Prevalence and Risk Factors of Relapse in Pulmonary Sarcoidosis: A Systematic Review and Meta-analysis

doi:10.21203/rs.3.rs-3618799/v1

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Systematic Review

Prevalence and Risk Factors of Relapse in Pulmonary Sarcoidosis: A Systematic Review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-3618799/v1

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Background and Aim:

Relapses in pulmonary sarcoidosis (PS) adversely affect the clinical management and prognosis of the disease, but there is a paucity of data on their incidence and risks. We aimed to systemically review and meta-analyze the available studies for evaluating the pooled weighted incidence and risk factors for relapse in the disease.

Methods:

We systematically searched electronic databases, including PubMed, Google Scholar, Scopus and Embase, and performed a manual search to collect eligible studies published until 31 October 2023. The prevalence and risk factors for relapse of PS were analyzed by a random effect model using proportions with 95% confidence intervals (CIs).

Results:

Of the 1402 records retrieved, 26 studies met the inclusion criteria. All these studies were from tertiary centers. Mean age of the relapse groups was 45.94 years (SD 10.87). The prevalence of relapse in sarcoidosis (843 relapses in 2698 sarcoidosis subjects) varied from 11–67%, with a pooled prevalence of 0.34 [95% CI, 0.28–0.40]. Relapses were more common in blacks than in white individuals [0.72 (0.65–0.79) vs [0.27 (0.20–0.34), p = 0.00]. There were no significant differences in subgroups based on age, sex, location, or type of study. Although not reaching statistically significance, the number of relapses were higher in the female as compared to males [Risk difference 0.05(95% CI: -0.01-0.11, p = 0.09)].

Conclusion:

Our study shows a pooled incidence of PS relapse of 34%, suggesting a regular follow-up of the patients for early detection of relapse and improved prognosis of the disease.

Pulmonology

Pulmonary Sarcoidosis

Relapse

Prevalence

Risk Factors

Sarcoidosis is a non-necrotizing granulomatous inflammatory disease affecting barrier organs including the lungs (i.e., pulmonary sarcoidosis), skin (i.e., cutaneous sarcoidosis), and eyes (i.e., ocular sarcoidosis).^[1–5] The disease occurs worldwide and primarily affects young or middle-aged adults, with an annual incidence of 1 to 15 per 100,000 depending upon region, race and demographics.^{[6, 7]} Of these sarcoid types, our focus is on pulmonary sarcoidosis (PS), as it represents approximately 90% of sarcoidosis cases and accounts for the majority of the disease related morbidity and mortality.^{[2, 4]} A major hurdle in the clinical management of PS is the occurrence of relapses. They mainly occur when anti-sarcoid treatment is tapered or stopped after achieving remission, and this cycle of remission and relapse continues for years and years, adversely affecting the clinical management and prognosis of the disease. ^[8–11]. However, data on the true prevalence of the disease relapse is limited. An accurate evaluation of baseline clinical and laboratory factors may facilitate the prediction of relapse in PS, but data on specific risk factors involved in the disease relapse, is also limited. Since this information would be crucial for developing clinically relevant strategies for the early detection and prevention of relapse and improving the clinical management and outcome of PS, aim of the present study was to systemically review and meta-analyze the available studies and evaluate the pooled weighted prevalence and risk factors for relapse in the disease.

Study Protocol and Registration

We performed a systemic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (www.prisma-statement.org). We registered the review protocol (INPLASY202380056, doi: 10.37766/inplasy2023.8.0056).

Search Strategy:

We performed a comprehensive advanced literature search of four electronic databases, including PubMed/MEDLINE, Google Scholar, Scopus and Embase, to identify all studies reporting pulmonary sarcoidosis and relapse until 31 October 2023. The search was independently carried out by two authors (NKT and ZH) using the following Boolean combinations of MeSH terms: ((((Pulmonary) OR (Lung)) AND (Sarcoidosis)) OR (Sarcoid)) AND (Relapse)) NOT ((Neuro))) NOT (Cardiac)) NOT (Hepatic)) NOT (Splenic)) NOT (Gastrointestinal)) NOT (Review)) NOT (Case Report)) using English language and full-text articles as filters. In addition, we manually searched the reference list, similar studies and citations of included studies as other or extra sources to identify any additional studies missed in the electronic search.

Inclusion and Exclusion Criteria:

We included eligible studies using the following inclusion criteria: (i) full-text prospective or retrospective observational cohort, case–control, cross-sectional study, case series, or clinical trials published in the English language in a peer-reviewed journal, (ii) studies reporting relapse of pulmonary sarcoidosis with or without involvement of other organ systems of patients of all age groups, and (iii) studies reporting risk factors underlying relapse of pulmonary sarcoidosis with or without involvement of other organ systems. We excluded ineligible studies using the following exclusion criteria: (i) studies published in non-English language or a non-peer-reviewed journal; (ii) reviews, case reports, opinion articles, meta-analyses, editorials and conference abstracts/posters; and (iii) studies reporting single organ isolated disease of neuro, cardiac hepatic splenic or gastrointestinal sarcoidosis.

Study Selection:

To select eligible studies, we first removed duplicate records from the total identified studies using EndNote (version 21.0) and manual checks. The remaining studies with no duplicates were subjected to two-level systems to select eligible studies. In the first level, two authors (NKT and ZH) independently screened the identified studies by titles and abstracts to select relevant full-text articles. In the second level, the same authors independently reviewed the full texts of the relevant studies considering eligibility criteria to select the eligible studies for inclusion in the meta-analysis. Any disagreement between the two author reviewers was resolved by mutual discussion to reach a consensus. Any unresolved disagreement between the two authors was arbitrated by a third author (AK).

Data Extraction:

The following data from the text and supplementary information of each included study were extracted and recorded by two authors (NKT and ZH) using a predesigned MS Office Excel worksheet. First author name, publication year, country, study design, patient numbers and demographics, sarcoidosis organ involvement, anti-sarcoid treatment, timing of remission after treatment, timing of relapse, criteria of PS diagnosis, and criteria of remission and relapse. Any disparity between the extracted data of the two authors was re-examined, and a consensus was achieved following mutual discussion. In addition, the extracted data were independently reviewed by an additional author (AK).

Assessment of Quality, Publication Bias and Heterogeneity:

Two independent reviewers (ZH and NKT) assessed the quality of each included study. We used a modified 11-item list based on the Strengthening the Reporting of Observational Studies in Epidemiology checklist for observational studies^{[12, 13]} and the Cochrane Risk of Bias tool for randomized controlled trials^[14] and Risk Of Bias In Non-randomized Studies of Interventions for nonrandomized studies.^[15] A cutoff value of 75% was chosen to classify the studies of high and low quality. A high quality was defined as a quality score of > 75%, and low quality was defined as a quality score of < 75%.^[16] We reported significant statistical heterogeneity if the Higgins inconsistency index (I²) was ≥ 50%.^[15] We assessed publication bias visually by constructing a funnel plot. We also used Egger’s, and Begg-Majumdar tests to evaluate publication bias.^{[17, 18]}

Statistical analysis:

We calculated the prevalence of relapse of PS in each included study by computing the proportion (number of subjects with relapse or presumed relapse divided by the total number of sarcoidosis subjects) with 95% confidence intervals (CI). The proportions were first turned into a quantity using the Freeman-Tukey variant of the arcsine square root transformed proportion. We subsequently calculated the pooled proportion (back transform of the weighted mean of the transformed proportions) using the DerSimonian‒Laird random effects model.^[19] Univariate subgroup analysis was done in groups for age, gender, ethnicity, type of study, year of study, place of study. We used Cochrane’s Q formula for calculating pooled mean standard deviation for age. We used the STATA (version 18.0, Stata Corp, College Station, TX) option for estimating the effect sizes.

We identified a total of 1402 studies through different electronic databases and manual searches. Of these, 87 studies were removed as duplicates, and 1242 studies were excluded for having irrelevant titles and abstracts or being reviews, case reports, or editorials. The remaining 81 studies were selected for full-text screening for eligibility. Of these, 55 studies not meeting the eligibility criteria were excluded. Thus, 26 cohort studies were found to be eligible and included in the meta-analysis. The PRISMA flow chart depicting the literature search and selection of eligible studies is shown in Fig. 1.

We contacted authors telephonically or by email to obtain further information, if available. All studies were conducted at tertiary care centers with a total of 2698 subjects with 843 relapses. Fourteen studies were retrospective, eleven studies were prospective, and one study was ambispective (Table 1).

Table 1

Characteristics of included studies
No.	Author	Year	Country	Design	Data (of patients evaluated for relapse)	Remarks
1.	Dhooria et al.^[20]	2023	India	Prospective	Patients = 86 Relapses = 39	SARCORT trial. High-dose prednisolone was not superior to a lower dose in sarcoidosis.
2.	Ozdemirel et al.^[21]	2023	Turkey	Retrospective	Patients = 73 Relapses = 16	A small study, inflammatory markers in sarcoidosis with insignificant correlation.
3.	Guliyeva et al.^[22]	2023	Turkey	Retrospective	Patients = 52 Relapses = 14	A multicenter experience on pediatric sarcoidosis from Turkey
4.	Feng et al.^[23]	2022	China	Retrospective	Patients = 123 Relapses = 24	A high BAL neutrophil was associated with a greater relapse.
5.	Madan et al.^[24]	2022	India	Ambispective	Patients = 327 Relapses = 73	The largest study from India on clinico - demographic profile of sarcoidosis patients. (Data from unpublished literature).
6.	Morar et al.^[25]	2022	South Africa	Retrospective	Patients = 102 Treated = 89 Relapses(treated) = 54.	A study on sarcoidosis patients from Africa with a description of relapse.
7.	Spyropoulos et al.^[26]	2022	Greek	Prospective	Patients = 147 Relapses = 42	Sarcoidosis phenotypes in a Greek population.
8.	Gavrysyuk. et al. ^[27]	2021	Ukraine	Prospective	Patients = 84 Relapses = 28	Methotrexate and Methylprednisolone in Pulmonary Sarcoidosis: outcomes.
9.	Gavrysyuk et al.^[28]	2021	Ukraine	Prospective	Patients = 108 Relapses = 56	The factors that correlated to higher relapses were: 1) use of glucocorticoids; 2) slow developing symptoms; 3) extrapulmonary lesions; 4) bronchoconstriction; 5) concomitant chronic diseases.
10.	Murata et al.^[29]	2021	Japan	Retrospective	Patients = 103 Exacerbation & relapses = 23	Exacerbation and relapses were presented with combined data. These patients had higher incidences of hilar adenopathy, ocular, & cardiac disease, longer disease duration & oral glucocorticoid use at diagnosis.
11.	Nath et al. ^[30]	2019	India	Retrospective	Patients = 120 Relapses = 29	Univariate analysis showed that a higher Scadding stage, transaminitis, and fatigue were significantly associated with a higher relapse rate. However, multivariate analysis showed fatigue as the single important factor related to relapse.
12.	Zheng et al.^[31]	2019	China	Retrospective	Patients = 243, followed up = 203, treated = 96; relapse(treated) = 30	A history of smoking and increased circulating neutrophils (> 70%) were significant predictors of relapse.
13.	Belhomme et al.^[32]	2018	France	Retrospective	Patients = 34 Relapses = 10	Immunoglobulin levels & sarcoidosis outcome: no significant relation was seen
14.	Ozyilmaz et al.^[33]	2018	Turkey	Prospective	Patients = 29 Relapses = 13	Sarcoidosis prognosis with HLA typing
15.	Mañá et al.^[34]	2017	Spain	Prospective	Followed up = 587/640 Relapses(treated) = 30/266 Relapses (spontaneous remission) = 22/209	A greater age (> 40 years), pulmonary involvement, or splenic involvement, and the need of treatment were associated with chronic sarcoidosis.
16.	Liu et al.^[35]	2016	China	Prospective	Patients = 42 Relapse = 20	Treg/Th17 ratio was negatively correlated with relapse and positively with treatment response.
17.	Baculard et al.^[36]	2001	France	Retrospective	Patients = 17 Relapses = 04	Pulmlonary sarcoidosis in children.
18.	Kim et al.^[37]	1999	South Korea	Prospective	Patients = 16 Relapses = 04	ICAM-1 can be a predictor in sarcoidosis.
19.	Johns et al.^[8]	1999	USA	Retrospective	1967 Series: Patients = 60; Relapse = 30 1976 Series: Followed up = 146/192; Relapse = 102/146 Total: 36 males (18 white & 18 black); 67 females (13 white & 54 black); Relapses: 18 whites and 56 blacks.	A clinical series on sarcoidosis patients from a longitudinal retrospective data.
20.	Rizzato et al. ^[9]	1998	Italy	Retrospective	Patients = 702, Corticosteroids = 239 Treatment stopped = 82 Relapses = 30/82	Complete article details were not available.
21.	Gottlieb et al.^[10]	1997	Philadelphia	Historic, concurrent & prospective	Total patients = 337 Relapse (treated) = 76/103 Relapse (spontaneous remission = 10/118	The study showed a higher relapse rate in the patients treated with corticosteroids; either indirectly reflecting the disease severity or a steroid related delayed granuloma resolution.
22.	Wyser et al.^[38]	1997	South Africa	Prospective	Patients = 15 Relapses = 07	Cyclosporin in pulmonary sarcoidosis and outcomes.
23.	Hunninghake et al.^[11]	1994	US	Prospective	Patients = 37 Relapses = 05	Outcomes of treatment of sarcoidosis.
24.	Takada et al.^[39]	1993	Japan	Retrospective	Patients = 76 Relapses = 36	A study on the clinical course and prognosis of sarcoidosis.
25.	Prior et al.^[40]	1991	UK	Prospective	Patients = 25 Relapses = 06	Serum Interferon-gamma in pulmonary sarcoidosis & corticosteroids.
26.	Baumann et al.^[41]	1990	US	Retrospective	Patients = 15 Relapses = 10	Chest X ray correlation in sarcoidosis relapse.

Table 2

Definition of Relapse by various researchers
Study	Definition of relapse
Murata et al.^[29] 2021, Japan	Reappearance of former signs or symptoms after remission, such as BHL or parenchymal infiltration on chest X-rays or chest CT scans, or appearance of dyspnea or dry cough Exacerbation: Sudden worsening of stable disease, or increased frequency of symptoms.
Nath et al.^[30] 2019, India	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 24h urinary calcium.
Mañá J et al.^[34] 2017, Barcelona, Spain	Reappearance of the disease during the decreasing phase or until 2 years after the suppression of treatment. Recurrence was defined as the reappearance of the disease after at least 1 year of spontaneous remission.
Liu Y, Q. et al^[35]. 2016, China	Clinical or radiological recurrence after treatment withdrawal.
Gottlieb JE et al.^[10] 1997, Philadelphia	Return of clinical manifestations severe enough to warrant treatment, following a sustained (longer than 1 month) remission of symptoms without administration of corticosteroids. Relapse were identified from the induced remission and spontaneous remission.

Primary outcome (Relapse in sarcoidosis)

A clear definition of relapse was used in five studies, while the rest of the studies used recurrence of symptoms after stopping treatment, which was considered presumed relapse. The prevalence of relapse in sarcoidosis varied from 11–67%, with a pooled prevalence of 0.34 (95% confidence interval 0.28–0.40)

Subgroup analysis:

Gender: In eight studies, data for gender was available for relapse in males and females, one author KM gave the data on request by e-mail communication. Apparently, the prevalence of relapse was higher in females than males, there were 226 relapses out of 724 female sarcoidosis 0.32 (0.23–0.42) 126 relapses out of 445 male sarcoidosis 0.26 (0.16–0.36). Risk difference between the two groups was 0.05(95% CI: -0.01-0.11, p = 0.09) Although, there was no significant difference between the two groups, p-value was approaching significance. (Fig. 3)

Age: Mean age of the relapse groups was 45.94 years (SD 10.87) vs No-relapse 46.02 years (SD 11.46). There was also no significant difference between the age of the relapse group and the patients without relapse. (Fig. 4)

Other factors: We performed a univariate subgroup analysis by calculating the pooled prevalence of relapse in the following: black vs white, setting of the study: Eastern vs Western part of globe, retrospective vs prospective or ambispective and studies after 2000 AD vs before 2000 AD. Although only two studies provided information on ethnicity, relapses were more common in blacks than in white individuals [0.72 (0.65–0.79) vs [0.27 (0.20–0.34), p = 0.00] (Fig. 5). However, there was no statistically significant difference in the pooled prevalence across other subgroups. (Fig. 6)

Heterogeneity and publication bias:

There was significant heterogeneity for the primary outcome, with an I² value of 91.6%, H² 11.92 Q (25) = 402.04, p = 0.00. The visual inspection of funnel plot did not reveal any publication bias as it was symmetrical. (Fig. 6) The statistical tests did not reveal any publication bias (Begg-Mazumdar: Kendall’s tau = 0.10, P = 0.48; Egger’s intercept = 2.83 (95% CI: -0.62 to 6.28), p = 0.10)

Sarcoidosis relapse may be defined as the recurrence of clinical complaints after a definite remission of variable time with or without radiological changes that may warrant the reinitiation of treatment. (Table 2) Disease relapse may be associated with increased serum ACE, serum calcium and 24hour urinary calcium levels. As evident in our meta-analysis, sarcoidosis relapses are common, as these have a pooled prevalence in about one-third of treated patients. The clinical course of PS is heterogeneous and variable, ranging from an asymptomatic self-remitting disease to a symptomatic chronic disease with fibrosis and dysfunctions of the lungs and other involved organs, leading to impaired quality of life (QoL) and fatal conditions or even death.^{[42, 43]} These patients with chronic disease require treatment to prevent organ dysfunction/damage or death and to improve or maintain QoL. Glucocorticoids (GC) (e.g., prednisolone) and GC replacement therapies such as cytotoxic agents (e.g., methotrexate) and biologics (e.g., infliximab) are commonly used for the treatment of PS patients.^{[2, 44, 45]} These relapses of PS occur within one year of treatment-induced remission and may be symptomatic (i.e., clinical relapse causing reappearance of sarcoid symptoms of lungs or other involved organs) or asymptomatic (i.e., radiological or biochemical relapse that causes worsening of radiological imaging and functional decline of the lungs or other involved organs but no clinical symptoms of the disease).^{[11, 46]} During a relapse, patients may have a recurrence of preexisting symptoms or laboratory findings and/or the appearance of new symptoms or laboratory findings of different etiology.^[47] Moreover, there is no standard definition or definitive test for the relapse of PS, so there is a need to evolve one.

Relapse may typically occur after one month to a year of tapering the therapy or its discontinuation. However, later relapses, even 2 to 3 years after stopping treatment, are also described. ^[8–10]

Relapse must be differentiated from progression, which has been defined as the worsening of symptoms such as dyspnea, fatigue, and other pulmonary or extrapulmonary complaints. There is a symptom-free period in relapse, which is lacking in patients with disease progression.

Available information reveals that in several instances individuals described labeled as “relapses” may not be true relapses but be an exacerbation or disease progression due to inadequate duration of treatment or in other words they could have not been in remission.

Relapse may be restricted to the lungs as a single organ isolated disease or may disseminate from the lungs to tissues and organs of other systems, including cardiovascular, nervous, gastrointestinal, renal, and bone marrow, as multisystem sarcoidosis.^[48–51] The patients usually have recurrence of specific symptoms such as cough, dyspnea, chest-tightness or pain, and a range of other disabling nonspecific symptoms (e.g., fatigue) depending upon the organ involvement.^{[52, 53]} The diagnosis of relapse in PS is established by disease-compatible clinical and radiological features, histologic evidence of non-necrotizing epithelioid cell granulomas in the lungs and other involved organs, and exclusion of other causes of granulomatous inflammation, including mycobacterial and fungal infections, malignancy, and drug-induced sarcoid-like reactions.^{[54, 55]} Recently, several biomarkers derived from target tissues or granuloma-forming inflammatory cells have been reported to support the diagnosis and prognosis of the disease, but their validity in routine diagnosis of relapse is yet to be demonstrated. They include angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL2R), chitotriosidase (CTO), neopterin, CCL18, hypercalcemia, and hypercalciuria.^[56–58]

The use of corticosteroids, however, is postulated to be a risk factor for sarcoidosis relapse.^[28] The process of granuloma formation in sarcoidosis has been conjectured to play an important role in clearing the triggering antigen.^[59] Therefore, an attempt to suppress immunity may result in the persistence of the responsible antigen and an increased probability of disease relapse following treatment discontinuation. In a retrospective observational study, it was found that a higher Scadding stage, presence of transaminitis, and fatigue in the patient were significantly associated with a higher relapse rate in univariate analysis. However, multivariate analysis showed fatigue as the single important factor that was statistically related to disease relapse.^[30] In a study conducted by Yi Zheng et al., a history of smoking (HR = 3.674 95% CI 1.573–8.581, P = 0.003) and higher circulating neutrophils (> 70%) (HR = 2.211, 95% CI 1.073–4.557, P = 0.032) were significant positive predictors of disease relapse in patients with pulmonary sarcoidosis who were treated with corticosteroids.^[31] Gottlieb et al. considered that symptomatic clinical manifestation in patients with sarcoidosis was the most important factor associated with sarcoidosis relapse, as many such patients may not present with significant radiological changes or changes in serum ACE levels. Additionally, no statistically significant association was observed between the duration of immunosuppression and the time to relapse. However, the study showed that the patients who were either asymptomatic and did not require immunosuppression or if symptomatic and had erythema nodosum or only upper airway sarcoidosis without pulmonary involvement had a good prognosis and fewer chances of relapse in comparison to the patients with hepatic, cardiac and neurological involvement, reflecting the higher severity of their disease.^[10]

Another clinical significance of relapse is that it leads to long term treatment. Long-term therapy is known in sarcoidosis. In a study by Baughman et al. from a follow-up of patients from the ACCESS group^[60], half of the patients who started therapy continued it, while only 10% of those who did not start therapy did so later.^[61]

Ethnic differences have been observed in response to treatment, two studies have reported difference between higher relapse rates in black.^{[11, 62]} However, in our subgroup analysis, we did not notice any significant differences as far as the eastern or western part of globe is concerned.

Currently, high-confidence remission establishment is an interesting area of research, and there is a need to develop an ideal biomarker that can demonstrate minimal residual disease. Identification of an ideal biomarker to monitor disease activity and documenting remission with high confidence and predicting relapses with biomarkers is an area of ongoing exploration. Different studies have evaluated using PET/CT scans to assess sarcoidosis treatment and predict relapses. This difference in response on PET between various studies can be attributed to the different drugs used and the varying durations of treatment.^[63] PET scans after treatment can predict future relapse risk, not clinical response. Patients who have a complete metabolic response have a lower risk of future relapses.^[64] Those without any response on PET scan have a lower risk of future relapses.^[65]

The major challenge in the management of these patients is the possibility of recurrent relapses after treatment cessation. Therefore, the role of frequent follow-ups is of utmost importance in the success of treatment.

A major limitation of our study is the significant amount of heterogeneity present in the studies. However, we used a random effect model to overcome this issue. The definition of relapse is also not uniform across various studies. A longitudinal retrospective or prospective long-term multicentric study of these patients will reveal insight into the unexplored course of the disease.

Conflict of interest: None

Ethical issues: Registration was obtained prior to the review.

Acknowledgement: Authors would like to acknowledge the encouraging inputs of Prof R. P. Baughman for initiating this review. We also personally thank Dr. Sahjal Dhooria and Dr. Karan Madan for providing additional information by e-mail communication. We thank our Senior Research Fellow Shivani Srivastava for arranging references and compiling EndNote libraries. I also thank Mohammad Haider for formatting the paper and tables.

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SUPPLEMENTARYTABLE1QUALITYSTUDYNOS.docx
Table S1: Newcastle Ottawa score (NOS) to assess the quality of the studies included in the systematic review of literature and meta-analysis

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Prevalence and Risk Factors of Relapse in Pulmonary Sarcoidosis: A Systematic Review and Meta-analysis

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INTRODUCTION

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Search Strategy:

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Study Selection:

Data Extraction:

Assessment of Quality, Publication Bias and Heterogeneity:

Statistical analysis:

RESULTS

Primary outcome (Relapse in sarcoidosis)

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Heterogeneity and publication bias:

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