Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: Drug survival is a marker for treatment sustainability in chronic diseases such as psoriasis. OBJECTIVE: The aim of these analyses was to assess survival of biologic treatments in the PSOriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a large, prospective, international, disease-based registry of patients with psoriasis receiving (or eligible for) systemic therapy in a real-world setting. Drug survival is defined as the time from initiation to discontinuation (stop/switch) of biologic therapy on registry. The number of patients who discontinued each treatment and the duration of therapy were recorded. Using Kaplan-Meier survival curves and Cox-regression analyses [hazard ratios (HR) and 95% confidence intervals (CIs)], time to discontinuation was compared across cohorts undergoing first-, second- or third-line treatment with ustekinumab, infliximab, adalimumab or etanercept. RESULTS: As of the 2013 data cut, 12 095 patients with psoriasis were enrolled in PSOLAR. Of the 4000 patients initiating any new biologic therapy, approximately 3500 started a first-line, second-line or third-line biologic therapy during the registry. Lack of effectiveness was the most common reason for discontinuation across biologic therapies. Based on the multivariate analysis, significantly shorter times to discontinuation were observed for infliximab [HR (95%CI) = 2.73 (1.48-5.04), P = 0.0014]; adalimumab [4.16 (2.80-6.20), P < 0.0001]; and etanercept [4.91 (3.28-7.35) P < 0.0001] compared with ustekinumab [reference treatment]) for first-line biologic use; results were similar for treatment effects for second/third-line therapies. Although limited in power, analyses in patients with concurrent psoriatic arthritis confirmed by a rheumatologist reflect observations in the overall psoriasis population. CONCLUSION: Drug survival was superior for ustekinumab compared with infliximab, adalimumab and etanercept in patients with psoriasis.

[Type I cryoglobulinemia with a fatal outcome]. / Crioglobulinemia tipo I de desenlace fatal.

Type I cryoglobulinemia, a condition associated with lymphoproliferative disorders, is caused by monoclonal immunoglobulins that precipitate at low temperatures. It mostly involves the skin and pathology study shows no signs of vasculitis. Management is usually based on immunosuppressive drugs associated with plasmapheresis for severe disease. The use of rituximab has recently been described for resistant cases. We present an unusual case of long-standing type I cryoglobulinemia associated with a monoclonal gammopathy of unknown significance. The patient developed extremely severe skin lesions with histological signs of vasculitis. The patient died due to the onset of noncutaneous manifestations of the cryoglobulinemia and complications of the immunosuppressive treatment.

Biological agents in the treatment of psoriasis.

Psoriasis is a chronic immune-mediated inflammatory disease, with an estimated prevalence of 1-3% worldwide. It is considered to be a multisystemic disorder, primarily affecting the skin and joints (psoriatic arthritis), and associated with other inflammatory conditions such as inflammatory bowel disease and coronary heart disease among others. Today, thanks to recent scientific advances that have allowed us to deepen our understanding of the pathogenesis of psoriasis, we count with an expanded therapeutic armamentarium that includes targeted therapy in the form of ''biologics''. These agents have gained popularity as safe, effective, and convenient alternatives for the treatment of chronic moderate to severe plaque psoriasis. This review will focus on the main biologics used in the treatment of moderate to severe plaque psoriasis: efalizumab, alefacept, etanercept, infliximab, adalimumab and the new Interleukin (IL) 12/23 inhibitors.

Immunohistochemical evaluation of toxic epidermal necrolysis treated with human intravenous immunoglobulin.

AIM: Toxic epidermal necrolysis (TEN) is a severe drug reaction characterized by massive epidermal cell death. The authors of the current study and others have noted improved outcomes in TEN patients treated with human intravenous immunoglobulin (IVIG), purportedly due to its ability to inhibit the fas/fas-ligand (Fas-L) apoptotic pathway, but published case series evaluating TEN through the use of immunohistochemical antibody stains for Fas and Fas-L before and after IVIG treatment are lacking. The authors hypothesized that due to IVIG's ability to arrest the evolution of TEN, expression of Fas/Fas-L on keratinocytes would be decreased or absent following IVIG treatment. METHODS: Ten patients diagnosed with TEN underwent biopsies of their lesions prior to and five days after treatment with IVIG. Seven post-treatment biopsies were of sufficient quality to undergo evaluation. RESULTS: All ten pretreatment biopsies had Fas and Fas-L expression by immunohistochemistry, while six out of seven (85.7%) post-treatment biopsies failed to demonstrate Fas or Fas-L expression. One of seven post-treatment biopsies stained positive for Fas and Fas-L. CONCLUSION: This reduced immunohistochemical expression of apoptotic markers may represent IVIG inhibition of the pathogenic mechanism of TEN. Alternatively reduced Fas and Fas-L may be a feature of reepithelialization in TEN, or characteristic of rapidly proliferating epidermis.

In vivo mediator release and degranulation of mast cells in hematoporphyrin derivative-induced phototoxicity in mice.

This study was designed to assess the role of the mast cell in the early phase of hematoporphyrin derivative (HPD)-induced phototoxicity. BALB/c mice were rendered phototoxic by i.p. injection of hematoporphyrin derivative, followed by exposure to 13.6 kJ/m2 of 400-410 nm radiation. The phototoxic response was quantified by measurement of ear thickness immediately before the irradiation, and at 0, 0.5, 1, 1.5, and 2 h after. At these time-points, determinations of serum histamine and plasma leukotriene C4 levels and histologic examination of the ears were undertaken. Mice injected i.p. with buffered saline and subsequently irradiated served as controls. In mice exposed to HPD and radiation, a maximal peak increased ear-thickness of 125.7 +/- 14.4% (mean +/- SEM) was noted at 2 h; this was associated with a net increased serum histamine of over 120% and histologic evidence of mast cell degranulation. In addition, moderate increases in plasma levels of leukotriene C4 were observed at 0 h and 1.5 h in the HPD- and irradiation-treated animals. These data provide direct evidence for the participation of mast cells in the early phase of HPD-induced phototoxicity.

Cimetidine-induced augmentation of allergic contact hypersensitivity reactions in mice.

BALB/c mice were treated with cimetidine (100 mg/kg) or saline, intraperitoneally, twice daily, from days 0-2 or days 7-9 after sensitization with 0.1%, 2,4,6-trinitro-1-chlorobenzene (TNCB) on day 0. On day 7, the mice were challenged with 1% TNCB to one ear. Ear swelling responses (as an index of sensitization), serum histamine levels, and biopsy specimens of challenged ears were evaluated in groups of cimetidine- or saline-treated mice at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after challenge. Additional controls included mice injected with saline or cimetidine and challenged with, but not sensitized to, TNCB (irritant controls). Treatment with cimetidine during the induction but not the elicitation of allergic contact hypersensitivity (ACH) produced a significant enhancement of the response throughout the first 48 h. There was no effect of cimetidine on antigen-presenting cells within the epidermis which might account for this enhancement. Similarly, no difference in mast cell morphology or serum histamine levels between cimetidine- and saline-treated groups was observed. Histologically, the cimetidine-treated animals showed a more intense cellular infiltrate, which was most noticeable at 24 to 48 h, at which time numerous subcorneal and perifollicular neutrophilic abscesses were observed. To further investigate the mechanism of action of cimetidine, mice were injected with cyclophosphamide (150 mg/kg) 2 d prior to sensitization. Mice treated with cyclophosphamide alone or in combination with cimetidine showed no additive or synergistic effect upon the ear swelling response. We conclude that enhancement of ACH by cimetidine is independent of any effect on mast cells or antigen-presenting cells, but may relate to a cimetidine-induced inhibition of the induction of T-suppressor cells at the time of sensitization.

Mast cell participation during the elicitation of murine allergic contact hypersensitivity.

In order to evaluate mast cell participation in allergic contact hypersensitivity (ACH), BALB/c mice were sensitized with 0.1% trinitrochlorobenzene (TNCB). Immediately before challenge and at 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after challenge with 1% TNCB, groups of animals had ear thickness measured, had blood collected for histamine determinations, and had both ears removed for histologic evaluation of mast cells. The increase in ear swelling was triphasic with peak increases at 1.5 h (14.3 +/- 1.6 X 10(-2) mm; mean +/- SEM), 8 h (19.9 +/- 1.8 X 10(-2) mm), and 24 h (30.2 +/- 2.9 X 10(-2) mm). A triphasic pattern of increased serum histamine was noted at 1-4 h (117% over control levels), at 12 h (131%), and at 48 h (133%). Examination of the tissue specimens from challenged animals showed modest (1+) degranulation of mast cells between 1 and 6 h with extensive (2+) degranulation at 12 h. In addition, hypogranulated mast cells were evident between 1 and 6 h, at 24 h, and at 48 h. There were no statistically significant differences in mast cell numbers at any time. Neither platelets nor other formed elements of the blood contributed to the increased blood histamine levels. These data show that mast cells are activated in a triphasic pattern during ACH, and thus suggest both early and late roles for the mast cell and its products in the evolution of ACH.

Pagetoid reticulosis. Histiocyte marker studies.

Epidermal mononuclear cell infiltrate from three patients with pagetoid reticulosis was examined for the presence of the cytoplasmic markers lysozyme, alpha 1-antitrypsin and alpha 1-antichymotrypsin, using specific antisera and a peroxidase-antiperoxidase technique. Many of the infiltrating cells possessed these markers, indicating that they belonged to the monocyte-macrophage-histiocyte series.

Generalized atrophic sarcoidosis with ulcerations.

A 53-year-old man presented to the Manhattan (NY) Veterans Administration Hospital with a 20-year history of generalized atrophic lesions associated with lower extremity ulcerations. Cutaneous biopsy specimens and other laboratory data confirmed the diagnosis of sarcoidosis involving the skin, lungs, eyes, joints, bones, pituitary gland, gonads, and liver. To our knowledge, generalized atrophic sarcoidal lesions have not been described previously in the English literature. Ulcerated cutaneous sarcoidal lesions, though recognized, are only rarely seen in the disease. The ulcerations, but not the atrophic lesions, responded to prednisone therapy.

Increased plasma histamine level in eosinophilic fasciitis.

In a patient with eosinophilic fasciitis, a biopsy specimen obtained within 4 weeks of the onset of symptoms showed infiltration of the subcutis and fascia with mast cells, and there was up to a 19-fold increase in plasma histamine levels. The patient improved and experienced softening of the skin when treated with systemic corticosteroids and a histamine2-receptor antagonist, and her plasma histamine level returned to normal. Tissue mast cell infiltration and excessive plasma histamine levels were not present in two otherwise similar patients with eosinophilic fasciitis who were studied 7 months after disease onset. It is possible that mast cells play a pathogenic role in some patients with eosinophilic fasciitis.

Elevated plasma histamine levels in systemic sclerosis (scleroderma).

Systemic sclerosis is characterized by excessive deposition of collagen and other matrix proteins in the skin and internal organs. One hypothesis supports fibroblast stimulation for production of excess amounts of collagen by factors present in the blood or released by cells composing inflammatory tissue infiltrates. Increased numbers of mast cells are present in the involved skin of patients with systemic sclerosis, and histamine has been thought to be a possible mediator of fibrosis in this and other fibrotic conditions. We therefore measured plasma histamine levels in 32 patients with systemic sclerosis and found elevated levels in 18 patients (56%). Elevated plasma histamine levels were more common in patients with diffuse disease (74%), in contrast to limited disease (31%). The degree of clinical activity and the duration of disease could not be correlated with histamine levels.

Analysis of antibiotic susceptibilities of skin wound flora in hospitalized dermatology patients. The crisis of antibiotic resistance has come to the surface.

BACKGROUND: Results of an ongoing surveillance of antibiotic resistance in hospitalized dermatology patients are presented. Bacterial isolates cultured from patients with skin wounds admitted to a tertiary care dermatology inpatient unit from May 1995 through May 1996 were evaluated for resistance to commonly used antibiotics. Comparison was made with a previous survey of the same inpatient service from 1992. Our results show an alarming trend toward antibiotic resistance. OBSERVATION: In superficial skin wounds, Staphylococcus aureus constituted 77% of isolates. In leg ulcers, the frequencies of S aureus and Pseudomonas aeruginosa were approximately equal, constituting 43% and 42% of cultures, respectively. Fifty percent of S aureus isolates from leg ulcers were resistant to oxacillin, with 36% of pseudomonad isolates resistant to ciprofloxacin. In superficial wounds, oxacillin resistance in S aureus approached 25%. A comparison of antibiotic resistance profiles using data collected in 1992 for patients admitted to the same inpatient service revealed a marked increase in oxacillin and ciprofloxacin resistance in S aureus and P aeruginosa in leg ulcers, respectively (from 24% to 50% oxacillin resistance in S aureus and from 9% to 24% ciprofloxacin resistance in P aeruginosa), and superficial wounds (24% to 36% ciprofloxacin resistance in P aeruginosa). CONCLUSION: This study demonstrates the rapid emergence of antibiotic-resistant bacteria as a problem of growing significance in hospital dermatology and highlights the importance of local surveillance programs to aid in selecting antibiotic treatments.

Amebiasis and trypanosomiasis.

Parasitic diseases, once limited to developing countries, may be seen in the United States with increasing frequency as air travel links continents. When cutaneous manifestations of these diseases are a part of the clinical picture, dermatologists are often called upon to contribute to the diagnosis. Amebiasis may result in painful anogenital ulcers; African trypanosomiasis (sleeping sickness) often begins with the trypanosomal chancre at the site of parasitic entry, and American trypanosomiasis (Chagas' disease) most commonly presents as Romaña's sign. Epidemiology, pathophysiology, immunology, clinical presentation, and treatment are reviewed for each of these diseases.

Other novel immunosuppressants.

The use of immunosuppressive agents in dermatology has increased widely. The role of these medications has become increasingly important for the treatment of dermatologic disorders in an inpatient setting, where there is frequently a requirement for highly potent, fast-acting, effective agents. This article presents an overview of the general application, mechanisms of action, metabolism, and adverse effects commonly associated with systemic immunosuppressive agents used in dermatology.

Inpatient dermatology. A prescription for survival.

Currently, only a minority of dermatologists participate in the primary hospital care of patients with severe skin disease. However, an opportunity exists to alter this course. We believe the current course is a detriment to our specialty, and as a specialists we should provide the care for the full spectrum of dermatologic diseases. Moreover, by not delivering complete dermatology care, our specialty also stands to lose respect from both our patients and peers. Our experience at UM suggests that the creation of a cadre of dermatology hospitalists at selected academic medical centers would allow improved patient hospital care, education, and research.

Inpatient dermatology. The difficulties, the reality, and the future.

Changes in the health care delivery system have profoundly affected medical dermatology in the United States. Although a significant number of patients are still being admitted for skin and skin-related disorders, only a minority are now admitted by dermatologists. An analysis of the mechanics of such a change and a national perspective is presented.

The effect of health care delivery systems on admission to and treatment at an inpatient dermatology unit.

The University of Miami Department of Dermatology has maintained an active inpatient unit. Analysis of data from a 12 month period from 1995-1996 showed 562 admissions. Cutaneous lymphoma, psoriasis, and chronic wounds accounted for over half the admissions. Most patients were insured by a fee-for-service system, and compared to patients insured by managed care systems or patients who were indigent, fee-for-service patients had the shortest length of stay. Using a case mix severity index, indigent patients had the greatest disease severity followed by fee-for-service patients. Patients enrolled in managed care systems had the least severity suggesting that factors other than disease severity alone may play a role in determining why patients are admitted.

Microbiologic evaluation of cutaneous wounds in hospitalized dermatology patients.

The purpose of this study is to identify predictability of wound flora which may be helpful in the selection of empiric antibiotic therapy of wound infections while awaiting the results of bacterial cultures. Toward this end, results of an ongoing microbiologic surveillance of skin wound flora in hospitalized dermatology patients are presented. Bacterial isolates cultured from patients with skin wounds admitted to a tertiary care dermatology inpatient unit were evaluated and comparison was made to a previous survey of the same inpatient service done in 1992. Microbiologic evaluation of superficial skin wounds, leg ulcers, and pressure ulcers showed that Staphylococcus aureus was the principal isolate in superficial wounds (77%) compared to the equal prevalence of S. aureus (43%) and Pseudomonas aeruginosa (42%) cultured from leg ulcers. Cultures from pressure ulcers grew Proteus mirabilis as the dominant isolate. These data agree with previous surveillance data from the same inpatient base performed in 1992 and support the relatively predictable wound flora cultured from skin wounds in our hospital inpatient unit over the 4 years surveillance period. This predictability can enhance empiric antibiotic selection for wound infections while awaiting the results of bacterial culture, and supports the value of local microbiologic surveillance programs in the management of wound infections.