Andreas V. Hadjinicolaou

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 In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search.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.

On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

This review discusses mechanisms that link allelic variants of major histocompatibility complex (MHC) class II molecules (MHCII) to immune pathology. We focus on HLA (human leukocyte antigen)-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (I-Ag7 or Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7), share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP because of poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.

Alternative activation in systemic juvenile idiopathic arthritis monocytes

Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition. The association with macrophage activation syndrome, and the therapeutic efficacy of inhibiting monocyte-derived cytokines, has implicated these cells in SJIA pathogenesis. To characterize the activation state (classical/M1 vs. alternative/M2) of SJIA monocytes, we immunophenotyped monocytes using several approaches. Monocyte transcripts were analyzed by microarray and quantitative PCR. Surface proteins were measured at the single cell level using flow cytometry. Cytokine production was evaluated by intracellular staining and ELISA. CD14(++)CD16(-) and CD14(+)CD16(+) monocyte subsets are activated in SJIA. A mixed M1/M2 activation phenotype is apparent at the single cell level, especially during flare. Consistent with an M2 phenotype, SJIA monocytes produce IL-1β after LPS exposure, but do not secrete it. Despite the inflammatory nature of active SJIA, circulating monocytes demonstrate significant anti-inflammatory features. The persistence of some of these phenotypes during clinically inactive disease argues that this state reflects compensated inflammation.

The efficacy and safety of cryoprecipitate in the treatment of acquired hypofibrinogenaemia

Acquired hypofibrinogenaemia can result in haemorrhage and significant morbidity and mortality. Cryoprecipitate is well established as the treatment of acquired hypofibrinogenaemia in the UK. Although its use is being superseded by fibrinogen concentrate in a number of other countries (Warmuth et al, 2012), there remains a paucity of clinical data on the relative merits of both products, leading to significant variation in clinical practice between institutions (Tinegate et al, 2012; Wikkelsø et al, 2013;) This retrospective, noncontrolled observational study aimed to determine the safety and efficacy of cryoprecipitate in improving plasma fibrinogen levels, coagulation parameters and clinical status in acute and chronic acquired hypofibrinogenaemia. Clinical and laboratory details of patients who were treated with cryoprecipitate in a large teaching hospital between October 2010 and September 2011 were acquired from the electronic records of the hospital’s transfusion service. For each patient, demographic data were collected, as well as primary cause of hypofibrinogenaemia. Plasma Clauss fibrinogen levels, prothrombin time (PT) and activated partial thromboplastin time (aPTT) were recorded prior to cryoprecipitate administration, and subsequent levels noted at both 24 and 72 h following administration. Medical records were used to confirm the indication for cryoprecipitate administration and any subsequent adverse effects post-administration. All cryoprecipitate was sourced from National Health Service Blood and Transplant with a standard adult dose comprising 2 pools (10 units) of cryoprecipitate with a quoted mean dose of 1575 mg of fibrinogen per pool. During the 12-month study period cryoprecipitate was given on 143 separate occasions. Of these, 89 (62 2%) met our inclusion criteria. Our cohort comprised 50 males and 39 females with a mean age of 51 8 years (Table I). All work was undertaken with approval from the local Research Ethics Committee. Across all groups, the mean fibrinogen level was 1 01 g/l (standard deviation [SD] 0 52) at baseline, and the administration of an average of 2 04 units (SD 0 98) of cryoprecipitate increased the average level of fibrinogen by 0 79 g/l (SD 0 89; P < 0 0001) by 24 h, reaching 1 80 g/l, and then by a further 0 41 g/l (SD 1 23; P = 0 02) between 24 and 72 h, to a final mean value of 2 21 g/l. This increase was significantly greater in the acute group compared to the chronic group both at 24 h (increment of 1 00 vs. 0 46 g/l, P = 0 0013) and 72 h (increment of 1 68 vs. 0 40 g/l, P = 0 0006). The average fibrinogen level before administration of cryoprecipitate was similar in the two disease groups (acute vs. chronic; mean 1 02 g/l [SD 0 60] vs. 0 99 g/l [SD 0 37]; P > 0 05 [not significant]), and the amount of cryoprecipitate administered was comparable in the two cohorts, with 2 15 units (SD 0 97) in the chronic group and 1 98 units (SD 0 98) in the acute group. At 24 h post-cryoprecipitate the mean fibrinogen level was higher in the acute group when compared to the chronic group (2 02 g/l [SD 1 03] vs. 1 45 g/l [SD 0 51]; P = 0 0009). This observation was also true at the 72-h time-point (acute 2 70 g/l [SD 1 25] vs. chronic 1 39 g/l [SD 0 95]; P = 0 0004). Despite cohort differences, the increase in fibrinogen level was statistically significant for both cohorts between baseline and 24 h (acute, P ≤ 0 0001; chronic, P = 0 0001). The fibrinogen level continued to rise significantly between 24 and 72 h in the acute group (P = 0 003) but failed to do so in the chronic group (P = 0 14 [not significant]; Fig. 1). Significantly, there were no acute adverse transfusion reactions reported as a direct result of the cryoprecipitate administration; in particular, no cases of transfusion-associated circulatory overload or transfusion-transmitted infection (TTI) were noted. The current study demonstrates that cryoprecipitate is an effective and safe method of increasing the plasma fibrinogen level in hypofibrinogenaemic patients. It is most effective in the absence of any chronic underlying cause for hypofibrinogenaemia where endogenous production of fibrinogen can resume once the acute insult has ceased. It proved less effective when used in patients with underlying hepatic insufficiency. These findings contribute to the growing debate over the continued use of cryoprecipitate in the UK, which was initially developed for the treatment of haemophilia A and only subsequently found a role in the treatment of hypofibrinogenaemia. Concerns about its usage have focused on the potential risks of TTI and variability in fibrinogen content of individual units, together with issues surrounding controlled thawing, transport to patients and timely administration. These concerns have intensified with the ready availability of plasma-derived pasteurized fibrinogen concentrate, which may theoretically overcome many of the potential disadvantages of cryoprecipitate. Previous data on cryoprecipitate was limited to isolated case reports and a small study comparing its activity to fresh frozen plasma in patients with liver failure, which observed a

Local Activation and Systemic Dysregulation of T Lymphocytes in Sjögren’s Syndrome

T cells are implicated in both local and systemic pathophysiology of primary Sjögrens syndrome (PSS). Lymphocytic infiltrates in exocrine glands are dominated by CD4+ T cells, some contributing to ectopic lymphoid tissue, others, unusually, exhibiting cytotoxic potential. Cytokine secretion patterns are complex, with Th1 and Th17 components implicated in pathology. Circulating T cells exhibit phenotypes consistent with hyperactivation, cytokine imbalance, and homeostatic alterations; CD4 lymphopenia is recognized as a risk factor for developing lymphoma. Evidence of oligoclonal expansion is found locally and systemically. Functional alterations (e.g. cytokine secretion profile, migratory potential, target cell interactions) are less clearly defined. Attempts at T cell-targeted therapy of PSS have been limited, although therapy targeted at other arms of the immune response may also affect T cells. A better understanding of T-cell dysregulation in PSS is required in order to understand its contribution to disease, aid prognosis, and improve therapeutic interventions aimed at this aspect of the disease.

Is the continued use of UK plasma sourced cryoprecipitate justified? Response to Makris.

throp, C., Balendran, G. & Besser, M. (2014) The efficacy and safety of cryoprecipitate in the treatment of acquired hypofibrinogenaemia. British Journal of Haematology, 166, 458–461. NCJDRSU (2014) Variant Creutzfeldt-Jakob Disease: Current Data (June 2014). www.cjd.ed.ac. uk/documents/worldfigs.pdf The National Creutzfeldt-Jakob Disease Research & Surveillance Unit.