Girish M. Mody

Experience with azathioprine in systemic sclerosis associated with interstitial lung disease

Abstractthe aim of this study was to evaluate the safety and efficacy of azathioprine in the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SSc). The records of patients with SSc with ILD who were treated with azathoprine were reviewed. Patients were treated with azathioprine and low-dose prednisone if they had progressive pulmonary symptoms (deterioration in the dyspnea score) or poor or deteriorating lung function. Response was classified as improved if the FVC increased more than 10% from baseline, and stable if it remained within 10% of baseline. Serial dyspnea scores were recorded. Eleven patients were treated with azathioprine, three of whom received treatment for 6 months or less owing to adverse effects (nausea, leukopenia and pulmonary tuberculosis in one patient each). The remaining eight patients received at least 12 months’ treatment and the results suggested an improvement in the mean percent predicted FVC from a baseline value of 54.25±3.53 to 63.38±6.15 after 12 months (p=0.101). Overall, five patients improved and three remained stable. The mean dyspnea score (n=8) improved from a baseline of 1.55±0.19 to 0.50±0.19 at 12 months (p=0.011). This is the first case series of patients with SSc-associated ILD treated with azathioprine. Our results suggest that azathioprine may have a role in stabilizing lung function and improving symptoms in SSc, although this needs confirmation by a randomized controlled trial.

Improving musculoskeletal health: Global issues

Musculoskeletal (MSK) disorders are among the leading reasons why patients consult a family or primary health practitioner, take time off work and become disabled. Many of the MSK disorders are more common in the elderly. Thus, as the proportion of the elderly increases all over the world, MSK disorders will make a greater contribution to the global burden of disease. Epidemiological studies have shown that the spectrum of MSK disorders in developing countries is similar to that seen in industrialised countries, but the burden of disease tends to be higher due to a delay in diagnosis or lack of access to adequate health-care facilities for effective treatment. Musculoskeletal pain is very common in the community while fibromyalgia is being recognised as part of a continuum of chronic widespread pain rather than a narrowly defined entity. This will allow research to improve our understanding of pain in a variety of diffuse pain syndromes. The availability of newer more effective therapies has resulted in efforts to initiate therapy at an earlier stage of diseases. The new criteria for rheumatoid arthritis, and the diagnosis of axial and peripheral involvement in spondyloarthritis, permit an earlier diagnosis without having to wait for radiological changes. One of the major health challenges is the global shortage of health workers, and based on current training of health workers and traditional models of care for service delivery, the global situation is unlikely to change in the near future. Thus, new models of care and strategies to train community health-care workers and primary health-care practitioners to detect and initiate the management of patients with MSK disorders at an earlier stage are required. There is also a need for prevention strategies with campaigns to educate and raise awareness among the entire population. Lifestyle interventions such as maintaining an ideal body weight to prevent obesity, regular exercises, avoidance of smoking and alcohol abuse, intake of a balanced diet and nutrients to include adequate calcium and vitamin D, modification of the work environment and avoidance of certain repetitive activities will prevent or ameliorate disorders such as osteoarthritis, osteoporosis, rheumatoid arthritis, gout and MSK pain syndromes including low back pain and work-related pain syndromes. These prevention strategies also contribute to reducing the prevalence and outcome of diseases such as hypertension, cardiovascular diseases, diabetes and respiratory diseases. Thus, prevention strategies require urgent attention globally.

Articular manifestations of human immunodeficiency virus infection.

Prospective studies of HIV-positive and HIV-negative individuals, longitudinal prospective studies of HIV-positive patients and the African experience with spondyloarthropathies have provided support for a direct role of HIV infection in producing a variety of articular manifestations. The most common manifestations are arthralgia and the spectrum of spondyloarthropathies, but distinct entities such as HIV-associated arthritis and the painful articular syndrome have also been reported. Although initial reports described patients with mainly asymmetric oligoarthritis, a polyarticular presentation is now seen frequently. In Caucasians, HIV-associated reactive arthritis resembles reactive arthritis in non-HIV-infected persons. Reactive arthritis, psoriatic arthritis and undifferentiated spondyloarthropathy were uncommon in Africa and are now detected more often with the HIV epidemic. Although early reports in Western communities reported asymmetrical oligoarthritis as the usual pattern, polyarticular involvement is now seen frequently. Intravenous drug abuse is the most likely risk factor for septic arthritis, even in HIV-infected persons in Western communities, while HIV infection itself may be more important in developing countries where most patients do not receive highly active antiretroviral therapy (HAART). Recent reports have drawn attention to the development of avascular necrosis of the bone in HIV-positive patients and the risk factors include HAART itself, complications of HAART, HIV infection per se or concomitant conventional risk factors. Many patients respond to conventional symptomatic therapy, and disease-modifying drug therapy is necessary for patients who have persistent and progressive arthritis. The use of HAART can modify the prevalence or expression of the articular syndromes.

Challenges in the management of rheumatoid arthritis in developing countries

Rheumatoid arthritis (RA) is a systemic autoimmune disease which is characterized by chronic inflammation of the joints. Patients experience chronic pain and suffering, and increasing disability; without treatment, life expectancy is reduced. It is imperative to identify patients early so that control of inflammation can prevent joint destruction and disability. Although great advances have been made in the developed nations, early diagnosis remains a great challenge for developing countries during the Bone and Joint Decade (2000-2010) and beyond. Developing countries face important and competitive social, economic, health- and poverty-related issues, and this frequently results in chronic diseases such as RA being forgotten in health priorities when urgent health needs are considered in an environment with poor education and scarce resources. Epidemiological studies in developing countries show a lower but still important prevalence in different regions when compared to that in Caucasians. It seems that the severity of RA varies among different ethnic groups, and probably starts at a younger age in developing countries. Practising rheumatologists in these regions need to take into account several important problems that include suboptimal undergraduate education, inadequate diagnosis, late referrals, lack of human and technical resources, poor access to rheumatologists, and some deficiencies in drug availability. Infections are very important in RA, and special care is needed in developing countries as some endemic infections include tuberculosis, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. These infections should be carefully taken into account when medications are prescribed and monitored. This chapter presents published information covering the main challenges faced in these environments, and suggests strategies to overcome these important problems in RA management.

Kallikrein cascade and cytokines in inflamed joints.

Rheumatoid arthritis is a chronic multi-system disease of unknown aetiology. The current hypothesis is that an unknown antigen triggers an autoimmune response in a genetically susceptible individual. The predominant pathological change is that of an inflammatory synovitis, characterised by cellular infiltrates and angiogenesis, with subsequent bone and cartilage destruction. These pathological changes are as a result of the activation of a variety of cells, inflammatory mediators, and effector molecules. The pro-inflammatory kinins and cytokines appear to play a central role in the pathogenesis of rheumatoid arthritis. Sufficient evidence exists that establishes a key role for the kallikrein-kinin cascade in inflamed joints. In addition, there appears to be an inter-relationship between cytokines and kinins in the inflammatory process. Kinins induce the release of cytokines, and cytokines have been shown to augment the effects of kinins. This may lead to an enhancement and perpetuation of the inflammatory process. In this review, we report a first study, correlating markers of disease with the kallikrein-kinin cascade and with cytokines.

Prevention of musculoskeletal conditions in the developing world

Musculoskeletal conditions are an increasingly common problem across the globe due to increased longevity and increased exposure to risk factors such as obesity and lack of physical activity. The increase is predicted to be greatest in developing countries, and there is thus an urgent need for the implementation of strategies and policies that will prevent and control these conditions. The ideal is modification of the risk factors in the whole community, and this will have wide-ranging health benefits as these risk factors are common to other major conditions. Changing peoples behaviour is a challenge; targeting those at highest risk is potentially more effective, providing that there are both affordable ways of identifying those at risk and affordable interventions. Early intervention in those with a condition such as rheumatoid arthritis is probably the most cost-effective approach, but requires diagnostic capacity--in clinical skills and/or technology--as well as access to care. There is now much evidence for what can be achieved, but the challenge is how to implement these different strategies in developing countries where there are competing priorities for limited resources. The key strategy is to raise awareness among the public, health professionals, and policy makers of the importance of musculoskeletal health, of what can be achieved by prevention and treatment, and to ensure that policies reflect this. It is also necessary to educate the public to know when to seek care, and health-care workers to recognize the early signs of musculoskeletal conditions.

RHEUMATOLOGIC MANIFESTATIONS OF MALIGNANCY

The association of rheumatic syndromes and malignancy is highlighted in this review. The prevalence of malignancy in a series of patients with unclassified rheumatic syndromes is reported. The spectrum of arthropathies associated with malignancy includes bilateral knee effusions, sacroiliitis, and adult-onset Stills disease. There are further reports on the well-recognized association between dermatomyositis and malignancy. The importance of screening for malignancy in patients with classic dermatomyositis as well as dermatomyositis sine myositis is highlighted. The association of mixed cryoglobulinemia with hepatitis C virus infection, hepatocellular carcinoma, and non-Hodgkins lymphoma is discussed. Finally, the association of miscellaneous rheumatic features such as autoantibodies, vasculitis, carpal tunnel syndrome, and multicentric reticulohistiocytosis with malignancy is described.

Initiation but no execution - modulation of peripheral blood lymphocyte apoptosis in rheumatoid arthritis - a potential role for heat shock protein 70

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease, which causes synovial damage. Persistence of lymphocyte infiltrates in the rheumatoid synovium has been attributed to abnormal apoptosis. While not comprehensively investigated, perturbations in peripheral blood lymphocyte (PBL) apoptosis may also be involved in perpetuation of autoimmune processes in RA.MethodsWe investigated total, CD4+ and CD19+ PBL apoptosis in our study cohort by monitoring the translocation of phosphatidylserine using the Annexin-V assay. To examine the role of death receptor mediated apoptosis as well as activation-induced-cell-death (AICD), PBLs were labeled with CD95/Fas and CD69 markers and enumerated by flow cytometry. Proteolytic activity of initiator and executioner caspases was determined by luminometry. DNA fragmentation assays were used to examine whether apoptotic signals were transduced to the nucleus. Quantitative PCR arrays were used to investigate apoptotic pathways associated with RA-PBLs. Since heat-shock-protein-70 (HSP70) is an inducible protein which modulates apoptotic signals, we determined HSP70 levels by intra-cellular flow cytometry and western blots.ResultsThe RA-PBLs showed signs of elevated apoptosis whilst in circulation. These include increases in the loss of plasma membrane asymmetry, indicated by increased externalization of phosphatidylserine (especially in B-lymphocytes). RA-PBLs showed a bias to CD95/Fas mediated apoptotic pathways, but low levels of the CD69 marker suggested that this was not associated with immune activation. Although downstream markers of apoptosis such as caspase-3/7 activity, were increased, no DNA fragmentation was observed in RA-PBLs. Interestingly, elevated levels of apoptosis did not correlate with absolute lymphocyte counts in RA patients. Levels of HSP70 were highly elevated in RA-PBLs compared to controls.ConclusionThe results suggest that while apoptosis may be initiated in RA-PBLs, they may lack commitment to fully executing the apoptotic program. This may be related to inhibition on apoptotic transduction by HSP70. This study provides evidence that abnormalities in RA-PBLs apoptosis may occur whilst still in circulation and may contribute to pathogenesis of the disease.

A comparison of bone mineral density in Indians with psoriatic polyarthritis and healthy Indian volunteers

Frediani et al. [1] recently reported the presence of significant systemic osteoporosis in psoriatic arthritis. Psoriatic arthritis (PsA) has been reported to be commoner in Indians than in other Oriental ethnic groups in Asia [2], and a lower bone mineral density (BMD) has been shown in Indian teenagers in South Africa [3]. We therefore undertook a prospective cross-sectional study to assess BMD in Indians with psoriatic arthritis and controls. BMD was measured by dual energy X-ray absorptiometry (DEXA) at the lumbar spine and total femur in 20 patients with PsA (premenopausal women and men <55 years) and 20 ageand sex-matched Indian controls. Although there was no significant difference between the PsA patients and controls in the mean BMD (g/cm) at the lumbar spine (0.979±0.11 vs. 0.989±0.11; p=0.79) or total femur (0.874±0.11 vs. 0.923±0.12; p=0.20), 60% of the PsA group and 45% of controls showed evidence of demineralization (T score <minus 1 SD at one site). In addition, there was a significant correlation between the number of damaged joints and the degree of disability with a reduction in the BMD. Although there was no correlation between the BMD and the duration of PsA, patients with PsA for >9 years (n=10) had a lower BMD at the lumbar spine than did those with PsA for <9 years (n=10) (0.930±0.12 vs. 1.028±0.09; p=0.02) (Table 1). The small sample size and the presence of demineralization in many of our controls probably contributed to our failure to detect a difference in the mean BMD between PsA patients and controls. However, our findings support the observations by Frediani et al. [1] and suggest that PsA may be a risk factor for bone demineralization in Indian patients, especially in the presence of extensive joint damage and or functional limitation.

Rheumatologic manifestations of gastrointestinal disorders.

Rheumatologic features are among the most common extraintestinal manifestations of gastrointestinal disorders. They are an important cause of morbidity and continue to generate interest among researchers. Over the past year, reports have focused attention on inflammatory bowel disease and coeliac disease. Among the hepatic disorders, cryoglobulinemia, Sjögrens syndrome, and other immunological disorders have been reported in association with hepatitis C virus infections. Rheumatologic manifestations are well-documented in association with pancreatic disorders. There are also a number of interesting and unusual case reports that are reviewed.