Journal of Dermatology for Physician Assistants

The official journal of the Society of Dermatology Physician Assistants

Exploration into chronic wounds on the left lower leg yields unlikely diagnosis

By Cynthia Faires Griffith, MPAS, PA-C, and Loderick A. Matthews, BS

Cynthia Faires Griffith, MPAS, PA-C, is a Dermatology Physician Assistant at UT Southwestern Medical Center in Dallas, Texas, where she also earned her Masters of Physician Assistant Studies. Ms. Griffith is the co-founder of the UT Southwestern High-Risk Skin Cancer Transplant Clinic, a twice-monthly clinical initiative to serve patients who are immunosuppressed after solid organ or bone marrow transplant. She also practices general adult medical dermatology. She is Dermatology Grand Rounds Department Editor for the Journal of Dermatology for Physician Assistants (JDPA) and is a guest lecturer in the UT Southwestern PA program and a lecturer at local, regional, and national conferences. She is a member of the Texas Academy of Physician Assistants, the Society for Dermatology Physician Assistants, and the American Academy of Physician Assistants. She was awarded UT Southwestern’s PA of the Year in 2017. When not practicing, Ms. Griffith is an avid sailor, marathoner, and long-distance cyclist.

Loderick A. Matthews, BS, is a research associate in the Cutaneous Immunopathology Laboratory in the Department of Dermatology at the University of Texas Southwestern Medical Center in Dallas, Texas. Loderick frequently contributes fluorescent microscopy photographs to case studies presented by residents and faculty at the Department of Dermatology Grand Rounds. When Loderick is not in the lab, he is a runner, cyclist, and a working musician.

Disclosures: The authors have disclosed no potential conflicts of interest, financial or otherwise, relating to the content of this article.

ABSTRACT
An 82-year-old man presented with a three-year history of wounds on the left lower leg and appearance of new blisters on the same leg. This case highlights clinical manifestations, causes, diagnostic work-up, and treatment for this condition.

CLINICAL VIGNETTE
An 82-year-old man was referred to dermatology outpatient clinic for nonhealing wounds on the lower legs. The patient had a medical history of chronic kidney disease stage 3, hypertension, gout, type 2 diabetes mellitus (T2DM), depression, and vitamin D deficiency. He also had a history of skin shearing trauma as a result of repeated falls on the left lower leg for the past three years. He has had home health/wound care for the past three years, treating wounds on his lower legs with Xeroform® and Hydrofera Blue® dressings. He also regularly wrapped compression bandages on the lower legs as part of the wound care routine but, two weeks prior to presentation at dermatology, “took a break” from using the compression bandages. Since making this change in his routine, he noticed the appearance of new blisters filled with clear fluid located under the skin on the left lower leg and left tibial tuberosity, which were all areas of previous trauma. He reported no history of blisters on the feet, right leg, arms, or scalp. The patient denied experiencing itching, malodorous drainage, or pain and did not have a history of similar blistering.

The patient’s list of current medications included dulaglutide, hydralazine, insulin, levothyroxine, and losartan. Physical examination revealed erosions on the left tibial tuberosity with some erosions on an erythematous base. Of note, these erosions did not appear undermined. Figure 1 shows the patient’s left lower leg and left tibial tuberosity with chronic erosions and ulcers with granulation tissue. Unrelated to the leg erosions, the patient had an abrasion on the right vertex of the scalp and left arm from involvement in a car accident four days before his appointment.

DIAGNOSIS
A punch biopsy for histopathology was taken from the edge of the erosion on the left leg. (Figure 2). A shave biopsy for histopathology was performed to remove a 4×5 mm bulla on an erythematous base; the entire bulla was shave biopsied (Figure 3). Normal appearing skin within 1 cm of the bulla was punch biopsied for direct immunofluorescence.

The patient’s serum (blood) was taken for indirect immunofluorescence for autoantibodies against skin and enzyme-linked immunosorbent assays (ELISA). The histopathology from the punch biopsy of the erosion and the shave biopsy of the bulla showed a sub-epidermal vesicle with an inflammatory infiltrate of eosinophils, neutrophils, and lymphocytes. Type IV collagen was on the floor of the blister.

The perilesional skin punch biopsied for direct immunofluorescence revealed Immunoglobulin G (IgG), third component of complement (C3), and fibrin in the epidermal basement membrane (Figure 4). The patient’s serum tested for indirect immunofluorescence was positive for autoantibodies against the epidermal side of 1 M NaCl split skin at a titer of ≥40 (Figure 5).

The patient’s serum was then tested for IgG autoantibodies against baculovirus-derived BP180 and BP230 by ELISA. The patient was negative for IgG autoantibodies against both BP180 and BP230. The patient’s clinical picture and biopsy and directand indirect immunofluorescence are compatible with the diagnosis of bullous pemphigoid (BP).

DISCUSSION
BP is an acquired autoimmune blistering disease. In this condition, autoantibodies against skin, specifically against BP180 and/or BP230 within the hemidesmosomes. Hemidesmosomes hold basal keratinocyte cells to the dermis. As a result, tense blisters form as the epidermal skin cells separate from the dermis. Prior to development of the blisters, itching can be present. In some patients, itching and urticaria can be the prodrome before the blisters; in other patients, pruritus can be the only presenting symptom with blisters never developing.

BP typically presents in patients after age 60, but it can appear earlier in life. It can be localized to one body surface area, typically the lower legs/feet, or generalized. Typical locations for BP are trunk and extremities. There is also a subset of patients whose mucous membranes are affected, and this is classified as mucous membrane pemphigoid.

Painful erosions on the mucosa are present in 10 to 30 percent of patients.1 The oral mucosa is the most frequent location of mucosal involvement; less frequently, BP involves other mucosal sites, such as the larynx, genitals, and anus.

BP can also be induced or triggered by a variety of medications, including nonsteroidal anti-inflammatory drugs (NSAIDS); diuretics like furosemide, antihypertension medications including betablockers, ace inhibitors, calcium channel blockers, and antibiotics like rifampicin, penicillin, and quinolones.2 Drug-induced BP tends to affect younger patients. The eruption can appear up to three months after ingestion of the culprit medications.3 Another medication class more recently associated with drug-induced BP are dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors or gliptins).4 The patient described in this case was on sitagliptin from 2009 to July 2019. The patient reported that the bullae developed starting April 2020, nine months after he stopped taking sitagliptin. Infections, UV light, or trauma can also cause of flare of BP or induce onset of new blisters.

Diagnostic Testing. Biopsy for histopathology should be taken from an intact bulla (using shave or punch technique) or punch biopsy from the edge of an erosion. Place these tissues samples in formalin. The pathologist will be looking to see the level of the skin that is separating to cause the blister formation; in the case of BP, this will be a subepidermal blister. Histology also elucidates the cell types present in the skin including lymphocytes, neutrophils, and eosinophils.5

A biopsy of perilesional skin, meaning normal appearing skin that is within 1 cm of the blister, can be sampled with punch biopsy and placed in Michel’s media for direct immunofluorescence testing. This testing looks for autoantibodies and other immunoreactants in skin to identify the type and where they are deposited within the skin. The patient’s skin is cross sectioned and examined for in situ deposits of IgG, IgA, IgM, C3, and fibrinogen. Deposits of IgG or C3 in the basement membrane zone, or more specifically on the epidermal side of the blister, supports the diagnoses of bullous pemphigoid (Figure 4). Other blistering disease can present with different deposits in different locations. For example, IgA in the dermal papillae is characteristic of dermatitis herpetiformis.

Further tests that can be done to gain additional evidence for a diagnosis of BP is indirect immunofluorescence testing (IDIF) and ELISA. IDIF can be used to see if the patient’s blood carries autoantibodies, specifically IgG, that localizes to the epidermal side of 1 M NaCl split skin, which could suggest that the IgG autoantibodies are binding to the hemidesmosomes (180 and 230) and causing the blistering. In IDIF, the patient’s serum is incubated on a substrate; for suspected BP, the substrate is salt split skin, washed extensively and then rabbit anti human IgG with a fluorescent marker is incubated on the skin and the bound patient’s autoantibodies, if present. The rabbit anti human IgG binds to the patient’s IgG and marks it with a florescent tag. Then the specimen is examined using fluorescent microscopy to see if there is deposition of the patient’s IgG from their blood onto the skin substrate and, if so, where the deposition is (e.g., epidermal or dermal side of the salt split skin). Linear deposition of IgG along the epidermal side of salt split basement membrane supports the diagnosis of BP. Figure 5 shows this linear deposition in our patient. In IDIF, the substrate for BP is salt split skin, but there are multiple substrates that can be used for different disease processes. For example, when testing for pemphigus vulgaris, the substrate typically used for IDIF is monkey esophagus because 1 M NaCl split skin is a poor substrate to probe with autoantibodies from patient sera because the desmogleins, the antigen associated with pemphigus targeted by the autoantibodies that mediate this autoimmune disease process, are buried between the keratinocytes of normal human skin.

To further illuminate the target of the binding of the patient’s autoantibodies, the serum is tested by ELISA. In ELISA, the patient’s serum is diluted in a buffer, incubated in a well of a plate that is coated with the antigen of interest, BP180 or BP230 in this case, washed extensively and an enzyme conjugated anti-human IgG antibody is applied and incubated. After further washing, the enzyme substrate is added to the plate and if the patient’s autoantibodies have bound the antigen, a color change is observed. This color change is read by a plate reader that measures the absorbance of transmitted light and produces a readout that can be quantified against the standards provided by the kit manufacturer. This patient was negative by ELISAs for BP180 and BP230 autoantibodies. However, this result could be due to the proteins used in this specific assay are bacculovirus derived and may not present the antigenic determinate that is targeted by the patient’s autoreactive IgG. Further, the diagnosis of BP is based on the entire clinical picture, not just a single negative test.

Treatment Considerations. If the disease is localized to an area as it was in this patient, topical treatment is the treatment of choice. High-potency topical steroids like clobetasol would be a good option. For mucous membrane involvement, high-potency topical steroid can also be used in the mouth, typically the ointment or gel is better tolerated for oral lesions.

If the patient has extensive disease covering more body surface area, other treatments like antibiotics specifically doxycycline in combination with nicotinamide can be utilized to slow the formation of additional bullae. Oral steroids are a mainstay of therapy if topical therapy is not feasible given body surface involvement; however, this can be detrimental to patient’s bone and cardiovascular health when used long term so steroid-sparing agents like azathioprine, mycophenolate, or rituximab are also used in refractory BP to arrest development of bullae.

CLINICAL VIGNETTE CONTINUED
This patient was prescribed topical clobetasol to use on the left knee. He used this not on the open skin but on intact skin. As he had traumatic skin erosions from falls, the knee was covered with wound dressing with Vaseline then nonstick pad and then coban wrap. Care was taken to not shear off the tops of the blisters that developed with his dressing changes. The bullae healed with a little milia formation within three weeks of this treatment (Figure 6). Since then, the patient was started on doxycycline and nicotinamide. He did not develop any new bullae. He did not tolerate the doxycycline due to gastrointestinal upset, so this was held. He continues to have no new bullae.

REFERENCES:

1. Kridin K, Bergman R. Assessment of the prevalence of mucosal involvement in bullous pemphigoid. JAMA Dermatol. 2019;155(2):166-171. doi: 10.1001/jamadermatol.2018.5049.
2. Stavropoulos PG, Soura E, Antoniou C. Drug-induced pemphigoid: a review of the literature. J Eur Acad Dermatol Venereol. 2014;28(9):1133-40. doi: 10.1111/jdv.12366.
3. Lee SG, Lee HJ, Yoon MS, Kim DH. Association of dipeptidyl peptidase 4 inhibitor use with risk of bullous pemphigoid in patients with diabetes. JAMA Dermatol. 2019;155(2):172-177. doi:10.1001/jamadermatol.2018.4556
4. Clarindo MV, Possebon AT, Soligo EM, Uyeda H, Ruaro RT, Empinotti JC. Dermatitis herpetiformis: pathophysiology, clinical presentation, diagnosis and treatment. An Bras Dermatol. 2014;89(6):865-877. doi:10.1590/abd1806-4841.20142966
5. Clinical features and diagnosis of Bullous Pemphigoid and Mucous Membrane Pemphigoid. Leiferman K, UptoDate June 2020.
6. Dermatitis Herpetiformis Oakley A DermnetNZ 2001

 

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