Varun Dhir

Increased T-lymphocyte apoptosis in lupus correlates with disease activity and may be responsible for reduced T-cell frequency: a cross-sectional and longitudinal study

Apoptosis of lymphocytes is increased in patients with lupus. This may be pathogenic leading to increased load of autoantigens or may be a bystander effect of immune activation. A major unresolved issue is whether apoptosis is related to disease activity. Also its association with lymphocyte frequencies, anti-nucleosomal antibodies and serum IL 10 levels needs to be explored further. The aims of this study are to measure T- and B-lymphocyte apoptosis in patients with lupus and look at the effect of disease activity in a cross-sectional and longitudinal design and to determine frequency of T and B cells, level of anti-nucleosomal antibodies and serum IL 10 and assess their relationship with apoptosis. This study included 41 patients with SLE and 20 controls. A cutoff value of 4 in systemic lupus erythematosus disease activity index (SLEDAI) was used to separate active from inactive SLE. The frequency and degree of apoptosis of T and B lymphocyte were enumerated by flow cytometry using peripheral blood mononuclear cells (PBMCs) stained with CD3/CD19 and annexin V/PI. The data for T/B cell frequency are represented as % of these cells in the PBMC population, whereas percentage of apoptotic cells is out of total T or B cells. Serum anti-nucleosomal antibodies and IL 10 were assayed using ELISA. A repeat assessment of these parameters was carried out in 11 active patients when they became inactive. We found higher T-lymphocyte apoptosis in patients with SLE versus controls (14.8 ± 9.2, 7.2 ± 3.0; P < 0.05) and a lower frequency of T cells (72.7 ± 12.6, 79.9 ± 5.8; P < 0.05). T-lymphocyte apoptosis was higher in patients with active disease compared with inactive (18.5 ± 11.3, 11.6 ± 5.4; P = 0.05). Further, T-lymphocyte apoptosis directly correlated with SLEDAI (r = 0.37, P < 0.05) and inversely with T-cell frequency (r = −0.29, P < 0.05). Anti-nucleosomal antibodies correlated with SLEDAI but not apoptosis. On longitudinal follow-up, a decline in T-cell apoptosis was seen in patients with SLE, however this was not statistically significant. We confirmed a higher degree of apoptosis in T-lymphocytes in patients with SLE and found a direct correlation of T-cell apoptosis with disease activity. Patients had reduced T-cell frequency, which inversely correlated with T-cell apoptosis and may suggest a cause-effect relationship.

Fibromyalgia is common and adversely affects pain and fatigue perception in North Indian patients with rheumatoid arthritis.

Objectives. Fibromyalgia (FM) has been shown to be common in patients with rheumatoid arthritis (RA), but studies on Asian patients are lacking. It remains unclear whether FM has an adverse influence on pain, fatigue, quality of life, and mood in these patients, and what its relationship is with disease activity. We studied prevalence and effects of FM in North Indian patients with RA and associations of RA with disease activity. Methods. This cross-sectional study included 200 RA patients and an equal number of controls. Presence of FM was defined using the American College of Rheumatology 1990 criteria. Pain and fatigue scores were assessed using a 10 cm visual analog scale. Quality of life and presence of depression/anxiety were determined using validated questionnaires. Disease activity and functional disability in RA patients was assessed using the Disease Activity Score 28-3 and Health Assessment Questionnaire, respectively. Results. FM was present in 15% of patients with RA compared to 2.5% of controls in the North Indian population. RA patients with FM did not differ from those without FM in terms of age, gender, current disease-modifying agents, or steroid use. RA patients with FM had higher disease activity and worse functional disability. The number of tender and swollen joints was higher in patients with FM, but correlated poorly with each other. RA patients with FM had higher pain and fatigue scores but were not different in the quality of life or mood. Conclusion. FM is more common in North Indian patients with RA compared to controls. It adversely affects the pain and fatigue felt by RA patients. Disease activity and FM influence each other.

Leflunomide-induced DRESS syndrome with renal involvement and vasculitis

DRESS or drug reaction (or rash) with eosinophilia and systemic symptoms belongs to the severe cutaneous adverse reaction group and is characterized by hematological abnormalities and visceral organ involvement. Although most often related with anticonvulsant and sulfonamide use, it is reported with numerous other drugs. We report an unusual case of DRESS syndrome due to Leflunomide, also complicated by renal involvement in the form of granulomatous interstitial nephritis and vasculitis. On a review of the literature, eight similar cases were found, and these are discussed.

Assessment of premature atherosclerosis in systemic lupus erythematosus patients with and without nephritis

Background Risk of subclinical atherosclerosis is increased in patients with systemic lupus erythematosus (SLE). We correlated carotid intima media thickness (CIMT) and endothelial dysfunction through flow-mediated dilation (FMD) in SLE patients with the SLE Disease Activity Index (SLEDAI). Methods This single-centre cross-sectional study recruited 100 consenting SLE outpatients (ACR 1997 criteria) out of which 50 had nephritis, with disease duration of ≥2 years for SLE and ≥6 months for lupus nephritis. We measured baseline laboratory levels, CIMT and FMD (after brachial BP cuff inflation up to 200 mmHg for five minutes), and calculated SLEDAI. Results Mean age was 29.88 ± 6.53 years; 95/100 were female. CIMT showed positive correlation (p = 0.037; rho = 0.209), and FMD showed inverse correlation with patient’s age (p = 0.011; rho = –0.252). CIMT and FMD were more deranged in patients aged ≥25 years (p < 0.05). CIMT was not significantly different between SLE patients with and without nephritis (p > 0.05), whereas SLEDAI and FMD were more deranged in nephritis patients (p < 0.05). In patients without nephritis, FMD showed significant inverse correlation with disease duration (p = 0.043; rho = –0.288) and urine albumin (p = 0.045; rho = –0.285). In nephritis patients, the correlation between age of the patient was significantly positive with CIMT (p = 0.001; rho = 0.441) and significantly inverse with FMD (p = 0.028; rho = –0.312). Conclusion SLE patients with nephritis are at a higher risk to develop arterial stiffening, leading to early end-organ damage. Early aggressive treatment may prevent endothelial dysfunction. FMD using vascular ultrasonography on the brachial artery represents a non-invasive, repeatable and useful method for the assessment of endothelial dysfunction.

Comparison of two different folic acid doses with methotrexate – a randomized controlled trial (FOLVARI Study)

IntroductionThere is reasonable evidence that folic acid 5–10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity.MethodsThis was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18–75 years of age, not be on MTX and have active disease as defined by ‘Modified Disease Activity Score using three variables’ (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed.ResultsAmong 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4 % (95 % confidence interval −27.4 to 12.7 %) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7 %, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7 %, p = 1.0) or cytopenias (4.3, 4.3 %, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3 %, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (−1.1 ± 1.0, −1.3 ± 1.0, p = 0.2) and ‘European League Against Rheumatism’ good or moderate response occurred in 56.9 and 67.4 % (p = 0.3).ConclusionsEven with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week).Trial RegistrationClinicaltrials.gov NCT01583959 Registered 15 March 2012

A case series and review of Poncet's disease, and the utility of current diagnostic criteria.

Poncets disease is a well recognized form of reactive arthritis in the presence of extra‐articular tuberculosis. There are very limited case reports even from countries where tuberculosis is common and there are no accepted diagnostic criteria for Poncets disease. In the present study we are describing clinical features of Poncets disease from a tuberculosis‐endemic region along with a proposal of a new diagnostic criteria.

Lupus pancreatitis – early manifestation of active disease

Sir, We read with interest the recent article on pancreatitis in lupus. We searched for cases of acute pancreatitis among our lupus in-patients seen over last 10 years at our centre, a university hospital. Pancreatitis was defined as the presence of acute abdominal pain with either raised amylase or swelling of pancreas on ultrasonography (USG)/computer tomography (CT). There were 10 admissions (nine patients) for pancreatitis out of 1300 admissions (550 patients) of lupus. Mean age at onset of pancreatitis was 30.5 yrs (SD 8.6) and all were females. In one patient pancreatitis was present at onset, and in two it was present at the time of diagnosis of lupus. Lupus was active (SLEDAI > 4) in nine with high disease activity (SLEDAI> 12) in six. Four patients had proteinuria more than 1 gram per day (two with active sediments) and two had neuropsychiatric lupus (NPSLE). Six patients were on steroids (median prednisolone dose 10mg) and none was on immunosuppressives. All the remaining four had intermittently received steroids in the last 6 months (many without a diagnosis). Table 1 lists other the characteristics of these patients. Abdominal pain was present for a median duration of 1.5 days before admission (interquartile range, IQR1⁄4 0.5–5.5). Amylase was raised in nine, USG showed pancreatic swelling in nine and CT in both cases in which it was done. Gall stones (GSD) was found in only one patient (with inactive lupus). Severe pancreatitis was present in three, with organ failure in two (renal failure, shock) and necrosis on CT/USG in two. High dose steroids (1mg/kg prednisolone) was given to all except the patient with GSD. Pulse methylprednisolone (15mg/kg) was given in addition to six patients and pulse cyclophosphamide (CYC) 0.5–1 g to four patients. Mean duration of hospitalization was 15.7 days (SD 5.3). Major complications occurred in four patients and they were: encephalopathy with deep venous thrombosis, peritonitis with acute renal failure, myocarditis with shock and E. coli sepsis with right atrial clot. Two patients died due to sepsis and possible pulmonary embolism (one had severe pancreatitis, both had active lupus). On follow-up, three patients received 6 pulses of CYC (given monthly) for proliferative lupus nephritis and one received 3 pulses (given monthly) for NPSLE, followed by azathioprine. One patient died one year later due to uncontrolled diabetes mellitus probably related to pancreatic atrophy. This study suggests that in one-third of patients pancreatitis occurs very early in disease and in another one-third it occurs in the first 2 years, similar to a recent report. In a review of 77 cases, 44% had developed pancreatitis within 1 year of diagnosis of lupus (in 22% it was a presenting feature). However, a study from Mexico found that only 14 of 49 episodes occurred within 2 years of onset of lupus and a study from USA found a median gap of 5 years from diagnosis of systemic lupus erythematosus (SLE) to pancreatitis. This may be due to a higher proportion of cases due to gallstones and toxic-metabolic causes in these two studies. We found active SLE in most patients, similar to the review of 77 cases in which 67 patients had ongoing lupus symptoms. Also, Derk and co-workers found 19 of 25 cases of pancreatitis occurred in active lupus (active renal disease in 14) and the Mexican study found a median mexSLEDAI of 9 in patients with idiopathic pancreatitis.

Clinical features and long‐term outcomes of 105 granulomatosis with polyangiitis patients: A single center experience from north India

To describe the clinical features, treatment and long‐term outcomes in north Indian patients with granulomatosis with polyangiitis (GPA).

Giant cell arteritis in India: Report from a tertiary care center along with total published experience from India

OBJECTIVES Giant cell arteritis (GCA) is a granulomatous large vessel vasculitis with very scarce data from India. The purpose of this study was to present a comprehensive data of all published Indian cases along with our experience from North India. MATERIALS AND METHODS This was a retrospective study of all patients diagnosed to be having GCA according to the American College of Rheumatology criteria at a large tertiary care hospital. The demographic data, clinical, investigations, treatment details, and outcomes were noted. Details of all case series and case reports published from India were pooled along with our experience in order to generate a cumulative data of all cases from India. This was then compared with several large published case series from South America, Europe, and Asia. RESULTS A total of 72 patients (17 patients in the present series and another 55 patients from other Indian case series and case reports) were identified. The findings of our study are similar to the studies published from other parts of the world, except for the onset of the disease a decade earlier, a male predilection, a lower temporal artery biopsy positivity, and a higher incidence of ophthalmic complications. CONCLUSIONS Indian patients with GCA have an earlier age of onset, male preponderance, and higher ophthalmic complications.

Randomized Controlled Trial Comparing 2 Different Starting Doses of Methotrexate in Rheumatoid Arthritis

PURPOSE Methotrexate (MTX) remains the gold standard disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). Few studies have compared different starting doses of MTX in RA. We hypothesized that starting with a higher MTX dose may be more effective but associated with more adverse effects. We compared a starting dose of 7.5 versus 15 mg per week of MTX followed by similar fast escalation. METHODS This was an open-label (blinded assessor), parallel-group, randomized controlled trial that included RA patients aged 18 to 65 years, not on MTX, and having active disease (Disease Activity Score for 28 joints using 3 variables [DAS28(3)] ≥5.1). Patients were randomized to receive MTX at a starting dose of 7.5 mg (group 1) or 15 mg (group 2) per week. The dose of MTX was escalated by 2.5 mg every 2 weeks to a maximum of 25 mg. Patients were seen every 4 weeks, and dose escalation was continued if DAS28(3) was >2.6 and there were no laboratory abnormalities (transaminitis [>2 × upper limit of normal] or cytopenia). The primary endpoint was change in disease activity at 12 weeks (assessed by using the DAS28[3]). Secondary endpoints were patient withdrawals and episodes ofcytopenia or transaminitis. Adverse effects were ascertained by using a questionnaire. Both intention-to-treat and per-protocol analyses were performed. FINDINGS We enrolled 100 patients (female:male ratio, 78:22) with a mean (SD) age of 43.6 (10.8) years and a disease duration of 4.7 (4.8) years. At baseline, patients had a mean DAS28(3) of 6.2 (0.7) and a Health Assessment Questionnaire score of 1.3 (0.6). Group 1 (7.5 mg) and group 2 (15 mg) included 47 and 53 patients, respectively, with no significant differences in baseline characteristics. At 12 weeks, the mean dose of MTX reached was 17.3 (4.6) mg in group 1 and 23.6 (3.0) mg in group 2 (P < 0.001). The 2 groups had a similar number of patient withdrawals. The mean change in DAS28(3) at 12 weeks in group 1 (-0.47 [0.86]) and group 2 (-0.55 [0.79]) was not significantly different (P = 0.60). The change in the Health Assessment Questionnaire score was also similar in the groups. The frequency of episodes of transaminitis (6 and 7; P = 0.8) and cytopenia (1 and 2; P = 0.9) did not differ significantly between groups 1 and 2, respectively. Results remained the same according to the per-protocol analysis. Among adverse effects, nausea was more common in group 2 compared with group 1 (relative risk, 1.6 [95% CI, 1.1-2.2]). IMPLICATIONS There were no significant differences in efficacy between the 2 starting doses of MTX. The fast escalation of dose in both groups may have blunted any advantage of starting at a higher dose. Nausea occurred more commonly in patients started on 15 mg of MTX. We suggest longer trials to confirm our findings. ClinicalTrials.gov identifier: NCT01404429.