Symmetrical Skin Lesions on the Gluteal Region in a Patient with Anti-Laminin-332 Mucous Membrane Pemphigoid.

Mucous membrane pemphigoid (MMP), previously called cicatricial pemphigoid, is a rare subepidermal immunobullous disorder that primarily affects the mucous membranes (1,2). MMP is divided into two major subtypes, anti-BP180-type MMP and anti-laminin-332 (previously called laminin 5 or epiligrin) MMP. Anti-laminin-332 MMP is known to be associated with malignant tumors (3), which may cause overexpression of autoantibodies and induce autoimmunity to laminin-332 (4). MMP primarily affects the mucous membranes, and widespread skin lesions are rare. In MMP, circumscribed skin lesions have been previously reported as occurring on the head, neck, and upper trunk (5). We report a case of anti-laminin-332 MMP presenting with symmetrical skin lesions characteristic of MMP on the weight-bearing areas of the gluteal region. A 66-year-old Japanese man presented with a month-long history of multiple erosions and blisters on the mucous membranes and skin, with conjunctival hyperemia, nasal obstruction, oral pain, and hoarseness of voice. Three days before the first visit, he was diagnosed with gastric cancer with liver metastasis by gastrointestinal endoscopy and abdominal ultrasound examination for tarry stool. Physical examination demonstrated erosions and tense bullae on the conjunctivae, tongue, and lips (Figure 1, a,b), as well as erosive erythematous skin lesions on the nape, right index finger, both legs, and symmetric lesions on the gluteal region (Figure 1, c). His body weight was 86 kg. Laboratory examinations showed slight liver dysfunction and elevation of C-reactive protein levels. Histopathologic examination of the skin lesions demonstrated subepidermal blisters with lymphocytic and eosinophilic infiltrates (Figure 1, d,e). Direct immunofluorescence (IF) revealed linear deposits of IgG and C3, but not IgA, along the basement membrane zone (BMZ) (Figure 1, f,g). An IgG subclass study showed IgG1 and IgG4 deposits. Indirect IF on normal human skin revealed weak positivity for IgA anti-keratinocyte cell surface antibodies and IgG anti-BMZ antibodies, which were bound to the dermal side of 1 mol/L NaCl-split skin (Figure 1, h). IgG immunoblot analyses of both normal human epidermal and dermal extracts showed negative results (including BP230, BP180, 290 kDa type VII collagen, and 200 kDa laminin-γ1). Immunoprecipitation using radio-labeled cultured keratinocyte lysate demonstrated positive reactivity with laminin-332 (Figure 1, i). We established the diagnosis of anti-laminin-332 MMP. We started treatment with oral minocycline (200 mg/day) and niacinamide (900 mg/day) with topical corticosteroids without any effect after 2 weeks of therapy. Administration of oral prednisolone (40 mg/day) with topical corticosteroids and alprostadil ointment on the skin lesions, as well as beclometasone dipropionate powder on the oral lesions resulted in significant improvement of mucocutaneous lesions within 10 days. Although the gastric cancer and liver metastasis initially responded to chemotherapy with fluorouracil and cisplatin, the patient succumbed to multiple organ failure 9 months after the initial visit. Anti-laminin-332 antibodies were originally detected by immunoprecipitation, as in our case. Immunoblotting of purified human laminin-332 have been subsequently developed, which detects the 165/145 kDa α3, 140 kDa ß3, and 105 kDa γ2 subunits of laminin-332 in various patterns (6). Today, the ELISA system uses laminin-332 preparations as adjunct diagnostic tools in MMP (7). Occasionally, a wide spectrum of autoantibodies is detected in MMP, for example, MMP with IgG antibodies to both BP180 and laminin-332, which were considered to be developed via epitope spreading. Detection of circulating IgA autoantibodies against the skin have also been reported in MMP (8). However, the pathogenic significance and mechanisms of coexistence of IgG anti-laminin-332 antibodies and IgA anti-keratinocyte cell surface antibodies found in our case are currently unknown. It is generally considered that IgG1 antibodies activate complements and are pathogenic in MMP, while IgG4 antibodies behave as blocking antibodies and are protective. In our case, direct IF revealed IgG1 and IgG4 deposits; the same was reported in a previous case report (9). The pathogenic roles of autoantibodies with different IgG subclasses need to be analyzed in further studies. Conjunctival mucosal lesions in MMP may occur by rubbing of the eyes due to irritation. Blinking subjects the conjunctivae to repeated friction. Vocal cords vibrate during breathing and speaking. The tongue moves while eating and drinking; in particular, the tip of the tongue gets into frequent contact with the inner sides of the incisor teeth. In the present case, characteristic symmetrical skin lesions were seen on the weight-bearing areas of the gluteal region on bony prominences which receive mechanical stresses in the sitting position. These skin lesions were subjected to repeated stretch and pressure stresses, but no ischemic changes were observed, such as decubitus ulcers. Therefore, the symmetrical skin lesions in the gluteal region as well as the ocular and oral mucosal lesions seen in our patient might have resulted from the same mechanism of pathogenesis. We reported a case of anti-laminin-332 MMP presenting with symmetrical gluteal skin lesions, probably induced by mechanical stress. MMP primarily affects the mucous membranes, and widespread skin lesions are rare. Our case emphasizes that clinicians need to specifically check for the presence of skin lesions on weight-bearing parts of the body during examination of patients with suspected MMP.

Case of pemphigoid with immunoglobulin G antibodies to BP180 C-terminal domain and laminin-γ1 (p200) developed after pneumococcal vaccination.

Pemphigoid cases have been reported in association with vaccination, including pneumococcal vaccination in infants but not in adults. There are also sporadic reports of pemphigoid diseases involving reactions to multiple autoantigens. We herein report a 75-year-old Japanese patient with pemphigoid who had immunoglobulin G antibodies to both the BP180 C-terminal domain and laminin-γ1 (p200), which developed 1 day after pneumococcal vaccination.

Dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid in a patient with acquired reactive perforating collagenosis.

Bullous pemphigoid (BP) is a common autoimmune blistering disorder with unknown etiology. Recently, increasing numbers of BP cases which developed under the medication with dipeptidyl peptidase-4 inhibitors (DPP4i), widely used antihyperglycemic drugs, have been reported in published works. Here, we report a case of DPP4i (teneligliptin)-associated BP that developed in a 70-year-old Japanese man. Interestingly, the patient had acquired reactive perforating collagenosis (ARPC), which is also known to be associated with the onset of BP. In the present case, clinical, histopathological and immunological findings suggested that DPP4i rather than ARPC was associated with the onset of BP.

Effects of maxacalcitol ointment on skin lesions in patients with psoriasis receiving treatment with adalimumab.

Adalimumab is a biologic that is very effective for treatment of psoriasis. However, recalcitrant or recurrent lesions sometimes occur during treatment. Maxacalcitol is an active vitamin D3 ointment that is effective in treatment of psoriasis. Topical therapy may be beneficial in treatment of recalcitrant or recurrent lesions during treatment with systemic therapy, but there is little evidence on this topic. We investigated the effect of maxacalcitol on skin lesions during treatment with adalimumab in patients with psoriasis. Twelve patients with psoriasis were randomly assigned to two groups after informed consent - treatment with adalimumab only (n = 6), and treatment with adalimumab and maxacalcitol (n = 6) - and they were evaluated every 4 weeks for 44 weeks. Exacerbation was defined as an increase of the Psoriasis Area and Severity Index (PASI) score. The interval between adalimumab treatments was elongated to 3-4 weeks from 2 weeks according to the individual patient's condition. The PASI score was evaluated every 4 weeks, and the frequency of exacerbations was counted. The overall improvement in PASI score was not statistically different between the two groups, but the frequency of exacerbations was significantly less in the maxacalcitol combination group compared with the adalimumab monotherapy group (Mann-Whitney U-test, P < 0.05). The better control of skin lesions in patients who elongated the interval of adalimumab administration was achieved in the maxacalcitol combination group compared with the adalimumab monotherapy group. Topical maxacalcitol treatment is effective and useful in controlling skin lesions in patients with psoriasis when used in combination with adalimumab.

Possible paraneoplastic syndrome case of bullous pemphigoid with immunoglobulin G anti-BP180 C-terminal domain antibodies associated with psoriasis and primary macroglobulinemia.

A 61-year-old Japanese man developed bullous skin lesions during topical therapy for psoriasis vulgaris. Physical examination demonstrated numerous tense bullae and scaly erythemas on the trunk and extremities. Histopathology of the skin biopsy demonstrated subepidermal bullae and lymphocytic infiltration with eosinophils in the dermis. Direct immunofluorescence revealed linear deposits of immunoglobulin (Ig)G, IgA and C3 along the basement membrane zone. Indirect immunofluorescence of 1 mol/L NaCl-split skin showed IgG reactivity with both epidermal and the dermal sides. IgM reactivity with both the epidermal and dermal sides was also detected. Enzyme-linked immunosorbent assays showed negative results for both BP180 and BP230. Immunoelectrophoresis of serum and bone marrow aspiration revealed underlying primary macroglobulinemia with M-proteinemia of IgM-κ type. Immunoblot analysis revealed IgG, but not IgM, antibodies to recombinant protein of BP180 C-terminal domain. We diagnosed the present case as bullous pemphigoid with IgG anti-BP180 C-terminal domain autoantibodies associated with primary macroglobulinemia and psoriasis vulgaris. Systemic administration of prednisolone 30 mg/day resulted in dramatic improvement of both bullous and psoriatic skin lesions. When the bullous and psoriatic lesions relapsed, DRC chemotherapy (dexamethasone, rituximab and cyclophosphamide) for macroglobulinemia was performed. Then, the psoriatic lesions improved and the bullous lesions disappeared. We suggested that the present case may be paraneoplastic syndrome of bullous pemphigoid associated with primary macroglobulinemia and psoriasis vulgaris.

Streptococcus pneumoniae-associated hemolytic uremic syndrome in a splenectomized adult patient.

A 62-year-old splenectomized woman was admitted because of upper respiratory tract symptoms, general fatigue, and purpura. Laboratory data demonstrated microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure, and a positive Streptococcus pneumoniae (SP) urinary antigen test. A renal biopsy showed thrombotic microangiopathic changes. She was diagnosed with hemolytic uremic syndrome (HUS) secondary to SP infection. Methylprednisolone pulse therapy in addition to antibiotic therapy led to prompt improvement of her symptoms and laboratory abnormalities. This is the first adult case of SP-associated HUS successfully treated without hemodialysis. SP infection should be considered as a causative etiology in all splenectomized patients with HUS.

Cutaneous polyarteritis nodosa in a patient with Crohn's disease.

A 19-year-old Japanese woman with a 4-year history of Crohn's disease (CD) developed high fever, polyarthralgia, and painful subcutaneous nodules of the legs. A skin biopsy showed panarteritis with fibrinoid necrosis in the deep dermis. Endoscopic examination showed aphthous lesions in the entire colon. She was diagnosed with cutaneous polyarteritis nodosa (PAN) associated with CD. Steroid therapy improved her symptoms. To our knowledge, this is the first Japanese case of cutaneous PAN associated with CD.

Monoclonal immunoglobulin deposition disease associated with membranous features.

BACKGROUND: Very few cases of non-organized and non-Randall-type monoclonal immunoglobulin deposition disease (MIDD) associated with membranous features have been reported. Information on clinicopathological features and prognosis in this entity is limited. METHODS: We reviewed 5443 renal biopsies processed at our department, and identified three patients with MIDD associated with membranous features. We evaluated clinicopathological features and outcomes in these patients. RESULTS: All patients had proteinuria, and one patient developed nephrotic syndrome. Renal insufficiency was not observed. Cryoglobulin or monoclonal protein in serum and urine was not detected. A renal biopsy showed thickening of the glomerular capillary walls and spike formation. Tubulointerstitial and vascular alterations were mild or absent. Immunofluorescence studies revealed granular IgG3-kappa deposits in two patients and IgG1-kappa deposits in one patient, along the glomerular capillary walls. Immunofluorescence studies using antibodies specific for gamma-heavy chain Fab containing C(H)1 domain, C(H)2 domain and C(H)3 domain did not show any apparent deletion. On confocal microscopy, glomerular colocalization of light and heavy chains was observed. Electron microscopy showed predominant subepithelial granular deposits without distinct ultrastructural organization. All patients were treated with steroids, and good effects were observed. A follow-up renal biopsy performed in one patient showed histological improvements. No patient developed myeloma or other haematological malignancy during the course of follow-up (mean 44 months). CONCLUSIONS: MIDD associated with membranous features is an extremely rare but distinctive entity. Our study suggests glomerular deposition of a nondeleted whole immunoglobulin molecule. Patients with this entity appear to respond well to steroid therapy.

The HLA-DRB1*1501 allele is prevalent among Japanese patients with anti-glomerular basement membrane antibody-mediated disease.

BACKGROUND: We aimed to clarify the relationship between HLA-DRB1(*)1501 and anti-glomerular basement membrane (GBM) antibody-mediated disease in Japanese patients. MATERIALS: Samples were collected from 16 anti-GBM antibody-positive patients who were admitted to our department or related hospitals from December 1990 to October 2005. We analysed clinical and laboratory data, kidney biopsy findings, and the HLA-DR phenotypes and HLA-DRB1 alleles of the patients. RESULTS: Among the 16 patients, 15 had HLA-DR15 [the phenotype frequency (PF) was 93.8%], 7 were positive for DR4 (the PF was 43.8%) and 5 were positive for DR9 (the PF was 31.3%). The allele frequency of HLA-DRB1(*)1501 was 46.4% (13/28), which was significantly different from Japanese controls (11.6%) (P < 0.001). In contrast, the frequency of HLA-DRB1(*)1502 was not different from controls (0/28). The odds ratio of HLA-DRB1(*)1501 in these patients was 6.4 (95% CI: 2.4-16.5). CONCLUSION: The present study demonstrated that Japanese patients with anti-GBM antibody-mediated disease are very likely to carry the HLA-DRB1(*)1501 but not the HLA-DRB1(*)1502 allele.

Hypertrophic cranial pachymeningitis in a patient with Cogan's syndrome.

A 63-year-old man presented with chronic headache and bilateral hearing loss. A physical examination showed bilateral conjunctivitis. Circulating anti-Cogan peptide antibodies were detected by dot blot analysis. He was diagnosed as having Cogan's syndrome (CS). Steroid therapy led to dramatic improvement of his symptoms and abnormal laboratory findings. During a tapering course of steroid therapy, he suffered from headache. An ophthalmoscopic examination revealed papillary edema. Magnetic resonance imaging of the brain showed hypertrophic cranial pachymeningitis (HCP). After steroid pulse therapy, HCP was improved. To our knowledge, this is the first case of CS complicated with HCP.

Nodular mesangial lesions, marked mesangiolysis, and fingerprint deposits of unknown origin in a patient with nephrotic syndrome: a unique combination of glomerular lesions.

A 46-year-old woman developed nephrotic syndrome at the age of 16 in 1973. On the basis of the histological findings of the first renal biopsy, she was diagnosed as having minimal change nephrotic syndrome. Initial treatment with steroid was effective, but she had several relapses during tapering of the daily dose of steroid. The second renal biopsy, performed in 1997, disclosed glomerular lobulation, mesangial proliferation, nodular mesangial lesions, and mesangiolysis. From 2001, the degree of proteinuria increased, with urinary protein being 5 g/day in January 2003, when a third renal biopsy was performed. On light microscopy, the glomerular lesions were similar to those observed in 1997. Immunofluorescence microscopy revealed coarse granular stainings for IgG, IgA, IgM, kappa, lambda, and C3 in the mesangial area and along the capillary walls. On electron microscopy, fingerprint structures were observed in the mesangial and subendothelial deposits. There were no characteristic fibers in the nodular lesions. On the basis of clinical and laboratory findings in this patient, we excluded disease entities in which nodular mesangial lesions, mesangiolysis, and fingerprint deposits had been reported. To our knowledge, such a unique combination of glomerular lesions has not been described previously in the literature.

Interaction of the spectrin-like repeats of alpha-actinin-4 with humanin peptide.

BACKGROUND: Podocyte alpha-actinin-4 (actinin-4) is an essential component of the glomerular filtration barrier. We recently reported that the central rod spectrin-like repeats (R1-R4) of actinin-4 have a high affinity to puromycin aminonucleoside (PAN), which can induce nephro-sis in animals. The aim of this study was to identify endogenous molecules that interact with the actinin-4 R1-R4 domain. METHODS: To identify such molecules, we performed a bacterial two-hybrid screening of a human kidney cDNA library using as a bait human actinin-4 R1-R4. We further verified the identified interactions by in vitro affinity assays and immunofluorescent studies of cultured human embryonic kidney HEK293 cells. To investigate the expression of the identified molecules in podocytes, in situ hybridization, and immunohistochemical studies were performed. RESULTS: One isolated cDNA from the library encoded humanin, a recently identified antiapoptotic peptide. In vitro affinity assays showed specific interactions of recombinant actinin-4 R1-R4, R1, R2, R3, and R4 proteins with humanin-Sepharose. PAN had no effect on these interactions. Green fluorescent protein-fused humanin and endogenous actinin colocalized mainly in the perinuclear cytoplasm of HEK293 cells. Altered colocalization was not observed by the addition of PAN. In situ hybridization and immunohistochemistry showed the expression of humanin in podocytes. CONCLUSIONS: Our results suggest that humanin is a novel binding partner of the actinin-4 R1-R4 domain in podocytes. Humanin and PAN are unlikely to compete for the same binding surface in actinin-4.

Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.

BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations.

Immune complex-type glomerulonephritis with unusual giant deposits in a patient with active rheumatoid arthritis.

A 61-year-old woman with rheumatoid arthritis (RA) developed small digital ulcers, proteinuria, and hematuria. Serological studies disclosed high titers of antinuclear antibody and rheumatoid factors (RF; IgM-RF and IgG-RF), and an increased level of circulating immune complexes. These findings suggested an active immunological state of RA. A renal biopsy showed periodic acid-Schiff-positive giant deposits in the mesangial area and subepithelial space. Immunofluorescence microscopy revealed strong stainings for IgG, IgA, IgM, Kappa, Lambda, C3, C1q, and fibrinogen in a granular pattern. Electron microscopy showed giant granular deposits (diameter, up to 4.6 micro m) without specific fibrillary structure in the mesangial area and subepithelial space, and partially in the subendothelial space. There were no findings of vasculitis, such as endothelial proliferation or fibrinoid necrosis of small arteries. This is the first report of immune complex-type glomerulonephritis with unusual giant deposits in a patient with RA in an active immunological state.

Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy.

BACKGROUND: Several studies have shown a predominant glomerular deposition of IgG4 in patients with idiopathic membranous nephropathy (MN), whereas significant depositions of other IgG subclasses have been shown in patients with lupus-associated MN and bucillamine-induced MN. METHODS: We examined the distribution patterns of glomerular IgG subclass deposits in 10 patients with malignancy-associated MN (M-MN) and in 15 patients with idiopathic MN by immunofluorescence (IF) microscopy. RESULTS: The glomerular IF intensities of IgG1 and IgG2 were significantly stronger in the malignancy group than in the idiopathic group (P<0.05). In contrast, there were no differences in glomerular IF intensities of IgG3 and IgG4 between the two groups. CONCLUSION: Our findings suggest that the distribution patterns of glomerular IgG subclass deposits are different in idiopathic MN and M-MN. The strong IF intensity of glomerular IgG1 and IgG2 in M-MN may provide a possible predictor for this condition.

Analysis of mutations in alpha-actinin 4 and podocin genes of patients with chronic renal failure due to sporadic focal segmental glomerulosclerosis.

Although the pathogenesis of idiopathic focal segmental glomerulosclerosis (FSGS) may be heterogeneous, autosomal dominant and recessive forms of FSGS are recognized. Recently, mutations in alpha-actinin 4 (ACTN4) and podocin genes were reported in patients with such familial FSGS. However, whether mutations in ACTN4 and podocin genes are associated with sporadic FSGS has not been determined. In the present study, we clarified the relation between mutations in ACTN4 and podocin genes and sporadic FSGS. We analyzed these reported mutations in ACTN4 and podocin in five patients with chronic renal failure due to therapy-resistant FSGS by direct sequencing of polymerase chain reaction products of ACTN4 and podocin. We found a C to T transition at nucleotide 465 in the ACTN4 gene in all of patients, and a T to C transition at nucleotide 954 in exon eight of podocin gene in two of five patients, resulting in no amino acid substitutions. Other mutations were not found in ACTN4 and podocin genes. Our findings suggest that sporadic FSGS is a heterogeneous disease, since ACTN4 and podocin genes are not found in our patients with sporadic FSGS.