Rheumatoid arthritis: advances in treatment strategies.

Rheumatoid arthritis (RA) is characterised by severe joint and bone damage due to heightened autoimmune response at the articular sites. Worldwide annual incidence and prevalence rate of RA is 3 cases per 10,000 population and 1%, respectively. Several genetic and environmental (microbiota, smoking, infectious agents) factors contribute to its pathogenesis. Although convention treatment strategies, predominantly Disease Modifying Anti Rheumatic Drugs (DMARDs) and Glucocorticoids (GC), are unchanged as the primary line of treatment; novel strategies consisting of biological DMARDs, are being developed and explored. Personalized approaches using biologicals targetspecific pathways associated with disease progression. However, considering the economic burden and side-effects associated with these, there is an unmet need on strategies for early stratification of the inadequate responders with cDMARDs. As RA is a complex disease with a variable remission rate, it is important not only to evaluate the current status of drugs in clinical practice but also those with the potential of personalised therapeutics. Here, we provide comprehensive data on the treatment strategies in RA, including studies exploring various combination strategies in clinical trials. Our systematic analysis of current literature found that conventional DMARDs along with glucocorticoid may be best suited for early RA cases and a combination of conventional and targeted DMARDs could be effective for treating seronegative patients with moderate to high RA activity. Clinical trials with insufficient responders to Methotrexate suggest that adding biologicals may help in such cases. However, certain adverse events associated with the current therapy advocate exploring novel therapeutic approaches such as gene therapy, mesenchymal stem cell therapy in future.

Vitamin D deficiency: concern for rheumatoid arthritis and COVID-19?

Vitamin D is an immunomodulatory hormone with an established role in calcium and phosphate metabolism and skeletal mineralization. Evidence showing its immunological benefits by regulating essential components of the innate and adaptive immune system is prevalent. Vitamin D deficiency is reported worldwide and is thereby found to be associated with various immune-related diseases. Rheumatoid Arthritis and COVID-19 are two such diseases, sharing a similar hyperinflammatory response. Various studies have found an association of lower Vitamin D levels to be associated with both these diseases. However, contrasting data is also reported. We review here the available scientific data on risk factor association and supplementation benefits of Vitamin D in Rheumatoid Arthritis and COVID-19, intending to critically evaluate the literature.

Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. METHODS: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. RESULTS: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. CONCLUSION: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

Physicians Perception of Rheumatology Practice and Training in India.

OBJECTIVE: To assess physicians' perception and their felt competence in dealing with patients with rheumatic complaints. METHODS: We assessed the quantum of rheumatological disorders seen by physicians in India, their felt competency in dealing with such patients, and their perceived adequacy of undergraduate and postgraduate medical training in Rheumatology by means of an anonymized questionnaire conducted at the annual national conference of internal medicine specialists. RESULTS: Our analysis of 333 respondents revealed that while they saw an average of 10 patients with rheumatic complaints every month, the felt competence in dealing with such cases was only a median of 6/10 (interquartile range 5-7). About 75% professed little or no exposure to Rheumatology as undergraduates, whereas only 20% perceived adequacy of training during internal medicine residency to treat such diseases confidently. 78.37% and 67.7% perceived an inadequacy of rheumatology training at undergraduate and postgraduate level respectively, and 83% felt the need for further training or sensitization in Rheumatology. CONCLUSION: There remains an unmet need to enhance existing undergraduate and postgraduate internal medicine curricula in India to impart greater skills in the diagnosis and management of rheumatic diseases. Initiatives and government funding to establish short-term training courses in Rheumatology for established internal medicine faculty, to enable them to provide basic Rheumatology services at their respective hospitals, are urgently needed.

Evaluation of reticulocyte hemoglobin for assessment of anemia in rheumatological disorders.

OBJECTIVE: The aim of this study was to evaluate the role of reticulocyte hemoglobin (Ret He) estimation in subtyping of anemia and to find the correlation of Ret He with the severity of anemia. METHODS: Ninety-four patients with rheumatic diseases with anemia were enrolled. Blood samples were taken to determine various parameters. Patients were divided into three groups: iron deficiency anemia, anemia of chronic disease with iron deficiency and anemia of chronic disease depending on the iron status and inflammatory markers. Analysis of variance and Pearson correlation coefficient were used. Receiver operating characteristic analysis was used to evaluate the accuracy of the parameters in differentiating anemia. RESULTS: Statistically significant differences among groups were seen with regard to parameters such as erythrocyte sedimentation rate, C-reactive protein, serum ferritin, total iron binding capacity, transferrin saturation, transferrin receptor protein, soluble transferrin receptor/log ferritin and Ret He. Ret He correlates with the subtype of anemia in patients with rheumatic disorders but it does not correlate with the severity of anemia. Soluble transferrin receptor/log ferritin, Ret He and serum ferritin values were the best parameters to differentiate between various groups. Ret He (pg) values of <24, 24-26.5 and >26.5, while serum ferritin levels (µg/L) of <35, 35-178 and >178 were highly sensitive and specific for iron deficiency anemia, anemia of chronic disease with iron deficiency and anemia of chronic disease groups, respectively. CONCLUSION: In cost constraints settings, a simple investigation like Ret He alone or with serum ferritin can help us to diagnose and differentiate between the different types of anemia accompanying rheumatological disorders without doing other serum iron studies and expensive tests like transferrin receptor protein which are not readily available.

Medical arthroscopy: A tool for diagnosis and research in rheumatology.

Arthroscopy is an important diagnostic procedure which can be used in rheumatology practice to provide direct visualization of the joint cavity, permitting macroscopic evaluation of the synovium, sampling for histopathologic and microbiologic examination and the potential therapeutic benefit of lavage. The term 'medical arthroscopy' is used here to refer to arthroscopy performed by rheumatologists for these purposes. This term differentiates arthroscopy performed by orthopedic surgeons for structural interventions such as meniscal debridement and ligament repair. Medical arthroscopy finds a place in rheumatology as an aid to diagnosis, to confirm the presence of synovitis when not expected, to provide histologic or microbiologic diagnosis, and potential stratification for therapy, for example in rheumatoid arthritis, as well as a range of other research purposes. It is performed with local anesthetic using a small bore arthroscope, most usually inserted into the knee, although the wrist and metacarpophalangeal joints may also be inspected in this way. In experienced hands it is well tolerated, safe and complications are comparable to those reported by orthopedic surgeons.

Musculo-skeletal ultrasound in rheumatology practice.

In rheumatology ultrasound is a relatively new but rapidly developing field, and now forms an important part of curriculum of rheumatology training programs in European countries. Ultrasound is now an accepted procedure to differentiate between arthralgia and arthritis, to look for erosions in early arthritis which is otherwise not visible on plain radiographs, to scan tendons in enthesopathies and to image blood vessels. It is particularly useful in early undifferentiated arthritis, where presence of synovitis by ultrasound can predict development of rheumatoid arthritis. It is also useful to aid in diagnosis of a wide variety of rheumatic conditions like gout, vasculitis and scleroderma. It facilitates correct placement of needle during intra-articular injections.The advantages of ultrasound are it is relatively inexpensive, noninvasive, lacks radiation and the images are acquired in real time. Following in the footsteps of the cardiologist who are using echocardiography are the rheumatologists who are increasingly using ultrasound in their clinics, such that some authors have likened the US probe to the rheumatologist's stethoscope.

Expression of TNF-alpha and related signaling molecules in the peripheral blood mononuclear cells of rheumatoid arthritis patients.

We examined the role of tumor necrosis factor (TNF-alpha) and its related signaling intermediates leading to apoptosis/proliferation in the peripheral blood mononuclear cells (PBMCs) of RA patients. The constitutive expression of mRNA for TNF-alpha receptors (TNFR-I and TNFR-II) and the adapter molecules, such as the TNF receptor-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), receptor interacting protein (RIP), and TNF receptor-associated factor 2 (TRAF-2) were analyzed by reverse transcriptase-PCR (RT-PCR) in PBMCs from control and RA cases. PBMCs of RA patients showed a significant increase in TNF-alpha and TNFR-I expression as compared with that from control subjects along with significantly increased constitutive expression of TRADD, RIP, and TRAF-2 mRNA. There was a decrease in expression of FADD in RA patients, but the difference was not significant as compared to controls. These data suggested enhanced signaling by the TNFR-I-TRADD-RIP-TRAF-2 pathway and suppressed signaling by the TNFR-I-TRADD-FADD pathway in PBMCs of RA patients. However, the regulatory mechanisms for TNF-alpha induced signaling may not be explained only by these pathways.

Anti-MBL autoantibodies in patients with rheumatoid arthritis: prevalence and clinical significance.

Occurrence of autoantibodies in patients' sera is the characteristic feature of autoimmune disorders. We assessed the presence of anti-mannose binding lectin (MBL) autoantibodies in the sera of 107 rheumatoid arthritis (RA) patients and 121 control subjects by enzyme immunoassay. Elevated levels of anti-MBL autoantibodies in the sera of RA patients (P<0.0001) was detected for the first time. The ratios of anti-MBL positive in RA patients and controls were respectively 60.7% and 1.65%. Experiments were then designed to understand the functional relevance of these autoantibodies. An inverse correlation of anti-MBL autoantibodies with serum MBL levels (P=0.001) and MBL complex activity (P=0.02) was observed without genetic association between MBL polymorphisms and anti-MBL autoantibody secretion. A significant increase (P=0.038) in the level of anti-MBL autoantibodies was observed in 23 synovial fluid samples in comparison to the serum samples. Moreover, the anti-MBL autoantibodies were found to be more often present in the sera of RA patients (60.75% sensitivity, 98.35% specificity and 0.913 area under the ROC curve) in comparison to the IgM and IgG isotypes of rheumatoid factors (RF). Anti-MBL autoantibodies were still positive in 25.23% RA patients when both the RF isotypes were negative. Also, in RA patients, at all stages of disease activity and joint deformity, anti-MBL autoantibodies were more often present than both the RF isotypes. Therefore, the significant presence of anti-MBL autoantibodies enunciates that anti-MBL autoantibodies might have a diagnostic value; however, more studies are needed to confirm the role of anti-MBL autoantibodies in the diagnosis of rheumatoid arthritis.

Altered expression and glycosylation of plasma proteins in rheumatoid arthritis.

Altered glycosylation of plasma proteins has been directly implicated in the pathogenesis of rheumatoid arthritis (RA). The present study investigated the changes in the Concanavalin-A (Con-A)-bound plasma proteins in the RA patients in comparison to that of the healthy controls. Two proteins (MW approximately 32 kDa and approximately 62 kDa) showed an alteration in expression while an altered monosaccharide profile (high mannose) was observed in the approximately 62 kDa protein in the samples collected from RA patients. The 2-dimensional polyacrylamide gel electrophoresis analysis of the Con-A-bound plasma samples showed a large number of protein spots, a few of which were differentially expressed in the RA patients. Some unidentified proteins were detected in the RA patients which were absent in the control samples. The present study, therefore, enunciates the role of carbohydrates as well as that of the acute phase response in the disease pathogenesis.

Association of mannose-binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis in an Indian cohort of case-control samples.

Single nucleotide polymorphisms in the mannose-binding lectin (MBL2) gene, as well as the serum MBL2 level, have been associated with various autoimmune diseases. We investigated whether such polymorphisms and/or the serum MBL2 level were associated with rheumatoid arthritis (RA) in an Indian population. The frequency of the B variant (codon 54) of the MBL2 gene was quite frequent in the healthy Indian population and was significantly (P=6.35x10(-6)) lower in RA patients. We replicated this association (P=1.78x10(-5)) in an independent cohort of control individuals. Promoter polymorphism at -550 nt showed a significant overrepresentation (P=0.003) of the minor allele G in severe RA patients compared with the less severe group. Haplotype LYA frequency was significantly (P=0.03) high in the less severe group, while the frequency of the HYA haplotype was significantly (P=0.04) increased in the severe RA patients. No statistically significant difference in serum MBL2 was observed as a whole, but the individuals homozygous for the LYA haplotype had significantly lower (P=0.017) serum MBL2 levels compared with individuals homozygous for the HYA haplotype. Therefore, the B variant of the MBL2 gene may be associated with protection from RA in our study population, and the promoter polymorphism (-550 nt) seems to have some role in disease progression.

Tumor necrosis factor-alpha microsatellite polymorphism association with rheumatoid arthritis in Indian patients.

BACKGROUND: Level of TNF-alpha increases significantly in synovial fluid of rheumatoid arthritis (RA) patients. It is proposed that tumor necrosis factor (TNF) microsatellite alleles may influence its expression and presumably can contribute to the disease severity. However, there is a lack of such study to predict any such association with RA in an Indian population. METHODS: In this study, we investigated the differential pattern of distribution of TNF microsatellite alleles in an Indian population and its association with RA. One hundred eighteen RA patients and 120 healthy individuals were genotyped for TNF microsatellite alleles using Genescan. Odds ratio was calculated to demonstrate the correlation between allelic distribution and clinical severity. RESULTS: The study shows that distribution of TNF microsatellite alleles in an Indian population is very different from other Asian Oriental and Western populations, except for some similarities with an Italian population. Frequency of microsatellite TNFd3 allele (9.24 vs. 3.85%, chi(2)=5.6, p < or =0.0179, OR=0.393, 95% CI=0.177-0.87) and more interestingly TNFd3 containing haplotypes has been found significantly reduced in patients. On the contrary, TNFb5 allele frequency increased in the patients (22.3 vs. 30.8%, chi(2)=4.4, p < or =0.036, OR=1.55, 95% CI=1.027-2.344) as compared to controls. Furthermore, significant increase in frequency of this allele in severe patients (22.3 vs. 33.8%, chi(2)=6.22, p < or =0.013, OR=1.78, 95% CI=1.132-2.798) along with the significant increase in haplotypes containing this allele supports the association of TNFb5 with disease severity. CONCLUSIONS: In an Indian population, TNFb5 may be considered as a risk factor, whereas TNFd3, unlike others, may be protective for RA.