Boosting Vaccine Response in Autoimmune Rheumatic Disease Patients With Inadequate Seroconversion: An Analysis of the Immunogenicity of Vector-Based and Inactivated Vaccines.

BACKGROUND: An additional dose of COVID-19 vaccine is being offered to vaccinated people, especially those immunocompromised. The most widely available vaccines in India are the adenoviral vector-based AZD1222 (ChAdOx1 nCoV-19) and the heat-inactivated (BBV152). This study investigated the efficacy of both vaccines in patients with autoimmune rheumatic diseases (AIRD). OBJECTIVES:  To compare final anti-SARS-CoV-2 antibody titers, neutralization of pseudovirions by these antibodies, and T cell responses between patients of AIRD who had received the third dose of AZD1222 and BBV152 vaccines. METHODS: Patients with stable AIRD who had completed two doses of COVID-19 vaccination but had a suboptimal response (anti-receptor binding domain (RBD) antibody<212) were randomized (1:1) to receive either AZD1222 or BBV152 as a booster dose. Patients with previous hybrid immunity or those who developed COVID-19 during the trial were excluded. Antibody titers, neutralization of Wuhan and Omicron pseudovirions, and interferon release by T cells (enzyme-linked immunosorbent spot (ELISpot)) in response to the Spike antigen were measured four weeks after this booster dose. RESULTS: 146 were screened, 91 were randomized, and 67 were analyzed per protocol. The third dose improved antibody titers (p<0.001), neutralization of the Wuhan strain (p<0.001), and T cell interferon release (p<0.001) but not neutralization of the Omicron strain (p=0.24). Antibody titers were higher (p<0.005) after ADZ1222 boost (2,414 IU (interquartile range (IQR): 330-10,315)) than BBV1222 (347.7 IU (0.4-973)). Neutralization of the Wuhan stain was better (AZD1222: 76.6%(23.0-95.45) versus BBV152 (32.7% (0-78.9), p=0.03 by ANCOVA). Neutralization of Omicron (0 (0-28.4) vs 0 (0-4.8)) and T cell interferon release (57.0 IU (23.5-95) vs 50.5 IU (13.2-139)) were similar. CONCLUSION: The third dose improved all parameters of immunogenicity in AIRD patients with previous inadequate responses except Omicron neutralization. The vector-based vaccine exhibits notable efficacy, particularly in antibody titers and neutralizing the Wuhan strain. TRIAL REGISTRATION: CTRI/2021/12/038928.

Efficacy and safety of curcumin in maintaining remission during disease-modifying antirheumatic drug withdrawal in rheumatoid arthritis at 52 weeks: a phase III double-blind, randomized placebo-controlled trial.

Curcumin has anti-inflammatory properties but current evidence is limited to advocate its use in rheumatoid arthritis (RA). We explored whether curcumin could maintain remission in patients with RA while tapering conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARD). In this patient-and investigator-blinded trial, adults with RA in sustained remission for more than six months were randomized to oral curcumin (1 g) with piperine (5 mg) twice daily or matching placebo. Patients who had received biological DMARDs or curcumin supplements in the last 6 months were excluded. csDMARD were tapered and stopped sequentially as per a fixed protocol. The primary outcome was flare-free survival at 52 weeks. The secondary outcomes were flare rate, correlation of serum curcuminoid levels with flares and safety. 200 patients (100 per arm) entered the trial with comparable baseline characteristics. Per protocol analysis included 92 and 93 participants in the curcumin and the placebo group, respectively. Flare-free survival at week 52 was similar between both groups (60% versus 64%; p = 0.76). The median time to flare was similar [Curcumin: 219 days (IQR: 123) versus placebo: 214 days (95.8); p = 0.067]. Cox proportionate regression modelling showed that the flare-free survival was independent of serum curcuminoid levels [adjusted HR = 0.99 (95% CI: 0.97-1.0)]. The model showed that flare-free survival was not associated with age, gender, seropositivity, or csDMARD used at baseline. No serious adverse effects were noted. Curcumin did not impact the flare-free survival in patients with RA in remission during the tapering of csDMARDs despite achieving adequate serum levels.Trial registration: CTRI/2018/04/013279.

Correlates of breakthrough Omicron (B.1.1.529) infections in a prospective cohort of vaccinated patients with rheumatic diseases.

BACKGROUND: Data on the effectiveness of SARS-CoV-2 vaccines and the durability of protection against the prevalent Omicron variant are scarce, especially in patients with autoimmune rheumatic diseases (AIRDs). Hence, we prospectively studied Omicron breakthrough infections in patients with AIRDs and attempted to isolate associated risk factors. METHODS: Patients with AIRDs who had completed primary vaccination with either AZD1222 or BBV152 vaccines were included and prospectively followed up from January 2022 onwards for the development of breakthrough Omicron infections. The time interval from the last event [2nd dose of vaccination (V) or past COVID-19 infection (I) whichever was later] to Omicron infection was recorded. Patients were divided based on the events and their order of occurrence into V + V, V + I, I + V, V + I + V, and V + V + I groups. The incidence of breakthrough infections and their predictors were studied with a focus on the vaccine type and hybrid (H) immunity (vaccinated individuals with a history of COVID-19 infection). RESULTS: We included 907 patients with AIRDs (53.5 ± 11.7 years and a male-to-female ratio of 1:5.1), and the majority of patients had received AZD1222 (755, 83.2%). Breakthrough infections were observed in 158 of 907(17.4%) of which 97 (10.4%) were confirmed by RT-PCR. Breakthrough infections were significantly greater in the V versus the H group (15.7% and 3.5%, log-rank test, p = < 0.01). Among the hybrid group, the order of infection and vaccination had no bearing on the risk of breakthrough infections. On multivariate analysis, breakthrough infections were significantly lesser in the H versus the V group [HR: 0.2(0.1-0.4); p = 0.01]. CONCLUSION: The risk of breakthrough Omicron infections in fully vaccinated patients with AIRDs was 17.4% with a significantly lower risk in patients with hybrid immunity.

Withholding methotrexate after vaccination with ChAdOx1 nCov19 in patients with rheumatoid or psoriatic arthritis in India (MIVAC I and II): results of two, parallel, assessor-masked, randomised controlled trials.

Background: There is a necessity for an optimal COVID-19 vaccination strategy for vulnerable population groups, including people with autoimmune inflammatory arthritis on immunosuppressants such as methotrexate, which inhibit vaccine-induced immunity against SARS-CoV-2. Thus, we aimed to assess the effects of withholding methotrexate for 2 weeks after each dose of ChAdOx1 nCov-19 (Oxford-AstraZeneca) vaccine (MIVAC I) or only after the second dose of vaccine (MIVAC II) compared with continuation of methotrexate, in terms of post-vaccination antibody titres and disease flare rates. Methods: MIVAC I and II were two parallel, independent, assessor-masked, randomised trials. The trials were done at a single centre (Dr Shenoy's Centre for Arthritis and Rheumatism Excellence; Kochi, India) in people with either rheumatoid arthritis or psoriatic arthritis with stable disease activity, who had been on a fixed dose of methotrexate for the preceding 6 weeks. Those with previous COVID-19 or who were positive for anti-SARS-CoV-2 nucleocapsid antibodies were excluded from the trials. People on high-dose corticosteroids and rituximab were also excluded, whereas other disease-modifying antirheumatic drugs were allowed. In MIVAC I, participants were randomly assigned (1:1) to stop methotrexate treatment for 2 weeks after each vaccine dose or to continue methotrexate treatment. In MIVAC II, participants who had continued methotrexate during the first dose of vaccine were randomly assigned (1:1) to withhold methotrexate for 2 weeks after the second dose of vaccine or to continue to take methotrexate. The treating physician was masked to the group assignments. The primary outcome for both MIVAC I and MIVAC II was the titre (absolute value) of anti-receptor binding domain (RBD) antibody measured 4 weeks after the second dose of vaccine. All analyses were done per protocol. The trials were registered with the Clinical Trials Registry- India, number CTRI/2021/07/034639 (MIVAC I) and CTRI/2021/07/035307 (MIVAC II). Findings: Between July 6 and Dec 15, 2021, participants were recruited to the trials. In MIVAC I, 250 participants were randomly assigned and 158 completed the study as per the protocol (80 in the methotrexate hold group and 78 in the control group; 148 [94%] were women and 10 [6%] were men). The median post-vaccination antibody titres in the methotrexate hold group were significantly higher compared with the control group (2484·0 IU/mL, IQR 1050·0-4388·8 vs 1147·5 IU/mL, 433·5-2360·3; p=0·0014). In MIVAC II, 178 participants were randomly assigned and 157 completed the study per protocol (76 in the methotrexate hold group and 81 in the control group; 135 [86%] were women and 22 [14%] were men). The methotrexate hold group had higher post-vaccination antibody titres compared with the control group (2553·5 IU/ml, IQR 1792·5-4823·8 vs 990·5, 356·1-2252·5; p<0·0001). There were no reports of any serious adverse events during the trial period. Interpretation: Withholding methotrexate after both ChAdOx1 nCov-19 vaccine doses and after only the second dose led to higher anti-RBD antibody titres compared with continuation of methotrexate. However, withholding methotrexate only after the second vaccine dose resulted in a similar humoral response to holding methotrexate after both vaccine doses, without an increased risk of arthritis flares. Hence, interruption of methotrexate during the second dose of ChAdOx1 nCov-19 vaccine appears to be a safe and effective strategy to improve the antibody response in patients with rheumatoid or psoriatic arthritis. Funding: Indian Rheumatology Association.

Immune thrombocytopenia with multi-organ dysfunction syndrome as a rare presentation of scrub typhus: a case report.

BACKGROUND: Scrub typhus is an acute infectious illness caused by Orientia tsutsugamushi. It is endemic to a part of the world known as the "tsutsugamushi triangle". Humans are accidental hosts in this zoonotic disease. About a third of patients admitted with scrub typhus have evidence of multi-organ dysfunction. Multi-organ dysfunction secondary to scrub typhus carries a high mortality rate. CASE PRESENTATION: We report a 65-year old lady who was admitted in a Tertiary Care Center in the state of Kerala in India, with 7 day history of fever, myalgia and reduced urine output. Head to foot examination revealed the presence of an eschar on her chest. One week prior to the onset of her illness she had gone trekking through a hilly forest area. She was clinically suspected to have scrub typhus, which was later confirmed with laboratory tests. She developed multi-organ dysfunction syndrome secondary to this illness. Though there was an improvement in the multi-organ dysfunction, thrombocytopenia alone failed to improve. Bone marrow study was done which was suggestive of immune thrombocytopenia. Patient was given a course of steroids with which the thrombocytopenia improved. CONCLUSION: Failure of platelet count to normalize even after there has been a general improvement of other markers of multi-organ dysfunction in scrub typhus should prompt the clinician to consider other potential causes of thrombocytopenia. An unusual finding as this calls for further research to understand the molecular mechanisms behind such an event. Further, considering the close similarity in clinical presentation of several tropical illnesses, meticulous history taking and a detailed physical examination needs to be emphasized.

The forgotten view: Chest X-ray - Lateral view.

With CT (computed tomography) chest gaining more importance as a diagnostic tool, chest X-ray especially the lateral view is taken less commonly nowadays. Besides CT chest is also proven to be superior to chest X-ray in patients with major blunt trauma. We are presenting a 68-year old male who was partially treated from outside for a left sided pneumonia. He came to our hospital because of persisting chest pain. Chest X-ray, frontal view (postero-anterior) was almost normal except for a mild opacity in the left lower zone. CT scan of the chest revealed a fluid collection posteriorly enclosed within enhancing pleura. Chest X-ray, left lateral view showed a corresponding posterior pleural based opacity. We are presenting this case to highlight the importance of the lateral view of the chest X-ray. In selected cases there is still a role for the lateral view. With the three dimensional visualization provided by the CT, the lateral view of the chest may be easier to understand. Consequent to the initial diagnosis by CT further follow up can be done with the chest X-ray. In a limited way this mitigates unnecessary expenditure and more importantly prevents the patient from exposure to harmful radiation in the form of repeated CT.

Aches, pains and headache: an unusual combination of hypothyroidism, vitamin D deficiency, cervical radiculopathy and cortical vein sinus thrombosis.

A young obese woman was admitted with vague aches and pains, including a headache. At first a provisional diagnosis of depression/myofacial pain syndrome was considered. Later, on evaluation, she was diagnosed to have hypothyroidism and vitamin D deficiency. One week into treatment, her neck pain and headache got worse. Examination of the fundus showed tortuous vessels, papilloedema and intraretinal haemorrhages. MR venogram of the brain was performed, which revealed the presence of thrombosis in the left transverse sinus, left sigmoid sinus and left internal jugular vein. This report is an unusual presentation of neuropsychiatric symptoms in a patient where overlapping diagnoses confound the clinical picture and test the clinical acumen of the physician. A careful history followed by a focused clinical examination and evaluation will help to delineate potential confounders. The report further highlights the importance of clinical medicine even in this era of 'investigative medicine'.