Fiona Goldblatt

New therapies for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which continues to cause significant morbidity in affected persons. In the past few years, a number of new exciting therapeutic options have become available. These reflect the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. A number of these therapies are outlined in the following review, including the various biological modifiers, in particular, anti‐tumour necrosis factor‐α agents and interleukin‐1 (IL‐1) receptor antagonists, which have been developed in recognition of the role of pro‐inflammatory cytokines in RA. Also notable, is the current interest centring on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. To evaluate this therapeutic option for RA, salient features from recent rituximab trials have been collated. Finally, a selection of other therapeutic alternatives, including anti‐IL‐6 receptor monoclonal antibody and tacrolimus, and newer anti‐rheumatic therapies presently in development are summarized.

Impaired Opsonization with C3b and Phagocytosis of Streptococcus pneumoniae in Sera from Subjects with Defects in the Classical Complement Pathway

ABSTRACT Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2−/− subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.

Clinical aspects of autoimmune rheumatic diseases.

Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substantial morbidity and mortality. Efforts to create international consensus within the past decade have resulted in the publication of new classification or nomenclature criteria for several autoimmune rheumatic diseases, specifically for systemic lupus erythematosus, Sjögrens syndrome, and the systemic vasculitides. Substantial progress has been made in the formulation of new criteria in systemic sclerosis and idiopathic inflammatory myositis. Although the autoimmune rheumatic diseases share many common features and clinical presentations, differentiation between the diseases is crucial because of important distinctions in clinical course, appropriate drugs, and prognoses. We review some of the dilemmas in the diagnosis of these autoimmune rheumatic diseases, and focus on the importance of new classification criteria, clinical assessment, and interpretation of autoimmune serology. In this era of improvement of mortality rates for patients with autoimmune rheumatic diseases, we pay particular attention to the effect of leading complications, specifically cardiovascular manifestations and cancer, and we update epidemiology and prognosis.

New therapies for systemic lupus erythematosus

In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10‐year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.

Association of Kikuchi–Fujimoto's disease with SLE

demonstrated good efficacy of B-lymphocyte depletion therapy in RA. Rituximab has also shown great promise in other autoimmune diseases including lupus, myositis and ANCA-associated vasculitis, in addition to showing promise for the haematological associated autoimmune diseases including idiopathic thrombocytopenic purpura and others [3–5]. Since we originally used rituximab, further evidence for a role for B cells in the pathogenesis of autoimmune pneumonitis has emerged [6]. Given the recent evidence challenging the efficacy of cyclophosphamide and high-dose steroid in scleroderma-related ILD the rationale for formally testing other therapies including B-lymphocyte depletion is considerable [7]. There is very limited data on the role of rituximab for ILD. Adams et al. [8] have reported a stabilization of DLCO with cyclophosphomide and rituximab in a group of six patients with juvenile onset systemic sclerosis [8]. Other options including stem cell transplantation have been tried but would not have been suitable in our case [9]. Thus far, the evidence for antitumour necrosis factor blockers including infliximab for ILD is conflicting. Our patient had clinical scleroderma with a serological profile that was certainly compatible with autoimmunity, where it has been predicted that drugs in the rituximab class may be efficacious [10]. She had a degree of irreversible pulmonary fibrosis at initial therapy, which may have lessened the benefit of rituximab therapy; so early use may be more beneficial. Since our patient was in extremis at the first clinical presentation, HRCT was not obtained immediately before the initial rituximab therapy. It is possible that rituximab is removing antibodies that are directly pathogenic so could be fundamentally treating a root cause of the clinical manifestations. Formal clinical trials are warranted.

Estimating Indirect Costs in Primary Sjogren's Syndrome

Objective. To estimate the indirect costs associated with primary Sjögren’s syndrome (pSS) compared with rheumatoid arthritis (RA) and community controls. Methods. Data were obtained from 84 women patients with pSS as part of a study to develop a systemic activity measure, from 87 consecutive women patients with RA attending a hospital clinic, and from 96 women community controls on a general practice list. A modified economic component of the Stanford Health Assessment Questionnaire was used to assess lost productivity. Results. Using a conservative model, the estimated total annual indirect costs (95% CI) were £7677 (£5560, £9794) for pSS, £10,444 (£8206, £12,681) for RA, and £892 (£307, £1478) for controls. Using a model that maximizes the estimates, the equivalent figures were £13,502 (£9542, £17,463), £17,070 (£13,112, £21,028), and £3382 (£2187, £4578), respectively. These were all significantly greater at p < 0.001 for patient groups than for the control group. Conclusion. pSS is associated with significantly increased indirect costs equivalent to 69%–83% of that for patients with RA. This needs to be taken into account when evaluating the overall economic consequences of pSS.

Prevalence of sicca symptoms in a South Australian cohort with systemic sclerosis

Background:  The presence of sicca symptoms is a frequent finding in patients with systemic sclerosis (SSc). The aim of this study was to examine the prevalence of sicca symptoms in a South Australian cohort of SSc patients and correlate this to a number of parameters, including autoantibody status, use of anticholinergic medication, age and the presence of functional anti‐muscarinic‐3 receptor (M3R)‐blocking antibodies.

Anti-CD20 Monoclonal Antibody in Rheumatoid Arthritis and Systemic Lupus Erythematosus

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antibody therapy for this patient group has also been established. Results of the open trials have been encouraging, particularly in patients not responding to usual therapies, and a randomised controlled trial is underway.

Antibodies to Blood Group Antigens Mimic Pemphigus Staining Patterns: A Useful Reminder

Pemphigus is a clinically important autoimmune skin disease characterised by intercellular substance antibodies, detected by indirect immunofluorescence on monkey oesphagus tissue. It has been observed that anti-A and anti-B blood group antibodies can produce staining patterns similar to that seen in pemphigus, yet this potential problem is not well recognised. We have demonstrated false positive pemphigus staining with blood group O sera and describe features by fluorescence and confocal microscopy, which may be useful in distinguishing true from false positive pemphigus staining.

Impaired C3b/iC3b deposition on Streptococcus pneumoniae in serum from patients with systemic lupus erythematosus.

OBJECTIVE To determine whether opsonization of Streptococcus pneumoniae with C3b/iC3b is impaired in serum from patients with SLE. METHODS The ability of serum samples from 30 patients with SLE, 20 with non-SLE rheumatic diseases (RA, PsA, AS, SS) and 20 healthy controls to opsonize S. pneumoniae (strains D39 and Io11697) with C3b/iC3b was assessed using a standardized FACS technique and a FACSCalibur flow cytometer. Results were compared among the three groups using analysis of variance, followed by pairwise comparisons among groups using the Mann-Whitney U-test. RESULTS The proportion of bacteria positive for C3b/iC3b was significantly lower in serum from patients with SLE (strain D39: 60.3% +/- s.e.m. 2.87, strain Io11697: 55.3% +/- 3.8) compared with healthy controls (strain D39: 70.6% +/- 2.0, P = 0.01; strain Io11697: 67.8% +/- 2.6; P = 0.05) and non-SLE rheumatic controls (strain D39: 69.8% +/- 3.1; P = 0.03). For the patients with SLE, there was no association between C3b/iC3b deposition and serum complement levels or measurable classical pathway activity. C3b/iC3b deposition on S. pneumoniae was significantly lower in serum from SLE patients with a past history of pneumonia (n = 3) compared with those without (n = 27; P = 0.03). CONCLUSIONS Opsonization of S. pneumoniae with C3b/iC3b was significantly reduced in serum from patients with SLE compared with non-SLE rheumatic disease and healthy controls. Failure to appropriately activate the immune system via complement may contribute to the increased susceptibility of SLE subjects to infections, and may correlate with a risk of pneumonia in a subgroup of SLE patients.