Localized bullous pemphigoid with noncollagenous 16A domain negative, antibullous pemphigoid 180 autoantibody after an orthopedic surgery with implant

Dear Editor, Bullous pemphigoid (BP) is the most common autoimmune blistering disease, predominantly affecting the elderly. Type XVII collagen (COL17, also called BP180) plays a central pathogenic role in BP. The noncollagenous 16A (NC16A) domain, an extracellular region of COL17, is recognized by autoantibodies in 80%–90% of BP cases.[1] Here, we present an unusual young female patient, who had BP autoantibodies targeting the non-NC16A region following an orthopedic surgery with the implant. A 28-year-old woman was admitted due to fractures after trauma involving the right femur and left radius and ulna and received open reduction and internal fixation with titanium-coated plates and screws. Two days after operation, asymptomatic tense blisters were noted around the surgical scar on her right leg and left forearm. There were neither mucosal lesions nor blisters or rashes observed on other sites. The total BP disease area index (BPDAI) score was 5 with the erosion/blister BPDAI score as 3 and urticaria/erythema BPDAI score as 2. She had no underlying disease and did not use dipeptidyl peptidase-4 inhibitor. Skin examination revealed scattered tense blisters with erosion and focal exuberant granulation tissue over the scar from the aforementioned orthopedic intervention [Figure 1a]. Four days later, various sized and confluent vesicles erupted in linear distribution [Figure 1b].Figure 1: Shifty morphology at different stages: scattered blisters with erosions and red shiny papules (a) and confluent tense vesicles (b) Along the scar. A subepidermal blister with mixed infiltration containing eosinophils and neutrophils under histopathology (×100) (c). Direct immunofluorescence revealed linear deposits of immunoglobulin G along the basement membrane zone (d).The histopathological examination revealed subepidermal blister with mixed inflammatory infiltrate, including eosinophils and neutrophils [Figure 1c]. The direct immunofluorescence (DIF) study demonstrated linear deposits of immunoglobulin (Ig) G at the basement membrane zone (BMZ) [Figure 1d] and negative for IgA or C3 depositions. Indirect immunofluorescence (IIF) on monkey esophagus with the IgG class demonstrated positive anti-BMZ antibody at the titer of 1:80, and the linear deposits were on the roof side using the salt-split skin technique with 1 mol/L sodium chloride. In addition, while the result of enzyme-linked immunosorbent assay (ELISA) for autoantibodies against BP180 NC16A was negative, the positive result of BP180 full-length ELISA (index: 21.97 U/ml [cutoff <4.64]) confirmed that the patient's circulating antibodies reacted with non-NC16A regions of BP180.[2] Taken together, the diagnosis was consistent with BP. Treatment was initiated with clobetasol propionate ointment and prednisolone 20 mg/day but showed limited effects. Azathioprine 100 mg/day was added and the recalcitrant blisters improved. We tapered the dose to maintain the complete resolution since the implant removal was not considered yet due to the incomplete fracture union. Trauma, surgical wounds, and bone fractures were well-recognized factors that can trigger BP.[1] Regulatory T cell (Treg) has recently been described as helping maintain the peripheral immune tolerance of BP180 as well as in suppressing the inflammation triggered by the binding of antibodies to BP180.[1] In our case, surgery or implant might induce BP by causing a physical stress, hypersensitivity, or cytotoxicity reaction, which activated the immune system to produce autoantibodies to basement membrane proteins, in a similar way proposed by Mai et al.[3] It could be possible that the hypersensitivity or cytotoxicity reaction of surgery with implant facilitates epitope spreading, a phenomenon that frequently occurred in BP, and the autoantibodies recognized the secondary epitopes on BP180 instead of the immunodominant NC16A domain. We reviewed cases of BP after orthopedic surgery in the literature [Supplementary Table 1].[4-6] Except our patient, there were three men and four women, and the previous seven cases aged between 61 and 85 years old. Titanium implant was used for total knee arthroplasty for six patients and open reduction and internal fixation for one patient. Acute localized blister formation started as fast as 2 days after operation but might also delay to 9 months. The acute onset of BP might be attributed to the cytotoxicity of titanium implant. Five patients had generalized eruption with blisters progression to the face, trunk, and extremities in 10 days–5 months. The reason why the disease is localized rather than affecting the entire body skin in the other three patients, including the present case, could be explained by the lesser degree of severity, the earlier control of the disease or the insufficient follow-up duration.[5,6] Patch test was performed in two cases. There was 1 + reaction to titanium (IV) oxalate hydrate in one patient and a negative result in the other. DIF study was performed in seven patients and all showed positive IgG autoantibodies against BMZ with five and three cases showed variable titer of C3 and IgA autoantibodies individually. With IIF, three of four cases had IgG autoantibodies and two cases further demonstrated positive IgG on the epidermal side on salt-split skin. Besides our patient, ELISA was done in the other two cases. One of them had BP180 antibody detected, but the other patient showed negative results for both BP180 and BP230 antigens. Recently, a history of bone fracture was considered a risk factor for anti-BP180 autoantibody development in an asymptomatic subgroup.[7] Another scenario in the elderly could be that there were low-liter autoantibodies, and the inflammatory microenvironment including Treg cells was changed after surgery or implant. Trauma, the pathogenic immune cells, and ages synergistically induced BP and led to localized or generalized eruption.Supplementary Table 1: Eight cases of bullous pemphigoid after orthopedic implants in total knee arthroplasty and open reduction and internal fixationCONCLUSION We present the first young case of BP after surgery and implant with comprehensive immunology surveillance and also discuss the possible mechanism and review the literature. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent form. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement The datasets generated during and/or analyzed during the current study are publicly available. Financial support and sponsorship Nil. Conflicts of interest Prof. Chao-Kai Hsu, an Associate Editor at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.