Muhammad K. Nisar

Non-infectious pulmonary toxicity of rituximab: a systematic review

OBJECTIVE Rituximab (RTX), a B-cell depleting mAb, has been reported to cause pulmonary toxicity in many patients. As the use of this biologic is increasing, we have undertaken a systematic review of the literature to gauge the nature and extent of non-infection-related RTX-induced lung disease. METHODS A systematic literature review was undertaken to document all reported cases of RTX-associated interstitial lung disease (RTX-ILD), evaluating the epidemiological, clinical, radiological, histopathological, laboratory and management data from the available primary sources. The search was conducted using PubMed, the Cochrane Library and EMBASE up to June 2010 using the terms RTX in the advanced search option without limitations and all relevant publications reviewed manually. In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search. Identified articles were included if they displayed a potential relationship between the administration of RTX and ILD following exclusion of other likely causes. RESULTS A total of 121 cases of potential RTX-ILD were identified from 21 clinical studies/trials, 30 case reports and 10 case series. The most common indication for RTX was diffuse large B-cell lymphoma. RTX-ILD occurred more frequently in male patients and was most common during the fifth and sixth decades of life. In most cases, RTX was part of combination chemotherapy, but in 30 (24.7%) cases it was given as monotherapy. The mean and median number of cycles of RTX before disease onset was four, but cases following the first cycle or as late as the 12th cycle were also identified. The mean time of onset, from the last RTX infusion until symptom development or relevant abnormal radiological change was 30 days (range 0-158 days). Abnormal radiological findings were similar in all patients, with diffuse bilateral lung infiltrates apparent on chest radiographs and/or thoracic CT. Hypoxaemia was seen in all cases and pulmonary function tests were uniformly abnormal with a characteristic diffusion capacity deficit and restrictive ventilatory pattern. RTX-ILD was fatal in 18 cases. CONCLUSION ILD is a rare but potentially fatal complication of RTX therapy. This diagnosis should be considered in any patient who develops respiratory symptoms or new radiographic changes while receiving this biologic agent.

Non-infectious pulmonary complications of newer biological agents for rheumatic diseases—a systematic literature review

OBJECTIVE Lung disease is commonly encountered in rheumatological practice either as a manifestation of the underlying condition or as a consequence of using disease-modifying therapies. This has been particularly apparent with the TNF-α antagonists and exacerbations of interstitial lung disease (ILD). In view of this, we undertook a review of the current literature to identify non-infectious pulmonary complications associated with the newer biologic agents used for the treatment of rheumatic conditions. METHODS A systematic literature review (SLR) was conducted using PubMed, the Cochrane Library and EMBASE for reviews, meta-analyses, clinical studies and randomized controlled trials, case studies and series, published up to June 2010 using the terms rituximab (RTX), certolizumab, golimumab (GOL), tocilizumab (TCZ) and abatacept in the advanced search option without limitations. In addition, abstracts from International Rheumatology conferences and unpublished data from the Food and Drug Administration, the European Medicines Agency and drug manufacturers were used to complement our search. References were reviewed manually and only those articles that suggested a potential relationship between the biological agent and lung toxicity, following exclusion of other causes, were included. RESULTS Reported non-infectious pulmonary adverse events with TCZ included a fatal exacerbation of RA-associated ILD, new-onset ILD, idiopathic pulmonary fibrosis and allergic pneumonitis, as well as three cases of microbiological culture-negative pneumonia. Although RTX had a higher incidence of pulmonary toxicity, only 7 of the 121 cases reported involved rheumatological diseases. GOL treatment was associated with four cases of non-infectious pulmonary toxicity and two cases of pneumonia with negative microbiological studies. There were no episodes of pulmonary toxicity identified for either certolizumab or abatacept. CONCLUSION Our results highlight an association between the use of newer biologic agents (TCZ, RTX and GOL) and the development of non-infectious parenchymal lung disease in patients with RA. Post-marketing surveillance and biologic registries will be critical for detecting further cases of ILD and improving our understanding of the pathophysiology of this process. As the use of these drugs increases, clinicians must remain vigilant for potential pulmonary complications and exercise caution in prescribing biologic therapies, particularly to rheumatological patients with pre-existing ILD.

Interleukin-6 and cytochrome-P450, reason for concern?

Interleukin 6 (IL-6) plays a central role in the immunopathogenesis of rheumatoid arthritis (RA) and tocilizumab [TCZ] (an anti-IL-6 receptor antibody) has been shown to be effective in the treatment of the condition. As up-regulation of IL-6 reduces the activity of cytochrome P450 (CYP) enzymes, blockade of this cytokine may enhance CYP function. This may lead to reduced bioavailability of CYP-metabolized drugs. Due to the increasing use of TCZ, we undertook a systematic literature review to explore such interactions. Our search was conducted in MEDLINE, EMBASE, Web of Science, FDA and EMEA websites for in vitro and in vivo studies, clinical trials and reviews mentioning TCZ and CYP on the basis of the title and abstract. Appropriate articles were further screened based on full-text review to select only those reporting IL-6, TCZ and their potential interaction with CYP-metabolized drugs. Two in vitro studies showed that TCZ-reversed IL-6 induced reduction of CYP isozymes. CYP3A4 mRNA expression was most reduced by IL-6 followed by CYP2C9 and CYP2C19. This change was prevented with TCZ. Three clinical studies investigated the interaction showing simvastatin (CYP3A4 substrate) bioavailability reduced by TCZ and omeprazole bioavailability was decreased by TCZ-induced CYP2C19 activity. The bioavailability of dextromethorphan (CYP2D6 and CYP3A4 substrates) was shown to be unaffected by TCZ treatment. The observed increase in CYP isozyme activity by TCZ is of clinical relevance as the bioavailability of the CYP isozyme substrates were decreased in vivo. As CYP3A4 is the isozyme responsible for the largest proportion of drug metabolism, it is probable that the bioavailability of other drugs may be reduced by TCZ. Thus, clinicians should exercise caution when co-prescribing TCZ and CYP-metabolized drugs. More studies are required to investigate this interaction further.

Chikungunya and bilateral sacroiliitis–is there a link?

Chikungunya (CKG) is an arthritogenic mosquito-transmitted alphavirus that manifests itself as a febrile illness and often progresses to severe and incapacitating polyarthralgia (1). Several reports have demonstrated persistent polyarthritis akin to seronegative peripheral arthropathy (2). However, to our knowledge, imaging-confirmed axial disease has not been described in this context. We report the case of an Asian lady who developed axial spondyloarthropathy (SpA) after contracting CKG while visiting India during an outbreak. Informed consent was obtained from the patient.

Lemierre's syndrome: a rare cause of septic polyarthritis.

Lemierre’s syndrome is a very rare disease which can cause severe sepsis in previously healthy young adults. The syndrome was Wrst described by Andre Lemierre in 1936 who documented 20 cases of throat infection followed by anaerobic septicaemia [1]. In the last 15 years, there has been a rise in incidence possibly related to restriction in antibiotic use for sore throat [2]. We report a case of Lemierre’s syndrome causing disseminated septic emboli and polyarthritis in a previously healthy young man.

Pulmonary Complications of Biological Therapies in Children and Adults with Rheumatic Diseases

The management of rheumatic conditions, including those occurring in children, has improved dramatically over the last decade following the introduction of biologic disease-modifying anti-rheumatic drugs (bDMARDS) into the therapeutic arsenal. The benefits have been realised in multiple aspects of disease including signs and symptoms, bone and cartilage destruction, disability and quality of life. Overall, bDMARDS have an acceptable safety profile in the short to medium term in adults and children, however, that following longer term use remains unclear. As these drugs target key signalling molecules and cells of the immune system, adverse events are not unanticipated. In this review we will discuss pulmonary complications of biologic therapies used in the management of rheumatic diseases in both children and adults.

TNF antagonists and shingles: is vaccination advisable?

We read with interest the report by Galloway et al 1 on the risk of skin and soft tissue infections (including shingles) in patients exposed to tumour necrosis factor (TNF) antagonists from the British Society of Rheumatology biologics register (BSRBR). In the light of our recently published systematic literature review of the risk of shingles in rheumatoid arthritis (RA) patients, we would like to address several issues raised in the report.2 The authors state that the incidence of shingles is 1.6/100 patient-year (PY) in the anti-TNF cohort compared with 0.8/100PY in the non-biologic disease modifying anti-rheumatic drug (nbDMARD) group. However, it is well established that RA patients have an inherently higher risk of shingles irrespective of treatment modality.3 In a retrospective analysis of data from a US managed care database (n=122 272) and a UK general practice research database (n=38 621), an increased risk of shingles was found among all patients with RA …

Combining secukinumab and apremilast to successfully treat refractory psoriatic skin and joint disease: A novel approach

A 23-year-old male with childhood-onset chronic plaque psoriasis presented in our unit with recalcitrant skin and joint disease. Both his father and sister had challenging psoriasis as well. His prior treatments included a variety of oral immunomodulators, ciclosporin (discontinued because of severe mood changes), sulfasalazine (stopped due to erythrodermic flare), and methotrexate (both oral and subcutaneous) up to 25 mg weekly for 2 years with little benefit. Intractable nausea led to frequently missed doses and poor adherence.

Adherence to biologic therapy – Does it vary with ethnicity?

BackgroundPoor adherence to therapy remains a significant barrier to improving clinical outcomes in rheumatic diseases and carries a major financial burden. It has been linked to medication related patient beliefs, which were reported to differ between ethnic groups. Little is known about these variations in biologic therapies cohorts. The purpose of this study was to identify potential determinants of adherence to biologic drugs including an assessment of the influence of beliefs about medicines and compare determinants of adherence between patients of Caucasian versus other ethnicities (OE). Relationship of adherence to disease outcome was further explored. MethodsA prospective survey was undertaken of patients with inflammatory arthritis prescribed self-administered subcutaneous biologic therapies at our centre. Data were collected using a) self reported adherence b) five item compliance questionnaire for Rheumatology (CQR5) and c) Beliefs about Medications questionnaire (BMQ) specific-five items each for necessity and concern scales. The replies were assessed against the disease activity score measured on the day of recruitment to the survey. Results80 patients contributed to the survey. 90% were prescribed TNF inhibitors. 40 patients were of Caucasian origin and 40 belonged to OE-predominantly of South Asian descent (85%). Disease activity score (DAS) was significantly higher in OE patients with 3.7 (standard deviation (SD) 1.3) compared to Caucasian patients with a DAS of 2.9 (1.6) (p = 0.031). Negative beliefs (i.e. higher concern scale scores) about therapy were significantly more prevalent (24/40) (60%) in the OE group compared to the Caucasian cohort (14/40 (35%) (p = 0.043). 17/40 (42.5%) of OE patients were poorly adherent to biologic therapy compared to 12/40 (30%) of Caucasian participants (p = 0.308). Most respondents (68/80, 85%) agreed that their biologic therapies were necessary for their health. Amongst 12/80 (15%) who disagreed, only two were in the non-adherent group. ConclusionTo our knowledge, this is the first study to demonstrate ethnic differences in disease activity score and related negative beliefs regarding subcutaneous biologic therapies in people with rheumatic diseases.

SAT0357 Tuberculosis and Biologics: Real World Experience from High Tuberculosis Prevalence Area

Background Biologic agents have led to a sea change in the management of inflammatory arthritis however higher risk of opportunistic infections particularly tuberculosis (TB) is well recognised. This has led to the development of TB screening guidelines. Objectives The aim of this study was to investigate the prevalence of latent TB in patients prescribed biologic therapy in a TB endemic area (prevalence 50/100,000) and to assess the risk of subsequent reactivation. Methods Retrospective case note review of all patients with inflammatory arthritis ever prescribed biologic therapy between 1998 and 2014 at our centre. Results 299 patients (109 men: 190 women) who have had biologic therapy over sixteen years were included. Mean age upon commencing the biologic was 51 years. 203 (68%) participants had rheumatoid arthritits, 30 (10%) psoriatic arthritis, 48 (16%) axial spondyloarthropathy and 18 (6%) juvenile idiopathic arthritis. 218 (73%) patients were Caucasian, 59 (20%) Asian, 15 (5%) Afro-Caribbean and the remaining 7 were mixed race. 239 (80%) prescriptions were issued for TNF inhibitors (98 for etanercept and remaining for monoclonal antibodies). 33 patients had rituximab, 17 had tocilizumab and 3 were initiated on abatacept. Seven had stopped TNF inhibitors. Median duration of biologic therapy was 4.2 years for those who remained on treatment prior to stopping or switching therapies. Prior to the implementation of TB screening in the unit in 2007, 112 patients underwent clinical assessment, chest x-ray and check for BCG scar. One patient of Asian origin developed extra-pulmonary TB within six weeks of adalimumab initiation. Following a year of antiTB treatment, he restarted the biologic therapy with no ill effect. 187 participants underwent additional interferon gamma release assay (IGRA) testing as part of new protocol (T Spot test). 18 (10%) had positive test with normal chest xrays. Six patients were white, 9 of Asian origin and 3 others. Three Caucasian patients had borderline result. All had 3 months of isoniazid and rifampicin with simultaneous prescription of biologic agent (13 had TNF antagonist, 5 rituximab and 3 tocilizumab). No cases of active TB infection were observed. Conclusions Prevalence of latent TB in patients with inflammatory arthritis prescribed biologic therapy in an endemic area is 10%. The risk is independent of ethnicity and warrants careful screen and monitoring in all patients. Adherence to strict screening protocol reduces the risk of active TB infection irrespective of the biologic therapy employed. Disclosure of Interest None declared