Martina Biggioggero

Updating on the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease whose pathogenesis is multifactorial lying on genetic, environmental factors and on abnormalities of both the innate and the adaptive immune system. The induction, maintenance and progression of the disease are a multi-step process that may take long time eventually leading to tissue injury. Several genes have been associated to SLE susceptibility; each of them displaying a small effect suggesting the need of an association. However, the gene-gene and gene-environment interactions are still matter of research. Environmental factors, both external such as physical and infectious agents and internal such as gender and hormonal profile, may influence the disease manifestation. SLE is characterized by a complex array of immune abnormalities affecting both the innate and the adaptive immunity. All these processes play a role in the defective clearance of chromatin material that is overexposed to the afferent limb of the immune system leading to an autoimmune response facilitated by defective regulatory mechanisms. The production of a wide panel of autoantibodies represents the ultimate events responsible for tissue aggression. Finally, tissue damage is influenced by the presence of local factors responsible for the final aggressivity of the lesions and of the clinical manifestations.

The geoepidemiology of the antiphospholipid antibody syndrome

Antiphospholipid antibodies (aPL) can be detected by functional (lupus anticoagulant) and/or by solid phase assays (anti-cardiolipin and anti-beta2 glycoprotein I). Although detectable in 1-5% of asymptomatic apparently healthy subjects, persistent aPL are significantly associated with recurrent arterial/venous thrombosis and with pregnancy morbidity. Such an association is the formal classification tool for the antiphospholipid syndrome (APS). The prevalence of the syndrome with no associated systemic connective tissue diseases (primary APS) in the general population is still a matter of debate since there are no sound epidemiological studies in the literature so far. aPL display higher prevalence in systemic lupus erythematosus and rheumatoid arthritis than in other systemic autoimmune diseases. However not all the aPL positive lupus patients display the clinical manifestations. Comparable findings may be found in the paediatric population, although anti-beta2 glycoprotein I antibodies are detected in healthy children more frequently than in adults. High prevalence of aPL has been also reported in clinical manifestations that are not formal APS classification criteria: heart valve disease, livedo reticular, nephropathy, neurological manifestations, and thrombocytopenia. Antiphospholipid antibodies can be associated with infectious processes, active vaccination, drug administration and malignancies. Their prevalence and titres are lower and the relationship with the APS clinical manifestations are less strong than in the previously mentioned conditions. Ethnicity was also reported to influence the prevalence of aPL.

Standardization of autoantibody testing: a paradigm for serology in rheumatic diseases

Autoantibody measurement is an excellent tool to confirm the diagnosis of rheumatic autoimmune diseases. Hence, reliability and harmonization of autoantibody testing are essential, but these issues are still a matter of debate. Intrinsic variability in analytes and reagents as well as heterogeneity of the techniques are the main reasons for discrepancies in inter-laboratory variations and reporting of test results. This lack of reliability might be responsible for wrong or missed diagnoses, as well as additional costs due to assay repetition, unnecessary use of confirmatory tests and/or consequent diagnostic investigations. To overcome such issues, the standardization of autoantibody testing requires efforts on all aspects of the assays, including the definition of the analyte, the pre-analytical stages, the calibration method and the reporting of results. As part of such efforts, the availability of suitable reference materials for calibration and quality control would enable the development of a reliable reference system. Strong-positive sera from patients have been used as reference materials in most of the autoantibody assays for rheumatic diseases; however, antigen-affinity-purified immunoglobulin fractions or in some cases reliable monoclonal antibody preparations offer more adequate tools for standardization. Systematic assessments of reference materials are currently underway, and preliminary results appear to be encouraging.

IL1 and TNF gene polymorphisms in patients with juvenile idiopathic arthritis treated with TNF inhibitors

Objective: To investigate the genetic contribution of cytokine gene polymorphisms (interleukin 1 (IL1) and tumour necrosis factor α (TNFα)) on disease phenotype and on response to TNF-blocking agents in a population of patients with juvenile idiopathic arthritis (JIA). Methods: A cohort of 107 consecutive patients with JIA who were receiving treatment with anti-TNF agents was enrolled in this study. Analysis of genetic polymorphisms for IL1B +3954, IL1RA +2018, TNFα −238 and TNFα −308 was performed by enzyme-linked oligo sorbent assay, and compared with those obtained from 630 healthy Caucasians and 263 adult patients with rheumatoid arthritis. Relevant demographic, clinical and laboratory data were collected from clinical charts and entered into a customised database, and χ2 analysis was performed to compare cytokine polymorphisms with disease type according to the International League of Associations for Rheumatology criteria, presence of uveitis, rheumatoid factor and anti-nuclear antibody positivity, erosive disease, frequency of adverse effects to anti-TNF and clinical response after 3 months. Results: The T/T genotype of the IL1B +3954 polymorphism was absent in patients with JIA and present in 5% of controls (p = 0.015). No significant correlation was found between the studied polymorphisms and clinical or laboratory variables considered. Clinical response to TNF inhibitors at 3 months was not associated with the genetic polymorphisms considered. Conclusion: In our cohort, the absence of the rare IL1B +3954 gene polymorphism was associated with JIA, but without specificity to particular disease phenotypes. The TNF and IL1 gene polymorphism studied did not seem to be associated with response to anti-TNF treatment.

Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies

OBJECTIVE The aim of this study was to evaluate the survival on treatment with second-line biologic therapy in RA patient non-responders to TNF inhibitors (TNFis) by comparing treatments with a second anti-TNF (cycling strategy) or with agents with a different mechanism of action (MoA; swap strategy). METHODS RA patients treated with biologics since 1999 who stopped a first-line TNFi and started a second-line biotherapy were included in this cohort study. After adjusting for propensity scores, drug retention rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare survival curves and the Cox regression model was used to compare risk for discontinuation between the two groups. RESULTS Two hundred and one patients discontinued the first TNFi, switching to a second anti-TNF [n = 119 (59.2%)] or to abatacept [n = 26 (31.7%)], rituximab [n = 40 (48.8%)] or tocilizumab [n = 15 (18.3%)]. Drug survival was significantly higher in the swap group than in the cycling group (P < 0.0001). After adjustment for propensity scores, probability of treatment retention in the swap group was significantly higher (hazard ratio = 2.258, 95% CI 1.507, 3.385), even after stratification according to the reason for the first TNFi discontinuation (P = 0.005). No significant differences emerged when comparing the retention rates of different MoAs (P = 0.51) in the swap group. CONCLUSION In the clinical practice setting, the best option for managing TNFi non-responders seems to be swapping to a different MoA, with no differences between abatacept, rituximab and tocilizumab, irrespective of the reason for first TNFi discontinuation.

Immune function in children born to mothers with autoimmune diseases and exposed in utero to immunosuppressants.

The administration of immunosuppressive drugs during pregnancy is often necessary in women with autoimmune diseases. Teratogenicity of immunosuppressives during pregnancy has been evaluated, only few data exist about the effects on immune systems. We therefore performed a pilot study on the influence of foetal exposure to immunosuppressives on immune function of babies born to mothers with autoimmune disorders. We investigated serological and cellular parameters as indicators of immune system status. We included in the study 14 babies (mean age 11 months, range 1—24) born to mothers with autoimmune diseases and exposed in utero to different immunosuppressants and, as controls, 14 babies whose mothers had autoimmune manifestations but did not receive immunosuppressive therapy. We evaluated: (i) complete blood count, (ii) immunoglobulin levels and IgG subclasses, (iii) antibody response to hepatitis B vaccine, (iv) leukocyte subpopulations and (v) interleukin-2 and interferon γ in vitro production by resting or activated peripheral blood mononuclear cells. We did not find statistically significant differences between exposed and not exposed babies or among treatments for the tested parameters. Immunosuppressive regimens currently in use for controlling maternal autoimmune disorders do not significantly affect the immune status of the offspring. Lupus (2007) 16, 651—656.

Ultraviolet light exposure is not a requirement for the development of cutaneous neonatal lupus

Cutaneous neonatal lupus erythematosus (NLE) is a rare disorder, linked to the presence of transplacentally acquired maternal autoantibodies (anti-ENA). NLE skin lesions frequently appear in the second or third month of life, and ultraviolet exposure is thought to be an initiating factor since it can externalize intranuclearautoantigens at the cell surface. We report a baby who was born already with an extensive NLE rash, suggesting that sun exposure is not a requirement for the development of NLE skin lesions. A 31-year-old woman affected with mixed connective tissue disease gave birth to a female after 38 weeks of gestation. Pregnancy was uneventful and no perinatal complications were seen. The mother was positive for anti-RNP, but negative for anti-SSA/Ro and SSB/La autoantibodies. Already at birth, an extensive scarring rash with a few erythematosus lesions was present on the babys face and scalp; this progressed over the following months, and subsequentlystabilized. Anti-RNP were present in the babys serum. Due to the unusual features of the disease expression, a skin biopsy was performed at age 5 months; results were consistent with the diagnosis of NLE, showing mononuclear cell infiltration and immunoglobulin deposition. No other features of NLE were detected. This observation is unusual for: (1) the presence of an NLE rash in the absence of anti-SSA/Ro;(2) the scarring and atrophic characteristicsof the lesions; and (3) the development already in utero. This latter finding argues against sun exposure being necessary for lesion induction.

Type I interferon therapy and its role in autoimmunity

Interferons (IFNs) display a pleiotropic effect on different cell types of both the innate and the adaptive immunities being able to affect the immune responses. The ability of IFNs, and in particular of type I IFN, to activate dendritic cells and to modulate the expression of major histocompatibility classes I and II molecules supports their potential role also in the development and maintenance of tolerance. When tolerance breakdown has occurred, immunocomplexes generated by the reaction of nuclear antigens and specific autoantibodies can further induce type I IFN production. Accordingly, high acid-labile type I IFN plasma levels, overexpression of IFNα-induced transcripts and the association with genes closely related to type I IFN response represent the rationale for the so-called IFN signature in systemic lupus erythematosus, a prototypical autoimmune disease. The role of IFNs in autoimmunity is further supported by their direct and deleterious impact on target tissues. The therapeutic use of IFNs is based on their antiviral and antiproliferative effect. Type I IFN administration, in particular, is associated with the appearance of autoimmunity, although less frequently than expected. Such an event takes place mostly in patients with previous autoimmune manifestations and can be characterized by the appearance of autoantibodies only or of a clinically overt disease. IFN therapy cessation is usually, but not always, required for controlling the autoimmune disorders.

Cutting-Edge Issues in Coronary Disease and the Primary Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is the most frequent cause of venous and arterial thrombotic events in young patients. The brain arterial tree is primarily affected, but coronary ischemic manifestations are also relatively frequent. Coronary involvement was suggested to be closely related to the accelerated atherosclerosis linked to the underlying disease in APS associated to systemic autoimmune diseases, in particular, systemic lupus erythematosus. However, arterial ischemic events can occur in primary APS—with no other systemic disorders—even in the absence of traditional cardiovascular risk factors and overt atherosclerosis. From a biological point of view, this finding speaks in favor for a pro-coagulant activity of anti-phospholipid antibodies rather than for their role in atherosclerotic plaque formation. On the other hand, the clinical challenge is to avoid the risk to misdiagnose young patients with potentially life-threatening symptoms, such as myocardial infarction (MI). In fact, the occurrence of nonspecific symptoms related to coronary ischemic events is frequently misdiagnosed because of its rarity in young patients. This issue is well illuminated by two cases of MI in young patients reported in the manuscript together with a systematic review of the associations and implications of coronary ischemic events in APS.

Ten-year drug survival of anti-TNF agents in the treatment of inflammatory arthritides.

Postmarketing Phase IV