Rajiva Gupta

Tracheobronchial stenosis (TBS) is seen in around 16-23% of granulomatosis with polyangiitis (GPA) patients and can often be a severe functional impairment and life-threatening event.[1] Tracheobronchial stenosis can be a sole manifestation or progression that may not correlate with other GPA disease activity features and antineutrophil cytoplasmic autoantibody (ANCA) titers.[2,3] This condition needs a multidisciplinary approach owing to its complexity. Apart from immunosuppression, multiple other modalities have been tried in the therapeutics of TBS associated with GPA. Tracheobronchial stenting is one of these. A 50-year-old female patient was evaluated at our center in February 2016 with history of hearing loss, inflammatory arthritis, and saddle nose for four years and new-onset worsening of hoarseness of voice, cough and breathlessness for three months. She was being treated as GPA based on clinical features and anti-myeloperoxidase (MPO) positivity with oral steroids and weekly methotrexate of 22.5 mg. Further evaluation showed normal complete blood count but raised erythrocyte sedimentation rate with normal urine examination, renal functions and liver functions. Chest X-ray did not show any infiltrates. Cardiac evaluation was normal. High-resolution computed tomography (HRCT) of the chest with neck cuts showed circumferential thickening of trachea (Figure 1). Considering this as a disease activity, the patient was started on intravenous cyclophosphamide 15 mg/kg monthly for six months and oral steroids 1 mg/kg with further tapering. She clinically became better and was on oral prednisolone 5 mg/day and cotrimoxazole prophylaxis. She was planned for repeat HRCT of the chest and neck and maintenance treatment. However, the patient was lost to follow-up after six doses. In January 2017, she presented with two- week history of worsening of shortness of breath, wheeze and stridor. Further evaluation showed interval increase in circumferential thickening of trachea and bilateral main stem and lobar bronchi on HRCT of the chest and neck. However, repeat ANCA was negative for both proteinase 3 and MPO by line immunoassay and by indirect immunofluorescence for cytoplasmic and peri-nuclear ANCA. After initial treatment with broad-spectrum antibiotics and increased steroid dose, she had a marginal improvement. Considering this as a disease relapse, she was given rituximab 2 g two weeks apart. At subsequent follow-ups, the patient was doing well with just oral prednisolone 5 mg daily. At fourth month follow-up, HRCT of the chest with neck cuts was repeated and it showed reduction in wall thickening as compared to the previous scans (Figure 2). This time, the patient was given early rituximab 500 mg maintenance therapy and discharged on same dose of oral prednisolone and cotrimoxazole. She was doing well for six months; however, she presented to emergency with history of cough, fever and wheeze for 15 days. On evaluation, she had type 2 respiratory failure and needed biphasic positive airway pressure support. Also, she was given high-dose steroids under antibiotics cover. HRCT of the chest showed worsening as expected. There was no improvement with the existing treatment even after three weeks. Patient continued having carbon dioxide retention with high respiratory rate and deterioration of sensorium despite noninvasive ventilation support. She also developed hospital-acquired infection. Discussion with the respiratory team and relatives ensued and decision for tracheal stenting was established (Figures 3 and 4). Earlier stenting was avoided in view of long segment involvement. Post-procedure, she was put on ventilator and tracheostomized later in view of long-term ventilatory involvement. She was discharged after three weeks of hospital stay and later she suffered from post-procedure complications like tracheostomy site ulcer and its bleeding, subcutaneous emphysema and difficulty regaining activities of daily living. She was readmitted after a month with worsening of breathlessness and fever and was bound to have bilateral pneumonia. This time, she succumbed in view of sepsis and related acute kidney injury. This case highlights the difficulties in managing TBS associated with GPA. Since GPA is notorious for higher relapse rates, presence of TBS makes it worse. TBS develops in watershed area, at the junction of two separate embryological different growth centers. Recurrent exposure of already inflamed respiratory epithelium to gastric contents during laryngopharyngeal reflux episodes leads to initial granulomatous inflammation which is followed by circumferential scarring and airway narrowing. Type 2 respiratory failure is not uncommon and can occur because of the involvement of segmental and small bronchi and bronchioles. Endobronchial stenting also has a few complications including displacement of the stent and obstruction with secretions or granulation tissue. Rarely, the stent may perforate the airway wall, sometimes into the accompanying blood vessel. Most studies of endobronchial stenting demonstrate that it is an effective treatment modality for airway stenosis. The long-term efficacy of endobronchial stents is superior to laser ablation, debulking or dilatation therapy though the long-term patency of stents is uncertain. These patients often have ear, nose, and throat involvement and more commonly saddle nose deformity. TBS can progress in absence of any other systemic activity. Treatment modalities are limited and are as shown in Figure 5.[4,5] There are limited data on the usefulness of stenting in TBS associated with GPA. Two recent studies in fact showed that the relapse rate was high as 62% with higher stent restenosis.[6] Very few case reports have shown success with stenting.[7,8] Considering that TBS can progress irrespective of systemic activity of GPA, it is difficult to assess response to immunosuppression with cyclophosphamide or rituximab etc. clinically.

Objective Methotrexate (MTX) is the drug of first choice for the treatment of rheumatoid arthritis (RA), but is effective only in around 60% of the patients. Identification of genetic markers to predict response is essential for effective treatment within a critical window period of 6 months after diagnosis, but have been hitherto elusive. In this study, we used genome-wide genotype data to identify the potential risk variants associated with MTX (poor)response in a north Indian RA cohort. Materials and methods Genome-wide genotyping data for a total of 457 RA patients [297 good (DAS28-3≤3.2) and 160 poor (DAS28-3≥5.1) responders] on MTX monotherapy were tested for association using an additive model. Support vector machine and genome-wide pathway analysis were used to identify additional risk variants and pathways. All risk loci were imputed to fine-map the association signals and identify causal variant(s) of therapeutic/diagnostic relevance. Results Seven novel suggestive loci from genome-wide (P≤5×10⁻⁵) and three from support vector machine analysis were associated with MTX (poor)response. The associations of published candidate genes namely DHFR (P=0.014), FPGS (P=0.035), and TYMS (P=0.005) and purine and nucleotide metabolism pathways were reconfirmed. Imputation, followed by bioinformatic analysis indicated possible interaction between two reversely oriented overlapping genes namely ENOSF1 and TYMS at the post-transcriptional level. Conclusion In this first ever genome-wide analysis on MTX treatment response in RA patients, 10 new risk loci were identified. These preliminary findings warrant replication in independent studies. Further, TYMS expression at the post-transcriptional level seems to be probably regulated through an antisense-RNA involving the 6-bp ins/del marker in the overlapping segment at 3′UTR of TYMS-ENOSF1, a finding with impending pharmacogenetic applications.

Vascular changes in lupus nephritis (LN) may be the cause of renal function derangement without obvious changes in activity or chronicity indices. Although a few morphological studies of renal vasculature exist, arteriolar morphometric parameters in LN have not been evaluated. For this study, 40 patients with LN and 40 age-matched patients with minimal change disease (controls) were included. Their clinical features were noted, renal biopsy changes classified according to the modified World Health Organization classification of LN and activity and chronicity indices were calculated. Arteriolar morphometric parameters were obtained using manual tracing and an image analysis software. Appropriate statistical tests were applied to assess significance of difference between various groups. Arteriolar wall thickness as well as circumference was significantly higher in all classes of LN as compared with controls (P 0.05). An inter-class analysis of LN did not show any significant difference for any of the arteriolar morphometric parameters (P >0.05). No correlation was found between activity or chronicity indices and the various arteriolar morphometric parameters. This study demonstrates morphometric evidence of arteriolar wall changes in LN. Although no correlation was found with the histological features, further studies are required in this area

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Prevalence and clinical significance of anti-cyclic citrullinated peptide (CCP) antibodies in Indian patients with juvenile idiopathic arthritis (JIA). Anti-CCP antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in 78 patients with JIA which included all 3 major subtypes of the disease: pauciarticular, polyarticular afld systemic onset. Values above 5 relative units were taken as positive. Associations between antiCCP antibodies and clinical and laboratory and radiological parameters were determined. Anti-CCP antibodies were positive in only 2 of 34 (5.9%) patients with pauciarticular JIA and 3 of 17 (17.6%) of systemic,.pnset JIA, whereas it was positive in 13 of 27 (48.1%) of polyarticular JIA patients (p < 0.001). Furthermore, it was seen that among patients with polyarticular JIA, RF-lgM positive patients had higher rate of anti-CCP antibody positivity with 7 of 8 (87.5%) patients having positive anti-CCP antibody (p<0.001). Similarly, patients with erosions (11/19; p<0.001) and deformities (5/−10; p<0.001) were found to have significant association with anti-CCP antibody positivity. Anti-CCP antibodies could be detected more frequently in the sera of JIA patients with severe manifestations like-erosions and deformity. It was also more significantly associated with seropositive polyarticular JIA than other types. It can be presumed from these results that anti-CCP antibodies can be used as a marker to predict severe course of JIA at the onset to guide optimal aggressive therapy.

Systemic lupus erythematosus (SLE) can affect the menstruation, fertility, and pregnancy outcomes of the affected subjects. There is very little data on this aspect of the disease in Indian patients. Our aim was to study the menstrual, fertility, and pregnancy outcomes in these patients in comparison with patients of rheumatoid arthritis (RA) and also to study the effect of cyclophosphamide therapy on menstrual cycles in patients with SLE. Four hundred and twenty patients of SLE (210) and RA (210) were interviewed using a standard questionnaire and available medical records used. After disease-onset, the chances of adverse pregnancy outcomes were significantly more in patients with SLE compared to RA [OR = 5.17 (2.13–12.52); p ≤ 0.001]. Compared to the National average in India, the average number of living children is lesser in patients with RA (2.39 ± 1.39, p = 0.002), but more so in patients with SLE (1.44 ± 1.35, p = 0.001). A younger age at diagnosis and cyclophosphamide therapy was found to be independently associated with menstrual irregularities after disease-onset. We conclude that pregnancy outcome in patients with SLE in India is worse in comparison to patients with RA. Average family size of patients with SLE and RA is less when compared to National average in India. Patients with SLE are more prone for menstrual irregularities, especially those who receive cyclophosphamide treatment.

In patients with systemic sclerosis (SSc), antiphospholipid antibodies (aPL) have been reported to be associated with more severe manifestations including digital infarct, gangrene and pulmonary hypertension. But these findings are not consistent in all studies; moreover, there are no data available from Indian subcontinent. The objective of this study is to assess the prevalence of antiphospholipid antibodies in Indian SSc patients and correlate them with clinical and immunological features. Seventy-two patients were recruited prospectively from rheumatology clinic from 2002 to 2006. Their medical records were reviewed. Anticardiolipin antibodies (IgG, IgM) by ELISA and lupus anticoagulant (LA) were tested in standardized pattern and repeated after 6 weeks. Anti-β2 glycoprotein-I antibodies were done in patients who had aPL antibodies. Nineteen patients had diffuse cutaneous SSc and 53 had limited disease. Seven patients (9.7%) were positive for aPL antibodies in their sera. Only one patient had clinical features of antiphospholipid antibody syndrome and manifested with recurrent abortions and deep vein thrombosis. She was positive for aCL, LA and anti-β2 glycoprotein-I antibodies. Four patients were only aCL (IgG) positive in moderate titers and one each had only aCL (IgM) and LAC positivity. None of the clinical parameters showed an association with aPL antibody.

Background: The usefulness of anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies) to identify rheumatic arthritis (RA) from other rheumatic diseases presenting with joint pain is not well studied. Aims: We aimed to determine the sensitivity and specificity of anti-CCP antibodies in Indian RA patients with respect to non-RA rheumatic diseases and to study the relationship of anti-CCP antibodies and IgG, IgM and IgA rheumatoid factor in RA. Settings and Design: Case-control cross-sectional study carried out in the rheumatology division of All India Institute of Medical Sciences.Materials and Methods: Sixty-three patients with rheumatoid arthritis (RA) and 51 patients with non-RA rheumatic diseases having joint pain were included in the study. Sera were tested for anti-CCP antibodies (IgG) and IgA, IgM, IgG rheumatoid factor, using a commercially available enzyme-linked immunosorbent assay. Statistical Analysis: Statistical analysis was performed using SPSS statistical software version 11.5. Results: Fifty-four of 63 RA patients (85.71%) were positive for anti-CCP antibodies. In the non-RA group, anti-CCP antibody was positive in only 5 of 51 patients (9.8%). Our study found a sensitivity of 85% and a specificity of 90.19% with regard to the use of anti-CCP antibodies assay in patients with joint pain to correctly identify RA. Anti-CCP antibodies positive patients did not have more erosive disease. IgM-RF-positive patients had more erosion when compared to the IgM-RF-negative group. Thirty-two of 57 (56.1%) IgM-RF-positive patients had erosions, while no patient (0/6 patients) had erosions in the IgM-RF-negative group (P = 0.01) Conclusion: Anti-CCP antibodies have high sensitivity and specificity for diagnosis of RA, in Indian patients. Anti-CCP antibodies positive patients did not have more erosive disease in our study.