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Biological disease-modifying anti-rheumatic drugs (bDMARDs) are widely used for the treatment of chronic inflammatory rheumatic diseases. Since the introduction of tumor necrosis factor alpha (TNF-) inhibitors, the treatment of rheumatoid arthritis has been revolutionized. The approach of targeting TNF- has considerably improved the success of the treatment of rheumatoid arthritis. Their effectiveness has been extensively proven in randomized clinical trials and in clinical practice. Randomized clinical trials and post-marketing studies proved that patients undergoing TNF- inhibitors therapy are at increased risk of infectious disease, bacterial, viral, fungal, opportunistic, oncology and skin adverse effects such as psoriasis and angiitis of the skin. In this case report drug-induced cutaneous vasculitis developing during TNF- inhibitor (Etanercept) treatment for rheumatoid arthritis is described.

Drug-induced vasculitis and anticoagulant-related skin reactions are commonly encountered in the inpatient and outpatient settings. The spectrum of clinical presentation is broad and ranges from focal, skin-limited disease, to more extensive cutaneous and soft tissue necrosis, to potentially fatal systemic involvement. The prompt recognition of these adverse events can have a significant impact on patient morbidity and mortality. We highlight the key features of the clinical presentation with an emphasis on primary lesion morphology, distribution, and epidemiology of purpuric drug reactions. The proposed pathophysiology, histologic findings, and therapeutic interventions of these potentially life-threatening diseases are discussed.

Yuh Shan Lee1, Leonard Tan2, Choon Chiat Oh3, Yuen Li Ng4, Yeow Tee Goh1 and Daryl Tan1* 1Department of Hematology, Singapore General Hospital, Singapore 2Department of Pathology, Singapore General Hospital, Singapore 3Department of Dermatology, Singapore General Hospital, Singapore 4Department of Radiology, Singapore General Hospital, Singapore Cancer Science & Research: Open Access Open Access Case Report

Summary Bortezomib is the first proteasome inhibitor to be approved for use in haematological malignancies. Although a rash has been described as a common adverse event associated with the drug, it has not been well characterised. Based on three phase II studies of bortezomib in patients with non-Hodgkin lymphoma (140 assessable patients), we identified 26 patients who developed a unique erythematous maculopapular rash during treatment, six of whom underwent cutaneous biopsy. Punch biopsy in six patients revealed a perivascular lymphocytic infiltrate without evidence of lymphoma, consistent with a non-necrotising cutaneous vasculitis. The combined overall response rate was 41%. The response in the 26 patients who developed a rash was 73%, compared with 33% in patients who did not. The odds ratio for response given the development of a rash was 4·6 (95% CI, 1·7–12·4, P = 0·001). This is the first report to characterise a vasculitic rash associated with bortezomib, and to show a relationship between development of the rash and response to treatment. Unlike classic hypersensitivity type reactions, this vasculitic rash may not necessarily prompt cessation of drug. In fact, the development of an isolated cutaneous vasculitis may portend a better clinical response to bortezomib in some patients.

Many cases of cutaneous vasculitis are druginduced with histology revealing leukocytoclastic vasculitis (LCV). We present a case of levofloxacin- associated LCV successfully treated with prednisone and cessation of the offending drug. Although case reports describe a link between LCV and older fluoroquinolones, such as ciprofloxacin and ofloxacin, recent reports have implicated the newer fluoroquinolone levofloxacin. Recognition of fluoroquinoloneinduced cutaneous vasculitis is important as continuation or re-exposure of the offending agent may have life-threatening consequences.

Background Non healing cutaneous ulcers of lower limbs can have several different aetiologies. [1] It is likely that the patients with such ulcers would be treated with empirical therapies and may also undergo (unnecessary) venous procedures. Small vessel vasculitides (leucocytoclastic or non leucocytoclastic) are one of the important causes of non healing cutaneous leg ulcers. [2] Objectives The primary objective of this prospective study was to ascertain the cause of non healing cuatneous ulcers of the lower limbs. Methods Between May 2010 and April 2013 (3years) consecutive adult patients (age 18 to 75 years) who had one or more persistent leg ulcers (with or without a history of recurrent ulcerations in legs) for more than 2 years presenting to either departments were prospectively enrolled. Relevant details were extracted using a predefined proforma and included: demographic details, drug history, comorbidities, clinical features, investigations including ANCA, complement levels, cryoglobuilins, HIV and Hepatitis viral serology etc. and venous and arterial Dopplers, microscopy and culture of the ulcer swab in cases of infected looking ulcers. Biopsies were obtained from the ulcer edges and nonulcerated sites where skin lesions were also present. In cases of ulcers deemed to be a manifestation of a primary systemic vasculitis based on the EMEA classification, BVAS was used to assess disease activity. Results A total of 51 patients were assessed. Mean age was 53±10.3 years and 39 (76%) were male. Eight (16%) patients were diabetic. History of some type of venous surgery was present in 30 (59%) and 9 had such procedures more than once. Biopsy confirmed small vessel vasculitis of various types in a majority (76%) of patients (table 1). Drug induced cutaneous vasculitis was not present in this cohort. Table 2 shows that in 9 (18%) patients the leg ulcers were one of the manifestations of a primary systemic vasculitis i.e GPA, EGPA, MPA or PAN. Leg ulcers in these patients ran an indolent course with a variety of low to moderate grade of activity features reflected also in the BVAS range of 9 to 15. All patients with small vessel vasculitis were treated with immunosuppressive therapy including glucocorticoids with good effect [complete healing of ulcer(s) in 21 patients with no relapse in 24 weeks follow up period]. Conclusions In this cohort of patients with chronic non healing leg ulcers systematic assessment revealed small vessel vasculitis as the leading cause thus enabling specific measures of treatment being instituted. References Mekess JR et al. Causes, investigation and treatment of leg ulceration. British Journal of Dermatology 2003; 148: 388–401 Gonzalez-Gay MA et. Other vasculitides including small-vessel vasculitis. In: Oxford Textbook of Rheumatology 3rd ed, Isenberg DA et al (eds). OUP 2004, pp983-988. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1648

Background Bortezomib, recently approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma, is the first antineoplastic agent in a new class of drugs known as proteasome inhibitors. To date, rash has been described as a common adverse events associated with the drug. This rash is typically consistent with a hypersensitivity reaction. However, in two independent, single agent phase 2 studies of bortezomib in patients with non-Hodgkins lymphoma (one multicenter trial coordinated by Memorial Sloan Kettering Cancer, the second at the M.D. Anderson Cancer Center), we identified a subset of patients who developed a cutaneous vasculitis not previously reported with this therapy. Furthermore, development of this novel rash seems to correlate with a better response to bortezomib. Methods 18 patients who developed a unique erythematous maculopapular rash while receiving bortezomib were identified, 6 of whom underwent cutaneous biopsy reviewed by a dermatopathologist. The remaining patients were not biopsied, but exhibited a rash with identical clinical features. Results These rashes were distinct from the classic hypersensitivity rash more commonly noted with bortezomib therapy. They did not appear to be associated with any particular dose, tended to occur later in the course of treatment, and resolved with withdrawal of the agent, always returning with continuation of planned therapy with bortezomib. There was no evidence of multi-organ system involvement, and the rash was relatively asymptomatic. Punch biopsy revealed a perivascular lymphocytic infiltrate without evidence of lymphoma, sometimes associated with small vessel necrotizing vasculitis. While the overall response rate (CR + PR) in all patients was 38%, the response rate in patients with rash was 67%, compared with a response rate of 31% in patients who did not develop rash (see Table 1). Using measures of accuracy based on this data (see Table 2), the positive predictive value of vasculitic rash for response to bortezomib is 67% (95% confidence interval (CI) 41 – 87%), negative predictive value is 69% (CI 57 – 79%), sensitivity is 32% (CI 18 – 50%) and specificity is 90% (80 – 96%). Logistic regression analysis supports this association, and shows that the odds ratio for response given vasculitic rash is 4.4 (CI 1.5 – 13.1, p = 0.008). Conclusions This report is the first to describe a strong causal relationship between bortezomib and a cutaneous vasculitis. Recognition of this association should prompt a specific clinical evaluation and close monitoring of patients who develop bortezomib-associated rashes in the future. In contrast to classic hypersensitivity type reactions, the development of this vasculitic rash may not necessarily prompt cessation of drug. In fact, based on the limited experience presented here, the development of an isolated cutaneous vasculitis may portend a better clinical response in patients treated with bortezomib. Association of Vasculitic Rash with Response to Bortezomib No Rash Rash Total No Response 55 6 61 Response 25 12 37 Total 80 18 98 % Response 31% 67% 38% Rash and Response 95% Confidence Interval Sensitivity 32.43% 18.01% – 49.79% Specificity 90.16% 79.81% – 96.30% Positive Predictive Value 66.67% 40.99% – 86.66% Negative Predictive Value 68.75% 57.41% – 78.65%