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   Table of Contents - Current issue
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March 2019
Volume 14 | Issue 1
Page Nos. 1-86

Online since Thursday, March 14, 2019

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FROM THE EDITORS DESK  

But I Have Promises to Keep…… p. 1
Vikas Agarwal
DOI:10.4103/0973-3698.254212  
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EDITORIALS Top

Challenges in assessing the disease activity of takayasu arteritis p. 2
Durga Prasanna Misra, Anupam Wakhlu
DOI:10.4103/injr.injr_19_19  
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Is rituximab “The Wonder Drug” for antineutrophil cytoplasmic antibodies-associated vasculitis? p. 4
Saket Jha, GSRSNK Naidu, Aman Sharma
DOI:10.4103/0973-3698.254190  
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Advanced therapies for inflammatory rheumatic diseases in resource-poor settings p. 7
Vinod Chandran
DOI:10.4103/0973-3698.254191  
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Utility of CD64 expression on neutrophils as a marker to differentiate infectious versus noninfectious disease flares in autoimmune disorders p. 9
Ashutosh K Mangalam, Rajwardhan Yadav
DOI:10.4103/0973-3698.254192  
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ORIGINAL ARTICLES Top

Rituximab in relapsed/refractory antineutrophil cytoplasmic antibody associated vasculitis: A single-center prospective observational study p. 12
Ekbote Gayatri, Tanna Dhaval, Negalur Natasha, Bindroo Muzaffar, Raval Dhiren, Sharma Lucky, Rajiva Gupta
DOI:10.4103/injr.injr_138_18  
Background: Induction with cyclophosphamide (CYC) and glucocorticoids in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) has a relapse of 30%–50%. Studies show that rituximab (RTX) is superior to CYC in refractory/relapsed AAV. We prospectively analyzed efficacy and safety of RTX in CYC-failed cases of AAV. Methods: Patients with AAV who relapsed or were refractory to CYC therapy were given RTX 1 gm at 0 and 15 days, followed by maintenance with 500 mg every 4–6 months. All patients received oral prednisolone. Disease activity was defined by Birmingham Vasculitis Activity Score/Wegener's granulomatosis (BVAS/WG). Remission was defined by the European League Against Rheumatism criteria. Results: From August 2012 to July 2018, 67 patients with AAV were seen at our center; 21 patients who relapsed after inductions with CYC or were refractory to CYC received RTX; 8 (38%) were refractory and 13 (62%) were relapsed AAV; 20 were anti-proteinase 3 positive and 1 was anti-myeloperoxidase positive. All were granulomatosis with polyangiitis (GPA). Mean time to relapse was 12.04 ± 7.8 months. Most common indication for RTX was lung followed by ophthalmic, renal, ear nose throat, and nervous system involvement. Median follow-up after induction with RTX was 24 months. Mean BVAS/WG was 11.2 at baseline, 0.66 at the end of 3 months, 0.16 at the end of 6 months, and remained stable at that value at 18 months. At 24 months, 16 patients (76.19%) remained in remission. One was refractory to RTX treatment even after 2 years. Two patients died and two were still under follow-up. Conclusion: In our experience, RTX is a good induction and maintenance strategy for relapsed/refractory AAV.
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Prescribing patterns and safety of biologics in immune-mediated rheumatic diseases: Karnataka biologics cohort study group experience p. 17
Vineeta Shobha, Vijay Rao, Anu Mohan Desai, Ramesh Jois, Chandrashekara Srikantiah, BG Dharmanand, Sharath Kumar, Pradeep Kumar, Chethana Dharmapalaiah, KM Mahendranath, Shiva Prasad, Manisha Daware, Yogesh Singh, Uma Karjigi
DOI:10.4103/injr.injr_79_18  
Introduction: Biologics are widely used in Autoimmune rheumatologic diseases (AIRDs), however the need to capture real life data which monitors indications, adverse reactions cannot be over emphasized. Methods: This is a cross-sectional ambidirectional multi-center study conducted over 8 months from January 2016 to August 2016, across 12 tertiary care rheumatology centers in Karnataka, India conducted by members of the Karnataka Rheumatology Association. Results: The most common biologic prescribed is tumour necrosis factor antagonist etanercept. Commonest indication for biologics being Spondyloarthropathy group of disorders. The most common cause for stopping biologics is clinical improvement. Only 4.8% of patents discontinued biologics due to ADRs. Conclusion: The prescribing patterns, mode of use, prebiologics screening methods, and adverse event profile are similar across centres. Pre-screening for latent tuberculosis (TB) is consistent across centres, and TB prophylaxis appears to be effective in preventing its reactivation.
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Pentraxin 3 is better than conventional inflammatory markers for disease activity assessment in takayasu arteritis p. 21
Phani Kumar Devarasetti, Rajendra Varaprasad Irlapati, Liza Rajasekhar
DOI:10.4103/injr.injr_95_18  
Objective: The objective of this study is to measure plasma pentraxin 3 (PTX3) levels in Takayasu arteritis (TA) patients and to compare the accuracy of PTX3, high-sensitive C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) in distinguishing active disease from the inactive disease. Methods: In a prospective, cross-sectional study, TA patients fulfilling 1990 American College of Rheumatology criteria and healthy controls were enrolled in this study. The Indian Takayasu Clinical Activity Score (ITAS 2010) and ITAS ESR were recorded. Patients were divided into active, grumbling and inactive disease using physician global assessment. Plasma PTX3, hsCRP, and ESR were measured. Receiver operating curves for PTX3 (pg/ml), hsCRP (mg/L), and ESR (mm at 1 h) were constructed to differentiate active from the inactive disease. Inter-group comparisons were made using Mann–Whitney test. Results: Forty patients and 20 controls with median age of 26 and 24 years, respectively, were enrolled in this study. Median disease duration was 2 years. Fourteen patients had active, 8 grumbling, and 18 inactive disease. ITAS 2010 and ITAS ESR in active disease (5 [3–8.5], 7.5 [5–11.5]) were significantly higher than grumbling (0.6 (0–1.5], 2.5 [1–4.5]) or inactive disease (0.5 [0–1.3], 2 [1.7–3]) (P = 0.001). PTX3 (pg/mL) was higher in cases (505 [261–1358]) as compared to that of controls (317 [135–450]) (P < 0.026), in active disease (1335 [464–2128]) was higher than grumbling (689 [246–2114]), but significantly higher than inactive TA (369 [145–512]) (P < 0.001). ESR (mm/h) and hsCRP (mg/L) of 49 (33–61.2), 12.9 (4–21), respectively, in active disease was similar to grumbling (44 [31–63], 10.7 [3–14.7]), but significantly higher than inactive disease (38 [24–45], 1.8 [1.4–2.2]) (P = 0.03). Sensitivity, specificity, and area under the curve for ESR (>46 mm), hsCRP (17.1 mg/L), PTX3 (>745 pg/ml) was (55, 89, and 0.72), (46, 89, and 0.75), and (64, 95, and 0.82), respectively. Conclusion: Elevated PTX3 in TA demonstrates more accuracy than hsCRP and ESR in differentiating active from the inactive disease. These biomarkers may differentiate grumbling from inactive disease better than ITAS2010 or ITAS-ESR.
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Serum sclerostin levels in rheumatoid arthritis and correlation with disease activity and bone mineral density p. 28
Urmila Dhakad, Rasmi Ranjan Sahoo, Akhil Pawan Goel, Sourav Pradhan, Ragini Srivastava, Siddharth Kumar Das
DOI:10.4103/injr.injr_113_18  
Background: This study aims to assess serum sclerostin, an inhibitor of the Wnt/β-catenin signaling pathway, in rheumatoid arthritis (RA) and its correlation with disease activity and bone mineral density (BMD). Methods: RA patients (>18 years) fulfilling the ACR/EULAR (2010) criteria for RA were included. Postmenopausal women, those with other autoimmune diseases, secondary causes of osteoporosis, severe vitamin D deficiency, chronic liver disease, chronic kidney disease stage 3 and above, and those patients on anticonvulsants were excluded. Rheumatoid factor, anticitrullinated protein antibody, 25-OH Vitamin D estimation, plain radiographs of hands, and BMD measurement by dual-energy X-ray absorpiometry were done in patients. Disease activity was assessed by clinical disease activity index (CDAI). Serum sclerostin levels in RA patients and controls (age and sex matched) were measured by commercial enzyme-linked immunosorbent assay (ELISA) and the relationship of sclerostin with low BMD, ESR, CDAI, and erosion were explored. Results: The mean age of patients (n = 47) was 32.7 ± 6.8 years and mean disease duration was 4.2 ± 2 years. All patients were women, mean body mass index was 22.38±4.4 and mean vitamin D level was 27.9±16.4 ng/ml. 25.5% of RA patients had low BMD at least one site (Z-score: −2 or less). Serum sclerostin was significantly higher in patients compared to controls (8422 ± 3655 pg/ml vs. 6479 ± 1510 pg/ml, P = 0.002). Serum sclerostin levels did not correlate significantly with ESR (r = −0.31 and P = 0.048), CDAI (r = −0.11 and P = 0.45), BMD at lumbar spine (L1–L4, r = 0.14, and P = 0.35), femur neck (r = 0.06 and P = 0.67), and wrist (r = 0.12 and P = 0.41). Conclusion: Serum sclerostin levels were elevated in RA patients but did not correlate with disease activity and BMD.
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Dual antibody status predicts sustained remission in patients with rheumatoid arthritis p. 32
Praveen Pratap Jadhav, Jaya Dilip Avhad, Mahendra Mahajan, Asmanaz Mehemud Patel, Hemant Ramchandra Gavli, Janhavee Praveen Jadhav, Vaibhav Khandelwal
DOI:10.4103/injr.injr_107_18  
Background: Rheumatoid factor (RF) and anti-cyclic citrullinated protein (ACCP) estimation have been used to improve the diagnosis of rheumatoid arthritis (RA). However, their role in prognostication of RA, individually and in combination, is not well studied. This is, especially, true for Indian patients. Methods: Consecutive 945 patients who had their RF and ACCP determined were included in the study. They were followed up for 3 months to 24 months. Swollen joint count, erythrocyte sedimentation rate, disease activity score 28 (DAS 28), and Indian version of Health Assessment Questionnaire (HAQ) were checked during each visit. They were treated with conventional disease-modifying agents (DMARDS). Results: At presentation, patients with both antibodies positive had the most severe disease, while those with both antibodies negative had the least severe disease. Among discordant antibody status (one antibody positive and the other negative), patients with ACCP positivity presented with higher disease activity than with RF positivity. Patients with dual antibody positivity were much less likely to be in remission than with both negative antibodies. The percentage of patients in remission were 34.2, 29.5, 32.4, and 24.7, respectively, for RF−/ACCP−, ACCP+/RF−, ACCP−/RF+, and ACCP+/RF+. Both, ACCP (odds ratio [OR]: 0.76; 95% confidence interval [CI]: 0.74–0.78) and RF (OR: 0.68; 95% CI: 0.66–0.70) positivity were associated with lower odds of sustained remission (P < 0.05). Conclusion: Dual antibody-positive status at presentation carries poor prognosis, higher disease activity, higher HAQ score, and lesser chance of remission in RA patients with conventional treatment. Patients with both antibodies negative status had the best prognosis. Although patients with discordant antibody status had an intermediate prognosis, the ones with ACCP had higher disease activity at follow-up.
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Utility of anti-carbamylated protein antibodies in the diagnosis of early rheumatoid arthritis p. 37
Ashraf H Mohamed, Asmaa Enein, Noha Abdelsalam, Mona Balata, Sameh Abdellatif, Ehsan Rizk, Ahmed Fathy
DOI:10.4103/injr.injr_110_18  
Background: Anti-carbamylated protein (anti-CarP) antibodies are present in patients with Rheumatoid arthritis (RA) and may present before disease onset. Our aim is to investigate the diagnostic value of anti-CarP antibody in Egyptian RA patients. Methods: This cross-sectional study included 96 RA patients (56 patients with early disease and 40 patients with established disease) and 60 healthy controls. Demographic and clinical data, smoking status, and disease activity score were recorded. Laboratory tests included erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-citrullinated protein antibodies, and anti-CarP antibody. Results: Anti-CarP antibody levels in RA patients were significantly higher than in controls (8.80 ± 5.95 vs. 2.19 ± 1.01, P < 0.0001). Out of 96 RA patients; 74 (77.1%) were positive for anti -CarP anti body including 47patients with early RA while only 5 subjects (8.3%) in control group were positive. Receiver-operating characteristic curve study for diagnostic efficacy of anti-CarP antibody in early RA diagnosis demonstrated a significant area under the curve, 0.950 (95% confidence interval, 0.912–0.987, P < 0.0001) and yielded a sensitivity of 85.4%, a specificity of 93.3%, a positive predictive value of 0.90, and a negative predictive value of 0.86. Conclusion: Anti-CarP antibody is a useful biomarker for early RA diagnosis.
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A cross-sectional study of different rheumatic diseases and their respective comorbidities at a tertiary care hospital in India p. 42
Baikan Saiteja Yadav, Arindam Nandy Roy, Syeda Sana Fatima
DOI:10.4103/injr.injr_112_18  
Background: Rheumatic diseases have many outcomes, but less understood are many manifestations of additional health conditions that are associated with these diseases called co-morbidities. The more co-morbid illnesses one has, the greater the interference with medical management of rheumatic diseases. It is important to recognize such illnesses and to account for them in the care of the individual patient. There are few studies pertaining to different co-morbidities associated with rheumatic conditions. Therefore, this study was carried out to evaluate different rheumatic diseases and their frequency, associated co-morbid conditions and their variation based on age and body mass index (BMI). Methods: This cross sectional study was designed to survey 1000 consecutive patients who were diagnosed to have rheumatic diseases for co-morbidities at our institution. Patients of either gender with age ≥18 years were included. Data was collected regarding demographics detail, diagnosed disease and co-morbid condition. Analysis was done by IBM SPSS version 17.0 and R version 3.4, the association of rheumatic disease and co-morbidity with age and BMI was analyzed using Chi-square test. Results: We found that that rheumatic disease and co-morbidity increased significantly with age and body mass index (BMI) (P < 0.005). A substantial proportion of patients with rheumatic diseases (45%) were foud to have co-morbidities. The most common amongst them are hypertension, hypothyroidism and diabetes mellitus in descending order of frequency. Conclusion: C-morbidities which are amenable to therapeutic measures are common in individuals with rheumatic diseases. Early detection of such co-morbid condition is helpful should be an integral part of rheumatology patient care.
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REVIEW ARTICLE Top

Management of pain in rheumatic diseases p. 49
Neha Goyal, Mohit Goyal, Vinod Ravindran
DOI:10.4103/injr.injr_88_18  
Pain is often the presenting symptom of many rheumatic diseases, the predominant disabling symptom, the reason for frequent visits to the physician and a major cause of medical absenteeism, loss of work hours, and financial burden on the society. Pain in rheumatic diseases is now understood to be a result of interplay of inflammation, tissue damage, and neurogenic responses. Besides control of inflammation, the structural changes, central sensitization, and the associated issues of disturbances of sleep, mood, and cognition also need to be addressed. Apart from the useful addition of neuromodulators to our traditional repertoire of pain medications consisting of analgesics, nonsteroidal anti-inflammatory drugs, steroids, and opioids, there is a place for interventions in situations where pain persists even after reasonable control of widespread inflammation. These interventions are mostly percutaneous and have found applications in inflammatory, structural, as well as neurogenic pain. Interventional spine procedures, platelet-rich plasma therapy, ozone therapy, and radiofrequency ablation of neural structures have added new dimensions to the management of pain.
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TOPICAL REVIEW Top

Current treatment of osteoporosis Highly accessed article p. 57
Subramanian Nallasivan
DOI:10.4103/injr.injr_74_18  
Osteoporosis is ever increasing as life expectancy continues to increase across the world. Hypovitaminosis D has been found to be prevalent even in children and adults, and hence, it is imperative to educate the public on the nutrition for bone health. “Love your bones and joints” was the slogan by the World Health Organization to increase the awareness among the public. Bone density is assessed by Dual Energy X-ray Absorptiometry scan and the T score system. Although biomarkers have been studied in research, their clinical utility is still elusive. Regular exercise and adequate intake of Calcium and Vitamin D are important to maintain bone health. Bisphosphonates are the first line drugs in the management of osteoporosis both for primary and secondary prophylaxis. Second-line drugs include denosumab, teriparatide, and newer drugs such as abaloparatide, romosozumab, and calcitonin, which have found more real-life acceptance and efficacious in the long-term management of osteoporosis. Romosozumab, a monoclonal antibody may well become the ideal osteoporosis drug with effects on bone formation and resorption. Surgical treatment choices include – Vertebroplasty and kyphoplasty are being accepted in specific instances and selected centers with variable success.
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CASE-BASED REVIEW Top

Alopecia as the first manifestation of azathioprine myelosuppression in a genetically predisposed patient p. 61
Debashish Mishra, Shefali Khanna Sharma, Aman Sharma, Sanjay Jain, Varun Dhir
DOI:10.4103/injr.injr_127_18  
Azathioprine, an analog of mercaptopurine, is used for various inflammatory/autoimmune diseases in diverse fields such as rheumatology, ophthalmology, gastroenterology, and neurology. One of the dreaded side effects of this drug is myelosuppression, which can be either dose related or “idiosyncratic.” The latter group often manifests with sudden cytopenias and is often secondary to a genetic predisposition. Mutations in the genes thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) have been identified to predispose to severe myelosuppression with azathioprine. An important clinical clue that can precede the onset of myelosuppression is alopecia. Here, we describe the case of a young lady treated with azathioprine, who developed alopecia (progressing to alopecia totalis), which was followed by severe cytopenia – both of which recovered on stopping the drug. On genetic analysis, she was found to be homozygous for mutation in NUDT15 (C415T) but was negative for mutation in TPMT. We review various other cases reporting alopecia as a marker of azathioprine-induced myelosuppression and the genetic mutations described.
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Childhood polyarteritis nodosa presenting as central nervous system vasculitis p. 65
Sham Santhanam, Ravikumar Thambithurai, Nataraj Palaniappan, Mukul Vij, Srinivasan Kalyanasundaram
DOI:10.4103/injr.injr_129_18  
Childhood polyarteritis nodosa (c-PAN) is one of the rare causes of childhood central nervous system (CNS) vasculitis. Nervous system involvement is less common, with peripheral nervous system frequently involved than the CNS. To the best of our knowledge, a very few cases of c-PAN presenting as CNS vasculitis involving both the anterior and posterior circulation have been reported in the literature. Hence, we report a 14-year-old female presenting with extensive CNS vasculitis with severe neurological deficits. She also had systemic symptoms, myalgia, leg ulcers, weight loss, axonal neuropathy, and proteinuria. She was treated with pulse methylprednisolone, monthly intravenous pulse cyclophosphamide, and intravenous immunoglobulin. At the end of 3 months, her proteinuria came down significantly with no major improvement in her neurological status. Hence, c-PAN has to be considered in the differential diagnosis of childhood CNS vasculitis and if not picked up early can lead to severe neurological deficits.
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Livedoid vasculopathy with mononeuritis multiplex associated with protein S deficiency mimicking systemic vasculitis p. 69
Vikramraj K Jain, Krishnamurthy Hegde, Renuka Panchagnula
DOI:10.4103/injr.injr_97_18  
A 34-year-old female presented with recurrent ulcers over the bilateral lower limbs with mononeuritis multiplex. Possibilities considered were small-to-medium vessel vasculitis and vasculopathy. Skin biopsy was suggestive of livedoid vasculopathy (LV). Investigations revealed protein S deficiency. The patient was treated with anticoagulation and immunosuppression after which her symptoms improved. LV can be associated with thrombophilias, fibrinolytic disorders, autoimmune diseases, and malignancy. Polyarteritis nodosa closely mimics the disease and needs a deep dermal biopsy to differentiate.
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Guillain–barre syndrome as a presenting feature of systemic lupus erythematosus in a child and it's complete resolution with rituximab treatment p. 74
Rahul Reddy, Anu Punnen, Annie Bella, Sathish Kumar
DOI:10.4103/injr.injr_118_18  
Systemic lupus erythematosus (SLE) can present with varied neurological manifestations in children. Guillain–Barre syndrome (GBS) as a presenting feature of SLE is quite rare in children. We report a 9-year-old girl who presented with acute motor axonal polyradiculoneuropathy and noticed to have features of SLE. She was initially treated with intravenous immunoglobulins and corticosteroids with partial response. After starting rituximab, she showed dramatic recovery, proving the role of rituximab in GBS refractory to first-line medications in SLE. She remained in remission after 12 months of follow-up.
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LETTERS TO EDITOR Top

No impact of seronegativity on the efficacy of a biosimilar rituximab in biologic-naïve patients with active rheumatoid arthritis p. 77
Nedumooli Pottammal Jamshid, Vinod Ravindran
DOI:10.4103/injr.injr_158_18  
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Use of coffee for alleviating methotrexate intolerance in rheumatic diseases p. 79
Anand Narayan Malaviya, Sadhana Singh Baghel, Shallu Verma, Ravita Thakran, Christy Messi
DOI:10.4103/injr.injr_144_18  
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A case of relapsing polychondritis with laryngeal stenosis successfully controlled with biosimilar adalimumab (ZRC-3197) p. 81
Manish Dugar, Jaswinder Singh Saluja, A Sudhakar
DOI:10.4103/injr.injr_111_18  
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Progressive pseudorheumatoid dysplasia: A mimicker of juvenile idiopathic arthritis p. 83
Sikha Agarwal, Anuja Pethe, Anuja Nayak
DOI:10.4103/injr.injr_132_18  
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OBITUARY Top

Obituary Prakash Pispati p. 85
Rohini Handa
DOI:10.4103/injr.injr_169_18  
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