Abstract
Background
Familial sarcoidosis, a rare form of sarcoidosis involving multiple affected family members, is associated with a genetic predisposition.
Aim
This retrospective cohort study aimed to compare the clinical features, organ involvement, treatment and outcomes between familial and sporadic sarcoidosis in a well-defined Finnish population.
Methods
Data from 1130 patients with confirmed sarcoidosis diagnosed between 2008 and 2022 at Oulu University Hospital and Oulaskangas Hospital were analysed. Familial sarcoidosis was defined as disease occurring in at least one first-degree, second-degree or third-degree relative. Clinical characteristics, medication use and pulmonary function were compared between familial (n=68) and sporadic (n=1062) cases, with additional sex-specific analyses performed.
Result
Familial sarcoidosis accounted for 6.0% of all confirmed cases and was more common in women and first-degree relatives. Compared with sporadic cases, familial sarcoidosis was associated with higher rates of ocular and renal involvement and more frequent multiorgan disease. Thoracic manifestations were equally common in both groups and pulmonary function over time was comparable between familial and sporadic sarcoidosis. Within the familial group, women had a trend towards more diverse extrapulmonary manifestations whereas men more frequently presented with concurrent pulmonary and lymph node involvement. There were no major sex-specific differences between familial and sporadic sarcoidosis patients.
Conclusion
These findings indicate that familial sarcoidosis in the Oulu region constitutes a clinically recognisable subtype within the disease spectrum, warranting systematic family history assessment and further clinical and genetic research.
Keywords: Sarcoidosis, Systemic disease and lungs
WHAT IS ALREADY KNOWN ON THIS TOPIC
Familial clustering of sarcoidosis is well established and supports a genetic contribution to disease susceptibility, but prior studies have reported inconsistent findings regarding clinical differences between familial and sporadic forms.
WHAT THIS STUDY ADDS
In a large Finnish cohort, familial sarcoidosis accounted for 6% of all cases and was associated with more frequent ocular and renal involvement, higher prevalence of multiorgan disease and a trend towards more common medication use.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings suggest that familial sarcoidosis represents a clinically recognisable subtype within the disease spectrum, underscoring the importance of systematic documentation of family history and providing a basis for future genetic and translational studies on disease susceptibility and behaviour.
Introduction
Sarcoidosis is a multisystem granulomatous inflammatory disease characterised by non-caseating granuloma formation, most commonly affecting the lungs, lymph nodes, skin and eyes. Although the specific aetiology remains unknown, both environmental exposure and genetic predispositions are thought to contribute to disease development.1–3
Familial aggregation of sarcoidosis has been consistently reported across diverse populations. In Finland, studies from the 1950s through the 1980s documented familial cases in 3.6% to 4.7% of patients, with similar rates noted in Japan.4 More recent registry-based research from Sweden estimated a fourfold increased risk among first-degree relatives and a heritability of approximately 39%.2 Twin studies further support a strong genetic component: concordance was 14.8% in monozygotic twins compared with 1.2% in dizygotic twins, with an estimated heritability as high as 66%.1
The ACCESS (A Case–Control Etiologic Study of Sarcoidosis) study in North America confirmed familial clustering as a significant risk factor in both White and African American patients.5 A recent international systematic review reported a familial prevalence of 9.5%, with heritability ranging from 60% to 70% across ethnic groups.6
Despite evidence supporting heritability, the clinical characteristics distinguishing familial sarcoidosis from sporadic sarcoidosis remain poorly defined. In Finland, Pietinalho et al reported similar disease manifestations between groups, although familial cases presented slightly worse radiographic outcomes.4 In France, Pacheco et al reported a younger age at diagnosis, higher rates of pulmonary and cutaneous involvement, less frequent treatment and slower clinical recovery among familial cases.7 Smaller studies from Spain and the United States have also suggested phenotypic variation, including an increased frequency of Löfgren syndrome and ocular or hepatic involvement in familial cases.8 9
Sex-related differences in sarcoidosis have been described, including variations in disease presentation, organ involvement and prognosis.10 However, whether such differences exist within familial sarcoidosis or differ between familial and sporadic forms of the disease has not been well established.
Finland has a tax-funded universal healthcare system that provides comprehensive public health services with nominal client fees for all residents. In Finland, patients with suspected sarcoidosis or recurrence of previously diagnosed disease are referred from primary care settings, including public, occupational and occasionally private services, to public central or university hospitals for specialised diagnostic evaluation and treatment planning. Recent registry data from Finland report a stable incidence of 17 to 19 sarcoidosis cases per 100 000 adults annually, with the prevalence increasing from 85 per 100 000 in 2012 to 106 per 100 000 in 2022.11 Notably, multiorgan involvement increased from 11% to 34% over this period, whereas isolated pulmonary disease became less common. Despite these trends, contemporary data on familial sarcoidosis in Finland remain limited. The current study aims to address this gap by characterising familial sarcoidosis and comparing its clinical features, treatment and outcomes with those of sporadic cases, and to explore potential sex-related differences within and between these groups in a well-defined population.
Methods
Data collection
This retrospective cohort study included patients with sarcoidosis treated at Oulu University Hospital and Oulaskangas Hospital between 2008 and 2022. Patients were identified from electronic medical records via the International Classification of Diseases, 10th Revision (ICD-10) code D86.X, encompassing all sarcoidosis-related diagnoses. A total of 1341 patients with a primary or secondary sarcoidosis diagnosis were initially identified, of whom 1130 met inclusion criteria following a comprehensive review of electronic medical records. A study flowchart is provided in figure 1. Patients were excluded if clinical data were insufficient for evaluation, including cases with unavailable medical records or lack of sarcoidosis-specific clinical information in patients whose follow-up had been transferred to other hospital districts.
Figure 1. Flowchart of patient selection. ICD-10, International Classification of Diseases, 10th Revision.
Clinical data were collected via a structured data collection form. Investigators had full access to hospital electronic medical records for all eligible patients. The evaluation of sarcoidosis diagnosis, medication and organ manifestations was based on all data recorded in medical records and was not limited to fixed or predefined time points. The variables recorded included age at first hospital contact, sex, body mass index, smoking status at diagnosis and follow-up duration for all patients, and for those whose treatment in secondary care had been completed, organ involvement, sarcoidosis-related medication, clinical and radiological improvement, number of affected relatives, degree of kinship (first-, second-, or third-degree relative), and relationship to the patient. Patients were classified as having familial sarcoidosis if they had a confirmed diagnosis and ≥1 physician-documented relative with sarcoidosis.
Sex-stratified analyses comprised comparisons between men and women within familial sarcoidosis, along with separate between-group comparisons among men and among women (familial vs sporadic), to assess sex-specific differences in clinical characteristics and outcomes.
The follow-up time was calculated from the first visit to specialised care to the last recorded follow-up, with data updated in June 2025. Data were manually verified, de-duplicated and cross-checked against original records.
Pulmonary function testing
Pulmonary function tests (PFTs) included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁), the FEV₁%/FVC ratio and the corrected diffusing capacity for carbon monoxide (DLCO). Percent-predicted PFT values were based on contemporaneous Finnish reference values.12 13 PFT data were available from most patients with thoracic manifestation of sarcoidosis. These data were recorded at diagnosis and at the final follow-up. The interval between the first and last PFTs was measured in years.
Ethical considerations
This retrospective study is part of the Sarcoidosis Research Project (protocol number 38/2024). A research permit (10 February 2024) and healthcare data permit (19 March 2024) were granted by the Research Services Unit of the well-being Services County of North Ostrobothnia. No subject contact or interventions were involved. According to Finnish law (Medical Research Act 488/1999), ethics committee approval was not required; this was confirmed by the Chair of the local Research Ethics Committee. The study complied with EU General Data Protection Regulation (EU 2016/679) and national data protection legislation.
Statistical analysis
Statistical analyses were performed via IBM SPSS Statistics, V. 29.0 (IBM Corp., Armonk, NY). Categorical variables were compared via the χ² test or Fisher’s exact test, as appropriate. Continuous variables were assessed via independent-samples t-tests or paired-samples t-test when normally distributed (Shapiro-Wilk test); otherwise, the Mann-Whitney U test was applied. A two-tailed P value<0.05 was considered statistically significant.
Flow diagrams were generated via Lucidchart (Lucid Software Inc., South Jordan, UT).
Patient and public involvement statement
Patients or the public were not involved in the design or conduct, or reporting or dissemination plans of this research.
Results
This retrospective cohort included 68 patients (6.0%) with familial sarcoidosis and 1062 patients with sporadic sarcoidosis identified from the electronic medical records of Oulu University Hospital and Oulaskangas Hospital. The clinical characteristics of both groups are summarised in table 1. Among the familial cases, 55 patients (80.9%) had a first-degree relative with sarcoidosis, most frequently a mother-child relationship (32.4%) (online supplemental e-Table 1), and 20 patients (29.4%) reported ≥2 affected relatives.
Table 1. Clinical characteristics of patients with familial and sporadic sarcoidosis.
| Characteristics | Familial N=68 |
Sporadic N=1062 |
P value |
|---|---|---|---|
| Age (y) at diagnosis | 48.8±13.9 | 51.3±13.8 | 0.100 |
| Sex (male) | 28 (41.2) | 482 (45.4) | 0.499 |
| BMI at diagnosis, median (IQR)* | 26.8 (23.9–31.0) | 27.7 (24.6–31.1) | 0.250 |
| Smoking† | |||
| No smoking | 47 (69.1) | 650 (64.2) | 0.409 |
| History of smoking | 12 (17.6) | 219 (21.6) | 0.439 |
| Active smoking | 9 (13.2) | 144 (14.2) | 0.822 |
| Follow-up -time (y), median (IQR)‡ | 3.5 (2.0–8.5) | 2.9 (1.7–6.0) | 0.020 |
| Follow-up <2 y | 18 (26.5) | 336 (31.6) | 0.373 |
| Follow-up 2–5 y | 26 (38.2) | 401 (37.8) | 0.937 |
| Follow-up >5 y | 24 (35.3) | 324 (30.5) | 0.407 |
| Follow-up -time (treatment completed) (y), median (IQR)§ | 3.4 (1.8–7.4) | 2.6 (1.5–5.2) | 0.041 |
| Manifestation | |||
| Lungs and lymph nodes | 44 (64.7) | 630 (59.3) | 0.380 |
| Lymph nodes | 18 (26.5) | 248 (23.4) | 0.557 |
| Eyes | 14 (20.6) | 99 (9.3) | 0.003 |
| Skin | 11 (16.2) | 202 (19.0) | 0.561 |
| Kidneys | 8 (11.8) | 54 (5.1) | 0.019 |
| Lungs | 4 (5.9) | 69 (6.5) | 1.000 |
| Liver | 4 (5.9) | 30 (2.8) | 0.143 |
| Spleen | 4 (5.9) | 69 (6.5) | 1.000 |
| Heart | 3 (4.4) | 95 (8.9) | 0.266 |
| Joints | 5 (7.4) | 90 (8.5) | 0.747 |
| Bones | 2 (2.9) | 13 (1.2) | 0.227 |
| Organ involvement (No.) | |||
| 1 | 15 (22.1) | 235 (22.1) | 0.989 |
| ≥ 2 | 53 (77.9) | 827 (77.9) | 0.989 |
| ≥ 3 | 29 (42.6) | 311 (29.3) | 0.020 |
| On medication for sarcoidosis | 40 (58.8) | 525 (49.4) | 0.133 |
| Medication for pulmonary sarcoidosis | 25 (36.8) | 308 (29.0) | 0.173 |
| Medication for extra-pulmonary sarcoidosis | 23 (33.8) | 285 (26.8) | 0.210 |
| Sarcoidosis medication | |||
| Oral corticosteroid | 38 (55.9) | 472 (44.4) | 0.057 |
| Inhaled corticosteroid | 8 (11.8) | 82 (7.7) | 0.233 |
| Methotrexate | 5 (7.4) | 52 (4.9) | 0.383 |
| Azathioprine | 3 (4.4) | 19 (1.8) | 0.142 |
| Infliximab | 1 (1.5) | 11 (1.0) | 0.527 |
| Other | 0 | 39 (3.7) | 0.165 |
| Time on medication (m), median (IQR)¶ | 20.8 (9.9–45.3) | 17.1 (9.3–32.1) | 0.478 |
The data are presented as the number (%) or mean±SD unless otherwise indicated.
Data from 51 patients with familial sarcoidosis and 688 patients with sporadic sarcoidosis.
Data from 68 patients with familial sarcoidosis and 1013 patients with sporadic sarcoidosis.
Data from 68 patients with familial sarcoidosis and 1061 patients with sporadic sarcoidosis. Includes patients whose treatment continues in specialised care.
Data from 55 patients with familial sarcoidosis and 836 patients with sporadic sarcoidosis. Includes patients whose treatment in secondary care has been completed.
Data from 23 patients with familial sarcoidosis and 237 patients with sporadic sarcoidosis.
BMI, body mass index; y, years.
Most sarcoidosis diagnoses were biopsy-confirmed (64.7% familial vs 58.4% sporadic). With the remaining patients, diagnosis was established by the treating physician based on a combination of clinical presentation, laboratory results, imaging findings and supportive investigations in accordance with standard clinical practice. The follow-up time was significantly longer in the familial group in all patients (3.5 vs 2.9 years; p=0.020) and in those whose follow-up in secondary care had been finished (3.4 vs 2.6 years; p=0.041) (table 1). A smaller proportion of sporadic patients had >5 years of follow-up compared with familial cases (30.5% vs 35.3%), although this difference did not reach statistical significance (p=0.407).
Organ involvement
Thoracic involvement represented the most common organ manifestation across both cohorts (table 1). The most frequent extrapulmonary manifestations were cutaneous and ocular involvement. Patients with familial sarcoidosis had significantly higher rates of ocular (20.6% vs 9.3%; p=0.003) and renal (11.8% vs 5.1%; p=0.019) involvement. No statistically significant differences were observed for hepatic, neurologic or other sites, although a non-significant trend was observed for increased liver and neurologic involvement among familial cases (table 1).
Multiorgan disease (≥3 organs) was more common in the familial group (42.6% vs 29.3%; p=0.020). The proportion of patients with isolated organ disease did not differ significantly (table 1).
Medication and treatment response
Medication use for sarcoidosis trended higher in the familial group, although the difference did not reach statistical significance (table 1). Especially the use of oral corticosteroids tended to be greater among patients with familial sarcoidosis than among sporadic cases (55.9% vs 44.4%; p=0.057). Inhaled corticosteroid use for sarcoidosis was relatively uncommon in both groups (11.8% vs 7.7%; p=0.233), and no statistically significant differences were found in the use of azathioprine, methotrexate or infliximab (table 1). Patients with familial sarcoidosis were more likely to receive treatment for both pulmonary (36.8% vs 29.0%; p=0.173) and extrapulmonary manifestations (33.8% vs 26.8%; p=0.210) compared with those with sporadic disease, although statistical significance was not reached.
PFT results and clinical and radiological outcomes are presented in table 2 and online supplemental e-Table 2. FVC and FEV₁ values remained largely stable over time in both familial and sporadic sarcoidosis, with no meaningful or consistent differences in change between the groups. In contrast, DLCO values showed a decline over time in both groups (table 2, online supplemental e-Table 2). The longitudinal decline in DLCO reached statistical significance only in sporadic subgroup of patients (online supplemental e-Table 2).
Table 2. Pulmonary function test (PFT) results and clinical and radiological improvement in patients with familial and sporadic sarcoidosis.
| Variable | Familial | Sporadic | P value | N familial | N sporadic |
|---|---|---|---|---|---|
| FVC | |||||
| Diagnosis (%) | 91.5±15.6 | 90.8±15.8 | 0.744 | 54 | 755 |
| Last follow-up (%) | 93.0±16.6 | 90.5±16.3 | 0.335 | 45 | 648 |
| Diagnosis (L) | 3.9±1.1 | 3.9±1.2 | 0.744 | 53 | 757 |
| Last follow-up (L) | 3.9±1.2 | 3.8±1.2 | 0.534 | 45 | 651 |
| Δ FVC (L) | 0.08±0.4 | −0.02±0.4 | 0.107 | 39 | 547 |
| FEV1 | |||||
| Diagnosis (%) | 91.9±14.5 | 89.0±17.2 | 0.159 | 54 | 760 |
| Last follow-up (%) | 93.2±15.2 | 88.9±17.6 | 0.109 | 46 | 653 |
| Diagnosis (L) | 3.2±1.0 | 3.1±1.0 | 0.744 | 54 | 760 |
| Last follow-up (L) | 3.1±1.0 | 3.0±1.0 | 0.345 | 45 | 653 |
| Δ FEV1 (L) | −0.06±0.4 | −0.04±0.4 | 0.769 | 40 | 550 |
| FEV1%/FVC | |||||
| Diagnosis | 80.5±6.7 | 78.3±7.8 | 0.142 | 52 | 726 |
| Last follow-up | 78.8±7.1 | 76.8±9.0 | 0.069 | 56 | 786 |
| DLCO | |||||
| Diagnosis (%) | 90.5±16.8 | 86.9±16.4 | 0.358 | 46 | 690 |
| Last follow-up (%) | 85.3±14.5 | 84.5±17.2 | 0.877 | 36 | 579 |
| Δ DLCO (%) | −4.1±12.8 | −1.5±11.4 | 0.230 | 29 | 453 |
| Period between PFTs (y) | 2.9 (1.7–6.6) | 2.4 (1.6–4.0) | 0.105 | 40 | 560 |
| Clinical improvement | |||||
| Follow-up | 24 (39.3) | 386 (43.5) | 0.529 | 61 | 888 |
| Last follow-up | 33 (63.5) | 476 (61.3) | 0.761 | 52 | 776 |
| Radiological improvement | |||||
| Follow-up | 17 (31.5) | 359 (46.0) | 0.038 | 54 | 780 |
| Last follow-up | 26 (56.5) | 456 (65.2) | 0.231 | 46 | 699 |
The data are presented as the means±SDs (SD) and median (IQR).
DLCO, corrected diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; PFT, pulmonary function test.
Clinical and radiological treatment responses from the 6–12 month follow-up to the last follow-up visit in both the familial and sporadic groups are presented in table 2. No statistically significant differences in clinical treatment response were observed between the groups. However, radiological improvement appeared to be less common in the familial group at the 6–12 month follow-up (31.5% vs 46.0%; p=0.038), although this difference was no longer evident at the final follow-up visit at secondary care (56.5% vs 65.2%; p=0.231) (table 2).
Sex differences
Among the patients with familial sarcoidosis (n=68), 40 were women (58.8%), and 28 were men (41.2%) (table 3).
Table 3. Clinical characteristics of patients with familial sarcoidosis by sex.
| Characteristics | Men N=28 |
Women N=40 |
P value |
|---|---|---|---|
| Age (y) at diagnosis | 45.4±13.5 | 51.1±13.9 | 0.099 |
| BMI at diagnosis, median (IQR)* | 27.8 (24.7–32.4) | 26.6 (23.2–29.0) | 0.310 |
| Smoking | |||
| No smoking | 17 (60.7) | 30 (75.0) | 0.210 |
| History of smoking | 5 (17.9) | 7 (17.5) | 0.970 |
| Active smoking | 6 (21.4) | 3 (7.5) | 0.146 |
| Follow-up -time (y), median (IQR) | 3.5 (2.1–8.3) | 3.7 (1.9–8.7) | 0.862 |
| Follow-up <2 y | 7 (25.0) | 11 (27.5) | 0.818 |
| Follow-up 2–5 y | 12 (42.9) | 14 (35.0) | 0.512 |
| Follow-up >5 y | 9 (32.1) | 15 (37.5) | 0.649 |
| Follow-up -time (treatment completed) (y), median (IQR)† | 3.5 (2.0–8.2) | 3.1 (1.7–7.3) | 0.657 |
| Manifestation | |||
| Lungs | 0 (0.0) | 4 (10.0) | 0.137 |
| Lymph nodes | 6 (21.4) | 12 (30.0) | 0.430 |
| Lungs and lymph nodes | 22 (78.6) | 22 (55.0) | 0.045 |
| Extrapulmonary manifestations | 12 (42.9) | 24 (60.0) | 0.163 |
| Organ involvement (No.) | |||
| 1 | 4 (14.3) | 11 (27.5) | 0.196 |
| ≥ 2 | 24 (85.7) | 29 (72.5) | 0.196 |
| ≥ 3 | 11 (39.3) | 18 (45.0) | 0.639 |
| On medication for sarcoidosis | 15 (53.6) | 25 (62.5) | 0.462 |
| Medication for pulmonary sarcoidosis | 10 (35.7) | 15 (37.5) | 0.881 |
| Medication for extra-pulmonary sarcoidosis | 5 (17.9) | 18 (78.3) | 0.020 |
| Sarcoidosis medication | |||
| Inhaled corticosteroid | 4 (14.3) | 4 (10.0) | 0.708 |
| Oral corticosteroid | 13 (46.4) | 25 (62.5) | 0.221 |
| Methotrexate | 0 (0.0) | 5 (12.5) | 0.073 |
| Azathioprine | 1 (3.6) | 2 (5.0) | 1.000 |
| Infliximab | 0 (0.0) | 1 (2.5) | 1.000 |
| Clinical improvement | |||
| Follow-up‡ | 14 (58.3) | 10 (27.0) | 0.040 |
| Last follow-up§ | 15 (71.4) | 18 (58.1) | 0.326 |
| Radiological improvement | |||
| Follow-up¶ | 9 (37.5) | 8 (26.7) | 0.304 |
| Last follow-up** | 14 (66.7) | 12 (48.0) | 0.203 |
The data are presented as the number (%) or mean±SD unless otherwise indicated.
Data from 21 men and 30 women.
Data from 23 men and 32 women.
Data from 24 men and 37 women.
Data from 21 men and 31 women.
Data from 24 men and 30 women.
Data from 21 men and 25 women.
BMI, body mass index; y, years.
Men more frequently presented with combined lung and intrathoracic lymph node involvement (p=0.045). Women had more diverse extrapulmonary involvement, including neurologic (12.5% vs 0.0%; p=0.073), hepatic (10.0% vs 0.0%; p=0.137), articular (10.0% vs 3.6%; p=0.642) and osseous (5.0% vs 0.0%; p=0.508) involvement, although statistical significance was not reached (online supplemental e-Table 3). The extent of multi-organ involvement (at least three organs) was slightly higher among women (45.0% vs 39.3%; p=0.639).
Women showed poorer short-term clinical response at 6–12 months (27.0% improved vs 58.3% in men; p=0.040), were more often treated for extrapulmonary disease (78.3% vs 17.9%; p=0.020) and had a trend towards more frequently requiring second-line therapies (methotrexate or other drug) (table 3). The proportion of patients receiving medication for pulmonary involvement did not differ significantly between the groups (37.5% vs 35.7%; p=0.881) (table 3).
Familial women appeared to exhibit a more systemic disease phenotype compared with sporadic women (online supplemental e-Table 4); involvement of three or more organs appeared more common among familial women, although the difference did not reach statistical significance (45.0% vs 32.2%; p=0.097). Renal manifestations were significantly more common in familial women (12.5% vs 3.8%; p=0.024). In addition, oral corticosteroid use was more frequent in familial women than in sporadic women (62.5% vs 45.2%; p=0.034). Follow-up duration also tended to be longer in familial women (median 3.7 vs 3.0 years; p=0.074).
Among men, clinical characteristics were largely comparable between familial and sporadic sarcoidosis subgroups (online supplemental e-Table 5). However, ocular involvement was significantly more frequent in familial men than in sporadic men (21.4% vs 7.5%, p=0.009). In addition, as with women, follow-up time showed a tendency to be longer in familial men compared with sporadic men (median 3.5 vs 2.8 years, p=0.139).
Discussion
This retrospective cohort study is among the first to comprehensively assess the clinical characteristics, treatment patterns, and outcomes of patients with familial sarcoidosis. Familial sarcoidosis was more common in women (58.8%) and predominantly occurred among first-degree relatives (80.9%). Compared with the sporadic group, patients with familial sarcoidosis had significantly higher rates of ocular and renal involvement and were more likely to present with multiorgan disease. The duration of secondary care-level treatment was longer, and oral corticosteroid use tended to be higher in the familial group. Pulmonary function results were comparable between familial and sporadic cases. According to sex-stratified analyses, women with familial sarcoidosis tended to have more diverse extrapulmonary involvement than men, while men more often presented with pulmonary and mediastinal lymph node disease than women.
Familial sarcoidosis accounted for 6.0% of the confirmed cases in this cohort, which is consistent with previous reports from Western populations (4%–10%).4–6 Sarcoidosis was more common in women, reflecting previously observed sex distributions.10 14 15 First-degree relatives comprised 80.9% of familial cases, reinforcing the strong familial clustering reported in earlier studies.6 14 Mother-child relationships were the most common familial pairings, in line with earlier findings.4 6 In contrast to some reports suggesting a predominance of like-sex or female-female pairs,6 14 we did not observe such a pattern.
Age at diagnosis in both sporadic and familial groups aligned with established trends, with peak incidence in the fourth and fifth decades.14 15 In our cohort, men were diagnosed earlier than women, a trend that was more pronounced in the familial group. This observation is consistent with data indicating a male predominance in early-onset disease,15 16 but may also reflect regional variation, as some studies have reported earlier onset in women.14 Differences in age at diagnosis between familial and sporadic groups were not statistically significant, likely due to sample size limitations.
Patients with familial sarcoidosis exhibited more complex systemic diseases than those with sporadic form. Ocular and renal involvement were significantly more frequent in familial cases, while hepatic and neurologic involvement trended higher but did not reach statistical significance—possibly reflecting limited power. Familial women showed more renal involvement, whereas familial men showed more ocular involvement, compared with sporadic cases. All hepatic and neurologic cases in the familial group occurred in women. Prior studies have yielded conflicting results: some reported greater ocular and pulmonary involvement in sporadic cases,7 whereas others observed ocular and hepatic disease in familial cohorts.9 While renal and neurologic involvement have not been specifically associated with familial sarcoidosis, neurologic disease has been reported more frequently in women.15 Notably, patients with familial sarcoidosis may have greater awareness of disease manifestations, potentially leading to earlier symptom reporting and increased detection of extrapulmonary involvement. These discrepancies underscore the need for additional studies examining population-specific disease phenotypes and underlying genetic factors.
In Finland, the incidence of multiorgan sarcoidosis has increased in recent decades, whereas the incidence of isolated pulmonary disease has declined.11 A study by Pöyhönen et al reported a sharp increase in clinically manifested cardiac sarcoidosis, from 5 cases in 1990–1994 to 268 cases in 2015–2019, highlighting evolving diagnostic practices and potential regional clustering.17 Our findings reinforce this trend, with significantly higher rates of multiorgan involvement (≥3 organs) observed in familial cases.
Despite more extensive systemic manifestations, familial patients did not have a greater need for medication for pulmonary sarcoidosis, and pulmonary function trajectories were comparable to those of patients with sporadic disease over time. This is in line with earlier studies that have not demonstrated major pulmonary function differences between familial and sporadic sarcoidosis.7
Treatment patterns reflected the more extensive systemic involvement observed in familial sarcoidosis. The use of immunosuppressive agents such as oral corticosteroids or second-line therapies showed a trend toward being more frequent, suggesting a greater need for therapeutic escalation in patients with multiorgan disease.18
In our cohort, systemic treatment followed a stepwise approach consistent with international practice and current guidelines, with glucocorticoids used as first-line therapy when indicated and conventional immunosuppressive agents introduced as steroid-sparing treatment when necessary. Consistent with reports from Spain and the United Kingdom, corticosteroids were the most common treatment in both familial and sporadic sarcoidosis.14 19 However, the use of second-line agents and biologic therapy was lower in our cohort than in the Spanish study, which may reflect differences in clinical practice, disease phenotype, or healthcare access.
Sex-specific analyses suggested some variation in clinical patterns within familial sarcoidosis; however, these differences were largely similar to those observed in sporadic sarcoidosis. Men more often presented at a younger age with pulmonary-dominant disease, whereas women showed a broader spectrum of extrapulmonary involvement, including neurologic and hepatic manifestations, and experienced poorer short-term clinical outcomes. These observations represent trends rather than statistically robust differences due to small sample sizes in our cohort. However, they are consistent with previous reports describing more frequent extrapulmonary involvement in women and earlier pulmonary presentation in men.10 16 20
Sex-stratified comparisons between familial and sporadic sarcoidosis further suggested a more systemic disease pattern among women with familial disease, whereas clinical characteristics in men appeared largely similar between familial and sporadic forms. In both sexes, patients with familial sarcoidosis tended to have longer follow-up times than their sporadic counterparts, which may reflect a more complex disease course even among familial men despite the absence of clear differences in systemic manifestations.
Further studies with larger cohorts are needed to clarify these associations. In addition, a prospective study design would enable more detailed assessment of acute phenotypes, such as Löfgren syndrome, as well as within-family comparisons among affected relatives.
The strengths of this study include its extended follow-up duration, comprehensive electronic medical record review and detailed documentation of familial relationships. However, the study has limitations, including its retrospective design, restricted two-hospital setting, possible underreporting or misclassification of family history and the moderate size of the familial subgroup, which may have reduced statistical power, particularly for rare organ manifestations, PFT changes, and sex-stratified analyses. Due to the retrospective study design and research permit restrictions, analyses of phenotypic similarities among affected relatives were not feasible in the present study and should be addressed in future prospective family-based studies.
Overall, familial sarcoidosis in the Oulu region is associated with a distinct clinical phenotype characterised by increased ocular and renal involvement and a greater multiorgan burden, which in turn is reflected in longer follow-up times and a tendency toward higher medication use. These findings suggest that familial sarcoidosis may constitute a clinically recognisable subtype within the disease spectrum, highlighting the importance of systematic documentation of family history and supporting further genetic and translational research into disease susceptibility and clinical behaviour.
Supplementary material
Footnotes
Funding: This work was supported by the Foundation of the Finnish Anti-Tuberculosis Association and the Research Foundation of Pulmonary Diseases. JL has received grants for the study group from the Foundation of the Finnish Anti-Tuberculosis Association, the Research Foundation of Pulmonary Diseases, the Tampere Tuberculosis Foundation and Northern Finland Health Care Support Foundation (Terttu Foundation). RK has received grants for the study group from a state subsidy of Oulu University Hospital.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Data availability free text: Due to ethical and legal restrictions related to patient confidentiality, the data underlying this study are not publicly available. Additional study materials are available from the corresponding author upon reasonable request.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethics approval: This retrospective study is part of the Sarcoidosis Research Project (protocol number 38/2024). A research permit (10 February 2024) and health care data permit (19 March 2024) were granted by the Research Services Unit of the Wellbeing Services County of North Ostrobothnia. No subject contact or interventions were involved. According to Finnish law (Medical Research Act 488/1999), ethics committee approval was not required; this was confirmed by the Chair of the local Research Ethics Committee. The study complied with EU General Data Protection Regulation (EU 2016/679) and national data protection legislation.
Data availability statement
Data are available upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available upon reasonable request.