A case of anti-laminin γ1 (p200) pemphigoid developed after dipeptidyl peptidase-4 inhibitor administration.

A 73-year-old man with diabetes mellitus was referred to our department for ultraviolet treatment for erythematous skin lesions with itching. On dipeptidyl peptidase-4 inhibitor (DPP-4i) sitagliptin (Januvia®) for diabetes mellitus, the erythematous skin lesions appeared and spread to the whole body. At the initial visit, erythema multiforme-like skin lesions with crusts were observed on the trunk and extremities, and the patient was suspected to have drug eruption. Histopathology demonstrated eosinophilic infiltration in the superficial dermis and inflammatory cell infiltration in the epidermis. Sitagliptin was discontinued, and erythematous lesions improved with oral prednisolone. Thereafter the patient was treated with phototherapy and  betamethasone sodium phosphate infusion for residual prurigo. However, blistering skin lesions appeared 5 months later. Histopathological findings were subepidermal blisters with eosinophilic abscess, and bullous pemphigoid was suspected. CLEIAs for autoantibodies to desmoglein 1 (Dsg1), Dsg3 and BP180 were negative. Direct immunofluorescence showed linear depositions of immunoglobulin G (IgG) and C3 at the epidermal basement membrane zone, and indirect immunofluorescence detected IgG anti-epidermal basement membrane zone antibodies, reacting with the dermal side of 1M NaCl-split normal human skin. IgG antibodies reacted with 200 kDa laminin γ1 (p200) by immunoblotting using dermal extracts. These results indicated that this patient was diagnosed with anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration. Although reports of DPP-4i-related bullous pemphigoid have accumulated, cases of anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration are rarely reported.

Immune checkpoint inhibitor-related dermatologic adverse events.

Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D3 analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.

Ruxolitinib Cream Has Dual Efficacy on Pruritus and Inflammation in Experimental Dermatitis.

The goal of this study was to elucidate the anti-pruritic and anti-inflammatory efficacy of ruxolitinib cream in experimentally-induced dermatitis. Atopic dermatitis (AD), the most common chronic relapsing inflammatory skin disease, significantly impairs patients' quality of life, with pruritus being a common complaint. The sensation of itch results from the interplay between epidermal barrier dysfunction, upregulated immune signaling and the activation of the central nervous system. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in pro-inflammatory cytokine signaling in AD. Ruxolitinib cream is a potent and selective JAK1/2 inhibitor currently undergoing clinical evaluation in adults with mild-to-moderate AD (NCT03745638, NCT03920852 and NCT03745651). The efficacy of ruxolitinib cream was tested in murine models of acute and chronic dermatitis and was also characterized in an ex vivo human skin dermatitis model. Ruxolitinib cream was highly effective at ameliorating disease symptoms in multiple murine dermatitis models through downregulation of T helper (Th)2-driven inflammation, resulting in reduced skin thickening and decreased itch. Pathway analysis of mouse ear tissue and human skin explants underscored the role for ruxolitinib in ameliorating inflammation and reducing itch via modulation of the JAK-STAT pathway. Together, the data offer a strong rationale for the use of ruxolitinib cream as a potent therapeutic agent for the clinical management of atopic dermatitis.

Exanthems and drug reactions.

BACKGROUND: Drug reactions are a common cause of rashes and can vary from brief, mildly annoying, self limiting rashes to severe conditions involving multiple organ systems. OBJECTIVE: This article outlines an approach to exanthems that may be related to drug reactions and details appropriate management. DISCUSSION: Rashes related to drug reactions are both nonallergic and allergic. Nonallergic rashes are usually predictable and may be avoidable. Allergic rashes include morbilliform erythema, urticaria and angioedema, erythema multiforme and vasculitic rashes. The vast majority of cases are rapidly resolving and self limiting once the offending agent is removed. Early recognition and supportive measures are the keys to care in the majority of cases. However, an awareness of serious drug reactions (Stevens- Johnson syndrome and toxic epidermal necrolysis), which are potentially life threatening conditions and require immediate specialist assessment and treatment in hospital, is important.

Cutaneous side effects of anti-tumor necrosis factor biologic therapy: a clinical review.

BACKGROUND: Anti-tumor necrosis factor (anti-TNF) biologic agents have been associated with a number of adverse events. OBJECTIVE: To review the cutaneous reactions that have been reported in patients receiving anti-TNF therapy. METHODS: We performed a systematic MEDLINE search of relevant publications, including case reports and case series. RESULTS: Reported cutaneous events included infusion and injection site reactions, psoriasiform eruptions, lupus-like disorders, vasculitis, granulomatous reactions, cutaneous infections, and cutaneous neoplasms. Infusion reactions and injection site reactions were definitely associated with anti-TNF administration, whereas all other events had a varying strength of association and severity, not necessarily requiring drug discontinuation. LIMITATIONS: Most information was derived from spontaneous case reports, where ascertainment biases and frequency of reporting may impair detection methodology and causal relationships. CONCLUSIONS: As anti-TNF biologic agents are progressively being used in clinical practice, cutaneous adverse events will be encountered more frequently. Until more data are accumulated with respect to their pathogenesis and potential association with anti-TNF therapy, dermatologists should become more familiar with the clinical presentation and management of such events.

Management of tolerance induction in patients with suspected penicillin allergy--a case study.

BACKGROUND: In some diseases penicillin is the treatment of choice. Case studies have shown a good response for the treatment of circumscribed scleroderma or scleroderma adultorum of Buschke. A suspected allergy to penicillin in a patient's history may limit this helpful therapy option. Allergy testing is often inconclusive. If indicated, tolerance induction leading to therapy with penicillin can be carried out. PATIENTS AND METHODS: We present two patients with circumscribed sclerosis and scleredema Buschke, who had a suspected allergy to penicillin. Due to limited therapy options and in insufficient response to other therapeutics, the decision for a tolerance induction with penicillin was made. Penicillin was successfully administered by following a scheme of tolerance induction starting with oral doses and ending with high doses of intravenous penicillin G. RESULTS: In both cases, penicillin G, administered over a period of three weeks, was well tolerated up to the high dose of 3 x 10 Mega IU/day. Substantial clinical improvement was achieved in all cases without any complications. CONCLUSION: This case study demonstrates that a suspected allergy to penicillin does not preclude an eventual treatment with this valuable drug. Allergy testing should routinely be carried out first. If suspicion of an allergy persists, tolerance induction can be attempted according to the new scheme described here. Starting with a careful, initial oral dose regimen, treatment can be continued with an increasing intravenous dose followed by maintenance therapy with high-dose penicillin G. It should be clear that this policy is only restricted for patients who are at risk for a hypersensitivity to penicillin, i.e., because of a clinical manifested incompatibility in the past.

[Intolerance as consequence of hyperreactivity]. / Unverträglichkeit als Folge einer Hyperreaktivität.

Many patients complain about hyperreactivity of the skin or mucosal membranes, whereby rather harmless "triggers" lead to exaggerated reactions like running nose, bronchospasm, urticaria, etc. Most of these hyperreactivities have an underlying inflammation. It is important not to focus only on the triggers, but to look for the agent causing the inflammation and to avoid/treat it: elimination of the cause also eliminates the hyperreactivity. Four examples are presented where this cause--trigger model of hyperreactivity is illustrated (exercise induced asthma, pollen associated food allergy, flare-up reactions in drug allergy and hyperreactivity in chronic urticaria).

[Drug exanthema in connection with trimethoprim and sulfamethoxazole treatment, triggered by leech therapy]. / Arzneimittelexanthem in Zusammenhang mit Trimethoprim- und Sulfamethoxazol-Medikation -- Blutegeltherapie als triggernder Faktor.

In a 58-year-old hospitalized woman with gonarthrosis a leech therapy was applied to both knee joints. In the evening of the following day she observed strong pruritus in the area of the leech bites; in addition a maculopapular exanthema appeared on the torso and her lower extremities. The allergic reaction lasted four days. Administration of antihistamines only led to a slight improvement of the symptoms. A full restitution could only be achieved after a systemic dose of glucocorticoids on the fourth day after leech therapy. Eight days before beginning of the leech therapy a five-day antibiotic therapy with trimethoprim and sulfamethoxazole (Cotrim forte) had been administered to treat an uncomplicated urinary infection. Allergic reactions are well-known complications of these antibiotics and of leech therapy. The four-day duration of the allergic reaction after leech therapy, however, was untypical. In order to explain these symptoms, a prick test and an epicutaneous test for the antibiotic components were executed five weeks after the leech therapy. Furthermore, a second leech therapy was administered and a lymphocyte transformation test (LTT) was carried out. The results of the LTT showed a sensitization for sulfamethoxazole and a possible sensitization for trimethoprim, the results of the epicutaneous test showed a positive reaction to sodium lauryl sulfate, a component of the antibiotic. In the area of the leech bites a clear local skin reaction was observed. These results suggest a drug exanthema, in all probability triggered by the leech therapy.

CD30-positive T-cell-rich pseudolymphoma induced by gold acupuncture.

Cases of pseudolymphoma induced by intradermal gold injection or gold piercing have previously been described. Most of these cases showed the histopathological finding of B-lymphocyte predominant lymphocytoma cutis. We describe a patient with gold acupuncture-induced T-cell-rich pseudolymphoma. Some T cells showed positive staining with CD30. The lesions responded to an intralesional injection of triamcinolone acetonide.

Graft-versus-host disease-like immunophenotype and apoptotic keratinocyte death in paraneoplastic pemphigus.

Paraneoplastic pemphigus (PP) is an autoimmune disease, which is frequently associated with non-Hodgkin's lymphoma. Autoantibodies against components of the cytoplasmic plaque of epithelial desmosomes are usually present in the sera and are believed to play a major pathogenic part in acantholysis and suprabasal epidermal blistering. However, another typical histological feature of PP, interface dermatitis with keratinocyte dyskeratosis, is shared with skin diseases that involve epithelial damage mediated by T cells. Here, we present the detailed characterization of the cutaneous T-cell response in a patient with PP and demonstrate a selective epidermal accumulation of activated CD8+ T cells together with an increased local production of interferon-gamma and tumour necrosis factor-alpha, and a strong expression of HLA-DR and ICAM-1 on keratinocytes. Apoptosis was identified as a key mechanism of keratinocyte death, and appeared independent of the FAS/FAS ligand (FAS-L) pathway, as epidermal expression of FAS was not increased compared with normal skin, and FAS-L was undetectable on the protein and mRNA level. Triple therapy with high-dose corticosteroids, cyclophosphamide and intravenous immunoglobulins reduced levels of pemphigus-like autoantibodies and reversed the cutaneous inflammatory reaction leading to long-standing clinical remission. Our findings support the concept of a major contribution of cytotoxic T lymphocytes to the immunopathology of paraneoplastic pemphigus.

Subcutaneous infiltrates induced by injection of mistletoe extracts (Iscador).

Iscador, an aqueous extract of Viscum album L., has been widely used as an anti-cancer drug for several decades. Mistletoe lectins have the capacity to activate nonspecific defense mechanisms, and lectin-carbohydrate interactions may be involved in clinically applicable immunomodulation. During treatment with whole-plant mistletoe extract, an inflammatory reaction usually occurs at the site of the injection, early in therapy. These injection sites were examined histologically. Seven subjects received three subcutaneous injections of Iscador QuFrF or Iscador Qu Spezial (twice 0.1 mg and once 2.5 mg) during 9 days. In all subjects, examination of skin biopsies showed a normal epidermis. The dermal and subcutaneous regions contained a dense perivascular lymphocyte infiltrate and increased monocytes. We could not document any increase of plasma cells, eosinophils, mast cells, neutrophils, or granulocytes, as would be the case for a granulomatous infiltrate. In the blood, we observed a significant increase in neutrophils and monocytes 24 hours after administration of 2.5 mg of Iscador.

Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses.

We have examined the role of endogenously produced interleukin (IL) 4 and IL-10 in the regulation of inflammatory and immune reactions in the skin. In these experiments, irritant and contact hypersensitivity (CH) responses were elicited in mice with targeted disruptions of the IL-4 (IL-4T) or IL-10 (IL-10T) gene. Our study showed that IL-4T and wild-type (wt) mice exhibited equivalent responses to the irritant croton oil. In contrast, the response of IL-10T mice challenged with croton oil was abnormally increased. When IL-10T mice were exposed to a higher dose of irritant, irreversible tissue damage occurred. By comparison, any treatment of wt mice with croton oil resulted in far less tissue damage and resolution of inflammation. Neutralizing antibody studies demonstrated that the necrosis that occurred in IL-10T mice was due to the overproduction of tumor necrosis factor. The anti-tumor necrosis factor antibody treatment of IL-10T mice did not significantly reduce the edema or the influx of inflammatory cells, suggesting that these changes were due to the uncontrolled production of other proinflammatory cytokines. T cell-dependent immune responses were also evaluated using the contact sensitizer oxazolone. The response of IL-4T mice did not differ from wt mice. In contrast, IL-10T mice mounted an exaggerated CH response, increased in both magnitude and duration as compared with wt mice. Based on these studies, we have concluded that IL-10, but not IL-4, is a natural suppressant of irritant responses and of CH, and it limits immunopathologic damage in the skin.

Dermal inflammation in primates, mice, and guinea pigs: attenuation by second-generation leukotriene B4 receptor antagonist, SC-53228.

Granulocyte infiltration is a prominent feature of human psoriasis. Psoriatic lesional skin contains abnormally high amounts of immunoreactive leukotriene B4 (LTB4), a potent granulocyte chemotaxin in vivo and in vitro. SC-53228 [(+)-(S)-7-(3-}2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy}propoxy}-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], a second-generation LTB4 receptor antagonist, was tested topically and orally in phorbol ester-induced dermal inflammation in three species. Skin inflammation was induced by topical application of phorbol-12-myristate-13-acetate-(PMA/TPA) and assessed by ear thickness, levels of the neutrophil marker enzyme myeloperoxidase (MPO) and histological examination. In mice, SC-53228 inhibited inflammation with a topical ED50 value of 200 +/- 18 micrograms. When applied to guinea pigs, SC-53228 (100 micrograms) inhibited the MPO increase by 86%, while 1000 micrograms abrogated inflammation in rhesus macaques with no plasma accumulation of the drug. A 1% gel formulation was also efficacious in guinea pig PMA-induced epidermal inflammation. Furthermore, single oral dose administration to mice was efficacious (ED50 < 2.5 mg/kg) as was multidose administration to rhesus macaques. PMA-induced skin inflammation possesses some of the attributes of human psoriasis and an agent such as SC-53228 may have utility in the medical management of this condition.

Oral induction of immunological tolerance to chromium in the guinea pig.

Metal alloys used in dentistry may elicit adverse side-effects. Contact allergic reactions to metals released from such alloys are among the most frequently encountered problems. In an earlier study, we observed that oral contacts with nickel or chromium salts did not sensitize, but rather decreased the risk of subsequent sensitization to these metals. In the present study, we focused on chromium allergy and extended our earlier observations by further dose-response studies. In addition, we compared different chromium valencies as to their potential oral tolerogenic effects. Development of immunological tolerance in chromium-fed guinea pigs was demonstrated by their inability to develop chromium hypersensitivity after a subsequent immunization attempt. For these studies, the techniques of immunization and skin testing were first improved. One feeding with a high dose of K2Cr2O7 (containing hexavalent chromium) was effective in full tolerance induction. In contrast, trivalent chromium (CrCl3) induced a distinctly lower degree of tolerance, whereas metallic chromium powder was not detectably tolerogenic after a limited number of feedings. Dose-frequency-response studies with K2Cr2O7 showed that full tolerance could also be induced by an increase in the number of feedings with sub-optimal tolerogenic doses. The present results therefore support our hypothesis that long-lasting oral contact with chromium-releasing metal alloys may ultimately result in strong immune tolerance to this metal in subjects without previous skin contact with it. This view is further supported by recent insights into the unique tolerogenicity of oral, as compared with gastro-intestinal, allergenic contacts.

Olive oil as a cause of contact allergy in patients with venous eczema, and occupationally.

From 1985 to 1989, 13 cases of contact allergy to olive oil have been identified in the Departments of Dermatology of Kristianstad and Ostersund Hospitals. Known components of olive oil could not be proved to be the cause of the allergy. This high number of patients with contact allergy to olive oil and possible explanations are discussed.