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Early lesion of palisaded neutrophilic granulomatous dermatitis in ulcerative colitis

European Journal of Dermatology. Volume 17, Number 3, 234-7, May-June 2007, Clinical report

DOI : 10.1684/ejd.2007.0156

Summary

Author(s) : Akihiko Asahina, Hideki Fujita, Yuki Fukunaga, Yasuko Kenmochi, Tatsuo Ikenaka, Hiroyuki Mitomi , Department of Dermatology, Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan, Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan, Department of Internal Medicine, Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan, Department of Pathology, Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan.

Summary : Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare clinical entity of unknown cause. It often coexists with various autoimmune or immunoreactive systemic diseases, and thus it has been reported under multiple names. We describe a patient with quiescent ulcerative colitis, who presented with recurrent small tender papules, nodules and erythematous plaques, located mainly on her hands, together with finger swelling and polyarthralgia. The histopathologic picture indicated an early stage of PNGD with focal degeneration of collagen fibers but without distinct granuloma formation. The differentiation from neutrophilic dermatoses was necessary because of dense and diffuse infiltration of neutrophils with leukocytoclastic debris throughout the dermis, and the association of ulcerative colitis. Dapsone monotherapy was effective in improving the clinical symptoms. PNGD is only rarely associated with ulcerative colitis, and this case suggests that the concept of PNGD, especially in its early stages, might be considered in the wide spectrum of neutrophilic dermatoses.

Keywords : dapsone, interstitial granulomatous dermatitis, neutrophilic dermatosis, palisaded neutrophilic granulomatous dermatitis, ulcerative colitis

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ARTICLE

Auteur(s) : Akihiko Asahina¹, Hideki Fujita¹, Yuki Fukunaga², Yasuko Kenmochi², Tatsuo Ikenaka³, Hiroyuki Mitomi⁴

¹Department of Dermatology, Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan
²Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
³Department of Internal Medicine, Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan
⁴Department of Pathology, Sagamihara National Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan

accepté le 6 Decembre 2006

Palisaded neutrophilic granulomatous dermatitis (PNGD) is an unusual clinical entity of unknown cause, and it has been so far reported under multiple names, such as Churg-Strauss granuloma, Winkelmann granuloma, cutaneous extravascular necrotizing granuloma, and so on [1-3]. We herein report a woman with ulcerative colitis (UC), who suffered from recurrent tender small papules, nodules and erythematous plaques located mainly on her hands. Both the clinical and histopathological pictures were compatible with the diagnosis of an early stage of PNGD with indistinct granuloma formation. Of note, dense and diffuse infiltration of neutrophils with leukocytoclastic debris in the dermis suggested the necessity of differentiation from neutrophilic dermatoses (ND). Unlike ND, only a single case of PNGD has been described previously and only briefly in a patient with UC [3].

Case report

A 32-year-old woman was diagnosed as having UC at the age of 13, with no medication for the last 15 years because of inconspicuous symptoms. In December 2004, she visited our department because of recurrent multiple tender papules, nodules and infiltrated small erythematous plaques, which she had noticed for the previous 9 months and which were located mainly on her hands but also on her arms and feet. Typically, the eruptions disappeared spontaneously within a week, but new lesions appeared intermittently. On examination, most of the lesions were small in size, measuring approximately 5-10 mm in diameter, and they were present around her fingers and on the dorsal aspects of her metacarpophalangeal (MP) and proximal interphalangeal (PIP) joints (figure 1). An indurated papule was also present on her left big toe. No vesicles or pustules were observed. She had migratory polyarthralgia involving her hands and knees, with slight swelling of her fingers and morning stiffness. She complained of diffuse myalgia and occasional fatigue with a slight fever of 37-37.5 ^oC. She had no lymphadenopathy. Laboratory examinations showed slight iron-deficiency anemia (hemoglobin 10.7 g/dL, Fe 21 μg/dL, TIBC 379 μg/dL) and also eosinophilia (1194/μL) that might be caused by cedar pollinosis (Total IgE 614 IU/mL, IgE RAST for cedar pollen >100 Ua/mL), but no signs of inflammation with normal levels of CRP and ESR. Her immunoglobulin profile for IgM, G, and A was normal. Rheumatoid factor, as well as anti-nuclear antibody (ANA), was not detected.

A skin biopsy specimen was taken from the indurated reddish papule which had appeared a few days earlier on the dorsal aspect of her right MP joint. Histopathologically, the epidermis showed no apparent changes by hematoxylin and eosin stain, and there was no edema formation in the dermis. There was a dense infiltrate of inflammatory cells, especially neutrophils with leukocytoclastic debris, throughout the entire dermis, not only around dermal capillaries but also among collagen fibers (figure 2A). Focal degeneration of collagen was also observed as amorphous basophilic materials (figures 2A and B). The inflammatory infiltrate was intermingled with some histiocytes, lymphocytes and eosinophils. The capillaries showed some edema and perivascular inflammation with neutrophils, but there was neither extravasation of erythrocytes nor fibrinoid degeneration indicative of vasculitis (figure 2B). Immunohistochemical staining with CD68/PGM1 revealed the presence of many histiocytes dispersed throughout the dermis, although neither obvious palisading arrangement nor granulomatous reaction was observed (figure 3). CD8+ lymphocytes were found in small numbers mainly around capillaries in the upper dermis, but there was almost no infiltration of CD4+ lymphocytes (not shown).

We therefore made the diagnosis of an early stage of PNGD. X-ray films and MRI images of the hands showed sinovitis but with no bone erosion. Endoscopic analysis including biopsy confirmed mild proctitis related to UC. She had initially taken oral NSAIDs for 7 months without success. Topical application of the strongest class steroid ointment for 2 weeks also had no effect. Following the biopsy, she started oral potassium iodide at 900 mg/day, but it was ineffective and was discontinued after two weeks. She then started taking oral dapsone (DDS) at 75 mg/day. A rapid and remarkable improvement of the arthralgia and eruptions was observed within a few days, and new eruptions stopped emerging. This drug was finally tapered off according to the loss of any symptoms after 6 months, and she now requires occasional use of dapsone only infrequently when the symptoms recur.

Discussion

This case was diagnosed as an early stage of PNGD based on clinical and histopathological findings. However, clear differentiation from ND was difficult because of dense and diffuse neutrophil infiltration in the dermis without distinct granuloma formation, and also because of an association with UC.

Indeed, ND have a significant link to disorders of the internal organs, including inflammatory bowel diseases (IBD). Pyoderma gangrenosum (PG) [4, 5], Sweet’s syndrome [5] and neutrophilic dermatosis of the dorsal hands (NDDH) [6] occur in UC patients. Importantly, some eruptions show overlaps or indistinct features which cannot be categorized as one of the typical disorders of ND [7]. Pustular or vesiculopustular eruptions may be described as atypical Sweet’s syndrome, a variant of PG, or simply as pustular eruptions of UC or neutrophilic pustulosis [8]. Although they sometimes show leukocytoclastic vasculitis and are called pustular vasculitis, this vascular reaction is also observed in other ND and is presumably secondary to noxious products released from neutrophils, giving rise to the description of a neutrophilic vascular reaction rather than a primary process [9]. In addition, acute generalized exanthematous pustulosis, subcutaneous abscesses or pyoderma vegetans, all of which are also reported to be associated with UC, should be classified in the spectrum of ND [10]. In our case, the observed eruptions were different from any of them.

Our case also required differentiation from bowel-associated dermatosis-arthritis syndrome, characterized by arthritis, skin eruption and flu-like episodes, and which is rarely associated with IBD, such as UC [4, 11]. Bacterial overgrowth and deposition of circulating immune complexes may be implicated in its pathogenesis, but definitive evidence is lacking. The skin eruptions are macular at first, but soon become papulovesicular and then pustular [11]. Its distinction from certain ND, such as pustular eruptions of UC, may be difficult or even impossible [4, 12]. Our case did not seem to fit with bowel-associated dermatosis-arthritis syndrome, with regard to the rather limited distribution of the eruptions and no apparent pustules.

The etiology of PNGD is not known. The multiple names previously given to this disorder have led to confusion and have hampered efforts at further clinical study [2]. PNGD was initially described as a manifestation of patients with Churg-Strauss syndrome, and it was subsequently found to coexist with various autoimmune or immunoreactive systemic diseases, including lupus erythematosus, Wegener’s granulomatosis, rheumatoid arthritis (RA), Behcet’s disease and lymphoproliferative diseases [1-3, 13-16]. To our knowledge, there has been only one case of PNGD described in association with IBD, and the patient had chronic UC [3]. PNGD shows peculiar patterns of multiple and symmetrical firm nodules or papules of variable sizes colored from skin-colored to erythematous or violaceous, with or without central ulceration and crusting [2, 13, 14]. Some patients have tender lesions, as was observed in our patient. Early lesions may also appear as urticaria-like plaques or asymptomatic nonspecific eruptions [15]. The distribution of lesions was described as mainly on the distal upper extremities and fingers or elbows, and also, rarely, on the toes, thighs, trunk, or buttocks [2, 3, 13-15]. The histopathological findings are also quite variable, probably depending on the developmental stage. Although fully developed lesions show palisaded granulomas surrounding leukocytoclastic debris and altered collagen, early histopathological features are of diffuse, pandermal infiltration comprising mostly neutrophils, leukocytoclastic debris and amorphous basophilic materials as a result of focal degeneration of collagen fibers [1, 2, 13], as was observed in our case.

Immune complexes may be implicated in its pathogenesis [3] and leukocytoclastic vasculitis may be found, especially in early lesions [1]; however, the presence of distinct vasculitis is not mandatory to the diagnosis of PNGD [2]. Importantly, immunohistochemical staining revealed a high number of CD68/PGM1-positive histiocytes intermingled with neutrophils. Unlike PNGD, skin lesions of ND do not show marked infiltration of histiocytes unless they are in the late stage [17]. Moreover, the predominance of CD8+ T cells instead of CD4+ T cells in the infiltrate was consistent with another investigation [13].

The presence of polyarthralgia may be related to UC, but the activity of UC was unexpectedly low in our case. In this sense, the concept of interstitial granulomatous dermatitis with arthritis (IGDA) needs mentioning, which is typically associated with seronegative polyarthritis and myalgia [18-21]. The cord-like skin lesions were originally considered pathognomonic for IGDA, but some patients may have plaques and even papules that may be located on the dorsum of the hands [19] and fingers [20]. IGDA is often associated with autoimmune diseases, such as RA and systemic lupus erythematosus [18]. The histopathologic picture includes a few areas of degenerating collagen and is virtually identical to those observed in PNGD, except that IGDA consistently lacks leukocytoclastic vasculitis and usually has less infiltration of neutrophils [19]. Therefore, many authors have now come to regard IGDA in the same spectrum as PNGD [1, 14]. Although an early lesion of IGDA has not been well described with the histopathologic picture, the presence of polyarthralgia and myalgia in our case is in agreement with this view.

Finally, the concept of rheumatoid neutrophilic dermatitis (RND) merits description. RND is an uncommon manifestation of RA, and its lesions are symmetric, erythematous to yellow-colored papules, plaques, nodules, and urticarial lesions over the joints, extensor surfaces of the extremities, and trunk [22-24]. Mild pruritus and slight tenderness have been reported in some cases. Their occurrence in seronegative RA patients are reported [22, 23]. While RND may eventually evolve into rheumatoid nodules [22], RND is histopathologically similar to ND or Sweet’s syndrome, and therefore the entity of RND may merely be part of a spectrum of ND or neutrophilic vascular reaction [23, 24]. On the other hand, some but not all reported cases of RND may overlap with the concept of PNGD [2, 15], and they are then identical to rheumatoid papules [2, 16]. Therefore, an alternative interpretation is that our case represented RND occurring in seronegative RA with the concomitant association of UC.

Regarding the treatment, our initial attempt to use potassium iodide, which is sometimes effective in ND, was not successful. In contrast, dapsone yielded rapid and remarkable resolution of both the skin manifestations and arthralgia. Improvement of PNGD has been reported with topical corticosteroids or prednisone, but dapsone is also sometimes effective for PNGD [14, 16], in addition to Sweet’s syndrome, PG, NDDH and RND. This agent is also effective for the treatment of RA.

In conclusion, this report illustrated a rare case of an early stage of PNGD associated with quiescent UC. It was challenging to clearly differentiate the skin eruptions from ND because of histopathological similarities and a good response to dapsone. This case suggested that PNGD might be considered in the wide spectrum of ND, especially in its early stages. More reports of such cases should aid understanding of this rare condition.

Acknowledgements

Financial support: none: conflict of interest: none

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