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      Pneumocystis Jirovecii Pneumonia after Initiation of Tofacitinib Therapy in Rheumatoid Arthritis: Case-Based Review

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          Abstract

          The use of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) in rheumatic diseases is constantly increasing during the last decade. Tofacitinib is a new oral Janus Kinase (JAK) inhibitor, approved for rheumatoid arthritis (RA), psoriatic arthritis and ulcerative colitis. Safety data of tofacitinib derived from randomized controlled trials and long-term extension studies has demonstrated a moderate increase in the risk for common serious infections. We describe a case of Pneumocystis jirovecii pneumonia (PJP) in a woman on tofacitinib therapy for RA. Although tofacitinib use has been associated with the development of opportunistic infections, PJP has been rarely reported. PJP should be included in the differential diagnosis of patients with autoimmune disorders under newer oral JAK inhibitors therapy who present with fever, hypoxia and pulmonary infiltrates.

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          Most cited references15

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          Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials.

          To assess the efficacy of prophylaxis for Pneumocystis pneumonia (PCP), caused by Pneumocystis jirovecii (formerly Pneumocystis carinii), for immunocompromised non-HIV-infected patients by conducting a systematic review and meta-analysis. We searched for randomized controlled trials that compared prophylaxis using antibiotics effective against P jirovecii, given orally or intravenously, vs placebo, no intervention, or antibiotics with no activity against P jirovecii. In addition, we included trials that compared different PCP prophylactic regimens or administration schedules. The search included the Cochrane Central Register of Controlled Trials, PubMed, Latin American and Caribbean Health Sciences Literature, and conference proceedings. No language, year, or publication restrictions were applied. Two reviewers (H.G. and M.P.) independently searched, selected trials, extracted data, and performed methodological quality assessment. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis was performed using the random-effects model. Twelve randomized trials were identified, including 1245 patients (50% children) who had undergone autologous bone marrow or solid organ transplant or who had hematologic cancer. When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity. Pneumocystis pneumonia-related mortality was significantly reduced (RR, 0.17; 95% CI, 0.03-0.94), whereas all-cause mortality did not differ significantly (RR, 0.79; 95% CI, 0.18-3.46). Adverse events that required discontinuation occurred in 3.1% of adults and none of the children, and all were reversible. No differences between once-daily and thrice-weekly administration schedules were found. Balanced against severe adverse events, PCP prophylaxis is warranted when the risk for PCP is higher than 3.5% for adults. Adverse events are less frequent in children, for whom prophylaxis might be warranted at lower PCP incidence rates.
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            ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients.

            The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological malignancies. Immunofluorescence assays are recommended as the most sensitive microscopic method (recommendation A-II: ). Real-time PCR is recommended for the routine diagnosis of PCP ( A-II: ). Bronchoalveolar lavage (BAL) fluid is recommended as the best specimen as it yields good negative predictive value ( A-II: ). Non-invasive specimens can be suitable alternatives ( B-II: ), acknowledging that PCP cannot be ruled out in case of a negative PCR result ( A-II: ). Detecting β-d-glucan in serum can contribute to the diagnosis but not the follow-up of PCP ( A-II: ). A negative serum β-d-glucan result can exclude PCP in a patient at risk ( A-II: ), whereas a positive test result may indicate other fungal infections. Genotyping using multilocus sequence markers can be used to investigate suspected outbreaks ( A-II: ). The routine detection of dihydropteroate synthase mutations in cases of treatment failure is not recommended ( B-II: ) since these mutations do not affect response to high-dose co-trimoxazole. The clinical utility of these diagnostic tests for the early management of PCP should be further assessed in prospective, randomized interventional studies.
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              Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis

              Abstract To facitinib and baricitinib are two of the currently available Janus kinase (JAK) inhibitors for the treatment of patients with RA. Randomized controlled trials have shown that these JAK inhibitors are as efficacious as biological DMARDs. Safety profiles of these JAK inhibitors in randomized controlled trials and their long-term extension studies have been demonstrated; however, real world evidence remains to be established to bridge the gap between randomized controlled trials and rheumatology clinics. Fundamentally, no difference in the screening, prevention, and monitoring of infections between JAK inhibitors and biological DMARDs exists. However, increased risk of herpes zoster is probably common to all JAK inhibitors. No indication of increased risk for malignancy in patients with RA treated with JAK inhibitors has been reported. To evaluate risks of relatively rare serious adverse events such as thromboembolic events, gastrointestinal perforation, and interstitial lung disease in clinical settings, accumulation of cases with these events are needed. Continuous pharmacovigilance activity is absolutely warranted to establish the safety of JAK inhibitors in patients with RA and other rheumatic diseases.
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                Author and article information

                Journal
                Mediterr J Rheumatol
                Mediterr J Rheumatol
                MJR
                Mediterranean Journal of Rheumatology
                The Mediterranean Journal of Rheumatology (MJR)
                2529-198X
                September 2019
                30 September 2019
                : 30
                : 3
                : 167-170
                Affiliations
                2 nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens Medical School, Hippokration General Hospital, Athens, Greece
                Author notes
                Corresponding Author: Dimitrios Vassilopoulos, MD, Professor of Medicine – Rheumatology 2nd Department of Medicine and Laboratory, Clinical Immunology-Rheumatology Unit National and Kapodistrian University of Athens Medical School, Hippokration General Hospital, 114 Vass. Sophias Ave., 115 27 Athens, Greece, Tel.: +30 213 208 8516, Fax: +30 213 208 8399, e-mail: dvassilop@ 123456med.uoa.gr
                Article
                MJR-30-3-167
                10.31138/mjr.30.3.167
                7045858
                32185360
                dda1a642-2115-4905-a6c9-fa512955d826
                © 2019 The Mediterranean Journal of Rheumatology (MJR)

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 18 July 2019
                : 13 September 2019
                : 16 September 2019
                Categories
                Review

                rheumatoid arthritis,tofacitinib,pneumocystis jirovecii,pneumonia

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