Comparison of Risk Factors During First and Second Wave of COVID-19 in Patients with Autoimmune Rheumatic Diseases (AIRD): Results from KRACC Subset.

Background: The differential influence and outcome of various risk factors on occurrence of COVID-19 among patients with autoimmune rheumatic diseases (AIRD) during different COVID-19 peaks is underreported. Aim: To assess the impact and outcome of conventional risk factors, immunosuppressants, and comorbidities on the risk of COVID-19 among AIRD patients during the first two COVID-19 peaks. Design: Prospective, non-interventional longitudinal cohort study. Methods: This is a subset of the KRA COVID19 cohort undertaken during the initial wave of COVID-19 (W1) (Apr-Dec2021); and the 2nd-wave (W2) (Jan-Aug2021). Data collected included description of AIRD subsets, treatment characteristics, comorbidities, and COVID-19 occurrence. Risk factors associated with mortality were analysed. The incidence rate was compared with that of the general population in the same geographic region. Results: AIRD patients (n=2969) had a higher incidence of COVID-19 in the W2 (7.1%) than in the W1 (1.7%) as compared to the general population (Government bulletin). Age (p<0.01) and duration of AIRD (p<0.001) influenced COVID-19 occurrence in W2 while major disease subsets and immunosuppressants including glucocorticoids did not. The W2 had lower HCQ usage (Adjusted Odds Ratio [AOR]-0.81) and comorbidities like hypertension (AOR -0.54) and pre-existing lung disease (AOR -0.38;0.19-0.75) compared to W1. Older age (1.11) and coexistent diabetes mellitus (AOR 6.74) were independent risk factors associated with mortality in W2. Conclusions: We report 1.7 times higher occurrence, and no influence of major disease subsets or immunosuppressants including glucocorticoids on COVID-19. Age and diabetes were independent risk factors for mortality.

Risk factors associated with COVID-19 in systemic lupus erythematosus: Results from a longitudinal prospective cohort.

INTRODUCTION: Patients with SLE (systemic lupus erythematosus) have a higher risk of infection due to dysregulated immune system as well as long-term use of immunosuppressants (IS). This could influence the risk of COVID-19 and its outcome. METHODS: We conducted a longitudinal prospective study across 15 rheumatology centres during the first wave of the pandemic to understand the risk factors contributing to COVID-19 in SLE patients. During the 6 months follow-up, those who tested positive for COVID-19, their clinical course and outcome information were recorded. RESULTS: Through the study period (April-December 2020), 36/1379 lupus patients (2.9%) developed COVID-19. On analysing the COVID-19 positive versus negative cohort during the study period, male gender (adjusted RR 3.72, 95% C.I. 1.85,7.51) and diabetes (adjusted RR 2.94, 95% C.I. 1.28, 6.79) emerged as the strongest risk factors for COVID-19, in the adjusted analysis. There was no significant influence of organ involvement, hydroxychloroquine, glucocorticoid dosage (prednisolone< 7.5 mg or ≥ 7.5 mg/day) or IS on the risk of COVID-19. There was only one death (1/36) among the lupus patients due to COVID-19. CONCLUSION: Traditional risk factors rather than lupus disease process or IS influenced the risk of COVID-19 in our cohort.

A prospective longitudinal study evaluating the influence of immunosuppressives and other factors on COVID-19 in autoimmune rheumatic diseases.

BACKGROUND: We conducted this study to identify the influence of prolonged use of hydroxychloroquine (HCQ), glucocorticoids and other immunosuppressants (IS) on occurrence and outcome of COVID-19 in patients with autoimmune rheumatic diseases (AIRDs). METHODS: This was a prospective, multicenter, non-interventional longitudinal study across 15 specialist rheumatology centers. Consecutive AIRD patients on treatment with immunosuppressants were recruited and followed up longitudinally to assess parameters contributing to development of COVID-19 and its outcome. RESULTS: COVID-19 occurred in 314 (3.45%) of 9212 AIRD patients during a median follow up of 177 (IQR 129, 219) days. Long term HCQ use had no major impact on the occurrence or the outcome of COVID-19. Glucocorticoids in moderate dose (7.5-20 mg/day) conferred higher risk (RR = 1.72) of infection. Among the IS, Mycophenolate mofetil (MMF), Cyclophosphamide (CYC) and Rituximab (RTX) use was higher in patients with COVID 19. However, the conventional risk factors such as male sex (RR = 1.51), coexistent diabetes mellitus (RR = 1.64), pre-existing lung disease (RR = 2.01) and smoking (RR = 3.32) were the major contributing risk factors for COVID-19. Thirteen patients (4.14%) died, the strongest risk factor being pre-existing lung disease (RR = 6.36, p = 0.01). Incidence (17.5 vs 5.3 per 1 lakh (Karnataka) and 25.3 vs 7.9 per 1 lakh (Kerala)) and case fatality (4.1% vs 1.3% (Karnataka) and 4.3% vs 0.4% (Kerala)) rate of COVID-19 was significantly higher (p < 0.001) compared to the general population of the corresponding geographic region. CONCLUSIONS: Immunosuppressants have a differential impact on the risk of COVID-19 occurrence in AIRD patients. Older age, males, smokers, hypertensive, diabetic and underlying lung disease contributed to higher risk. The incidence rate and the case fatality rate in AIRD patients is much higher than that in the general population.

Role of secukinumab in ankylosing spondylitis with tubercular uveitis.

We present the case of a 32-year-old Indian male one-eyed individual with a history of unilateral panuveitis with HLA B 27 positive spondyloarthropathy on systemic immunosuppressant (Adalimumab). He developed recurrent inflammation in the same eye in a span of 2 years, later complicated with retinal vasculitis. On evaluation, he was diagnosed with tubercular uveitis and started on antitubercular treatment along with systemic steroids. Inview of Increased IOP due to steroid response, Inj. Secukinumab ( IL 17 A inhibitor) was started and significant improvement was noted.

The IRF5 rs2004640 (G/T) polymorphism is not a genetic risk factor for systemic lupus erythematosus in population from south India.

Background & objectives: Genetic aberrations disrupting toll-like receptor and interferon homeostasis enhance the risk of systemic lupus erythematosus (SLE). Raised serum interferon-alpha (IFN-α) levels in SLE patients have been ascribed to polymorphism (rs2004640 G/T) in interferon regulatory factor 5 (IRF5) gene, resulting in enhanced transcript splicing. A positive association between IRF5 polymorphism and SLE risk has been reported in many populations. This study was aimed to find out frequency of IRF5 rs2004640 G/T polymorphism in patients with SLE and healthy controls and to assess its influence on susceptibility, clinical and serological characteristics of SLE. Methods: IRF5 rs2004640 (G/T) polymorphism was analyzed in 300 SLE patients and 460 age and sex matched controls by real-time PCR. Results: The IRF5 rs2004640 (G/T) polymorphism did not confer risk of SLE or influence clinical or serological phenotype. However, the mutant allele conferred a borderline risk to develop thrombocytopenia (odds ratio: 2.05, 95% confidence interval: 0.97-4.3, P=0.06) in patients with SLE. Interpretation & conclusions: Our study revealed that the IRF5 rs2004640 polymorphism was not a risk factor for SLE in population from south India. It may, however, be a useful genetic marker for thrombocytopenia in SLE patients. Although we could not demonstrate susceptibility toward lupus in the presence of IRF5 rs2004640 (G/T) polymorphism, further exploration of the genetic variability of IRF5 may help uncover its pathogenic role in Indian SLE patients.

Renal involvement in primary Sjogren's syndrome: a prospective cohort study.

The objective of the study is to prospectively evaluate the spectrum of clinical and subclinical renal involvement in patients with primary Sjogren's syndrome (pSS). Of the 174 patients screened, seventy patients with pSS underwent renal function tests, urine examination, renal ultrasound, arterial blood gases, urine pH followed by urine acidification test and renal biopsy (if indicated). Renal tubular acidosis (RTA) was treated with alkali replacement and moderate-severe tubulointerstitial nephritis (TIN) was treated with oral prednisolone. Sixty-two patients completed 1-year follow-up. A comparison was made between patients with and without renal involvement. Thirty-five (50%) patients had renal involvement. They had a lower baseline eGFR (71.85 ± 18.04 vs. 83.8 ± 17, p = 0.005). Twenty-nine patients had RTA (25 complete and 4 incomplete). Eleven patients had urinary abnormalities. Patients with RTA (n = 29) were younger (34.9 ± 9 vs. 42 ± 11.3, p = 0.006), had fewer articular (34% vs. 78%, p = 0.001) and ocular sicca (62% vs. 88%, P = 0.01) than those without RTA (n = 41) and commonly presented with hypokalemic paralysis. On biopsy, TIN (9/17) and IgA nephropathy (3/17) were most common. On follow-up, there was no clinically significant change in eGFR; however, one patient with renal calculi and incomplete distal renal tubular acidosis (dRTA) progressed to complete dRTA. Two patients treated with steroids had marginal improvement in eGFR. Renal involvement in pSS is under-recognized with the most common manifestation being RTA presenting with hypokalemic paralysis. These patients are younger with less articular and sicca symptoms. Subclinical RTA may progress to complete RTA. Renal biopsy should be considered in all patients with renal involvement.

Comparing the efficacy of low-dose vs high-dose cyclophosphamide regimen as induction therapy in the treatment of proliferative lupus nephritis: a single center study.

Cyclophosphamide (CYC) has been the backbone immunosuppressive drug to achieve sustained remission in lupus nephritis (LN). The aim was to evaluate the efficacy and compare adverse effects of low and high dose intravenous CYC therapy in Indian patients with proliferative lupus nephritis. An open-label, parallel group, randomized controlled trial involving 75 patients with class III/IV LN was conducted after obtaining informed consent. The low dose group (n = 38) received 6 × 500 mg CYC fortnightly and high dose group (n = 37) received 6 × 750 mg/m2 CYC four-weekly followed by azathioprine. The primary outcome was complete/partial/no response at 52 weeks. The secondary outcomes were renal and non-renal flares and adverse events. Intention-to-treat analyses were performed. At 52 weeks, 27 (73%) in high dose group achieved complete/partial response (CR/PR) vs 19 (50%) in low dose (p = 0.04). CR was higher in the high dose vs low dose [24 (65%) vs 17 (44%)], although not statistically significant. Non-responders (NR) in the high dose group were also significantly lower 10 (27%) vs low dose 19 (50%) (p = 0.04). The change in the SLEDAI (Median, IQR) was also higher in the high dose 16 (7-20) in contrast to the low dose 10 (5.5-14) (p = 0.04). There was significant alopecia and CYC-induced leucopenia in high dose group. Renal relapses were significantly higher in the low dose group vs high dose [9 (24%) vs 1(3%), (p = 0.01)]. At 52 weeks, high dose CYC was more effective in inducing remission with decreased renal relapses in our population. TRIAL REGISTRATION: The study was registered at http://www.clintrials.gov . NCT02645565.

Effect of disease-modifying antirheumatic drug therapy on immune response to trivalent influenza vaccine in rheumatoid arthritis.

BACKGROUND & OBJECTIVES: Patients with autoimmune rheumatic diseases may be at an increased risk of infection due to disease and use of disease-modifying antirheumatic drug (DMARD) therapy. The present study was done to evaluate the immune response to influenza vaccination in patients with rheumatoid arthritis (RA). METHODS: Fifty one RA patients on stable methotrexate (MTX) therapy (≥15 mg/wk), 51 newly diagnosed DMARD-naïve RA patients and 45 healthy controls received a single dose of inactivated seasonal trivalent influenza vaccine. Blood samples were collected just prior to and four weeks after vaccination. Pre- and post-vaccination antibody titres against the three virus strains were measured by hemagglutination inhibition assay. The impact of age, gender, DMARD treatment and pre-vaccination seroprotection on response to the vaccine was assessed by binary logistic regression analysis for each of the virus strains. RESULTS: Pre-vaccination antibody titres were found to be high in the three study groups for all influenza strains, except for Yamagata strain, the titres for which were low in healthy controls. Trivalent influenza vaccination was found to be safe and stimulated a good antibody response in all study groups. On regression analysis, there was no association of age, gender or MTX therapy with vaccine response, except for Yamagata strain where healthy controls had higher positive immune response (P=0.008; odds ratio - 3.37, 95% confidence interval: 1.36-8.32). INTERPRETATION & CONCLUSIONS: Our results indicated that influenza vaccination was safe in RA patients with no detrimental effect on disease activity. MTX therapy at a dose ≥15 mg/wk did not affect the vaccine response. Presence of high pre-vaccination seroprotective antibody levels in the study population indicates the need for re-examination of recommended annual influenza vaccination in such subgroups of population.

Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA. MTX inhibits several enzymes of the folate and nucleotide pathways. Thymidylate synthase (TYMS) is an important enzyme in the de novo pyrimidine pathway responsible for DNA replication. The two common gene polymorphisms analyzed in TYMS are 28-bp tandem repeat polymorphism and a 6-bp insertion/deletion polymorphism. The present study was carried out to find the role of these TYMS gene polymorphisms with clinical phenotype, treatment response, and MTX adverse events in 254 patients with RA of south Indian Tamil ethnicity. TYMS gene polymorphisms were analyzed by PCR. The allele frequencies of TYMS gene polymorphisms did not differ between good and non-responders. However, the TYMS 28-bp tandem repeat 3R allele was higher in non-responders than in patients undergoing remission [64 vs 51.11%, p = 0.06, OR 0.58, 95% CI (0.34-1.00)]. The TYMS 6-bp deletion allele was higher in non-responders than good responders [78.20 vs 64.92%, p = 0.06, OR 0.51 95% CI (0.27-0.98)]. TYMS 3R allele and TYMS 6-bp deletion allele may favor non-response to MTX in south Indian Tamils. TYMS gene polymorphisms did not influence MTX adverse events.

Mannose-binding lectin (MBL) codon 54 (rs1800450) polymorphism predisposes towards medium vessel vasculitis in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple etiological factors. Mannose-binding lectin (MBL) plays a key role in innate immunity by activating antibody-independent lectin complement pathway, opsonisation, phagocytosis, and immune complex (IC) clearance. Genetic polymorphisms in the promoter and coding regions of MBL gene affect the circulatory levels and biological activity of MBL. Defects in MBL can lead to defective opsonisation and, hence, hamper clearance of apoptotic debris, the persistence of which can drive autoantibody formation in lupus. The exon1 variants at codon 52, 54, and 57 have been reported to augment the risk of SLE in different ethnic populations. Three hundred South Indian Tamil patients with SLE and 460 age-, sex-, and ethnicity-matched controls were genotyped for three polymorphisms at codon 52, 54, and 57 in exon1 of MBL gene by Taqman real-time PCR. The three polymorphisms in exon1 of MBL were observed not to confer risk of developing SLE. However, MBL codon 54 rs1800450 polymorphism was associated with the development of medium vessel vasculitis and gangrene (OR-2.29, CI 95% 1.08-4.83, p = 0.02), whereas, the ancestral allele G conferred protection (OR-0.44, CI 95% 0.21-0.93, p = 0.02). Genetic variants in the exon1 of MBL gene per se are not risk factors for SLE in South Indian Tamils. However, the association of codon 54 (rs1800450) with medium vessel vasculitis suggests that it may be a genetic modifier of clinical phenotype in SLE.

Tuberculosis mimicking primary systemic vasculitis: not to be missed!

Infections are an important differential diagnosis in patients presenting with features of systemic vasculitis. We report a young lady with constitutional features, leg ulcers, digital gangrene and absent peripheral pulses with cervical adenopathy. Chest imaging revealed multiple necrotic lung lesions and involvement of left subclavian artery at its origin from the aorta, Histopathology from cervical lymph nodes showed multiple caseated lymph nodes, which in the context of a positive Mantoux test led us to diagnose tuberculosis and institute appropriate therapy. This is only the second report of tuberculosis presenting as peripheral gangrene, cutaneous ulcers and absent pulses, and serves to educate rheumatologists regarding the need to consider infections as mimics of vasculitis, especially in the developing countries.

ATIC 347C>G gene polymorphism may be associated with methotrexate-induced adverse events in south Indian Tamil rheumatoid arthritis.

AIM: To find the association of ATIC 347C>G gene polymorphism with methotrexate (MTX) treatment response and MTX-induced adverse events in south Indian Tamil patients with rheumatoid arthritis. PATIENTS & METHODS: A total of 319 rheumatoid arthritis and 310 healthy controls were recruited for the study and ATIC 347C>G gene polymorphism was analyzed by PCR-RFLP method. RESULTS: The genotype and allele frequencies of ATIC 347 C>G SNP did not differ between good and nonresponders and hence this SNP was not found to be associated with MTX treatment response. However, the ATIC 347 GG genotype (p = 0.02; odds ratio [OR]: 4.46; 95% CI: 1.28-15.52) and mutant G allele was associated with MTX-induced gastrointestinal adverse events (p = 0.01; OR: 2.60; 95% CI: 1.27-5.35). CONCLUSION:  ATIC 347C>G gene polymorphism may be associated with the development of MTX induced gastrointestinal adverse events.

Multidrug resistance 1 (MDR1) 3435C>T gene polymorphism influences the clinical phenotype and methotrexate-induced adverse events in South Indian Tamil rheumatoid arthritis.

PURPOSE: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily targeting the synovial joints causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA, and approximately 10-30% of the patients fail to attain remission because of inefficacy of the drug or due to development of adverse events. Multidrug resistance 1 (MDR1) gene encodes for permeable glycoprotein (P-gp) which is an integral membrane protein for the transport of chemotherapeutic agents, immunosuppressive drugs etc. MDR1 3435C>T results in a wobble mutation in exon 26 but is associated with altered P-gp expression and reduced P-gp function. The present study was carried out to find the role of MDR1 3435C>T gene polymorphism with clinical phenotype, treatment response, and MTX adverse events in 336 RA and 329 healthy controls of South Indian Tamil ethnicity. METHODS: MDR1 3435C>T gene polymorphism was analyzed by TaqMan 5' nuclease assay. RESULTS: We found MDR1 3435T allele as a risk allele for contributing to high EULAR disease activity [p = 0.02, OR 1.50, 95% CI (1.06-2.13)]. Also, MDR1 3435CT genotype was associated with deforming disease [p = 0.02, OR 1.79, 95% CI (1.11-2.88)]. However, this SNP did not influence the MTX treatment response in these patients. MDR1 3435CT genotype was associated with MTX-induced adverse events [p = 0.01, OR 2.01, 95% CI (1.15-3.52)], and the 3435 TT genotype remained protective for the development of adverse events [p = 0.009, OR 0.40, 95% CI (0.21-0.78)]. Also, the heterozygous 3435 CT genotype was associated with gastrointestinal events [p = 0.02, OR 3.62, 95% CI (1.25-10.47)], and CT genotype remained protective in patients developing infection [p = 0.002, OR 0.05, 95% CI (0.006-0.460)]. CONCLUSION: MDR1 3435C>T gene polymorphism influences the clinical phenotype and adverse events to MTX in the South Indian cohort of patients with RA.

A comparative study of racecadotril and single dose octreotide as an anti-secretory agent in acute infective diarrhoea.

OBJECTIVE: To assess the efficacy of single dose of octreotide and compare it with another antisecretory agent racecadotril in the management of acute infective diarrhea. METHODS: A randomized control study was done in the Department of Medicine and Infectious Disease Hospital (Department of Preventive and Social Medicine) of SMS Medical College and Hospital. 150 patients with moderate to severe acute diarrheal illness needing hospitalization were randomly allotted into 3 categories of 50 patients each. The control group received only fluids and antibiotics, the racecadotril group received fluid, antibiotics and oral racecadotril at dose of 1.5 mg/kg three times a day and the octreotide group received octreotide (100 microgram stat) along with fluid and antibiotics. The following end points of the study were compared, namely- frequency, quantity and consistency of stools and fluid requirement per day. RESULTS: The mean (+/- SE) frequency of stools was significantly less (p < 0.001) from day 2 onwards in the octreotide group compared to the control and racecadotril group. Diarrhea stopped in half of the patients in the octreotide group by day 3. The consistency of stools changed significantly in the octreotide group (p < 0.001). No significant difference was seen between the racecadotril and control group (p > 0.05) in terms of the frequency and consistency of stools. The mean (+/- SE) quantity of stools was significantly decreased in the octreotide group (p < 0.001) on day 2 compared to the other two groups. The mean (+/- SE) quantity of fluid required was almost the same in all 3 groups on day 1 (p > 0.05) but it was significantly less in the octreotide group on day 2 (p < 0.001). No significant difference was seen with respect to the fluid requirement between the control and racecadotril group (p > 0.05). CONCLUSION: Patients who received single dose of octreotide fared better than those patients in control and racecadotril group in terms of frequency, quantity and consistency of stools passed. The fluid requirement was also less in octreotide group. However more trials need to be done to substantiate this finding before octreotide becomes a standard of therapy in acute infective diarrhea.