Recent Advances in Idiopathic Inflammatory Myopathies (IIM) - Rapid Discoveries of Myositis-specific Antibodies (MSAS) and Myositis-Associated Antibodies (MAAS) - Moving Towards 'Precision Medicine'.

The progress in the understanding of inflammatory muscle diseases over the past several decades has been slow but steady. The classification given by Bohan and Peter's in 1975 was based on clinical features. It served well, but inadequacies were also obvious. The increasing discoveries of autoantibodies in this group of disorders have helped in refining the classification of Bohan and Peter's to a large extent. At the present state of knowledge, it is now possible to classify and sub-classify this group of diseases using distinct clinical features combined with the type of autoantibodies in well-defined subsets. Not only the subsets help predicting the type of organ involvement and comorbidities but may also help choose a specific drug for a particular subclass. This approach may lead to the practice of precision medicine for inflammatory myositis.

A fascinating story of the discovery & development of biologicals for use in clinical medicine.

A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be prescribing for a patient evaluated in the morning outpatient department. For him/her, this is now routine, and the question of 'Who', 'How' and 'When' about these biologicals would be the last thing on their mind. However, for those who came to the medical profession in the 1950s, 1960s and 1970s, these targeted drugs are nothing short of 'miracles'. It would be a fascinating story for the young doctor to learn about the long journey that the dedicated biomedical scientists of yesteryears took to reach the final destination of producing such wonder drugs. The story is much like an interesting novel, full of twists and turns, heart-breaking failures and glorious successes. The biologicals acting as 'targeted therapy' have not only changed the natural history of a large number of incurable/uncontrollable diseases but have also transformed the whole approach towards drug development. From the classical empirical process, there is now a complete shift towards understanding the disease pathobiology focusing on the dysregulated molecule(s), targeting them with greater precision and aiming for better results. Seminal advances in understanding the disease mechanism, development of remarkably effective new technologies, greater knowledge of the human genome and genetic medicine have all made it possible to reach the stage where artificially developed 'targeted' drugs are now therapeutically used in routine clinical medicine.

Prevalence of cardiovascular disease and major risk factors in patients with rheumatoid arthritis: a multinational cross-sectional study.

To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins.

Screening for latent tuberculosis infection among patients with rheumatoid arthritis in the era of biologics and targeted synthetic disease-modifying anti-rheumatic drugs in India, a high-burden TB country: The importance of Mantoux and Quantiferon-TB Gold tests.

AIM: To test the validity of an augmented tuberculosis skin test (a-TST) combined with Quantiferon TB-gold® (QFTG) test for the screening of latent tuberculosis infection (LTBI) in patients with rheumatoid arthritis (RA) being considered for treatment with biologic disease-modifying anti-rheumatic drugs or targeted synthetic disease-modifying anti-rheumatic drugs. METHOD: Standard TST using 1 tuberculin unit (TU) of purified protein derivative (PPD, RT23 strain) was carried out. If the positivity was less as compared to the general population, then a-TST using 10 TU PPD was employed. Simultaneously, QFTG test was also performed. RESULTS: Using standard TST, 6/44 (13.6%), patients were positive compared to the reported figures of ~ 40% of the general population; 38 of the remaining TST-negative patients were then given an a-TST with 10 TU PPD; eight of them dropped out. Of the remaining 30 patients, eight (26.6%) were positive. Another 70 patients tested directly with a-TST; 22 (31.4%) were found positive. Thus, of a total of 100 patients tested with a-TST, 30 (30%) were positive. In 54 a-TST negative patients, QFTG was done; seven (13%) were positive. Thus, in combined a-TST with QFTG, 43% of the RA patients were found positive, suggestive of the presence of LTBI. CONCLUSION: Combined a-TST with QFTG testing gave 43% positivity among RA patients, which is close to the reported ~ 40% Mantoux positivity in the general population. Therefore, this method for the screening of LTBI in Indian patients with RA being considered for tumor necrosis factor alpha treatment could be satisfactory for offsetting TB flare. It may apply to other high-burden TB countries around the world.

Clinical characteristics of peripheral spondyloarthritis without psoriasis, inflammatory enteropathy or preceding infection, from a single rheumatology clinic in northern India.

The objective of this study was to characterise the peripheral arthritis of spondyloarthritis (pSpA) excluding psoriatic-, inflammatory enteropathy-related, post-infectious reactive-SpA and arthritis associated with axial SpA/ankylosing spondylitis (axSpA/AS). Patients presenting with the clinical features of the broad spectrum of SpA were screened for the presence of peripheral arthritis using the Assessment of SpondyloArthritis International Society (ASAS) criteria. The other conditions that could cause pSpA, e.g. psoriasis, inflammatory enteropathy, reactive arthritis and axSpA/AS, were excluded. Their assessment included clinical, laboratory and imaging features. Of a total of 405 patients seen within the spectrum of SpA, 25 (6.2%) patients were identified as pSpA with none of the conditions that could be attributed to their disease. The male to female ratio was 2.6:1; the pattern of involvement was predominantly lower extremity asymmetrical large joint oligoarthritis in persons below the age of 40 years (60% were <30 years of age). Some had soft tissue and/or extra-articular manifestations characteristic of SpA (36%) and family history (20%) of SpA spectrum of diseases. When compared to peripheral arthritis reported in axial axSpA/AS, root/central joint involvement was minimal in pSpA. Otherwise, the pattern of arthritis appeared similar. Exclusive peripheral arthritis without the presence of the other disease-defining conditions is uncommon, seen only in 6.2% of the SpA spectrum diseases. The pattern of joint involvement was similar to that observed with axSpA/AS except that the root/central joints were not seen.

The Nonradiographic Axial Spondyloarthritis, the Radiographic Axial Spondyloarthritis, and Ankylosing Spondylitis: The Tangled Skein of Rheumatology.

Since 1984 the diagnosis of ankylosing spondylitis (AS) has been based upon the modified New York (mNY) criteria with mandatory presence of radiographic sacroiliitis, without which the diagnosis is not tenable. However, it may take years or decades for radiographic sacroiliitis to develop delaying the diagnosis for long periods. It did not matter in the past because no effective treatment was available. However, with the availability of a highly effective treatment, namely, tumour necrosis factor-α inhibitors (TNFi), the issue of early diagnosis of AS acquired an urgency. The Assessment of SpondyloArthritis International Society (ASAS) classification criteria published in 2009 was a significant step towards this goal. These criteria described an early stage of the disease where sacroiliitis was demonstrable only on MRI but not on standard radiograph. Therefore, this stage of the disease was labelled "nonradiographic axial SpA" (nr-axSpA). But questions have been raised if, in search of early diagnosis, specificity was compromised. The Federal Drug Administration (FDA, USA) withheld approval for the use of TNFi in patients with nr-axSpA because of issues related to the specificity of these criteria. This review attempts to clarify some of these aspects of the nr-axSpA-AS relationship and also tries to answer the question whether ASAS classifiable radiographic axial spondyloarthritis (r-axSpA) term can be interchangeably used with the term AS.

Methods for Faster and Efficient Data Entry in Electronic Medical Records.

Data entry remains the slowest link in the value chain inhibiting growth of Electronic Medical Records and attendant benefits towards Meaningful use. We designed templates for user forms customized by specialty. Here, we demonstrate the functionality of our software and provide instructions on how these can be adopted by other developers.

Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): effect of adding caffeine to the management regimen.

The aim of this study was to investigate the effect of caffeine on the symptoms of methotrexate (MTX) intolerance in patients with RA. The follow-up patients with RA seen over a period of 11 months were included in this work. The degree of MTX intolerance, if present, was classified as 'moderate' and 'severe'. Those with intolerance were advised caffeine (coffee or dark chocolate) synchronised with the MTX dose. The effect was assessed as 'very good', 'good' or 'none'. Among 855 patients seen during this period, 313 (36.6 %) did not have any MTX intolerance, 542 (63.4 %) patients had some degree of MTX intolerance, 422 (77.8 %; 49.3 % of the total patients) had 'minimal' intolerance not requiring any intervention. The remaining 120 (22.1 %) of the 542 (14 % of the total 855) patients had 'moderate' or 'severe' MTX intolerance. Among these, 55 % had complete relief of symptoms and were able to continue taking the advised dose of MTX; 13.3 % had partial improvement and continued taking MTX but only with antiemetics; 7.5 % were minimally better but were somehow managing; 10 % were complete caffeine failure without any relief; 14.2 % did not like caffeine (coffee or dark chocolate) and did not want to take it. Caffeine relieved the symptoms of MTX intolerance in 55 % and partial relief in 13 % of the patients. A significant number of patients did not like to take caffeine (coffee or dark chocolate). It is of note that northern part of India is primarily a tea-drinking population where coffee is not a favourite drink.

Low-Dose Methotrexate (LD-MTX) in Rheumatology Practice - A Most Widely Misunderstood Drug.

Methotrexate (MTX) was synthesised as a folate antagonist for use in treating childhood leukaemia in 1940s. Gubner and colleagues in 1953 used several log-order lower doses of MTX that mimicked the anti-inflammatory properties of cortisone. They used it successfully in treating rheumatoid arthritis (RA). Their work was however overlooked because the Nobel Prize winning drug cortisone held sway in those days. With increasing awareness of the adverse effects of cortisone, interest was rekindled in discovering 'steroid-sparing' drugs. Hoffmeister and Willkens used low-dose MTX (LD-MTX) in treating RA patients in 1960s with impressive results. Pivotal trials in 1984-5 established the efficacy and safety of LD-MTX in treating RA that gained FDA approval in 1988. LD-MTX at doses <25-30 mg weekly as mini-pulses, is presently the standard-of-care for the treatment of RA. Its toxicities and adverse effects are rarely if ever life-threatening. This is in contrast to the high-dose methotrexate (HD-MTX) for treating malignancies at doses that are several log-orders higher and usually cause serious toxicities. While LD-MTX acts mainly as an anti-inflammatory drug by increasing tissue adenosine levels besides other mechanisms, HD-MTX has anti-proliferative cytotoxic action with different toxicity profile and adverse effects. In practical terms LD-MTX and HD-MTX are 2 different therapeutic agents. However, in developing countries like India the stigma attached to MTX as a cytotoxic 'cancer drug' still persists and most non-rheumatologists fear its use in RA. This review aims to allay such anxiety attached to LD-MTX so that they start using it in appropriate doses for treating RA.

Landmark papers on the discovery of methotrexate for the treatment of rheumatoid arthritis and other systemic inflammatory rheumatic diseases: a fascinating story.

This review highlights the story of how methotrexate (MTX), a drug discovered for the treatment of childhood leukemia, became the mainstay of treatment and the standard-of-care for rheumatoid arthritis (RA) and was also found useful for several additional related rheumatological diseases. As against several synthetic disease-modifying antirheumatic drugs (csDMARDs) for treating RA that were discovered serendipitously, the use of low-dose MTX (LD-MTX) was based on sound reasoning and astute observations made in the 1940s and 1950s. The difference between high-dose MTX (HD-MTX) used in the treatment of childhood leukaemia and other malignancies as against LD-MTX used in rheumatology is emphasized.

Treatment of rheumatoid arthritis (RA) in India-how and by whom: results from a speciality clinic-use of low-dose methotrexate (MTX) was inexplicably suboptimal.

This study was conducted in order to study (a) seropositive RA patients for their prior caregivers, diagnosis makers, drugs and doses taken and (b) the disease status at the first visit and the last visit, from the standpoint of whether they received optimum or suboptimum DMARD treatment. Prospectively entered data were extracted from a rheumatology-specific electronic health record for demography, diagnostic delay, prior caregivers, diagnosis makers, intake of DMARDs and glucocorticoids and disease activity state at first presentation and at the last visit using structured query language. Among 316 patients, prior caregivers were orthopaedicians (73.4 %), alternative systems of medicine practitioners (62 %), internists (38 %), rheumatologists (35.8 %), general practitioners (17 %) and others (12 %). The diagnosis of RA was made by rheumatologists (55.6 %), orthopaedicians (21 %), internists (12.6 %), physiotherapists (3.5 %), homeopaths (2.8 %), general practitioner (2.1 %), neurologists (1.4 %) and Ayurvedic physicians (0.7 %). The mean and the median diagnostic delay among 142 patients where information was available were 18 and 8.5 months, respectively (SD +23.2). Thirty-two percent of the patients had early disease, 48 % established disease and 20 % late disease at presentation. Sixty-six percent of the patients had taken DMARDs-methotrexate (56 %), hydroxychloroquine (46.2 %), leflunomide (18.7 %) and sulfasalazine (20.6 %)-and often in combinations. Different preparations, doses and schedules of glucocorticoids were taken orally or parentally by 51 %. Only one (0.3 %) patient had taken biological DMARDs prior to visiting this clinic. High or moderate disease activity was present in 84 % at the first clinic visit that fell to 14 % at the last clinic visit. The majority of patients with RA were treated by orthopaedicians and practitioners of alternative systems of medicine with only a third by rheumatologists. In 80 % of patients, the diagnosis was made 18 months at the onset, yet in 84 %, the disease control was poor. Non-use or suboptimal use of methotrexate appeared to be the main reason.

Comparison of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) from a single rheumatology clinic in New Delhi.

AIM: Comparison of ankylosing spondylitis (AS) with non-radiographic axial spondyloarthritis (nr-axSpA) classified with the recent ASsessment of spondyloArthritis International Society (ASAS) criteria. PATIENTS & METHODS: This study included 288 patients clinically diagnosed as having spondyloarthritis (SpA) where a satisfactory radiograph of sacroiliac (S-I) joints was available. The AS and the nr-axSpA groups were compared for the various SpA-related variables. RESULTS: Of 288 axSpA patients, there were 187 with AS. Of the remaining 101 patients without radiographic sacroiliitis, S-I joint magnetic resonance imaging (MRI) was available in 72; 54 of them showed active sacroiliitis thus classified as nr-axSpA according to the ASAS criteria. The remaining 18 patients with normal MRI and the other 29 patients without MRI of the S-I joints (total 47 patients), were classified as nr-axSpA using the 'clinical arm' of the ASAS criteria. On comparing the 187 AS with 101 patients in the nr-axSpA group, the AS group showed significantly more males, longer disease duration, more axial symptoms at disease onset, higher Bath Ankylosing Spondylitis Metrology Index and more syndesmophytes. Biologicals were offered significantly more often to the AS group but methotrexate as monotherapy or in combination with other disease-modifying anti-rheumatic drugs was offered more often in nr-axSpA group. There was no statistically significant difference between AS and nr-axSpA in other SpA parameters. CONCLUSION: The differences brought out between AS and nr-axSpA groups show that they may not be the same disease. A prospective long-term follow-up of large cohorts may help in clarifying if nr-axSpA is simply an early stage in the spectrum of SpA evolving into AS over time or is there inherent difference between them.

Seronegative arthritis in South Asia: an up-to-date review.

This article summarises the available information on seronegative arthritides from South Asian countries, namely India, Pakistan, Bangladesh, Sri Lanka, Nepal, and Bhutan. The diseases described are spondyloarthritides (SpA), including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel disease-related arthritis (IBDa), enthesitis-related arthritis (ERA) of the paediatric age group, and undifferentiated spondyloarthritis (uSpA). Relevant information on SpA from South Asia is scarce. However, the available publications indicate that these are commonly seen conditions. HLA-B27 is present in approximately 6-8 % of the normal population in the Indian subcontinent. In the SpA group, HLA-B27 has the highest frequency in AS patients (>90 %) and the lowest in PsA patients. Clinical features are similar to those reported in standard textbooks, but with a few exceptions: e.g., in South Asian countries ERA is the most common subset of juvenile idiopathic arthritis (JIA), whereas in the West the most common subset of JIA is oligoarthritis. Poverty is a major challenge in treating these diseases in South Asia; with poor health insurance coverage, only a few patients are able to afford biological treatment. Therefore, rheumatologists have attempted novel treatment strategies for those with an unsatisfactory response to standard non-steroidal anti-inflammatory drugs (NSAIDs) or coxibs.

Cost-effective use of investigations in developing countries.

In recent years, the cost of health care around the world has risen at a rate that is deemed unsustainable. It has been estimated that 20% of this could be saved by rationalising laboratory investigations and reducing inappropriate requisitioning of the investigations. There are several reasons for the excessive, redundant, inappropriate or unnecessary investigations and procedures, which in some instances are unethical practices. The impact in financial terms is more in developing countries such as India with <5% of the population having medical insurance and hardly any other third-party payer system. The 'Choosing Wisely' campaign of the American Board of Internal Medicine, Canadian Rheumatology Association's Choosing Wisely Committee and the 'Society for Less Investigative Medicine' (SLIM) initiative of the doctors of All-India Institute of Medical Sciences (AIIMS), New Delhi, all have provided recommendations to reduce unnecessary investigations, and these are among some of the efforts to reduce the cost of investigations without compromising the quality of care.

Computer-aided treat to target (T2T) Approach for the Rheumatology Patient.

Since 2001,we had been using a document template with manual calculators to assess the disease status during each visit and based on that, formulate a proper treatment plan for our patients We had good outcomes but the process was laborious and slow. From 2007 onwards, we shifted to a rheumatology specific EMR with automatic calculators. This article compares outcomes of Rheum Aid® (a clinician developed EMR for rheumatology) supported "Objectified Assessment" and prescription writing on patients with rheumatic diseases versus previous use of an MS Word® document template and shows better turnover and patient satisfaction.