Unrecognized cicatricial pemphigoid with oral manifestations and ocular complications. A case report

Cicatricial pemphigoid is an autoimmune bullous disease characterized by mucous membrane fibrosis with resulting scarring, predominantly in the conjunctival and oral mucosa, which rarely involves skin changes. The majority of patients present with painful erosions or desquamative scarring gingivitis, resulting in eating and drinking disorders. Typical ocular lesions include chronic scarring conjunctivitis with progressive subconjunctival fibrosis, fornix foreshortening and synechia formation between the bulbar and palpebral conjunctiva, occasionally resulting in blindness. A 69-year-old woman was admitted to our Department for intense pain and severe burning sensation in the oral cavity, induced by several erosions and solitary blisters, lasting for 3 years. She was also diagnosed with the right eye symblepharon, lid entropion, trichiasis, leukoma and blindness of the right eye. The diagnosis of cicatricial pemphigoid was based on clinical picture and histopathology combined with immunofluorescence methods, with therapy initiated thereupon. Systemic corticosteroid (methylprednisolone) therapy in combination with azathioprine proved successful in the treatment of oral lesions as well as for stabilization of ocular lesions. Unfortunately, the patient was diagnosed in the advanced stage when scarring had already occurred. Prompt recognition of cicatricial pemphigoid and close patient monitoring are an imperative for the future prognosis of the disease.     

Ocular mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is a systemic disease affecting the mucosal surfaces of the eyes, nose, mouth, upper respiratory, and gastrointestinal tracts. Ocular MMP causes inflammation and scarring of the conjunctival surface of the eye that can lead to blindness if not properly treated. Oral corticosteroids, dapsone, and immunosuppressive agents are used to treat ocular MMP with variable success. The most potent and successful treatment for ocular MMP has been daily oral cyclophosphamide, typically in combination with a limited course of oral prednisone. This regimen has been shown to be effective in controlling the ocular inflammation associated with the disease and halting the progression of scarring of the conjunctiva, the major source of ocular morbidity in this disease. Long-term, drug-free remissions have been reported after 12–24 months of this therapy. This article describes treatment modalities for ocular MMP, efficacies, and drug-related side effects associated with treatment, and provides recommendations for follow-up and monitoring of patients with ocular disease.     

Sarcoidosis in a patient with linear IgA disease

We report a patient with four conditions in association with linear IgA disease (LAD), only three of which have been reported previously; these latter are ulcerative colitis, autoimmune thyroid disease and carcinoma of the colon, although the carcinoma may have been caused by the ulcerative colitis in this case. Recently, our patient also presented with respiratory symptoms and was found to have sarcoidosis as well, a previously unreported association of this autoimmune bullous disorder. The aetiology of this development may be related to the patient's HLA status or possibly to his treatment with the immunosuppressive agent cyclophosphamide; it is also possible that it is coincidental.     

Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review

We report two patients with subepidermal autoimmune blistering diseases and inflammatory bowel disease (IBD) [one with linear IgA disease (LAD) and ulcerative colitis (UC), and the other with mucous membrane pemphigoid (MMP) and Crohn disease (CD)], and present a review of all previously reported cases. We reviewed the literature, and found 48 cases of patients with autoimmune blistering diseases and IBD. The blistering diseases were LAD (25 patients), bullous pemphigoid (BP) (21), MMP (1) and pemphigoid gestationis (1), while the IBD types comprised UC (40) and CD (8). We describe the clinical and immunopathological features and demographic characteristics of the patients. In all but one case, the diagnosis of IBD predated the development of the skin condition. The association was more common with LAD than BP. The immunopathogenesis of IBD and autoimmune blistering diseases is discussed and a link between them hypothesized, namely, that the presentation of multiple antigens to the immune system during the unregulated inflammation in the bowel wall results in excitation of the immune system and recognition of autologous antigens.     

Desquamative gingivitis and balanitis — linear IgA disease or cicatricial pemphigoid?

A 38-year-old man presented with gingival inflammation together with erosions of the penis. Direct immunofluorescence demonstrated linear deposits of IgA at the basement membrane zone; indirect immunofluorescence and immunoblotting were negative. Linear IgA disease (LAD) was therefore suspected and treatment with dapsone initiated but this was changed to sulfamethoxypyridazine and systemic corticosteroids because of methaemoglobinaemia. During 1-year follow-up the lesions continued to wax and wane although they were never as extensive as before. Eighteen months after disease onset there was scarring of the penis together with suspected fibrosis of the inflamed gingival region. In addition the patient was HLA DQ7(3) positive, a haplotype thought to be increased in patients with cicatricial pemphigoid (CP); LAD with scarring or CP with solely linear IgA deposits are possible diagnoses of his condition.     

Linear IgA bullous dermatosis associated with ulcerative colitis: A case report and literature review

We report the case of a 59-year-old Japanese woman who developed linear IgA bullous dermatosis during treatment for ulcerative colitis that manifested as pruritic vesicles with erythema on the trunk and scalp. Histopathological examination revealed subepidermal bulla with neutrophil and eosinophil infiltration in the upper dermis. Direct immunofluorescence revealed linear IgA deposits at the basement membrane zone, and indirect immunofluorescence using split skin revealed IgA reaction to the epidermal side (lamina lucida type). We reviewed 33 reported cases of linear IgA bullous dermatosis associated with ulcerative colitis and found that ulcerative colitis preceded the onset of linear IgA bullous dermatosis in 94% of the patients and that IgA-positive patients in split skin indirect immunofluorescence all showed the lamina lucida type, indicating that target antigens for serum IgA antibodies may reside in the lamina lucida. Regarding the pathogenetic association of ulcerative colitis and linear IgA bullous dermatosis, intestinal inflammation may induce the exposure and presentation of intestinal antigens that are cross-reactive to cutaneous antigens, stimulating autoimmune response to antigens of cutaneous basement membrane zones.     

Linear IgA disease associated with lymphocytic colitis

A 66-year-old woman presented with a bullous skin eruption and chronic diarrhoea. Lesional skin showed subepidermal blistering, and direct immunofluorescence of perilesional skin revealed linear deposits of IgA at the dermoepidermal junction, establishing a diagnosis of linear IgA disease (LAD). Chronic watery diarrhoea complicated by substantial loss of body weight preceded the skin eruption for several months. On endoscopy, the colon appeared macroscopically normal. On histology, the colon mucosa showed increased numbers of intraepithelial lymphocytes and infiltrates of mononuclear cells in the lamina propria, indicative of lymphocytic colitis. Treatment with methylprednisolone and dapsone led to complete clearing of the bullous skin eruption and marked improvement of the patient's diarrhoea. Gastrointestinal disorders such as lymphocytic colitis have rarely been reported in patients with LAD. Whether the simultaneous occurrence of these two diseases is coincidental or due to related pathogenetic mechanisms remains to be seen.     

Linear IgA disease associated with ulcerative colitis: the role of surgery

The association of linear IgA disease (LAD) with ulcerative colitis (UC) is well documented. One hypothesis for the association proposes immune exposure to autoantigens present in the colon, and subsequent targeting of these autoantigens in the skin. There are variable reports on the effect of bowel surgery on skin disease in such patients. We report a patient with LAD and UC who required colectomy to control her UC, but whose skin disease failed to resolve following surgery. A literature review revealed that in reported cases of this association, proctocolectomy has resulted in remission of skin disease in all cases where it has been performed, in contrast to variable results seen in cases where colectomy alone was performed.     

Psoriasis associated with ulcerative colitis and Crohn's disease

Background  Numerous reports have demonstrated the epidemiological, pathogenic, and genetic association between psoriasis and Crohn's disease. Nevertheless, the association between psoriasis and ulcerative colitis was rarely described.
Objective  This study aims to investigate the association between psoriasis and inflammatory bowel disease.
Study design  Case-control study.
Setting  The study was performed utilizing the large medical dataset of Clalit Health Services.
Methods  Psoriasis patients were compared to controls regarding the prevalence of inflammatory bowel disease in a case–control study using logistic multivariate models.
Results  The study included 12 502 psoriasis patients aged 20 years and above and 24 287 age- and sex-matched controls. The prevalence of both Crohn's disease and ulcerative colitis was significantly higher in psoriasis patients compared with the control group. In multivariate analyses, psoriasis was associated with Crohn's disease [odds ratio (OR), 2.49; 95% confidence interval (95% CI), 1.71–3.62] as well as ulcerative colitis (OR, 1.64; 95% CI, 1.15–2.33). This association was independent of anti-tumour necrosis factor-α therapy.
Conclusion  Psoriasis is associated both with Crohn's disease and ulcerative colitis. Future studies on comorbidities in patients with psoriasis should focus on ulcerative colitis.

Conflicts of interest

None declared.     

Linear IgA Dermatosis associated with ulcerative colitis: complete and sustained remission after total colectomy

Linear IgA dermatosis has been increasingly associated with inflammatory bowel diseases, particularly ulcerative colitis. A 13-year-old male patient with an 11-month history of ulcerative colitis developed vesicles, pustules and erosions on the skin of the face, trunk and buttocks and in the oral mucosa. The work-up revealed a neutrophil-rich sub-epidermal bullous disease and linear deposition of IgA along the dermoepidermal junction, establishing the diagnosis of linear IgA dermatosis. The patient experienced unsatisfactory partial control of skin and intestinal symptoms despite the use of adalimumab, mesalazine, prednisone and dapsone for some months. After total colectomy, he presented complete remission of skin lesions, with no need of medications during two years of follow-up. A review of previously reported cases of the association is provided here and the role of ulcerative colitis in triggering linear IgA dermatosis is discussed.     

Pyoderma gangrenosum involving the head and neck

In six patients with pyoderma gangrenosum, the head and neck region was a major site of ulcerative skin disease. In two patients, the disease was limited to this anatomic site. Corticosteroids were effective therapy in five cases. In one case, occurring in association with ulcerative colitis, total proctocolectomy was required to control ulcerative scalp disease. Detailed histologic examination of a primary lesion in one case with 0.5-micron sections demonstrated morphologic evidence of mast cell activation, suggesting that mast cells may contribute to the pathogenesis of the inflammatory process in pyoderma gangrenosum.     

Pulse methylprednisolone therapy for threatening periocular haemangiomas of infancy

Periocular haemangiomas of infancy can cause severe and rapid ocular damage. Oral corticosteroids remain the front-line treatment to minimize the consequences of these haemangiomas. The aim of this report is to summarize our experience with pulse intravenous methylprednisolone as an alternative therapy for periocular haemangioma when visual prognosis is engaged. Fifteen infants, who presented periocular haemangioma with functional impact on vision, received 2 mg/kg methylprednisolone intravenously twice a day for 2 days. Following pulse therapy, 2 mg/kg/day prednisolone was given orally with gradual tapering. No further visual impact was noticed following pulse therapy. Two patients relapsed, needing new pulses or, in one case, vincristine. No serious side-effects were recorded. Pulse methylprednisolone therapy permitted a particularly rapid shrinkage of haemangiomas and a complete disappearance of their visual impact within 2 days. Apparently more rapid than the usual oral corticosteroids, pulse intravenous methylprednisolone decreases the risk of ocular complications, which correlates with the duration of the influence of haemangiomas.     

Pyoderma gangrenosum associated with ulcerative colitis and subcutaneous and splenic abscesses

Pyoderma gangrenosum is a rare, chronic, inflammatory ulcerative skin disease of unknown etiology and pathogenesis. It is often associated with systemic disease. We describe a patient with pyoderma gangrenosum associated with ulcerative colitis and aseptic abscesses of the subcutis and spleen, which have been rarely reported previously. These manifestations were cleared by combined therapy with minocycline hydrochloride and diaphenylsulfone.     

Psoriasis and inflammatory bowel diseases

Psoriasis and inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are among the immune-mediated inflammatory diseases. This group includes approximately 80 disorders, some of which can at times be associated in a single patient. In psoriasis, Crohn's disease may be observed slightly more frequently, but ulcerative colitis and celiac disease are also an issue. The underlying relations between these disorders comprise: i) genetic data obtained by genome-wide association studies that show the involvement of shared predisposing loci and/or genes, for example, in innate immunity; ii) immunological data: these disorders share inflammation effector mechanisms, particularly the activation pathway of Th17 lymphocytes, which explains the efficacy of anti-TNF antibodies and anti-IL-12/23; and iii) environmental co-factors such as smoking, possibly certain food proteins (gliadin, etc.), and bacterial infections that are probably decisive elements in the genesis of these diseases.     

Delay in diagnosis: trauma- and coinfection-related cutaneous leishmaniasis because of Leishmania guyanensis infection

Trauma can trigger the onset of some lesions of cutaneous leishmaniasis (CL). In this study, we present the case of a 65-year-old man who developed persistent, ulcerative, nodular lymphangiitis at the site of elbow abrasions from a fall during a trip to northeastern Brazil. Skin and lymph node biopsy showed tuberculoid granulomatous inflammation and Grocott-methamine silver-positive yeast forms consistent with Sporothrix and Staphylococcus lugdunensis was identified from tissue culture. Antibacterial and antifungal treatment produced short-term healing. Crusted papules recurred at the sites of injury 3 months later and persisted despite therapy. After 15 months, two punch biopsies showed scarring and granulomatous inflammation; cultures and histochemical stains were negative for microorganisms. Because of refractory disease, multiple polymerase chain reaction (PCR) assays for infectious agents on DNA extracted from the biopsy specimens were performed, and Leishmania guyanensis was detected in all specimens. The patient refused pentavalent antimonial therapy and elected for excision of the CL lesions. After 2 years of follow up, he is without disease. CL should be considered in the differential diagnosis in patients who present with ulcerative, nodular lymphangiitis; have a history of travel to endemic regions; and describe a traumatic insult to the affected region. PCR methods for infectious agents increase the sensitivity and specificity of detecting causative agents in these patients who are negative by routine methods. In some, leishmaniasis may be an occult infection whose presence is heralded by trauma. Coinfection, by altering the immune response, may have facilitated the clinical acquisition of CL.     

Further evidence for an association between psoriasis, Crohn's disease and ulcerative colitis

To test the hypothesis that psoriasis is associated with Crohn's disease and ulcerative colitis, 204 patients with inflammatory bowel disease (116 with Crohn's disease and 88 with ulcerative colitis) and 204 age and sex matched controls were interviewed and examined. The prevalence of psoriasis in Crohn's disease (11.2%) and in ulcerative colitis (5.7%), was significantly greater than in the control group (1.5%). The prevalence of psoriasis in first degree relatives of patients with inflammatory bowel disease was also increased. It is suggested that there is a relationship between psoriasis, ankylosing spondylitis, sacroiliitis, peripheral arthropathy and inflammatory bowel disease, which may be explained by common genetic factors.     

Linear IgA disease and ulcerative colitis

Seventy adult patients with linear IgA disease were studied. Five (7.1%) also suffered from ulcerative colitis (the prevalence of ulcerative colitis in the U.K. is 0.05%). A further three patients with this association, from other British centres were also reviewed. In all cases, ulcerative colitis preceded the onset of skin disease, by a median of 6.5 years. The reason for this association remains unclear but the abnormalities in colonic mucosal B cells and mucosal IgA₁ production reported in patients with ulcerative colitis may be important in the subsequent development of IgA₁ mediated linear IgA disease.     

Cutaneous Hodgkin-type lymphoproliferative lesion associated with immunomodulatory therapy for ulcerative colitis

Immunomodulatory drugs have demonstrated efficacy in the therapy against autoimmune diseases such as rheumatoid arthritis, Crohn's disease or ulcerative colitis. Tumor necrosis factor-α (TNF-α) represents a target molecule for the treatment of these entities. Use of monoclonal antibodies can block the proinflammatory function of TNF-α. It has been shown that this action can reactivate quiescent chronic diseases as well as modify the immune response or potentiate carcinogens, thereby increasing the risk of secondary tumor development. In this context, different types of solid or hematological tumors have been documented. We present the case of a male with chronic ulcerative colitis who secondarily developed a cutaneous Hodgkin-type lymphoproliferative lesion associated with immunodeficiency. This secondary tumor developed after 6 months of treatment with anti-TNF-α.     

Cicatricial pemphigoid vegetans

A 58-year-old woman with ulcerative colitis of 5 years' duration was first seen in March 2002 with a 5-month history of widespread erosions on the palate and gingiva, subtle scarring of the conjunctiva, and xerostomia accompanying a flare of ulcerative colitis. No skin lesions were observed. Direct immunofluorescence study performed on the oral mucosa showed a linear distribution of immunoglobulin G (IgG) and immunoglobulin A (IgA) at the dermal-epidermal junction. Indirect immunofluorescence demonstrated the presence of circulating IgG anti-basement membrane zone antibody. This patient was successfully treated with sulfasalazine 3 g/day. Two years later, however, she developed extensive, well-defined pustules and vegetating erosions on the skin, symmetrically localized in the inguinal and axillary folds and on the upper inner thighs (Fig. 1). At that time, mucous membrane involvement, except for subtle scarring conjunctivitis, was not observed. Laboratory findings were normal, except for colonoscopy, which disclosed cobblestoning and histologically well-circumscribed granulomas, confirming the diagnosis of ulcerative colitis. On the basis of the clinical features and the flare of coexistent ulcerative colitis, this patient was suspected of having pyoderma gangrenosum. Skin biopsy specimens showed acanthosis, papillomatosis, pseudo-carcinomatous hyperplasia, and subepidermal blisters overlying an infiltrate of leukocytes and eosinophils, which also extended into the lower epidermis (Fig. 2). Direct immunofluorescence of the perilesional skin demonstrated a linear distribution of IgG and IgA at the dermal-epidermal junction. In vivo-bound IgG within the basement membrane zone was documented using laser scanning confocal microscopy, which disclosed the presence of immunoglobulins above collagen type IV and below laminin-5 (Fig. 3). Indirect immunofluorescence study showed the presence of circulating IgG anti-basement membrane zone antibody reacting with the roof and floor of salt-split skin. Characterization of the target antigen (courtesy of Professor Hashimoto of Kurume University, Kurume, Japan) was unsuccessful, as Western immunoblot study on both epidermal and dermal extracts was negative, as was immunoblot with purified laminin-5 and enzyme-linked immunosorbent assay with the NC16a epitope of BP180. Laser scanning confocal microscopy confirmed the diagnosis of cicatricial pemphigoid. Therapy consisting of prednisone 40 mg each morning and sulfasalazine 1.0 g three times daily led to rapid improvement of the skin lesions, but did not affect the conjunctival lesions. After 4 weeks, prednisone was tapered and sulfasalazine was continued at a reduced dose of 0.5 g three times daily. At that time, only post-inflammatory hyperpigmentation and atrophic scars were evident.