INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
Vol. 27, no. 2, 273-278 (2014)
LETTER TO THE EDITOR
GRANULOMA ANNULARIS REVEALING WEGENER'S GRANULOMATOSIS F. DEL PORTOI, M. PROIETTN, M. MUSCIANESP, F. TAMBURP, N. CIFANI4, L. FERRI!, S. NISTIC05, U. BOTTONP, G. BRUNO' and G. PRANTEDA2 I
U.0. C. Internal Medicine, Department ofMolecular and Clinical Medicine, Sant 'Andrea Hospital, Sapienza University ofRome, Italy; 'Unit ofDermatology, Sant 'Andrea Hospital, Sapienza University ofRome, Italy; 3 Unit ofDermatology, Complesso Integrato Columbus, Catholic University, Rome, Italy; "Department ofClinical Medicine, Faculty ofMedicine and Psychology, Sant 'Andrea Hospital, Sapienza University ofRome, Italy; 5Department ofHealth Sciences; University ofCatanzaro "Magna Grcecia", Catanzaro, Italy
Received January 25, 2014 - Accepted March, 2014 Skin manifestations are often associated with systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display pathognomonic dermatological features, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions. Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by E. coli. Skin manifestations are often associated to systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display dermatological features that are pathognomonic, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions (l, 2). Differential diagnosis among granulomatous diseases can be difficult, since they can present with similar or overlapping clinical features, thus auto-antibodies, such as antineutrophil cytoplasm antibodies (ANCA) are often helpful to make a definitive diagnosis (3, 4). Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by
Escherichia coli. Case report A 25-year-old man was admitted to our Department because of fever (38.5°C), cough and malaise which had initiated three months previously and was resistant to antibiotic therapy. On physical examination, he showed symmetrical and additive polyarthritis localized to the large joints of the lower limbs and to the large and small joints of the upper limbs, conjuntival redness, later identified as anterior uveitis, and a pulmonary abolition of the murmur at the right lower lobe. Skin examination detected small reddish nodules on the right elbow, where the skin was dry and scaly (Fig. 1). Laboratory tests showed normochromic normocytic anemia (haemogobin: 11.2 g/dL), increased C reactive protein (C-RP
Key words: Granuloma annularis, Wegener s granulomatosis, systemic autoimmune disease Mailing address: Prof. Steven Nistico, Associate Professor of Dermatology, University Magna Graecia, Catanzaro Viale Europa, Germaneto (Cl) 88100 Catanzaro, Italy Tel./Fax: +39 09613694001 e-mail: [email protected]
0394-6320 (2014) Copyright © by BIOLIFE. s.a.s. This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties
273
DISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.
274
F. DEL PORTO ET AL.
Table I. Clinical and histopathologic findings ofcutaneous lesions ofpatients with Wegener s granulomatosis.
Total patients
Daoud et al 1994
Frances et al 1994
Barksdale et al 1995
Comfere et al 2007
Carlos de souza 2010
30
35
46
17
39
14(47%)
26 (74%)
8 (16%)
12 (70%)
27 (70 %)
11 (22%)
1 (5%)
CLINICAL FEATURES Palpable purpora Pyoderma-like ulcer
8 (27%)
Papule
6 (20%)
5 (14%)
1 (5%)
Nodules
4 (13%)
6(17%)
10 (20%)
3 (17%)
Ulcerations
4 (13%)
6 (17%)
8 (16%)
5 (29%)
Maculae and erythema
2 (7%)
2 (4%)
Digital necrosis
1(2.8%)
Xanthoma
2 (5.7%)
Pustule
2 (5.7 %)
Livedo reticularis
1 (2.8%)
Bullae
3 (10%)
Petechiae
3 (10%)
12 (30%)
2 (4%)
2 (4%)
Violaceus plaques
1 (2%)
Abscess
1 (2%)
Cyst
1 (2%)
Annular urticarial lesios
1 (2%) 13 (33%)
Cutaneous vasculitis HISTOPATHOLOGIC FINDINGS Leukocytoclastic vasculitis
24 (80%)
Granulomatous inflammation
22 (63%)
23(31%)
12(70%)
5 (14%)
15 (19%)
2 (11%)
2 (2.7 %)
1(5%)
EN-like lesions:septal granulomatous panniculitis Palisaded extravascular necrotizing granuloma (Churg-Strauss like)
3 (10%)
2 (11%)
5 (14%)
nonspecific ulceration
3 (4%),
superficial dermal and epidermal necrosis without inflammation
2 (2.7%)
granuloma annulare
1 (1%)
chronic inflammation
23 (31%)
acute inflammatory lesions without vasculitis
7 (9%)
Mixed inflammatory pattern
5 (16%)
EN: erythema nodosum
13 mg/dl) and increased erytrocyte sedimentation rate (ESR 56 mm/h) values. Twenty-four-hour proteinuria was 3.2 g, thus nephrotic syndrome was diagnosed. Chest X-ray documented the presence of a parenchimal consolidation in the right lower lobe
and an enlargement of the right lung ilium, probably caused by lymphadenopathy. A total body computed tomography scan was performed which showed normal paranasal sinuses; presence of rare nodules not exceeding one centimetre in the lower lobes of
Int. J. ImmunopalhoI. Pharmacol.
Fig. 1. Multiple small reddish painless nodules on a slightly scaly skin on the right elbow.
Fig. 2. Granuloma anularis (EE stain 200x) characterized by minimal dermal necrobiosis with basophilic collagen bundles surrounded by palisading macrophages.
a
b Fig. 3. a) Interstitial necrotizing giant cellular granuloma centred on interlobular arterial wall of kidney tissue specimen (EE stain 200x). b) CD68 + macrophages (CD68 stain, 200x).
275
the chest, in the middle right lobe and in the apical segment of right upper lobe; presence of a round large parenchymal consolidation of about 3.5 em, with air bronchogram in the lateral segment of right lower lobe. Also, coexisting areas of ground-glass opacities predominantly in the upper lobes, nonconglomerate adenopathy, of an average diameter of 1.5 em, in the hilum bilaterally, in aorto-pulmonary window and in the right lower paratracheal space were shown. The pulmonary radiological finding directed the diagnosis towards a sarcoidosis with a concomitant pneumonia. To confirm the hypothesis ofsarcoidosis, a bronchoalveolar lavage (BAL) and a lung biopsy (LB) were carried out which were not diagnostic since BAL revealed an infection by Escherichia coli and LB displayed a "non specific granulomatous inflammation". At this point levofloxacin 500 mg/ die was started. Skin biopsy was consistent with the diagnosis of granuloma annulare (Fig. 2). During the hospitalization, a progressive increase of creatinine values up to 1.9 mg/dl occurred. An examination of the sediment was made, showing dysmorphic red blood cells with hyaline casts, therefore a renal biopsy was carried out which showed a pauci-immune necrotizing glomerulonephritis in the context of a systemic granulomatous vasculitis (Fig. 3). Auto-antibody screening revealed cANCA which were confirmed by EIA at the titre of 43.81 Vlml. Wegener's granulomatosis was diagnosed, therefore an immunosoppressive treatment combining high dose corticosteroids and cyclophosphamide was initiated (5). The patient was treated with prednisone 1 g per day for three consecutive days, followed by prednisolone at 50 mg daily and bolus intravenous of cyclophosphamide 1mg/Kg every two weeks for six months (6). The patient showed a dramatic response to treatment, achieving significant improvement. Systemic symptoms regressed and haemoglobin levels returned to a normal range. We witnessed a complete resolution of uveitis and arthritis as well as a progressive shrinkening of elbow skin lesions. Within the first month, elbow skin granuloma and skin scaliness had completely gone. Creatinine values returned to 0.9 mg/dl. Only proteinuria of about 1g/24 h remained, due to glomerular sclerosis already
F. DEL PORTO ET AL.
276
present at the time of diagnosis. Once remission was attained, treatment was changed to methotrexate (MTX) at 15 mg per week and prednisone at the maintained dose of 10 mg daily. After the first 18 months of treatment methotrexate was stopped and azatioprine 100 mg/die and hydroxychloroquine at the dose of 200 mg every day were subministered. No clinical flare-up or laboratory test reactivations were detected. cANCA persisted negative during the whole treatment. We have now reached 42 months of follow-up without signs of recurrence. DISCUSSION This case seems to be interesting since we describe a young man with Wegener's granulomatosis (WG), arising with atypical clinical manifestations. WG is an antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis with an incidence of 10/1.000.000 cases/year (3,4). It is a granulomatous inflammation involving the respiratory tract, and a necrotizing vasculitis affecting small to mediumsized vessels. Commonly WG targets kidneys, causing a rapidly progressive glomerulonephritis, leading to chronic renal failure. Positive cytoplasmic (c)-ANCA, directed against serine proteinase 3, are detectable in nearly 100% of patients with generalized WG (7). It is believed that ANCA play a role in the pathogenesis of the disease (8) and are useful for diagnosis and in evaluating treatment efficacy (9). Skin lesions, are generally uncommon in this disease, showing a prevalence of 14-30% of cases (8, 9). Dermatological manifestations usually appear concurrently with visceral involvement or after systemic signs and symptoms have developed, indicating the presence of an active systemic disease. In WG a wide spectrum of skin lesions may be encountered. Palpaple purpura represents the most common, however skin nodules, necrotizing ulcerations and necrotic papules have also been described (Table I), (10-13). Histological matching of such dermatological features in most of the cases is leukocytoclastic vasculitis, but also granulomatous inflammation and palisaded extravascular necrotizing granuloma (Table I) have been described. To the best of our knowledge, in the literature only one case of granuloma annulare (GA) has been reported in WG (14); the second case is here reported. First described
by T. Colcott Fox in 1985, GA is a common benign granulomatous dermatosis, affecting all age groups, clinically characterized by clusters of 1 to 2-mm dermal bumps (papules) that range in color from flesh-toned to erythematous, arranged in a circle or annular plaques (15). The etiopathogenesis of the disease has not been clearly defined. Some of the proposed pathogenic mechanisms include cellmediated immunity, leading to vasculitis and dermal degeneration (16) induced by external stimuli such as infection, insect bite, trauma and sun exposure (17, 18). AG occurs predominantly over the distal extremities, often near joints: hands, feet, wrists and ankles (19). Aside from the visible rash that may be slightly itchy, AG is usually painless. Most AG lesions regress spontaneously within 2 years, without leaving any atrophic scars. Sometimes, however, the rings can remain for many years. Histological examination reveals different patterns, however collagen fiber degeneration and dermal mucin deposition associated with palisaded granulomatous inflammation are the most frequently reported (20-22). Its pattern differs from the most common dermatoses (23-27). The case here presented seems to be of interest since AG has been described in a patient with WG, probably representing a rare dermatological manifestation ofthis disease. Skin lesions completely regressed with treatment ofWG and never presented after remission was attained, suggesting that dermatological features can be considered as marker of disease activity. REFERENCES I.
2.
3.
Reddy RR, Shashi Kumar BM, Harish MR. Cutaneous sarcoidosis - a great masquerader: a report of three interesting cases. Indian J Dermatol2011; 56(5):68-72. Daoud MS, Gibson LE, DeRemee RA, Specks U, el-Azhary RA, Su WP. Cutaneous Wegener's granulomatosis: clinical, histopathologic, and immunopathologic features of thirty patients. J Am Acad Dermatol1994; 31(4):605-12. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187-92.
Int. J. Immunopathol. Pharmacol.
4.
5.
6.
7. 8. 9.
10.
11.
12.
13.
Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004; 117(1):39-50. Macconi D, Zanoli AF, Orisio S, et al. Methylprednisolone normalizes superoxide anion production by polymorphs from patients with ANCApositive vasculitides. Kidney Int 1993; 44( 1):215-20. De Groot K, Harper L, Jayne DR, et al.; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibodyassociated vasculitis: a randomized trial. Ann Intern Med 2009; 150(10):670-80. Lamprecht P, Gross WL. Wegener's granulomatosis. Herz 2004; 29:47-56. Kallenberg CG. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis 2011; 70(S):59-63. Moosing F, Lamprecht P, Gross WL. Wegener's granulomatosis: The current view. Clinic Rev Allerg Immunol2008; 35:19-21. Pranteda G, Muscianese M, Grimaldi M, Fidanza L, Pranteda G, Narcisi A, Nistico' S, Bottoni U. Lichen sclerosus et atrophicus induced by carbamazepine: a case report. Int J Immunopath Immunopharm 2013; 26:791-93. Donato G, Nicoletti G, Gabriele A, Conforti F, Zuccala V, Amorosi A, Nistico S, Bottoni U. Neurocutaneous melanosis in a woman with multiple brain melanocytomas, cutaneous melanocytosis and oral involvement. Eur JInflamm 2013; 11(3):813-17. Barksdale SK, Hallahan CW, Kerr GS, Fauci AS, Stern JB, Travis WD. Cutaneous pathology in Wegener's granulomatosis. A clinicopathologic study of75 biopsies in 46 patients. Am J Surg Pathol1995; 19(2): 161-72. De Souza FH, Radu Halpern AS, Valente Barbas CS, Shinjo SK. Wegener's granulomatosis: experience from a Brazilian tertiary center. Clin Rheumatol
2010; 29(8):855-60. 14. Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare: histopathology and direct immunofluorescence. Arch Dermatol 1977; 113:463. 15. Gunes P, Goktay F, Mansur AT, Koker F, Erfan G. Collagen-elastic tissue changes and vascular involvement in granuloma annulare: a review of 35 cases. J Cutan Pathol 2009; 36(8):838-44.
277
16. Ziemer M, Grabner T, Eisendle K, Baltaci M, ZeIger B. Granuloma annulare - a manifestation of infection with Borrelia? J Cutan Patho12008; 35:1050-57. 17. AI-Hoqail IA,AI-Ghamdi AM, Martinka M, Crawford RI. Actinic granuloma is a unique and distinct entity: a comparative study with granuloma annulare. Am J Dermatopathol2002; 24: 209-12. 18. Stefanaki K, Tsivitanidou-Kakourou T, Stefanaki C, et al. Histological and immunohistochemical study of granuloma annulare and subcutaneous granuloma annulare in children. J Cutan Pathol 2004; 34:392-6. 19. Bianchi L, Costanzo A, Campione E, Nistico S, Chimenti S. Superficial and nodular basal cell carcinomas trated with an immune response modifier: a report of seven patients. Clin Exp Dermatol 2003; 28:24-26. 20. Shapiro PE. Non-infectious granulomas. In Elder D, Elenitsas R, Jaworsky C, Johnson B Jr. eds. Lever's histopathology of the skin, 8th ed. Philadelphia, PA: Lippincott-Raven, 1997; 311. 21. Chiricozzi A, Zhang S, Dattola A, Gabellini M, Chimenti S, Nistico S. Role of Th17 in the pathogenesis of cutaneous inflammatory diseases J BioI Regul HomeostAgents 2012; 26(3):313-18. 22. Chiricozzi A, Zhang S, Dattola A, Cannizzaro M.V, Gabellini M, Chimenti S, Nistico S. New insights in the pathogenesis ofcutaneous autoimmune disorders. J BioI Regul Homeost Agents 2012; 26(2): 165-170. 23. Saraceno R, Nistico SP, Capriotti E, Chimenti S. Monochromatic excimer light 308 nm in monotherapy and combined with topical khellin 4% in the treatment of vitiligo: A controlled study. Dermatol Ther 2009; 22:391-94. 24. Saraceno R, Nistico SP, Capriotti E, de Felice C, Rhodes LE, Chimenti S. Monochromatic excimer light (308 nm) in the treatment of prurigo nodularis. Photodermatol Photoimmunol Photomed 2009; 24:43-45. 25. Nistico S, Chiricozzi A, Saraceno R, Schipani C, Chimenti S. Vitiligo treatment with monochromatic excimer light and tacrolimus: Results of an open randomized controlled study. Photomed Laser Surg 2012; 30:26-30. 26. Nistico SP, Saraceno R, Chiricozzi A, Giunta A, Di Stefani A, Zerbinati N. UVA-l Laser in the treatment of palmoplantar pustular psoriasis. Photomed Laser
278
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Surg 2013; 31:434-38. 27. Chiricozzi A, Pitocco R, Saraceno R, Nistico SP,
Giunta A, Chimenti S. New topical treatments for psoriasis. Exp Op Pharmacother 2014; 15(4):461-70.
Vol. 27, no. 2, 273-278 (2014)
LETTER TO THE EDITOR
GRANULOMA ANNULARIS REVEALING WEGENER'S GRANULOMATOSIS F. DEL PORTOI, M. PROIETTN, M. MUSCIANESP, F. TAMBURP, N. CIFANI4, L. FERRI!, S. NISTIC05, U. BOTTONP, G. BRUNO' and G. PRANTEDA2 I
U.0. C. Internal Medicine, Department ofMolecular and Clinical Medicine, Sant 'Andrea Hospital, Sapienza University ofRome, Italy; 'Unit ofDermatology, Sant 'Andrea Hospital, Sapienza University ofRome, Italy; 3 Unit ofDermatology, Complesso Integrato Columbus, Catholic University, Rome, Italy; "Department ofClinical Medicine, Faculty ofMedicine and Psychology, Sant 'Andrea Hospital, Sapienza University ofRome, Italy; 5Department ofHealth Sciences; University ofCatanzaro "Magna Grcecia", Catanzaro, Italy
Received January 25, 2014 - Accepted March, 2014 Skin manifestations are often associated with systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display pathognomonic dermatological features, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions. Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by E. coli. Skin manifestations are often associated to systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display dermatological features that are pathognomonic, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions (l, 2). Differential diagnosis among granulomatous diseases can be difficult, since they can present with similar or overlapping clinical features, thus auto-antibodies, such as antineutrophil cytoplasm antibodies (ANCA) are often helpful to make a definitive diagnosis (3, 4). Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by
Escherichia coli. Case report A 25-year-old man was admitted to our Department because of fever (38.5°C), cough and malaise which had initiated three months previously and was resistant to antibiotic therapy. On physical examination, he showed symmetrical and additive polyarthritis localized to the large joints of the lower limbs and to the large and small joints of the upper limbs, conjuntival redness, later identified as anterior uveitis, and a pulmonary abolition of the murmur at the right lower lobe. Skin examination detected small reddish nodules on the right elbow, where the skin was dry and scaly (Fig. 1). Laboratory tests showed normochromic normocytic anemia (haemogobin: 11.2 g/dL), increased C reactive protein (C-RP
Key words: Granuloma annularis, Wegener s granulomatosis, systemic autoimmune disease Mailing address: Prof. Steven Nistico, Associate Professor of Dermatology, University Magna Graecia, Catanzaro Viale Europa, Germaneto (Cl) 88100 Catanzaro, Italy Tel./Fax: +39 09613694001 e-mail: [email protected]
0394-6320 (2014) Copyright © by BIOLIFE. s.a.s. This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties
273
DISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.
274
F. DEL PORTO ET AL.
Table I. Clinical and histopathologic findings ofcutaneous lesions ofpatients with Wegener s granulomatosis.
Total patients
Daoud et al 1994
Frances et al 1994
Barksdale et al 1995
Comfere et al 2007
Carlos de souza 2010
30
35
46
17
39
14(47%)
26 (74%)
8 (16%)
12 (70%)
27 (70 %)
11 (22%)
1 (5%)
CLINICAL FEATURES Palpable purpora Pyoderma-like ulcer
8 (27%)
Papule
6 (20%)
5 (14%)
1 (5%)
Nodules
4 (13%)
6(17%)
10 (20%)
3 (17%)
Ulcerations
4 (13%)
6 (17%)
8 (16%)
5 (29%)
Maculae and erythema
2 (7%)
2 (4%)
Digital necrosis
1(2.8%)
Xanthoma
2 (5.7%)
Pustule
2 (5.7 %)
Livedo reticularis
1 (2.8%)
Bullae
3 (10%)
Petechiae
3 (10%)
12 (30%)
2 (4%)
2 (4%)
Violaceus plaques
1 (2%)
Abscess
1 (2%)
Cyst
1 (2%)
Annular urticarial lesios
1 (2%) 13 (33%)
Cutaneous vasculitis HISTOPATHOLOGIC FINDINGS Leukocytoclastic vasculitis
24 (80%)
Granulomatous inflammation
22 (63%)
23(31%)
12(70%)
5 (14%)
15 (19%)
2 (11%)
2 (2.7 %)
1(5%)
EN-like lesions:septal granulomatous panniculitis Palisaded extravascular necrotizing granuloma (Churg-Strauss like)
3 (10%)
2 (11%)
5 (14%)
nonspecific ulceration
3 (4%),
superficial dermal and epidermal necrosis without inflammation
2 (2.7%)
granuloma annulare
1 (1%)
chronic inflammation
23 (31%)
acute inflammatory lesions without vasculitis
7 (9%)
Mixed inflammatory pattern
5 (16%)
EN: erythema nodosum
13 mg/dl) and increased erytrocyte sedimentation rate (ESR 56 mm/h) values. Twenty-four-hour proteinuria was 3.2 g, thus nephrotic syndrome was diagnosed. Chest X-ray documented the presence of a parenchimal consolidation in the right lower lobe
and an enlargement of the right lung ilium, probably caused by lymphadenopathy. A total body computed tomography scan was performed which showed normal paranasal sinuses; presence of rare nodules not exceeding one centimetre in the lower lobes of
Int. J. ImmunopalhoI. Pharmacol.
Fig. 1. Multiple small reddish painless nodules on a slightly scaly skin on the right elbow.
Fig. 2. Granuloma anularis (EE stain 200x) characterized by minimal dermal necrobiosis with basophilic collagen bundles surrounded by palisading macrophages.
a
b Fig. 3. a) Interstitial necrotizing giant cellular granuloma centred on interlobular arterial wall of kidney tissue specimen (EE stain 200x). b) CD68 + macrophages (CD68 stain, 200x).
275
the chest, in the middle right lobe and in the apical segment of right upper lobe; presence of a round large parenchymal consolidation of about 3.5 em, with air bronchogram in the lateral segment of right lower lobe. Also, coexisting areas of ground-glass opacities predominantly in the upper lobes, nonconglomerate adenopathy, of an average diameter of 1.5 em, in the hilum bilaterally, in aorto-pulmonary window and in the right lower paratracheal space were shown. The pulmonary radiological finding directed the diagnosis towards a sarcoidosis with a concomitant pneumonia. To confirm the hypothesis ofsarcoidosis, a bronchoalveolar lavage (BAL) and a lung biopsy (LB) were carried out which were not diagnostic since BAL revealed an infection by Escherichia coli and LB displayed a "non specific granulomatous inflammation". At this point levofloxacin 500 mg/ die was started. Skin biopsy was consistent with the diagnosis of granuloma annulare (Fig. 2). During the hospitalization, a progressive increase of creatinine values up to 1.9 mg/dl occurred. An examination of the sediment was made, showing dysmorphic red blood cells with hyaline casts, therefore a renal biopsy was carried out which showed a pauci-immune necrotizing glomerulonephritis in the context of a systemic granulomatous vasculitis (Fig. 3). Auto-antibody screening revealed cANCA which were confirmed by EIA at the titre of 43.81 Vlml. Wegener's granulomatosis was diagnosed, therefore an immunosoppressive treatment combining high dose corticosteroids and cyclophosphamide was initiated (5). The patient was treated with prednisone 1 g per day for three consecutive days, followed by prednisolone at 50 mg daily and bolus intravenous of cyclophosphamide 1mg/Kg every two weeks for six months (6). The patient showed a dramatic response to treatment, achieving significant improvement. Systemic symptoms regressed and haemoglobin levels returned to a normal range. We witnessed a complete resolution of uveitis and arthritis as well as a progressive shrinkening of elbow skin lesions. Within the first month, elbow skin granuloma and skin scaliness had completely gone. Creatinine values returned to 0.9 mg/dl. Only proteinuria of about 1g/24 h remained, due to glomerular sclerosis already
F. DEL PORTO ET AL.
276
present at the time of diagnosis. Once remission was attained, treatment was changed to methotrexate (MTX) at 15 mg per week and prednisone at the maintained dose of 10 mg daily. After the first 18 months of treatment methotrexate was stopped and azatioprine 100 mg/die and hydroxychloroquine at the dose of 200 mg every day were subministered. No clinical flare-up or laboratory test reactivations were detected. cANCA persisted negative during the whole treatment. We have now reached 42 months of follow-up without signs of recurrence. DISCUSSION This case seems to be interesting since we describe a young man with Wegener's granulomatosis (WG), arising with atypical clinical manifestations. WG is an antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis with an incidence of 10/1.000.000 cases/year (3,4). It is a granulomatous inflammation involving the respiratory tract, and a necrotizing vasculitis affecting small to mediumsized vessels. Commonly WG targets kidneys, causing a rapidly progressive glomerulonephritis, leading to chronic renal failure. Positive cytoplasmic (c)-ANCA, directed against serine proteinase 3, are detectable in nearly 100% of patients with generalized WG (7). It is believed that ANCA play a role in the pathogenesis of the disease (8) and are useful for diagnosis and in evaluating treatment efficacy (9). Skin lesions, are generally uncommon in this disease, showing a prevalence of 14-30% of cases (8, 9). Dermatological manifestations usually appear concurrently with visceral involvement or after systemic signs and symptoms have developed, indicating the presence of an active systemic disease. In WG a wide spectrum of skin lesions may be encountered. Palpaple purpura represents the most common, however skin nodules, necrotizing ulcerations and necrotic papules have also been described (Table I), (10-13). Histological matching of such dermatological features in most of the cases is leukocytoclastic vasculitis, but also granulomatous inflammation and palisaded extravascular necrotizing granuloma (Table I) have been described. To the best of our knowledge, in the literature only one case of granuloma annulare (GA) has been reported in WG (14); the second case is here reported. First described
by T. Colcott Fox in 1985, GA is a common benign granulomatous dermatosis, affecting all age groups, clinically characterized by clusters of 1 to 2-mm dermal bumps (papules) that range in color from flesh-toned to erythematous, arranged in a circle or annular plaques (15). The etiopathogenesis of the disease has not been clearly defined. Some of the proposed pathogenic mechanisms include cellmediated immunity, leading to vasculitis and dermal degeneration (16) induced by external stimuli such as infection, insect bite, trauma and sun exposure (17, 18). AG occurs predominantly over the distal extremities, often near joints: hands, feet, wrists and ankles (19). Aside from the visible rash that may be slightly itchy, AG is usually painless. Most AG lesions regress spontaneously within 2 years, without leaving any atrophic scars. Sometimes, however, the rings can remain for many years. Histological examination reveals different patterns, however collagen fiber degeneration and dermal mucin deposition associated with palisaded granulomatous inflammation are the most frequently reported (20-22). Its pattern differs from the most common dermatoses (23-27). The case here presented seems to be of interest since AG has been described in a patient with WG, probably representing a rare dermatological manifestation ofthis disease. Skin lesions completely regressed with treatment ofWG and never presented after remission was attained, suggesting that dermatological features can be considered as marker of disease activity. REFERENCES I.
2.
3.
Reddy RR, Shashi Kumar BM, Harish MR. Cutaneous sarcoidosis - a great masquerader: a report of three interesting cases. Indian J Dermatol2011; 56(5):68-72. Daoud MS, Gibson LE, DeRemee RA, Specks U, el-Azhary RA, Su WP. Cutaneous Wegener's granulomatosis: clinical, histopathologic, and immunopathologic features of thirty patients. J Am Acad Dermatol1994; 31(4):605-12. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187-92.
Int. J. Immunopathol. Pharmacol.
4.
5.
6.
7. 8. 9.
10.
11.
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