Comparative Effectiveness of Tofacitinib and Adalimumab in Axial Spondyloarthritis: A Real-World Clinical Context Multicenter Study.

INTRODUCTION: Tofacitinib, an oral Janus kinase inhibitor, is a putative choice in the treatment of axial spondyloarthritis (AxSpA). The objective of this study was to compare the effectiveness and tolerability of tofacitinib with adalimumab, in AxSpA, in a real-world clinical setting. METHODS: In this multicentric medical records review study, adult patients with active AxSpA treated with either tofacitinib 5 mg twice daily or adalimumab 40 mg subcutaneously fortnightly were recruited. Effectiveness was measured with Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Drug-cost analysis was calculated with Incremental Cost-Effectiveness Ratio (ICER drug ). RESULTS: Among the 266 patients, 135 were treated with tofacitinib and 131 with adalimumab (follow-up: 6.5 ± 1.6 months). Mean improvement of BASDAI (3.39 ± 0.09 vs. 3.14 ± 1.16, respectively) and that of ASDAS (1.78 ± 0.68 vs. 2.07 ± 2.08, respectively) were comparable between the adalimumab and tofacitinib groups. A higher proportion of patients achieved BASDAI50 response in the second (49.5% vs. 31.6%) and fourth month (83.9% vs. 62.8%) and ASDAS low disease activity in the fourth month (71.6% vs. 47.9%) in the adalimumab group. All disease activity measurements were similar by the sixth month in both groups. A higher proportion of patients in the tofacitinib group than in the adalimumab group required change in therapy (14.8% vs. 7.6%, respectively). ICER drug for adalimumab compared with tofacitinib was US $188.8 per patient in the adalimumab group for each person-month with BASDAI <4. CONCLUSIONS: Tofacitinib showed comparable effectiveness with adalimumab in patients with AxSpA at the sixth month, despite lesser response in the initial months, with favorable ICER drug .

A systematic review and meta-analysis of mycobacterial infections in patients with idiopathic inflammatory myopathies.

OBJECTIVES: Infections including tuberculosis (TB) are a leading cause of morbidity and mortality in idiopathic inflammatory myopathies (IIM). We systematically reviewed the prevalence of mycobacterial infections in patients with IIM. METHODS: We screened PUBMED, EMBASE and SCOPUS databases and conference abstracts (2015-20) for original articles using Covidence. Pooled estimates of prevalence were calculated. RESULTS: Of 83 studies (28 cohort studies, two case control and 53 case reports), 19 were analysed. Of 14 043 IIM patients, DM (54.41%) was the most common subset among TB. Most studies were from Asia with high prevalence (5.86%, 2.33%-10.60%). Pooled prevalence of mycobacterial infections among IIM was 3.58% (95% CI: 2.17%, 5.85%, P < 0.01). Disseminated and extrapulmonary forms (46.58%; 95% CI: 39.02%, 54.31%, P = 1.00) were as common as pulmonary TB (49.07%; 95% CI: 41.43%, 56.75%, P =0.99) both for I2=0. Muscle involvement, an otherwise rare site, was frequently seen in case reports (24.14%). M. tuberculosis (28.84%) was the most common pathogen followed by Mycobacterium avium complex (3.25%). Non-tuberculous mycobacteria were less common overall (6.25; 95% CI: 3.49%, 10.93%) I2=0, P =0.94. Subgroup analysis and meta-regression based on high vs low TB regions found prevalence 6.61% (2.96%, 11.33%) in high TB regions vs 2.05% (0.90%, 3.56%) in low TB regions. While death due to TB was occasionally reported (P =0.82), successful anti-tubercular treatment was common (13.95%). CONCLUSION: TB is common in IIM, particularly in endemic regions though current data is largely heterogeneous. Extra-pulmonary forms and atypical sites including the muscle are frequent. Limited data suggests fair outcomes, although larger prospective studies may offer better understanding.

Endemic infections, vaccinations, and variability of SARS-COV2 worldwide epidemiology: A cross-sectional study.

The present article aims to analyze epidemiologic aspects of the novel coronavirus pandemic (COVID-19) over different countries across the globe. While analyzing the overall spread of the disease, clusters of countries could be identified where the population-adjusted number of cases and mortality rates (MRs) were significantly different from the others. To draw a comparison over the countries at the same stage of infection, the nature and spread of the infection was evaluated at the 90th day of the pandemic for each country. It was observed that the countries with prevalent malarial transmission tended to have lesser population-adjusted COVID-19 caseloads. It was further observed that high population coverage of the Bacillus Calmette-Guérin vaccination was negatively associated with population-adjusted caseloads and MRs due to COVID-19. The present cross-sectional study is an attempt to bring in several social, economic, and structural confounders into understanding of the nature and spread of this novel pandemic globally.

Osteoarthritis: Prognosis and emerging therapeutic approach for disease management.

Osteoarthritis (OA), a disorder of joints, is prevalent in older age. The contemporary cure for OA is aimed to confer symptomatic relief, consisting of temporary pain and swelling relief. In this paper, we discuss various modalities responsible for the onset of OA and associated with its severity. Inhibition of chondrocytes receptors such as DDR2, SDF-1, Asporin, and CXCR4 by specific pharmacological inhibitors attenuates OA, a critical step for finding potential disease modifying drugs. We critically analyzed recent OA studies with an emphasis on intermediate target molecules for OA intervention. We also explored some novel and safe treatments for OA by considering disease prognosis crosstalk with cellular signaling pathways.

Quality of life among female patients with systemic lupus erythematosus in remission.

The objective is to assess quality-of-life (QoL) parameters among Indian female systemic lupus erythematosus (SLE) patients with durable remission. Indian female SLE patients in remission determined by the European consensus criteria and age-matched female control participants were included in the study. All included participants underwent measurements of QoL [Medical Outcomes Study Short-Form-12 (SF12)], Fatigue Severity Scale, and structured interview with a clinical psychologist. The population comprised of 126 female SLE patients [median age: 27.5 years [interquartile range (IQR): 11]; median disease duration: 36 months (IQR 26)] and 110 female controls [median age 30 years (IQR 9)]. Clinical remission was seen in 65.9% (83/126) and complete remission in 34.1% (43/126). Significant fatigue was present in 18.3% (23/126). Both SF-12 physical component summary (PCS) and mental component summary (MCS) were similar between SLE patients and controls [median PCS: 50.3 (IQR: 16.2) vs. 48.6 (IQR: 11.6); median MCS: 57.2 (IQR: 4.8) vs. 57.9 (IQR: 7.6)]. In generalised linear modelling, PCS was associated with fatigue [odd's ratio (OR) 0.012, 95% confidence interval (CI) 0.006-0.025, p < 0.001], disease duration ≥ 5 years (OR 23.16, 95% CI 1.548-346.58, p = 0.023), and complete remission (OR 33.16, 95% CI 4.43-248.15, p = 0.001); MCS with fatigue (OR 0.53, 95% CI 0.34-0.84, p = 0.007) and absence of depression (OR 3.65, 95% CI 1.07-12.44, p = 0.038). Patients with SLE in remission report significant fatigue in 18.3% of subjects. Both PCS and MCS scores are similar to healthy controls. Better PCS was associated with less fatigue, longer disease duration, and complete remission. Better MCS was associated with less fatigue and absence of depression.

Cyclophosphamide Versus Mycophenolate Versus Rituximab in Lupus Nephritis Remission Induction: A Historical Head-to-Head Comparative Study.

OBJECTIVE: We report comparative efficacy between high-dose cyclophosphamide (HDCyC), low-dose cyclophosphamide (LDCyC), mycophenolate mofetil (MMF) and rituximab in patients with lupus nephritis (LN). METHODS: We analyzed comparative efficacy of 4 induction regimens of biopsy-proven LN: LDCyC: 500 mg fortnightly, HDCyC: 750 to 1200 mg monthly, MMF: 1.5 to 3 g/d, and rituximab. Outcomes of 4 groups were analyzed at the sixth month. RESULTS: Among a total 222 patients, 26 received LDCyC (3-g total dose), 113 received HDCyC (mean, 5.1-g total dose), 61 received MMF (mean, 2.2 g/d), and 22 received rituximab (mean, 1.9-g total dose). Relapsing/refractory LN was 11 in HDCyC, 1 in LDCyC, 10 in MMF, and 14 in the rituximab group. Overall 16.2% had no improvement of proteinuria, 18% had partial response, and 65.8% (146/222) had complete response. Renal response (RR) was higher in HDCyC (90.3%) and rituximab (90.9%) groups compared with LDCyC (73%) and MMF (72%) groups. Rituximab was effective in relapsing disease (100% RR). Infection was highest with the HDCyC, followed by LDCyC and rituximab (p = 0.15), whereas the MMF group had a higher incidence of gastrointestinal adverse effects (p < 0.001). The following predictors of RR were identified: rituximab (odds ratio [OR], 20.4; 95% confidence interval [CI], 1.9-215.7; p = 0.012), renal Baseline Systemic Lupus Erythematosus Disease Activity Index at baseline (OR, 0.86; 95% CI, 0.75-0.99; p = 0.034), and duration of disease (OR, 0.98; 95% CI, 0.97-0.99; p = 0.009). CONCLUSIONS: High-dose cyclophosphamide and rituximab were the most effective therapeutic strategies in patients with LN, especially in the Indian context. Rituximab was highly effective in relapsing disease.

Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial.

Objectives: SSc is characterized by fibrotic changes in the skin and lung, and the mainstay of treatment has been CYC. B cell involvement suggests that rituximab (RTX) may also be of therapeutic benefit. The aim of the study was to compare the efficacy and safety of RTX compared with CYC in retarding the progression of interstitial lung disease and skin manifestations of primary SSc. Methods: We randomly assigned 60 patients of dcSSc, age 18-60 years with skin and lung involvement, to monthly pulses of CYC 500 mg/m2 or RTX 1000 mg × 2 doses at 0, 15 days. Primary outcomes were forced vital capacity (FVC) percent predicted at 6 months. Secondary outcomes were: absolute change in litres (FVC-l) at 6 months; modified Rodnan skin scores at 6 months, 6-min walk test, Medsgers score and new onset or worsening of existing pulmonary hypertension by echocardiographic criteria. Results: The FVC [%mean (s.d.)] in the RTX group improved from 61.30 (11.28) to 67.52 (13.59), while in the CYC group it declined from 59.25 (12.96) to 58.06 (11.23) at 6 months (P = 0.003). The change of FVC was 1.51 (0.45) l to 1.65 (0.47) l in the RTX group, compared with 1.42 (0.49) to 1.42 (0.46) l in the CYC group. The mRSS changed from 21.77 (9.86) to 12.10 (10.14) in the RTX group and 23.83 (9.28) to 18.33 (7.69) in the CYC group after 6 months. Serious adverse events were more common in the CYC group. Conclusion: RTX is a safe and effective alternative to CYC in the primary therapy of skin and lung manifestations of scleroderma. Trial registration: Clinical Trials Registry - India, www.ctri.nic.in, CTRI/2017/07/009152.

Temporal evolution of urate crystal deposition over articular cartilage after successful urate-lowering therapy in patients with gout: An ultrasonographic perspective.

OBJECTIVE: To detect evolution of ultrasonographic signs of deposition of monosodium urate crystals (MSUC) in gouty joints by serial ultrasonography after initiation of urate-lowering therapy (ULT). METHODS: Adult gout patients were examined by serial ultrasonography after initiation of ULT with target serum uric acid (SUA) < 6 mg/dL. RESULTS: Thirty-eight male patients with gout with mean age of 50 ± 11 years, median disease duration of 48 months and baseline mean SUA level of 8.8 ± 1.5 mg/dL were recruited. Ultrasonographic evidence of MSUC deposition was detected in 89.74% of first metatarsophalangeal (MTP) joints and 27.63% of knee joints. Double contour sign (DCS), tophi, and hyperechoic spots (HES) were detected in 77.63%, 43.42%, and 19.74% of first MTPs, respectively. SUA level normalizes and plateaus after fourth month of follow-up. DCS thickness reduced significantly throughout the follow-up period. Overall, 86.25% DCS and 100% HES disappeared with median time of 6 months and 5.7 months, respectively. SUA normalization was the only significant predictor of DCS disappearance. CONCLUSIONS: Serial ultrasonographic determination of DCS, tophi, or HES during hypouricemic therapy is a noninvasive, effective method to detect the lowering of burden of urate load in gouty joints.

Mycophenolate mofetil as induction and maintenance immunosuppressive therapy in adult primary central nervous system vasculitis: A prospective observational study.

To observe the clinical and angiographic effectiveness of mycophenolate mofetil (MMF) as induction and maintenance immunosuppressive therapy in primary central nervous system vasculitis (PCNSV). In this open-label prospective study done at a tertiary care neurology centre, adult patients with PCNSV, diagnosed by Calabrese's criteria, were recruited from 2017 to 2021 and treated with glucocorticoids, MMF and standard of care. Patients were followed-up and clinical and angiographic changes were recorded. Total 26 patients were recruited with median age 39 years (34-49) with a slight female predilection (61.5%). Angiographic diagnoses were: small vessels disease 11.5%; large vessels disease 42.3% and both in 46.2%. Median duration of follow-up was 24.5 months (14.25-38). Proportion of patients with severe disability (modified Rankin Score (mRS) 4-6) at baseline was 73.08% (19/26) which reduced to 7.69% (2/26) (p < 0.001). At the last follow-up mRS = 0 was achieved in 38.5% (10/26) and mRS of ≤ 1 was achieved in 69.2% (18/26). Median time to achieve a mRS ≤ 1 was 12 months (95% CI: 6.8-17.2). Angiography was repeated in 16 patients after a median duration of 13 months (10.5-19.7), out of which 10 (62.5%) showed improvement and 5 (31.2%) showed non-progression of lesions. MMF may be an effective immunosuppressive therapy in adult PCNSV as both induction and maintenance. Serial DSA of brain may be useful to monitor the effect of treatment. Key Points • Mycophenolate mofetil is effective as induction and maintenance immunosuppressive therapy in PCNSV. • Repeat angiogram may be useful to monitor treatment response in PCNSV.

Efficacy of leflunomide as a steroid-sparing agent in treatment of Indian giant cell arteritis patients: A 2-year follow-up study.

OBJECTIVES: To evaluate the effectiveness of leflunomide as a steroid-sparing agent among Indian patients with giant cell arteritis (GCA) and to assess the changes of "halo sign" within affected arteries, detected ultrasonographically, after remission. METHODS: In this prospective observational study, patients fulfilling American College of Rheumatology criteria for GCA and having halo sign in temporal artery ultrasound were treated with leflunomide and predefined tapering dose of prednisolone. Ultrasounds of temporal and axillary arteries were done at baseline and after remission were achieved. RESULTS: Twenty-two GCA patients were followed up for a median duration of 24 months (interquartile range, IQR: 18-33). All patients showed clinical improvement and steroids could be stopped in 17 out of 22 patients. Median time to achieve remission (symptom-free with normal inflammatory markers) was 3 (95% confidence interval [CI]: 2.4-3.6) months. Median time to achieve reduction to prednisolone dose <5 mg/d was 9 months (95% CI: 7-11). Prednisolone dose could be reduced in all patients while on leflunomide, suggesting steroid-sparing effect and a steroid-free remission could be achieved after a median of 14 months (95% CI: 9.4-18.6). Ultrasonographically, all patients showed improvement of halo signs, after 8 weeks (IQR 7.25-12). Seven patients experienced a clinical relapse after 12 months (IQR: 5-21) of initial remission. The predictors of relapse were duration of symptoms before initiation of immunosuppression therapy and delayed achievement remission by strict criteria. CONCLUSION: This study showed efficacy and safety of leflunomide as a steroid-sparing agent in Indian GCA patients.

Evaluation of Subclinical Hand Joint Synovitis by Ultrasonography in Patients with Psoriatic Arthritis and Cutaneous Psoriasis: A Case-Control Study.

Objectives: To find the frequency of subclinical hand joint synovitis (SS) in patients with psoriatic arthritis (PsA) and cutaneous psoriasis (PsC) compared to healthy controls (HC), and correlation of SS with disease activity. Methods: PsA patients (n= 52), without any past/current history of hand joint arthritis, PsC patients (n= 48), and 45 HC were recruited. Grey-scale and power Doppler Ultrasonography of bilateral hand joints were performed. The proportions of hand joints with SS were estimated in each group. A wrist-ray score was devised. Correlations were obtained between the number of joints with SS and disease activity parameters. Results: Higher proportion of PsA patients (55.8%) had SS than PsC (29.2%, p= 0.007), and HC (22.2%, p=0.001). Proportion of joints with SS was higher in PsA patients (5.38%) compared to PsC (2.92%, [p=0.0008]), and HC (1.11%, [p=0.0007]). Compared to HC, PsA patients had significantly higher bilateral ray 3 (p=0.002 and 0.01 for left and right ray 3, respectively), and right ray 4 involvement (p=0.037) and PsC patients had higher left ray 3 involvement (p=0.03). Wrist-ray score above 2.5 could distinguish patients of PsC with significant subclinical synovitis compared to controls (area under curve: 0.857, 95% confidence interval: 0.71-1.00). There was a significant correlation of SS with ESR in PsA group (p-value: 0.044), and with CRP in PsC group (p-value: 0.003), but not with other disease activity indices. Conclusion: SS was noted in approximately half of PsA and 1/3rd of PsC patients. Both PsA and PsC patients had a significantly higher number of hand joint SS than HC. Ray pattern of hand joint SS could be present in both PsA and PsC.

Efficacy and safety of intravenous and subcutaneous immunoglobulin therapy in idiopathic inflammatory myopathy: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis on the efficacy and safety of intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin (Ig) therapy in the treatment of idiopathic inflammatory myopathy (IIM) and juvenile dermatomyositis (JDM). METHODS: PubMed, Embase and SCOPUS were searched to identify studies on Ig therapy in patients with IIM and/or JDM (2010-2020). Outcome measures were complete response (CR) or partial response (PR) in terms of muscle power and extramuscular disease activity measures on the International Myositis Assessment and Clinical Studies Group (IMACS) core set domains. RESULTS: Twenty-nine studies were included (n = 576, 544 IIM, 32 JDM). Muscle power PR with pooled Ig therapy was 88.5% (95% confidence interval (CI): 80.6-93.5, n = 499) and PR with SCIg treatment was 96.61% (95% CI: 87.43-99.15, n = 59). Pooled PR with first-line use of IVIg was 77.07% (95% CI: 61.25-92.89, n = 80). Overall, mean time to response was 2.9 months (95% CI: 1.9-4.1). Relapse was seen in 22.76% (95% CI: 14.9-33). Studies on cutaneous disease activity and dysphagia showed significant treatment responses. Glucocorticoid and immunosuppressant sparing effect was seen in 40.9% (95% CI: 20-61.7) and 42.2% (95% CI: 20.4-64.1) respectively. Ig therapy was generally safe with low risk of infection (1.37%, 95% CI: 0.1-2.6). CONCLUSIONS: Add-on Ig therapy improves muscle strength in patients with refractory IIM, but evidence on Ig therapy in new-onset disease and extramuscular disease activity is uncertain.

Network theoretic analysis of JAK/STAT pathway and extrapolation to drugs and viruses including COVID-19.

Whenever some phenomenon can be represented as a graph or a network it seems pertinent to explore how much the mathematical properties of that network impact the phenomenon. In this study we explore the same philosophy in the context of immunology. Our objective was to assess the correlation of "size" (number of edges and minimum vertex cover) of the JAK/STAT network with treatment effect in rheumatoid arthritis (RA), phenotype of viral infection and effect of immunosuppressive agents on a system infected with the coronavirus. We extracted the JAK/STAT pathway from Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04630). The effects of the following drugs, and their combinations, commonly used in RA were tested: methotrexate, prednisolone, rituximab, tocilizumab, tofacitinib and baricitinib. Following viral systems were also tested for their ability to evade the JAK/STAT pathway: Measles, Influenza A, West Nile virus, Japanese B virus, Yellow Fever virus, respiratory syncytial virus, Kaposi's sarcoma virus, Hepatitis B and C virus, cytomegalovirus, Hendra and Nipah virus and Coronavirus. Good correlation of edges and minimum vertex cover with clinical efficacy were observed (for edge, rho = - 0.815, R2 = 0.676, p = 0.007, for vertex cover rho = - 0.793, R2 = 0.635, p = 0.011). In the viral systems both edges and vertex cover were associated with acuteness of viral infections. In the JAK/STAT system already infected with coronavirus, maximum reduction in size was achieved with baricitinib. To conclude, algebraic and combinatorial invariant of a network may explain its biological behaviour. At least theoretically, baricitinib may be an attractive target for treatment of coronavirus infection.

High-resolution ultrasonography in carpal tunnel syndrome: role of ancillary criteria in diagnosis and response to steroid injection.

OBJECTIVES: (1) Development and validation of a composite ultrasound score (cUSS) for the diagnosis of carpal tunnel syndrome (CTS). (2) To predict treatment response after local corticosteroid injection. METHODS: Wrists of CTS patients and controls were evaluated with high-resolution ultrasound and cross-sectional area of median nerve at carpal tunnel inlet (CSAp) and outlet (CSAd) and bowing of flexor retinaculum (FRB), flexor tenosynovitis, and intraneural vascularity and echogenicity changes were noted. Patients were prospectively followed after ultrasound-guided corticosteroid injection. RESULTS: We studied 479 wrists of 141 patients and 99 controls. Optimal cut-offs for diagnosing CTS were 9.5 mm2 and 10.5 mm2, respectively, for CSAp and CSAd. A cUSS consisting of the following parameters was developed: age, CSAp, CSAd, FRB, and flexor tenosynovitis and echogenicity changes. External validation of cUSS yielded sensitivity, specificity, and diagnostic accuracy of 91.7%, 87.1%, and 89.8%, respectively. Treatment responses from 88 injections (median duration of follow-up of 6 months) were available with satisfactory initial responses in 69.32% (61/88) and relapses in 30.86% (25/81). Median time to relapse was 2 months. Initial response was predicted by FRB (odds ratio (OR): 5.43, 95% confidence interval (CI): 1.45-20.3, p = 0.012). Relapse was predicted by age (hazard ratio (HR) 1.168, 95% CI: 1.076-1.268, p = 0.0002), male gender (HR: 8.1.02, 95% CI: 2.394-27.422, p = 0.0007), FRB, (HR: 46.982, 95% CI: 5.048-437.293, p = 0.0008), and higher body mass index (HR: 0.238, 95% CI: 0.064-0.892, p = 0.0332). CONCLUSIONS: The developed cUSS has a diagnostic accuracy of 88% for diagnosing CTS. Ultrasound parameters could predict both initial treatment response and relapse. KEY POINTS: • Anatomical ultrasound parameters in addition to nerve cross-sectional area is important for diagnosis of CTS. • A composite US score for diagnosis of CTS was developed with accuracy 88.6%. • Bowing of flexor retinaculum predicts short and long term response to local steroid injection.

Combination Therapy Against Indian Visceral Leishmaniasis with Liposomal Amphotericin B (FungisomeTM) and Short-Course Miltefosine in Comparison to Miltefosine Monotherapy.

Visceral leishmaniasis (VL) is endemic in Asia, East and North Africa, South America, and Southern Europe, and is a major public health problem in the Indian subcontinent. Miltefosine received approval in 2002 to treat VL in India, and the Indian National Vector Borne Disease Control Programme later adopted a single dose (10 mg/kg) of liposomal amphotericin B. We report results of a randomized trial comparing the efficacy of combination therapy with an Indian preparation of liposomal amphotericin B (single dose of 7.5 mg/kg) and short-course miltefosine (2.5 mg/kg/day for 14 days; n = 66) in comparison to miltefosine monotherapy (2.5 mg/kg/day for 28 days; n = 78). Nine patients in the miltefosine group and three in the combination therapy group had to discontinue therapy because of serious adverse events. At the end of the therapy, the clinical and parasitological cure rate was 100% in both groups. By per-protocol analysis, by 6 months after completion of treatment, 12 of 69 patients in the miltefosine monotherapy arm (17.4%, 95% CI: 10.24-28%) and none in the combination therapy arm had relapse. Over 5 years of follow-up, 10 patients in the miltefosine monotherapy arm (all within 0.5-2 years after completing therapy) and none in the combination therapy arm experienced post-kala-azar dermal leishmaniasis. Combination therapy offered benefits over miltefosine monotherapy for VL in India.