Costimulation Blockade in the Treatment of Rheumatic Diseases

The autoimmune response is executed via cognate interactions between effector immune cells and antigen presenting cells. Cognate interactions provide the immune effectors with specific signals generated through the antigen receptor as well as with second, non-specific signals, generated from the interaction of pairs of cell-surface molecules (costimulatory molecules) present on their plasma membrane. Disruption of this second, non-specific costimulatory signal results in the interruption of the productive (auto)immune response, leading to anergy, a state of immune unresponsiveness. The CD28:B7 families of molecules and the CD40:CD40L pair of molecules are considered as critical costimulatory elements. Disruption of the CD28:B7 interaction using a genetically engineered soluble form of the inhibitory molecule CTLA4 in vitro, as well as in experimental models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), led to the inhibition of the autoimmune response. Similarly, promising data stem from the use of an anti-CD40L monoclonal antibody (mAb) in murine SLE. While such treatments prevent the development of autoimmunity in animal models, this preventive approach is inapplicable to human diseases. However, the rational bench-to-bedside approach led investigators to clinical trials of CTLA4-Ig and of two different humanized anti-human CD40L mAbs in patients with RA and SLE, respectively. Initial experience with the use of CTLA4-Ig in patients with RA is encouraging, since in one short-term trial the construct was well-tolerated and produced clinically meaningful improvement of the disease in a significant proportion of those treated. Surprisingly, the anti-CD40L mAb treatment approach in human lupus was not fruitful, since short-term administration of the anti-CD40L mAb ruplizumab in lupus nephritis was correlated with life-threatening prothrombotic activity despite initial encouraging data in the serology and renal function of the patients. Also, IDEC-131 anti-CD40L mAb treatment did not prove to be clinically effective in human SLE, despite being well tolerated. Precise tailoring of the administration schemes for these novel therapeutic modalities is awaited.Finally, conceptually different approaches to block costimulation by inhibiting the induced expression of costimulatory molecules or the transmission of their specific intracytoplasmic signal have already produced encouraging preliminary results.     

Novel Mechanisms of Action of the Biologicals in Rheumatic Diseases

Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF-α) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-α agent does not imply a non-response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-α. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-α therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-α blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-α plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-α blocking action. The efficacy of an anti-C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects.     

Rheumatic Disease Autoantibodies in Autoimmune Liver Diseases

Background: Autoimmune liver diseases (ALDs) are known to be associated with systemic autoimmune rheumatic diseases (SARDs) and their autoantibodies. We aimed to study the prevalence of SARDs and related autoantibodies, as well as their prognostic implications in a group of patients with ALDs.

Methods: This was a cross-sectional study. Sixty patients with ALDs (38.3% with autoimmune hepatitis; 11.7% with primary biliary cirrhosis; 25% with primary sclerosing cholangitis and 25% with overlap syndrome) were studied for the presence of SARDs and their autoantibodies.

Results: There was autoimmune rheumatic disease in 20% of the studied sample. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were the commonest (11.6% and 5%, respectively). Antinuclear antibodies (ANAs) were present in 35% of the patients, followed by anti-Ro (20.0%); anti-nucleosome (18.3%); rheumatoid factor (10%) anti-CCP (8.3%); anti-RNP (8.3%); anti-ds-DNA (6.6%); anti-La (3.3%); anti-Sm (3.3%), anti-ribosomal P (3.3%). Anti-Ro (p = 0.0004), anti-La (p = 0.03), anti-RNP (p = 0.04) and anti-Sm (p = 0.03) were commonly found in patients with SARD, but not anti-DNA, anti-nucleosome and anti-ribosomal P. No differences were found in liver function tests regarding to the presence of autoantibodies.

Conclusions: There was a high prevalence of SARD and their autoantibodies in ALD patients. Anti-Ro, anti-La, anti-RNP and anti-Sm positivity points to an association with systemic autoimmune rheumatic diseases. The presence of autoantibodies was not related to liver function tests.     

铜锌超氧化物歧化酶在风湿性疾病患者滑膜中的变化

通过关节镜技术采取膝关节滑膜３８例，将组织标本进行冷冻切片４－６μｍ厚，放－２０℃贮存备用，应用免疫组法测定滑膜中ＣｕＺｎ－ＳＯＤ的沉积，其中类风湿关节炎（ＲＡ）１６例；反应性关节炎（ＲｅＡ）１０例；骨性关节炎（ＯＡ）７例；非滑膜炎（Ｎｏｎ－Ｓ）５例。     

The Third Eye of the Rheumatologist: Applications of Musculoskeletal Ultrasound in Rheumatic Diseases

Rheumatologists manage patients with rheumatic diseases, which are of a wide range of musculoskeletal pathologies. Without clarification of the exact location of pathologies and the degree of inflammation, rheumatologists may have an incorrect assessment, leading to inappropriate management. In everyday practice, physical examination is limited by its sensitivity and power of assessment. Musculoskeletal ultrasonography (MSUS) is inexpensive, readily available, and allows side-by-side image comparisons. Thus, during the past 10 years, MSUS has become the “third eye” of the rheumatologist, in that it allows more detailed examination of muscles, bones, and joints, just as the stethoscope provides further details about the respiratory and circulatory systems. We briefly introduce how rheumatologists in Taiwan use MSUS for the diagnosis and treatment for rheumatic diseases.     

Stem Cell Therapy in Autoimmune Rheumatic Diseases: a Comprehensive Review

The clinical management of autoimmune rheumatic diseases (ARD) has undergone significant changes in the last few decades, leading to remarkable improvements in clinical outcomes of many patients with mild to moderate ARD. On the other hand, severe refractory ARD patients often have high morbidity and mortality. Extensive basic research and clinical evidence has opened the door to new encouraging perspectives, such as the establishment of a role of stem cell transplantation (SCT) in the strategic management of ARD. Given the great heterogeneity of ARD, it is difficult to assign an optimal SCT regimen to all ARD patients. SCT remains a challenging mode of therapy in ARD patients from the standpoints of both efficacy and safety. As the clinical data of SCT in ARD increases and as we improve our understanding of stem cell biology and the downstream effects on the immune system, the future is promising for the development of optimal personalized SCT regimens in ARD.     

Subclass Distribution of IgA and IgG Antibodies Against Clq in Patients with Rheumatic Diseases

To obtain insight into the immunoregulatory mechanisms in patients with different rheumatic diseases, the occurrence and the subclass distribution of IgA and IgG antibodies against Clq (anti-ClqAb) was determined. In patients with systemic lupus erythaematosus (SLE) the highest frequency of increased serum levels of IgG anti-ClqAb were found, whereas IgA anti-ClqAb were predominantly present in patients with ankylosing spondylitis (AS) and patients with rheumatoid arthritis complicated by vasculitis (RV). In all the IgA anti-ClqAb positive AS and RV patients the antibody reactivity involved the IgAl subclass while the IgA2 subclass was found in 47% of the patients. Further characterization of the IgA anti-Clq binding activity in sera of AS patients revealed that both subclasses of IgA anti-ClqAb were predominantly polymeric; the binding of both IgA subclasses with solid phase CI q was inhibitable by aggregated fluid phase Clq; we found no delectable interference of rheumatoid factor in the test system for the measurement of IgA anti-ClqAb. In patients with SLE the IgG anti-ClqAb reactivity was mainly of the IgG2 and IgG3 subclass, whereas in the same patients the IgG anti-tetanus toxoid response was not restricted to these subclasses.
The predominance of IgG2 and IgG3 subclass of anti-ClqAb in sera of SLE patients, suggests a skewing of the anti-ClqAb response. The observation that the IgA anti-ClqAb of both subclasses is predominantly polymeric in nature and the notion that polymeric IgA is associated with activation of inflammation cascades, suggests that IgA anti-ClqAb may contribute to tissue damage.