Vir Singh Negi

Intravenous immunoglobulin therapy in rheumatic diseases

Prepared from the collective plasma of several thousand people, therapeutic intravenous immunoglobulin (IVIg) consists mostly of human polyspecific IgG. In addition to its use in primary and secondary immune deficiencies, IVIg is used in the treatment of several rheumatic conditions, including Kawasaki disease, dermatomyositis and antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. In these diseases, IVIg therapy generally involves the use of 2 g/kg administered over either 2 or 5 consecutive days. However, dosage regimens have not been thoroughly explored, and indications for IVIg in most rheumatic diseases, such as systemic lupus erythematosus, polymyositis and catastrophic antiphospholipid syndrome, derive from its off-label usage. Randomized clinical trials are warranted to support the evidence-based use of IVIg, and to identify the ideal administration protocols to maximize the benefits of what is a limited resource. Further research to improve the therapeutic application of IVIg relies essentially on the conception of next-generation immunoglobulin preparations and optimization of combined therapies with immunomodulatory drugs and biologic agents.

Susceptibility to SLE in South Indian Tamils may be influenced by genetic selection pressure on TLR2 and TLR9 genes.

INTRODUCTION Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with complex etiology. Genetics plays an important role in lupus pathogenesis through its influence on clinical and autoantibody phenotype of the disease. Toll like receptors (TLR) recognize molecular patterns of pathogens and activate the innate immune system. Their ability to identify nucleic acids makes them suitable candidates for investigation of their role in lupus pathogenesis. Hence, this study was carried out to analyze the G to A and C to T transitions in TLR2 and TLR9 genes respectively and to test their association with lupus susceptibility, clinical and autoantibody phenotypes in South Indian Tamils. METHOD Three hundred SLE patients fulfilling ACR 2012 criteria for SLE and 460 age, sex similar, ethnicity matched controls were recruited as cases and controls. TLR2 (R753Q) and TLR9 (-1237C/T) polymorphisms were analyzed by real time PCR. RESULTS The TLR2 gene remained monomorphic in patients and controls, the frequency of the homozygous wild type allele being 100% and 99.6% respectively. Hence, it did not confer susceptibility to SLE. The more frequent T allele of TLR9 gene conferred a significant risk to develop SLE (p=0.011, OR 1.69, 95% CI 1.1-2.6). Both the polymorphisms did not influence clinical or autoantibody phenotype of the disease. CONCLUSION Prevailing endemic infections in the Indian subcontinent may have exerted a selection pressure resulting in TLR2 gene remaining monomorphic and the TLR9 adapting to a mutation for its increased expression. These may have an additive effect in the presence of other genetic and environmental risk factors to confer susceptibility to SLE in South Indian Tamils.

Activation of NF-κB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism : Possible role of oxidative stress

This study evaluated oxidative stress, serum IgM and IgG, and nuclear factor (NF)-kappaB signaling in lymphocytes of hyperthyroidism patients. GSH content in lymphocytes was significantly lower and serum malondialdehyde, IgM and IgG levels were significantly higher in hyperthyroidism as compared to controls. In lymphocytes, the NF-kappaB signaling pathway was studied by western blot analysis of p65 and p-IkappaBalpha. Density of p-IkappaBalpha and p65 (in nuclear fraction) was significantly higher in hyperthyroidism as compared to controls. The density of p-IkappaBalpha and p65 had significant positive correlation with serum malondialdehyde level and negative correlation with lymphocyte GSH level in hyperthyroid cases. The serum IgG and IgM levels were correlated significantly with density of p-IkappaBalpha and p65. As immunoglobulin production is regulated by the NF-kappaB pathway, we conclude that the oxidative stress-induced activation of the NF-kappaB pathway might play a role in the rise of serum immunoglobulin level in hyperthyroidism.

A scoping review of the use of non-biologic disease modifying anti-rheumatic drugs in the management of large vessel vasculitis

Takayasus arteritis (TA) and Giant cell arteritis (GCA) comprise the large vessel vasculitides (LVV). Patients with LVV are treated with disease-modifying anti-rheumatic drugs (DMARDs), both conventional (cDMARDs) and biologic (bDMARDs). We undertook a scoping review to assess the effectiveness of cDMARDs in TA and GCA. We could identify 11 studies in TA and 18 studies in GCA. There were only 3 randomized controlled trials on methotrexate, one on hydroxychloroquine and two on cyclosporine in GCA, the others being case series (including all studies on TA). Most of these studies had small patient numbers (median 15 in TA and 27 in GCA). Outcome measures reported in different studies were heterogenous. Overall, methotrexate, leflunomide, azathioprine, mycophenolate mofetil and cyclophosphamide were effective in TA (low quality of evidence). Methotrexate (high quality of evidence), hydroxychloroquine and cyclosporine (moderate quality of evidence) appeared to be ineffective in GCA. Azathioprine (moderate quality of evidence), leflunomide, mycophenolate mofetil, cyclophosphamide and dapsone (low quality of evidence) were effective in GCA. There exists a paucity of high quality evidence to guide use of cDMARDs in TA and GCA. There is an unmet need to conduct large multi-centric randomized placebo-controlled trials to accurately assess the utility on cDMARDs in LVV.

Cytomorphologic Study of Hashimoto’s Thyroiditis and Its Serologic Correlation

OBJECTIVE To analyze the cytomorphologic spectrum of Hashimotos thyroiditis (HT) on fine needle aspiration cytology (FNAC) and to correlate cytologic findings with serologic parameters STUDY DESIGN One hundred fifty patients diagnosed with HT on FNAC were subjected to serologic studies. A detailed cytologic examination was done with an attempt to grade thyroiditis, lymphoid:epithelial (L:E) ratio and intensity of lymphocytic infiltrates. Any additional lesion or feature seen in association with HT was recorded. Thyroid hormonal assay and thyroid antibodies were evaluated using appropriate methods. Cytologic findings were correlated with the serologic parameters and analyzed using the chi2 test and Fishers exact test. RESULTS Apart from the usual cytomorphologic spectrum of HT, significant findings recorded in a fair number of cases were abundant colloid, follicular hyperplasia, fire flares, eosinophils and HT-associated neoplasms. Grading of thyroiditis and lymphocytic infiltration showed no correlation with the clinical severity of HT, while a high L:E ratio was strongly correlated with thyroid peroxidase positivity (p = 0.004). Presence of fire flares and macrophages correlated positively with hyperthyroidism, with p values of 0.002 and 0.005, respectively. Thyroid peroxidase positivity showed a strong association with HT (p = 0.001) as compared to HT coexisting with follicular hyperplasia/Hashitoxicosis/neoplasm. CONCLUSION The present study gives an account of the cytomorphologic spectrum of a large series of HT cases, with its serologic correlation, emphasizing the importance of a careful interpretation of fine needle aspiration smears in the presence of colloid, follicular hyperplasia or a coexisting neoplasm.

Publishing in black and white: the relevance of listing of scientific journals

Scientific publishing, including in the field of Rheumatology, is evolving rapidly. Predatory journals are one of the major threats to contemporary publishing, especially to eager and naïve authors. In this narrative review, we discuss mechanisms that authors can employ to white list genuine scientific journals and blacklist “predatory” ones. Inclusion of a journal in reputed indices such as Medline (but not just Pubmed), Web of Science, Scopus or Embase raises the likelihood that the journal is genuine, more so if it is included in the current Journal Citation Reports. Other commercially available whitelists also exist, so also whitelists published by regulatory authorities in some countries. A commercially available blacklist has emerged since the very useful Beall’s blacklist became defunct. In the absence of access to a whitelist or blacklist, certain characteristics such as repeated email solicitations for articles with an extremely narrow deadline from unknown sources, lack of inclusion in reputed indices, journals not published or endorsed by national or international society and scarcity of currently published articles should render authors suspicious of the genuine nature of a journal. National societies should work together to generate subject-specific (including Rheumatology specific) whitelists that can be available free of cost to authors from all over the world.

Q222R polymorphism in DNAse I gene is a risk factor for nephritis in South Indian SLE patients

Objective Systemic lupus erythematosus (SLE) is a multisystem disorder in which defective apoptotic clearance is considered to be an important factor in pathogenesis. DNAse I is associated with disposal of apoptotic nuclear debris. The defective enzyme production due to +2373 A to G (Q222R) in exon 8 is reported to be a genetic risk factor for SLE. SLE in Indians is reported to be severe. There are no genetic studies reported from India which have explored this aspect of DNAseI gene. This study aimed to analyze whether Q222R is a susceptibility factor for SLE and to study its influence on clinical manifestations and autoantibody production in South Indian Tamils. Method Three hundred SLE cases (based on ACR 1982 criteria) and 530 age, sex similar and ethnicity matched controls were recruited. All the cases and controls were genotyped for DNAse I Q222R polymorphism using PCR-RFLP method. Results DNAse I Q222R polymorphism is prevalent in our population. We observed higher frequency of Q/R in patients compared with controls (60% vs. 53%). This was found to be a genetic risk for SLE susceptibility (p = 0.04, odds ratio 1.5, 95% confidence interval 1–2.1). It also conferred a significant risk for development of nephritis (p = 0.007, odds ratio 1.93, 95% confidence interval 1.2–3.2). Conclusion DNAse I Q222R polymorphism is a potential genetic risk factor for SLE in South Indian Tamils. In addition, the mutant allele confers a significant risk for lupus nephritis.

Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes

Monogenic autoinflammatory syndromes are a rare group of disorders characterized by periodic episodes of systemic inflammation of endogenous origin. Sometimes, these diseases may present with features akin to vasculitis. We conducted a literature review on such vasculitic manifestations in described monogenic autoinflammatory syndromes utilizing the Online Mendelian Inheritance in Man (OMIM), Medline, and Scopus databases. Our search identified that Familial Mediterranean fever (FMF) can manifest with features of either small, medium, large, or variable-vessel vasculitis. Stimulator of interferon gene (STING)-associated vasculopathy of infancy (SAVI) is an interferonopathy that can mimic the presentation of medium-vessel or small-vessel vasculitis, whereas deficiency of adenosine deaminase 2 (DADA2) is another such mimic of medium-vessel vasculitis, associated in a significant number of patients with features of immunodeficiency. Occasional reports exist of vasculitic manifestations in tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) and chronic infantile neurologic cutaneous and articular disorder (CINCA), whereas mevalonate kinase deficiency can also mimic the presentation of small- or medium-vessel vasculitis. Clinicians should be aware of the possibility of autoinflammatory disease presenting as vasculitis to diagnose and treat the same appropriately.

Pharmacogenetic markers to predict the clinical response to methotrexate in south Indian Tamil patients with psoriasis

IntroductionDespite the advent of several new systemic therapies, methotrexate remains the gold standard for the treatment of moderate to severe psoriasis. However, there exists a significant heterogeneity in individual response to methotrexate. There are no consistently reliable markers to predict methotrexate treatment response till date.ObjectivesWe aimed to demonstrate the association of certain genetic variants in the HLA (HLA-A2, HLA-B17, and HLA-Cw6) and the non-HLA genes including T-helper (Th)-1, Th-2, Th-17 cytokine genes (IFN-γ, IL-2, IL-4, IL-10, IL-12B, and IL-23R), and T-regulatory gene (FOXP3) with the methotrexate treatment response in South Indian Tamil patients with psoriasis.MethodsOf the 360 patients recruited, 189 patients with moderate to severe psoriasis were treated with methotrexate. Of the 189 patients, 132 patients responded to methotrexate and the remaining 57 patients were non-responders. We analyzed the association of aforesaid polymorphisms with the methotrexate treatment outcome using binary logistic regression.ResultsWe observed that there were significant differences between genotype frequencies of HLA-Cw6 and FOXP3 (rs3761548) among the responders compared to non-responders, with conservative estimation. We observed that pro-inflammatory cytokines such as IFN-γ, IL-2, IL-12, and IL-23 were markedly reduced with the use of methotrexate, in comparison to the baseline levels, while the plasma IL-4 levels were increased posttreatment.ConclusionOur results serve as preliminary evidence for the clinical use of genetic markers as predictors of response to methotrexate in psoriasis. This might aid in the future in the development of a point-of-care testing (POCT) gene chip, to predict optimal treatment response in patients with psoriasis, based on their individual genotypic profile.

Urinary haptoglobin, alpha‐1 anti‐chymotrypsin and retinol binding protein identified by proteomics as potential biomarkers for lupus nephritis

The study was aimed at identification by proteomics and validation by enzyme‐linked immunosorbent assay (ELISA) of potential urinary biomarkers for lupus nephritis. Study subjects comprised 88 systemic lupus erythematosus (SLE) patients and 60 controls (rheumatoid arthritis, diabetes mellitus and healthy individuals). Based on the SLE disease activity index (SLEDAI), patients were classified as active renal (AR), active non‐renal (ANR) or inactive disease (ID). Urinary proteins from a group of patients with AR or ID were resolved by two‐dimensional gel electrophoresis and identified by matrix‐assisted laser desorption ionization–time of flight–mass spectrometry (MALDI‐TOF‐MS/MS). The selected biomarkers were validated by ELISA using samples from all patients and controls. AR patients were followed‐up for 12 months after start of therapy. Three urinary proteins, alpha‐1 anti‐chymotrypsin (ACT), haptoglobin (HAP) and retinol binding protein (RBP), were detected in patients with AR and not ID. Upon validation, ACT levels were higher in AR patients than the other groups (P < 0·001) and showed good correlation with renal SLEDAI (r = 0·577, P < 0·001) as well as SLEDAI (r = 0·461, P < 0·001). Similarly, HAP levels were > 10‐fold higher in AR than other groups (P < 0·001) and correlated well with renal SLEDAI (r = 0·594, P < 0·001) and SLEDAI (r = 0·371, P < 0·01). RBP levels were also higher in AR patients than in other groups (P < 0·05), except diabetes, and showed moderate correlation with renal SLEDAI (r = 0·284, P < 0·008) and SLEDAI (r = 0·316, P < 0·003). Upon follow‐up with treatment, levels of all three proteins declined at 6 and 12 months (P < 0·01). Multiple logistic regression identified ACT as the best marker to differentiate AR from ANR. Urinary HAP, ACT and RBP are potential biomarkers for lupus nephritis activity.