|Ahead of print publication
Experience of sarcoidosis and factors predicting relapse at a tertiary care institute in North India
Alok Nath1, Zia Hashim1, Ajmal Khan1, Mansi Gupta1, Zafar Neyaz2, Durga Prasanna Misra3, Ravi Mishra1, Shivani Srivastava1
1 Department of Pulmonary Medicinem, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Radio Diagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareilly Road, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Sarcoidosis is a multisystem, chronic granulomatous disease of unknown etiology. The clinical course of sarcoidosis is punctuated with remission and relapses, which is unpredictable.
Materials and Methods: This was a retrospective observational study in which case records of all patients with a confirmed diagnosis of sarcoidosis attending the outpatient department of pulmonary medicine department between January 2014 and December 2018 were evaluated. The diagnosis of sarcoidosis was confirmed by demonstration of noncaseating granuloma in cytopathology or histopathology along with a compatible clinical picture. Mantoux test, serum angiotensin-converting enzyme (ACE) levels, serum calcium, and 24-h urinary calcium were done.
Results: Sarcoidosis was found to be more common in females. Cough, breathlessness, fever, and fatigue were the predominant symptoms. Mantoux was negative in 95.83%, raised serum ACE was seen in 65.83%, hypercalcemia in 10.83%, and hypercalciuria in 30.0% of patients, respectively. Chest radiograph revealed that 14.17% of patients presented with Stage 1, 52.50% of patients with Stage 2, 15.83% of patients with Stage 3, and 17.50% of patients with Stage 4. Mediastinal lymphadenopathy was seen in contrast-enhanced computed tomography chest in 93.33%, septal thickening with nodularity in 61.67% and fibrosis in 25.83%. Corticosteroids were started in 97.5% patients and 24.17% patients relapsed after stopping or tapering corticosteroids.
Conclusion: Sarcoidosis is a common cause of bilateral hilar lymphadenopathy and interstitial lung diseases. Relapses are frequent after stopping corticosteroids, so patients should be followed up actively after stopping treatment.
Keywords: Clinical features, corticosteroids, relapse, risk factors, sarcoidosis
|How to cite this URL:|
Nath A, Hashim Z, Khan A, Gupta M, Neyaz Z, Misra DP, Mishra R, Srivastava S. Experience of sarcoidosis and factors predicting relapse at a tertiary care institute in North India. Indian J Rheumatol [Epub ahead of print] [cited 2019 Sep 22]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=264873
| Introduction|| |
Sarcoidosis is a multisystem, chronic disorder of unknown etiology, characterized by the formation of noncaseating granuloma. It is hypothesized to be an immune-mediated inflammatory response to an unidentified environmental trigger. It affects most commonly adults in the most productive years of their life. Although almost any organ may be involved, pulmonary involvement is the most common site of involvement. As it is a close mimic of tuberculosis, its diagnosis is even more cumbersome in countries with a heavy burden of tuberculosis. Advances in bronchoscopic techniques have increased the ease with which these cases are being diagnosed. Sarcoidosis is also an important cause of interstitial lung disease (ILD), according to a registry from India, 8.3% of ILDs were due to sarcoidosis. In another study from a tertiary care center of India, the incidence of ILD because of sarcoidosis was 42.2%. We planned this retrospective study to evaluate clinicodemographic profile and features associated with relapse among diagnosed patients of sarcoidosis presenting to our department.
| Materials and Methods|| |
This was a retrospective observational study in which case records of all patients with a confirmed diagnosis of sarcoidosis attending the Outpatient Department of Pulmonary Medicine Department of Sanjay Gandhi Postgraduate Institute of Medical Sciences between January 2014 and December 2018 were evaluated. All patients who presented with the compatible clinical picture were subjected to routine investigations, contrast-enhanced computed tomography (CECT) of the thorax, Mantoux test, serum angiotensin-converting enzyme (ACE) levels, serum calcium (both total and ionized) corrected to serum albumin levels, and 24-h urinary calcium. A detailed ophthalmologic evaluation and abdominal sonography were done in all patients for extrapulmonary involvement. The diagnosis of sarcoidosis was confirmed by demonstration of noncaseating granuloma in cytopathology or histopathology along with a compatible clinical picture.
All patients were treated according to a standard protocol of the unit. The symptomatic patients were started on oral corticosteroids (prednisolone) according to their body weight (0.5–0.75 mg/kg body weight), which was usually continued at the same dose for at least 3 months unless there were other compelling reasons to taper it faster. The patients were usually followed up at 6–8 weekly intervals for the resolution of symptoms and monitoring of side effects during the treatment. Tapering of the dose was usually started after 3 months gradually over 7–9 months. A repeat CECT was done at the end of 6 months to look for the response to treatment. If there was significant radiologic as well as the clinical resolution of symptoms, tapering was continued, and the treatment stopped at 9 months. However, if the significant radiological or clinical resolution of symptom was not there, then the patient was considered for the addition of a second-line agent. Patients have followed up 8–12 weekly intervals after stopping of corticosteroids for the maintenance of remission for 12–18 months. If there was an increase in symptoms, then CECT thorax, serum ACE levels, serum total, ionized calcium, and 24-h urinary calcium were repeated. Relapse was defined recurrence of significant symptoms along with radiological worsening in the form of an increase in the size of lymph nodes or appearance of parenchymal nodules or increase in serum ACE, serum calcium, and 24-h urinary calcium. Patients who relapsed were started on second-line maintenance immunosuppressive therapy for at least 18–24 months. All patients with significant extrapulmonary involvement and significant pulmonary parenchymal involvement were started on second-line immunosuppressant at the start of the treatment along with corticosteroids, which were tapered off rapidly over 8–12 weeks to the lowest maintenance dose. Patients without significant fibrosis were given corticosteroids only. However, if the pulmonary fibrosis was significant, then patients were started on second-line immunosuppressants along with steroids, which were tapered early to a minimum maintenance dose. In cases of significant pulmonary fibrosis, azathioprine was preferred over methotrexate.
Medical records were reviewed, and all the baseline demographic data, history of smoking, presence of comorbidities, clinical data, hematological, and biochemical profile were recorded. The radiographic staging was done as per Scadding staging, i.e., Stage 1 (lymphadenopathy only), Stage 2 (parenchymal abnormalities with lymphadenopathy), Stage 3 (parenchymal abnormalities without lymphadenopathy), and Stage 4 (pulmonary fibrosis). Treatment details concerning the dose and duration of corticosteroids and second-line immunosuppressive agent were also recorded. Hypercalcemia and hypercalciuria were defined if the corrected serum calcium was more than 10.8 mg/dL and 24-urinary calcium more than 200 mg, respectively. For serum ACE the cut off was taken as 120 (two times upper limit of normal) to differentiate it from nonspecific increase.
This study was carried out in accordance with the recommendations of the Institutional Ethics Committee, Sanjay Gandhi Postgraduate Institute of Medical Sciences.
| Statistical Analysis|| |
All statistical analyses were performed using the SPSS statistical software, version 22.0 (SPSS Inc., Chicago, IL, USA). Data were expressed in terms of percentages. Continuous variables were compared using a two-tailed independent-sample t-test. Categorical variables were compared using a Chi-square test when needed. For the univariate analysis, the Chi-square test was used. For the factors which were significant in univariate analysis, multivariate analysis by binary logistic regression was used. P < 0.05 was considered statistically significant.
| Results|| |
During the study, there were a total of 120 patients of confirmed cases of sarcoidosis. Male to female ratio was 0.81:1. The median time of symptomatic period was 12 months before the patient presented to our clinic. Mean age at presentation was 46.88 ± 10.9 years. The cough was the most common symptom which was seen in 114 (95%) patients. History of dyspnea, chest pain, fever, and fatigue was present in 68.3%, 28.3%, 40.0%, and 29.2% patients, respectively. History of intake of antitubercular treatment was present in 25 (20.8%) patients. Significant comorbidities were present in 49 (40.8%) patients; diabetes mellitus was the most common 25 (20.8%) followed by hypertension 8 (6.6%) and hypothyroidism 6 (5%). History of smoking was seen in 10 (8.3%) patients. The clinic-demographic parameters, symptoms, and comorbidities are summarized in [Table 1]. The diagnosis was confirmed by the demonstration of granulomatous inflammation in all patients, in 78 (65%) by cytology and in 77 (64.17%) by biopsy. Corrected serum calcium more than 10.8 mg/dL was seen in 13 (25.83%) patients and hypercalciuria (24-h urinary calcium >200 mg) was seen in 36 (30%) patients. The Mantoux was negative in 115 (95.8%) patients. Chest radiograph revealed that 17 (14.16%) patients presented with Stage 1, 63 (52.50%) patients with Stage 2, 19 (15.8%) patients with Stage 3, and 21 (17.5%) patients with Stage 4. Mediastinal lymphadenopathy was seen in CECT chest in 114 (95%), perilymphatic nodules in 74 (61.2%), and fibrosis in 31 (25.83%) [Table 2].
Extrapulmonary involvement was seen in 28 (23.3%) patients, the most common system involved was gastrointestinal system in eight patients (hepatosplenomegaly with hypodense lesions: 4, granulomatous hepatitis: 2, granulomatous cholecystitis: 1, and splenic space-occupying lesion: 1), renal involvement in the form of granulomatous interstitial nephritis in six patients, granulomatous uveitis in four patients, and facial nerve palsy in three patients [Table 3]. The median follow-up period was 26 months (range 12–60 months). Treatment in the form of corticosteroids was started in 117 (97.5%). Three patients (2.5%) were kept on observation as they did not have symptoms. Azathioprine was used in 48 (40%) patients as second-line agents, while methotrexate and mycophenolate were used in 7 (5.8%) and 3 (2.3%) patients, respectively. Main indications of using second-line drugs were a relapse, significant extrapulmonary involvement, significant pulmonary fibrosis, and contraindications for the use of corticosteroids such as uncontrolled blood sugars. Twenty-nine (24.71%) of our patients showed a relapse after stopping corticosteroids after a median of 4 months (range 2–9 months). Five patients were Mantoux positive. In one patient, GeneXpert from bronchoalveolar lavage was positive. All five patients were initially given anti-tuberculosis treatment and later on started on corticosteroids after repeating the radiology.
On univariate analysis, duration of symptoms, history of fatigue at presentation, aspartate aminotransferase (AST) >40 U/L at presentation, and alanine aminotransferase (ALT) >40 U/L at presentation were found to be significant. Higher stage (Stages 3 and 4) had P = 0.05, and extrapulmonary involvement had P = 0.06. However, after multivariate analysis, only the presence of fatigue at presentation remained significant predictor for relapse (odds ratio [OR] = 3.70, 95% confidence interval [CI] 1.31–10.41, P = 0.013). For the higher stage of extrapulmonary involvement was just near the level of significance (OR = 3.10, 95% CI 0.99–10.03, P = 0.058) [Table 4].
| Discussion|| |
Our study describes the clinical profile of 120 patients with a confirmed diagnosis of sarcoidosis. The cough was the most common presenting symptom, followed by dyspnea, fever, and fatigue. These are common nonspecific presenting symptoms, which are also common in patients with tuberculosis. Several published cohorts have described the clinical profile of sarcoidosis patients from India.,,, [Table 5] describes the clinical findings of sarcoidosis from Indian studies. Similar to other series, females outnumbered males in our cohort also. The Mantoux test was negative in 95% of patients, and about one-fourth of patients had a history of being treated for tuberculosis. Liver and spleen were the most common extrapulmonary organ involvement in our series which was demonstrated by Sharma et al. also, but in the cohort reported by Gupta et al., ophthalmic involvement was most common pulmonary organ involved. Type 2 diabetes mellitus was the most common comorbidity encountered in our cohort. Majority of patients were Scadding Stage 2, and mediastinal lymphadenopathy was the most common radiological abnormality on CECT thorax followed by nodules and interstitial thickening, which was similar to other published case series from India. The treatment of choice for starting treatment in sarcoidosis remains corticosteroid. In our study, due to the presence of symptoms in most cases corticosteroids were started in 97.5%.
|Table 5: Summary of clinical findings from major studies published from India|
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Relapses are quite common in patients with sarcoidosis after stopping therapy, but there is a paucity of data regarding predictors of relapse, and very fewer studies have described features associated with high chances of relapse in these patients. Several studies in the past have reported that relapses are quite frequent in patients with sarcoidosis ranging from 13% to 75%.,, This heterogeneity is probably because of different criteria and definition used for defining relapses. In some cases, an acute exacerbation may be termed as relapse and; disease may not be in remission, and symptoms flare when anti-inflammatory drugs were withdrawn. These relapses usually after 1-month up to 1 year after therapy is tapered or discontinued. In our study also, we noted that relapses were quite frequent (24.71%) after discontinuation of corticosteroid therapy. The relapse rates were similar to a recent study by Zheng et al. from China in which it was 31.25%. Very few studies have evaluated the factors associated with relapse in patients with sarcoidosis. In our study, univariate analysis revealed that increased duration of symptoms, history of fatigue and AST > 40, ALT > 40 at presentation and higher Scadding stage were significant factors predicting relapse. Other factors analyzed did not prove to be significant in predicting relapse. Curiously, in one study, it was also hypothesized that corticosteroid therapy itself might predispose to higher chances of relapse. The authors concluded that in newly diagnosed cases of sarcoidosis, corticosteroids should be judiciously when there are definite indications to initiate treatment and benefits unequivocally outweigh the risk. It was also proposed that after discontinuation of treatment, patients should be closely followed up for a considerable period to assess for relapse.
A higher Scadding stage (Stages 3 and 4) at the time of presentation was another factor associated with a higher rate of relapse in our study. In contradistinction to other studies, the smoking status and extrapulmonary involvement had no relationship with the chances of relapse. Although the values did not reach statistical significance, it was noteworthy that extrapulmonary involvement did have a trend toward a higher likelihood of relapse in our study also.
In the study by Zheng et al., increased serum lactate dehydrogenase (LDH) at baseline were also reported to be an important factor predicting higher rates of relapse. This appears logical also as increased serum LDH levels are also correlated with the presence of alveolitis. Unfortunately, this parameter was not evaluated in our study. In our study, another biochemical marker, i.e., asymptomatic transaminitis, was associated with higher chances of relapse in our cohort, a finding which has not been reported in other studies. A possible reason for this may be indirect evidence of the presence of liver involvement, which amongst extrapulmonary involvement may be associated with higher chances of relapse, which needs further evaluation in larger cohorts.
It is prudent to note that persistent subclinical disease activity itself may be an underlying factor associated with relapse or misinterpreted as relapse as discussed earlier. It is imperative to achieve a high degree of remission and a search for markers of residual disease activity is the need of the hour. In a recent study, the soluble interleukin-2 receptor and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan at the end of infliximab treatment were found to be independent predictors of relapse. FDG-PET has been evaluated to document disease remission in a couple of studies from India with conflicting results., In another study, the percentage of peripheral monocytes expressing very late antigen – 1, CD16, and CD69 was found to be abundant at presentation and decrease to normal levels during follow-up with disease remission. A combination of these markers, along with serial FDG-PET, may be used to evaluate disease activity and document remission for the safe discontinuation of corticosteroid or immunosuppressive therapy.
Sarcoidosis may present with musculoskeletal manifestations also. Although we have not specifically assessed musculoskeletal manifestations, a recent multicentric Indian study reported 117 patients with sarcoid arthritis, 88 with acute sarcoid arthritis, and 29 with chronic sarcoid arthritis. While acute sarcoid arthritis was generally self-limiting in its disease course, chronic sarcoid arthritis required immunosuppressive therapy in most patients, generally for extra-articular manifestations.
Our study has potential limitations due to its retrospective design and single-center experience. The study is fraught with the presence of selection bias also, and further well-designed prospective studies are needed to evaluate this aspect.
| Conclusion|| |
In summary, our study showed that in patients with sarcoidosis, there are frequent relapses. Higher Scadding stage, transaminitis, and fatigue were significantly associated with the relapse in univariate analysis. However, on multivariate analysis, only the presence of fatigue at presentation was associated with relapse.
This study was carried out in accordance with the recommendations of the Institutional Ethics Committee, Sanjay Gandhi Postgraduate Institute of Medical Sciences. The protocol was approved by the Institutional Ethics Committee, Sanjay Gandhi Postgraduate Institute of Medical Sciences. (Ethics Cell No. 2019-153-IMP-EXP-10).
The authors are thankful to Medical Record Department Sanjay Gandhi Postgraduate Institute of Medical Sciences for providing case records of all patients with a confirmed diagnosis of sarcoidosis which attended the outpatient department of pulmonary medicine department between January 2014 and December 2018 for conducting this retrospective observational study.
Financial support and sponsorship
Conflicts of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
| References|| |
Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160:736-55.
Miller BH, Rosado-de-Christenson ML, McAdams HP, Fishback NF. Thoracic sarcoidosis: Radiologic-pathologic correlation. Radiographics 1995;15:421-37.
Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, et al.
Interstitial lung disease in India. Results of a prospective registry. Am J Respir Crit Care Med 2017;195:801-13.
Dhooria S, Agarwal R, Sehgal IS, Prasad KT, Garg M, Bal A, et al.
Spectrum of interstitial lung diseases at a tertiary center in a developing country: A study of 803 subjects. PLoS One 2018;13:e0191938.
Tahir M, Sharma SK, Ashraf S, Mishra HK. Angiotensin converting enzyme genotype affects development and course of sarcoidosis in Asian Indians. Sarcoidosis Vasc Diffuse Lung Dis 2007;24:106-12.
Singh RB, Babu KS. Pulmonary sarcoidosis in a South Indian hospital: Clinical and lung function profile. Indian J Chest Dis Allied Sci 1999;41:145-51.
Bambery P, Behera D, Gupta AK, Kaur U, Jindal SK, Deodhar SD, et al.
Sarcoidosis in North India: The clinical profile of 40 patients. Sarcoidosis 1987;4:155-8.
Gupta SK. Sarcoidosis: A journey through 50 years. Indian J Chest Dis Allied Sci 2002;44:247-53.
Gupta D, Sharma OP. Sarcoidosis. In: Jindal SK, edior. Textbook of Pulmonary and Critical Care Medicine. 1st
ed. New Delhi: Jaypee Brothers Medical Publishers Pvt Ltd.; 2011. p. 1188-216.
Sharma SK, Mohan A, Guleria JS. Clinical characteristics, pulmonary function abnormalities and outcome of prednisolone treatment in 106 patients with sarcoidosis. J Assoc Physicians India 2001;49:697-704.
Khan NA, Donatelli CV, Tonelli AR, Wiesen J, Ribeiro Neto ML, Sahoo D, et al.
Toxicity risk from glucocorticoids in sarcoidosis patients. Respir Med 2017;132:9-14.
Zheng Y, Wang H, Xu Q, Yan X, Zhuang Y, Jiang H, et al.
Risk factors of relapse in pulmonary sarcoidosis treated with corticosteroids. Clin Rheumatol 2019;38:1993-9.
Gottlieb JE, Israel HL, Steiner RM, Triolo J, Patrick H. Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy. Chest 1997;111:623-31.
Baumann MH, Strange C, Sahn SA. Do chest radiographic findings reflect the clinical course of patients with sarcoidosis during corticosteroid withdrawal? AJR Am J Roentgenol 1990;154:481-5.
Johns CJ, Schonfeld SA, Scott PP, Zachary JB, MacGregor MI. Longitudinal study of chronic sarcoidosis with low-dose maintenance corticosteroid therapy. Outcome and complications. Ann N
Y Acad Sci 1986;465:702-12.
Baughman RP, Judson MA. Relapses of sarcoidosis: What are they and can we predict who will get them? Eur Respir J 2014;43:337-9.
Matusiewicz SP, Williamson IJ, Sime PJ, Brown PH, Wenham PR, Crompton GK, et al.
Plasma lactate dehydrogenase: A marker of disease activity in cryptogenic fibrosing alveolitis and extrinsic allergic alveolitis? Eur Respir J 1993;6:1282-6.
Chen H, Jin R, Wang Y, Li L, Li K, He Y, et al.
The utility of 18F-FDG PET/CT for monitoring response and predicting prognosis after glucocorticoids therapy for sarcoidosis. Biomed Res Int 2018;2018:1823710.
Maturu VN, Rayamajhi SJ, Agarwal R, Aggarwal AN, Gupta D, Mittal BR, et al.
Role of serial F-18 FDG PET/CT scans in assessing treatment response and predicting relapses in patients with symptomatic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2016;33:372-80.
Guleria R, Jyothidasan A, Madan K, Mohan A, Kumar R, Bhalla AS, et al.
Utility of FDG-PET-CT scanning in assessing the extent of disease activity and response to treatment in sarcoidosis. Lung India 2014;31:323-30.
] [Full text]
Heron M, Grutters JC, van Velzen-Blad H, Veltkamp M, Claessen AM, van den Bosch JM. Increased expression of CD16, CD69, and very late antigen-1 on blood monocytes in active sarcoidosis. Chest 2008;134:1001-8.
Arthritis in Sarcoidosis Group (ASG), Agarwal V, Agrawal V, Aggarwal A, Aggarwal P, Chowdhury AC, et al.
Arthritis in sarcoidosis: A multicentric study from India. Int J Rheum Dis 2018;21:1728-33.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]