sarcoidosis. Patch testing to the British standard, cosmetic/facial, medicament and dental series demonstrated an allergic reaction to benzoic acid 5% and cinnamic aldehyde 1%, and he was educated with regard to diet restriction. Injections of intralesional triamcinolone (10 mg mL 1) were initiated at 3-weekly intervals, with minimal improvement. Infliximab (5 mg kg 1) was administered in January 2008, with significant improvement after two infusions given 8 weeks apart. However, treatment had to be discontinued after a severe infusion reaction was experienced by the patient. Azathioprine was commenced in March 2008, but was ineffective. Subsequently, the patient commenced adalimumab in July 2008 (40 mg fortnightly, increased to weekly) for 9 months with no clinical response. Treatment with ustekinumab (45 mg, 3-monthly), commenced in August 2010, was partially effective, but the clinical improvement plateaued after 11 months and the treatment was subsequently discontinued. In spite of disease progression with increased lip swelling, drooling and right cheek swelling, the patient was reluctant to receive further systemic therapy. Lymecycline 408 mg daily was given from May 2011 for 3 months, with no response. In December 2011, the patient was experiencing significant emotional and psychological distress as a result of his facial disfigurement (Fig. 1), and scored 16 out of 30 in the Dermatology Life Quality Index (DLQI). Thalidomide 100 mg daily was commenced, and baseline nerve conduction studies were normal. Eight weeks into treatment, the patient’s British Journal of Dermatology (2014) 171, pp415–440
424 Correspondence
lip swelling improved dramatically and his DLQI score was five out of 30. Clinical improvement continued, with resolution of symptoms by November 2012 (Fig. 2), at which point the patient’s DLQI score was zero out of 30. Unfortunately, the patient reported dysaesthesia of the hands and feet. As such, the patient underwent nerve conduction studies, which showed evidence of a large-fibre peripheral sensory axonal neuropathy. Subsequently, thalidomide was discontinued in December 2012, and the signs and symptoms of OFG have gradually returned, with slight improvement in the neurological symptoms. OFG was first described by Wiesenfeld in 1985 and represents a noncaseating granulomatous disease of uncertain pathogenesis.1 Melkersson–Rosenthal syndrome and cheilitis granulomatosa of Miescher are also included in the spectrum of this disease. Allergy, infection or an underlying genetic susceptibility have been proposed as aetiological factors.1,2 A delayed hypersensitivity response to dental materials (dental amalgam and mercury), foods and food additives has been described, with benefits seen from a diet free of cinnamon and benzoates.2 The role of T-cell clonal expansion and cytokine production has been observed, and may explain the pathway to granuloma formation.3 This peripheral T-cell activation and dysregulation provides new opportunities to exploit targeted therapies.
(a)
(b)
Fig 1. Symptoms of orofacial granulomatosis in a 43-year-old man. (a) Cracked and fissured lips. (b) Swelling of the lips. British Journal of Dermatology (2014) 171, pp415–440
Fig 2. Resolution of symptoms of orofacial granulomatosis in a 43year-old man after 8 weeks of treatment with thalidomide 100 mg daily.
OFG may affect any age or ethnic group. Clinically, it can present with diffuse soft tissue swelling of the oral and maxillofacial regions. Labial swelling is usually persistent, nontender and the most frequent (up to 77% of patients) presenting symptom.4,5 Initially, the swelling is soft, but as the disease progresses fibrosis occurs and the lip begins to feel firm and rubbery. Other clinical findings observed include lip fissuring, oral ulcerations, cobblestoning of the buccal mucosa, gingival enlargment, mucosal tags and facial swelling. Histological assessment can be difficult; McCartan et al.5 reported that only 56% of their patients showed the classical features of OFG on biopsy. Treatment of OFG is difficult. Topical and intralesional steroids or topical immunosuppressants are first-line therapies. Systemic steroids may be considered if there is severe labial swelling, but use is limited by their side-effect profile.4 Antitumour necrosis factor (TNF) agents, such as infliximab and adalimumab, have shown benefit in patients with OFG, as well as those with oral Crohn disease.6,7 Thalidomide was originally introduced in 1957 as a sedative and antiemetic to improve morning sickness, but was withdrawn from the market owing to its teratogenic potential and risk of peripheral neuropathy. It was then reintroduced as a treatment for myelodyplastic syndrome and multiple myeloma with strict prescribing guidelines. Thalidomide has both immunomodulatory and antiinflammatory effects through the inhibition of TNF. It has been described in the treatment of refractory aphthous ulceration, with limited reports of benefit in OFG.8 Hegarty et al. reported the successful resolution of OFG with lowdose thalidomide.8 Thalidomide-associated peripheral neuropathy is unpredictable, and can be as low as 3%; despite this, the signs and symptoms of neuropathy are frequently reversible. The patient with severe OFG reported herein failed to respond to several immunosuppressive therapies, but had a dramatic clinical response to thalidomide; however, this was limited by the development of a peripheral neuropathy. Tha© 2014 British Association of Dermatologists
Correspondence 425 Funding sources: none.
lidomide may be considered as a therapeutic option in resistant cases of OFG as long as regular neurological assessment is carried out.
Conflicts of interest: B.K. is in receipt of unrestricted research grants from Abbott Ltd, Pfizer and Janssen, and works as an advisor to and consultant for Abbott Ltd, Pfizer and Janssen.
K. EUSTACE J. CLOWRY B. KIRBY A. LALLY
Department of Dermatology, St Vincent’s Hospital, Dublin 4, Ireland E-mail: [email protected]
Elevated serum thymus and activationregulated chemokine (TARC/CCL17) relates to reactivation of human herpesvirus 6 in drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS)
References 1 Kauzman A, Quesnel-Mercier A, Lalonde B. Orofacial granulomatosis: 2 case reports and literature review. J Can Dent Assoc 2006; 72:325–9. 2 Campbell HE, Escudiet MP, Patel P et al. Review article: cinnamonand benzoate-free diet as a primary treatment for orofacial granulomatosis. Aliment Pharmacol Ther 2011; 34:687–701. 3 Giovannetti A, Mazzetta F, Cavani A et al. Skewed T-cell receptor variable b repertoire and massive T-cell activation in idiopathic orofacial granulomatosis. Int J Immunopathol Pharmacol 2012; 25:503– 11. 4 Al Johani KA, Moles DR, Hodgson TA et al. Orofacial granulomatosis: clinical features and long-term outcome of therapy. J Am Acad Dermatol 2010; 62:611–20. 5 McCartan BE, Healy CM, McCreary CE et al. Characteristics of patients with orofacial granulomatosis. Oral Dis 2011; 17:696– 704. 6 O’Neill ID, Scully C. Biologics in oral medicine: oral Crohn’s disease and orofacial granulomatosis. Oral Dis 2012; 18:633– 8. 7 Elliott T, Campbell H, Escudier M et al. Experience with anti-TNFa therapy for orofacial granulomatosis. J Oral Pathol Med 2011; 40:14–19. 8 Hegarty A, Hodgson T, Porter S. Thalidomide for the treatment of recalcitrant oral Crohn’s disease and orofacial granulomatosis. Oral Surg Oral Med Pathol Oral Radiol Endod 2003; 95:578–85.
DOI: 10.1111/bjd.12948 DEAR EDITOR, Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a severe adverse drug-induced reaction. This syndrome is characterized by cutaneous eruptions, fever, haematological abnormalities (eosinophilia and/or atypical lymphocytosis) and severe visceral dysfunction.1,2 The reactivation of human herpesvirus (HHV)-6, as evidenced by increases in HHV-6 IgG antibody titres and DNA levels, has been reported in patients with DRESS/DIHS.2–4 It is often challenging to diagnose DRESS/DIHS due to its diverse symptoms; therefore, a scoring system (RegiSCAR system) has recently been developed in an attempt to define DRESS more appropriately.5 Thymus and activation-regulated chemokine (TARC/ CCL17) is one of the C–C chemokines that works as a ligand for C–C chemokine receptor 4, and plays important roles in the T helper 2-type immune response.6,7 We recently reported markedly higher serum TARC levels in patients with
(a)
(b)
TARC (pg/ml)
Fig 1. (a) Serum thymus and activationregulated chemokine (TARC) levels in the acute stage of drug eruption within 15 days of onset. TARC levels in patients with drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) were significantly higher than those in patients with Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or maculopapular erythema (MPE). (b) Serum TARC levels in patients with drug eruption between days 5 and 10 after onset. TARC levels in patients with DRESS/DIHS were significantly higher than those in patients with SJS/TEN or MPE. © 2014 British Association of Dermatologists
TARC (pg/ml)
P < 0·0001 P < 0·0001
70 000
70 000
60 000
60 000
50 000
50 000
40 000
40 000
30 000
30 000
P < 0·007 P < 0·003
26 730 ± 18 890 21 023 ± 17 040
20 000
10 000
0
20 000
2142 ± 3056
1543 ± 2770
DRESS/DIHS (n = 30)
SJS/TEN (n = 15)
MPE (n = 17)
0
4038 ± 3784
2408 ± 3562
10 000
DRESS/DIHS (n = 16)
SJS/TEN (n = 8)
MPE (n = 7)
British Journal of Dermatology (2014) 171, pp415–440
Reference 1 Katugampola RP, Anstey AV, Finlay AY et al. A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases. Br J Dermatol 2012; 167:4. Funding sources: none. Conflicts of interest: none declared.
Thalidomide in the treatment of refractory orofacial granulomatosis Fig 2. Bulla formation with hyper- and hypopigmentation and scarring.
The patient also suffered from a congenital bone marrow fibrosis of unknown cause. This was diagnosed at the age of 12 months. He presented with persistent anaemia, with bone marrow biopsy showing fibrosis. He has been transfusion dependent since the age of 1 year, but, despite transfusions, the anaemia became more difficult to control from the age of 7 years, with the concentration of haemoglobin generally being around 62 g dL 1 over the last 18 months. The marked worsening of anaemia preceded the onset of bulla formation by 2 months. We have prescribed a visible light sunscreen (Tayside Pharmaceuticals, Dundee, U.K.) and fingerless gloves as part of a rigorous regime of photoprotection, as the patient has a mild neutropenia caused by the marrow fibrosis, which increases his risk of skin infections. CEP caused clinical problems only when his anaemia relapsed owing to an unrelated bone marrow fibrosis. Anaemia drives the production of porphyrin as part of the increased drive to synthesize haem. This is the rationale for hypertransfusion – the standard treatment for CEP1 – which controls symptoms by increasing the concentration of haemoglobin sufficiently to suppress the production of porphyrin. The absence of symptoms when his anaemia was controlled suggests that the underlying CEP is mild. Even when the CEP became manifest owing to anaemia, the absence of porphyrin-induced haemolysis indicates mild disease. The early onset of symptoms and haemolytic anaemia are the two main predictors of poor prognosis in CEP. It is fortunate that the anaemia-related expression of CEP in this patient has not induced haemolysis, which would have made the marrow fibrosis-related anaemia even more difficult to control than it currently is. 1
Photodermatology Unit, St John’s Institute of Dermatology, London SE1 7EH, U.K. 2 Paediatric Dermatology Department, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, U.K. E-mail: [email protected] © 2014 British Association of Dermatologists
A. VERMA1 E. RASHIDGHAMAT1 A. MARTINEZ2 H. FASSIHI1 R. SARKANY1
DOI: 10.1111/bjd.12944 DEAR EDITOR, The treatment of orofacial granulomatosis (OFG) remains challenging, and spontaneous remission is rare. We report the case of a 43-year-old man with a 15-year history of swollen and cracked lips who initially presented to dermatology in 2007 following referral from oral medicine. Examination revealed thickened, indurated and fissured lips, cobblestoning of the buccal mucosa and lower labial mucosa, and angular cheilitis. A clinical diagnosis of OFG was made, and histology showed noncaseating granulomas. He was systemically well. Thorough radiological and endoscopic investigations revealed no evidence of inflammatory bowel disease, tuberculosis or sarcoidosis. Patch testing to the British standard, cosmetic/facial, medicament and dental series demonstrated an allergic reaction to benzoic acid 5% and cinnamic aldehyde 1%, and he was educated with regard to diet restriction. Injections of intralesional triamcinolone (10 mg mL 1) were initiated at 3-weekly intervals, with minimal improvement. Infliximab (5 mg kg 1) was administered in January 2008, with significant improvement after two infusions given 8 weeks apart. However, treatment had to be discontinued after a severe infusion reaction was experienced by the patient. Azathioprine was commenced in March 2008, but was ineffective. Subsequently, the patient commenced adalimumab in July 2008 (40 mg fortnightly, increased to weekly) for 9 months with no clinical response. Treatment with ustekinumab (45 mg, 3-monthly), commenced in August 2010, was partially effective, but the clinical improvement plateaued after 11 months and the treatment was subsequently discontinued. In spite of disease progression with increased lip swelling, drooling and right cheek swelling, the patient was reluctant to receive further systemic therapy. Lymecycline 408 mg daily was given from May 2011 for 3 months, with no response. In December 2011, the patient was experiencing significant emotional and psychological distress as a result of his facial disfigurement (Fig. 1), and scored 16 out of 30 in the Dermatology Life Quality Index (DLQI). Thalidomide 100 mg daily was commenced, and baseline nerve conduction studies were normal. Eight weeks into treatment, the patient’s British Journal of Dermatology (2014) 171, pp415–440
424 Correspondence
lip swelling improved dramatically and his DLQI score was five out of 30. Clinical improvement continued, with resolution of symptoms by November 2012 (Fig. 2), at which point the patient’s DLQI score was zero out of 30. Unfortunately, the patient reported dysaesthesia of the hands and feet. As such, the patient underwent nerve conduction studies, which showed evidence of a large-fibre peripheral sensory axonal neuropathy. Subsequently, thalidomide was discontinued in December 2012, and the signs and symptoms of OFG have gradually returned, with slight improvement in the neurological symptoms. OFG was first described by Wiesenfeld in 1985 and represents a noncaseating granulomatous disease of uncertain pathogenesis.1 Melkersson–Rosenthal syndrome and cheilitis granulomatosa of Miescher are also included in the spectrum of this disease. Allergy, infection or an underlying genetic susceptibility have been proposed as aetiological factors.1,2 A delayed hypersensitivity response to dental materials (dental amalgam and mercury), foods and food additives has been described, with benefits seen from a diet free of cinnamon and benzoates.2 The role of T-cell clonal expansion and cytokine production has been observed, and may explain the pathway to granuloma formation.3 This peripheral T-cell activation and dysregulation provides new opportunities to exploit targeted therapies.
(a)
(b)
Fig 1. Symptoms of orofacial granulomatosis in a 43-year-old man. (a) Cracked and fissured lips. (b) Swelling of the lips. British Journal of Dermatology (2014) 171, pp415–440
Fig 2. Resolution of symptoms of orofacial granulomatosis in a 43year-old man after 8 weeks of treatment with thalidomide 100 mg daily.
OFG may affect any age or ethnic group. Clinically, it can present with diffuse soft tissue swelling of the oral and maxillofacial regions. Labial swelling is usually persistent, nontender and the most frequent (up to 77% of patients) presenting symptom.4,5 Initially, the swelling is soft, but as the disease progresses fibrosis occurs and the lip begins to feel firm and rubbery. Other clinical findings observed include lip fissuring, oral ulcerations, cobblestoning of the buccal mucosa, gingival enlargment, mucosal tags and facial swelling. Histological assessment can be difficult; McCartan et al.5 reported that only 56% of their patients showed the classical features of OFG on biopsy. Treatment of OFG is difficult. Topical and intralesional steroids or topical immunosuppressants are first-line therapies. Systemic steroids may be considered if there is severe labial swelling, but use is limited by their side-effect profile.4 Antitumour necrosis factor (TNF) agents, such as infliximab and adalimumab, have shown benefit in patients with OFG, as well as those with oral Crohn disease.6,7 Thalidomide was originally introduced in 1957 as a sedative and antiemetic to improve morning sickness, but was withdrawn from the market owing to its teratogenic potential and risk of peripheral neuropathy. It was then reintroduced as a treatment for myelodyplastic syndrome and multiple myeloma with strict prescribing guidelines. Thalidomide has both immunomodulatory and antiinflammatory effects through the inhibition of TNF. It has been described in the treatment of refractory aphthous ulceration, with limited reports of benefit in OFG.8 Hegarty et al. reported the successful resolution of OFG with lowdose thalidomide.8 Thalidomide-associated peripheral neuropathy is unpredictable, and can be as low as 3%; despite this, the signs and symptoms of neuropathy are frequently reversible. The patient with severe OFG reported herein failed to respond to several immunosuppressive therapies, but had a dramatic clinical response to thalidomide; however, this was limited by the development of a peripheral neuropathy. Tha© 2014 British Association of Dermatologists
Correspondence 425 Funding sources: none.
lidomide may be considered as a therapeutic option in resistant cases of OFG as long as regular neurological assessment is carried out.
Conflicts of interest: B.K. is in receipt of unrestricted research grants from Abbott Ltd, Pfizer and Janssen, and works as an advisor to and consultant for Abbott Ltd, Pfizer and Janssen.
K. EUSTACE J. CLOWRY B. KIRBY A. LALLY
Department of Dermatology, St Vincent’s Hospital, Dublin 4, Ireland E-mail: [email protected]
Elevated serum thymus and activationregulated chemokine (TARC/CCL17) relates to reactivation of human herpesvirus 6 in drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS)
References 1 Kauzman A, Quesnel-Mercier A, Lalonde B. Orofacial granulomatosis: 2 case reports and literature review. J Can Dent Assoc 2006; 72:325–9. 2 Campbell HE, Escudiet MP, Patel P et al. Review article: cinnamonand benzoate-free diet as a primary treatment for orofacial granulomatosis. Aliment Pharmacol Ther 2011; 34:687–701. 3 Giovannetti A, Mazzetta F, Cavani A et al. Skewed T-cell receptor variable b repertoire and massive T-cell activation in idiopathic orofacial granulomatosis. Int J Immunopathol Pharmacol 2012; 25:503– 11. 4 Al Johani KA, Moles DR, Hodgson TA et al. Orofacial granulomatosis: clinical features and long-term outcome of therapy. J Am Acad Dermatol 2010; 62:611–20. 5 McCartan BE, Healy CM, McCreary CE et al. Characteristics of patients with orofacial granulomatosis. Oral Dis 2011; 17:696– 704. 6 O’Neill ID, Scully C. Biologics in oral medicine: oral Crohn’s disease and orofacial granulomatosis. Oral Dis 2012; 18:633– 8. 7 Elliott T, Campbell H, Escudier M et al. Experience with anti-TNFa therapy for orofacial granulomatosis. J Oral Pathol Med 2011; 40:14–19. 8 Hegarty A, Hodgson T, Porter S. Thalidomide for the treatment of recalcitrant oral Crohn’s disease and orofacial granulomatosis. Oral Surg Oral Med Pathol Oral Radiol Endod 2003; 95:578–85.
DOI: 10.1111/bjd.12948 DEAR EDITOR, Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a severe adverse drug-induced reaction. This syndrome is characterized by cutaneous eruptions, fever, haematological abnormalities (eosinophilia and/or atypical lymphocytosis) and severe visceral dysfunction.1,2 The reactivation of human herpesvirus (HHV)-6, as evidenced by increases in HHV-6 IgG antibody titres and DNA levels, has been reported in patients with DRESS/DIHS.2–4 It is often challenging to diagnose DRESS/DIHS due to its diverse symptoms; therefore, a scoring system (RegiSCAR system) has recently been developed in an attempt to define DRESS more appropriately.5 Thymus and activation-regulated chemokine (TARC/ CCL17) is one of the C–C chemokines that works as a ligand for C–C chemokine receptor 4, and plays important roles in the T helper 2-type immune response.6,7 We recently reported markedly higher serum TARC levels in patients with
(a)
(b)
TARC (pg/ml)
Fig 1. (a) Serum thymus and activationregulated chemokine (TARC) levels in the acute stage of drug eruption within 15 days of onset. TARC levels in patients with drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) were significantly higher than those in patients with Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or maculopapular erythema (MPE). (b) Serum TARC levels in patients with drug eruption between days 5 and 10 after onset. TARC levels in patients with DRESS/DIHS were significantly higher than those in patients with SJS/TEN or MPE. © 2014 British Association of Dermatologists
TARC (pg/ml)
P < 0·0001 P < 0·0001
70 000
70 000
60 000
60 000
50 000
50 000
40 000
40 000
30 000
30 000
P < 0·007 P < 0·003
26 730 ± 18 890 21 023 ± 17 040
20 000
10 000
0
20 000
2142 ± 3056
1543 ± 2770
DRESS/DIHS (n = 30)
SJS/TEN (n = 15)
MPE (n = 17)
0
4038 ± 3784
2408 ± 3562
10 000
DRESS/DIHS (n = 16)
SJS/TEN (n = 8)
MPE (n = 7)
British Journal of Dermatology (2014) 171, pp415–440
