The Convergence of Fibrosis and Granulomatous Inflammation: A Case Series on the Diagnostic and Therapeutic Challenges of Systemic Sclerosis and Sarcoidosis Overlap Syndrome

1. Introduction

Sarcoidosis is a multisystem disease of unknown etiology defined by multiple sterile noncaseating granulomas [1]. Almost any organ can be affected, however, lungs and mediastinal lymph nodes are by far most affected (> 90% of patients) visible on lung imaging as bilateral hilar lymphadenopathy and/or interstitial lung disease (ILD) [2]. Sarcoidosis can be associated with other autoimmune diseases as Hashimoto's thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, but the association with systemic sclerosis is rare [3,4]. In contrast to findings of mid- to upper-lobe interstitial lung disease (ILD) or/with hilar lymphadenopathy in sarcoidosis [5], the most common lung manifestation of systemic sclerosis is lower-lobe ILD, which is typically characterized by a nonspecific interstitial pneumonia pattern (groundglass opacities, traction brochiectasis, and honeycomb cysts) [6]. Distinction between lung involvement related to each disease is crucial due to different therapeutic approach.

2. Materials and Methods

2.1. Case Reports

Case 1

In 2014, a 31-year-old caucasian female presented with a three-year history of Raynaud’s phenomenon, arthralgias of the small joints of the hands, and progressive skin thickening involving the fingers, dorsal hands, and face. Immunological screening revealed high titers of anti-Scl70 antibodies (>200 UI/mL). Nailfold capillaroscopy demonstrated an "early" scleroderma pattern. While initial lung function tests (PFTs) were within normal limits, a baseline chest CT was not performed. The patient was diagnosed with systemic sclerosis (SSc) with limited cutaneous involvement and initiated treatment with calcium channel blockers and Methotrexate (10 mg/week). During annual surveillance three years later, a significant decline in pulmonary parameters was recorded: forced vital capacity (FVC) decreased from 101% to 91% of predicted, and DLCO fell from 82.8% to 71.5%. High-resolution computed tomography (HRCT) of the chest revealed bilateral ground-glass opacities in the lower lobes, consistent with a non-specific interstitial pneumonia (NSIP) pattern, alongside prominent bilateral hilar lymphadenopathy (Figure 1).

Laboratory investigations showed serum angiotensin-converting enzyme (ACE) levels at three times the upper limit of normal. Although the patient declined invasive diagnostic procedures (bronchoscopy and mediastinoscopy), a presumptive diagnosis of stage I sarcoidosis was made. A short course of low-dose prednisone (10 mg/day) was administered, resulting in the complete resolution of lymphadenopathy.

Seven years after the initial onset, the disease phenotype shifted to a rapidly progressive diffuse form. The modified Rodnan Skin Score (mRSS) increased from 15 to 32, accompanied by active digital ulcers, pitting scars, acro-osteolysis, and a transition to a "late" capillaroscopic pattern. Although PFTs were quite stable (FVC 91%, DLCO 69%), thorax CT revealed complete resolution of hilar adenopathies but extension of NSIP lesions (Figure 2).

Immunosuppression was switched to Mycophenolate Mofetil (2 g/day), and Bosentan (125 mg twice daily) was initiated for vasculopathy.

The clinical course was further complicated by an emergency admission for cardiac tamponade. Pericardiocentesis was performed, evacuating 1300 mL of serosanguinous fluid (negative for malignancy and infection). Due to a high risk of scleroderma renal crisis—driven by the diffuse skin subset, rapid mRSS progression, and anti-Scl70 positivity—high-dose glucocorticoids were avoided; the pericarditis was managed with non-steroidal anti-inflammatory drugs and colchicine.

Following continued progression of interstitial lung disease (ILD) into a fibrotic phenotype (honeycombing at the lung bases) (Figure 3) and persistent cutaneous activity, a multi-modal treatment escalation was implemented. The patient was started on: Rituximab: 1g every two weeks (two courses, six months apart) and Nintedanib: 150 mg twice daily as an anti-fibrotic agent.

Case2

A 40-year-old male, active smoker and construction worker, presented with a subacute onset of cough, exertional dyspnea, night sweats, and weight loss. Initial laboratory investigations revealed mild leukocytosis and a non-specific inflammatory syndrome. Despite multiple courses of empirical antibiotic therapy, his symptoms persisted. Initial PFTs were near-normal (FVC 91%, FEV1 80%). High-resolution computed tomography (HRCT) of the chest identified enlarged mediastinal and hilar lymph nodes, scattered bronchocentric micronodules (1–5 mm) in the mid-to-upper zones, and subpleural ground-glass opacities (Figure 4). Bronchoalveolar lavage (BAL) showed slight lymphocytosis, and a surgical wedge resection of a left lower lobe micronodule revealed only fibrosclerosis and anthracosis.

One year later, the patient developed acroparesthesia, inflammatory arthralgias, and skin thickening of the fingers, hands, and face (Figure 5). Immunological profiling confirmed high titers of anti-Scl70 antibodies (>200 UI/ml), and nailfold capillaroscopy showed an "early" scleroderma pattern. A diagnosis of systemic sclerosis (SSc) with limited cutaneous involvement was established. Radiographic incidental findings included a spotted bone pattern in the lower limbs, characteristic of osteopoikilosis (Figure 5). Treatment was initiated with Methotrexate (20 mg/week) and low-dose Prednisone (10 mg/day).

Figure 5. -A. Puffy hands with thickening of the skin in the fingers and dorsal part of the hands, B. Circumscribed sclerotic areas near the ends of the tibia and peroneum (osteopoikilosis) .

Figure 5. -A. Puffy hands with thickening of the skin in the fingers and dorsal part of the hands, B. Circumscribed sclerotic areas near the ends of the tibia and peroneum (osteopoikilosis) .

Despite therapy, PFTs demonstrated a decline to moderate restriction (FVC 59%, DLCO 66%). Repeated BAL showed significant lymphocytosis, and HRCT revealed persistent nodular infiltrates with emerging ground-glass opacities in the lower lobes. Following the self-discontinuation of glucocorticoids (GC) 18 months later, the patient experienced a severe flare characterized by painful red-blue subcutaneous nodules, worsening dyspnea, and a marked inflammatory syndrome (CRP 63 mg/dl). Follow-up CT (Figure 5) showed a significant increase in the size and number of paratracheal and hilar nodules. At this stage, serum ACE levels rose to five times the upper normal limit, confirming a diagnosis of stage II sarcoidosis complicating the underlying SSc. Glucocorticosteroids are restarted, Prednison 20mg/day.

Figure 5. Follow up thorax CT- symmetrical bronchocentric micronodular infiltrate, dense parenchymal opacification caused by conglomeration of nodules around the bronchovascular structures, mediastinal adenopathies.

Figure 5. Follow up thorax CT- symmetrical bronchocentric micronodular infiltrate, dense parenchymal opacification caused by conglomeration of nodules around the bronchovascular structures, mediastinal adenopathies.

Given the dual progression of skin involvement and interstitial lung disease (predominantly a non-fibrotic NSIP pattern), the immunosuppressive regimen was switched to mycophenolate mofetil. Under this regimen, the patient achieved stabilization of lung function and a partial regression of the lymphadenopathy and NSIP lesions at the one-year follow-up

Case 3

In July 2021, a 63-year-old male non-smoker with no relevant occupational exposure presented with persistent fever, dyspnea on mild-to-moderate exertion, cough, and joint swelling/arthralgia. High-resolution computed tomography (HRCT) of the chest revealed a bilateral reticulo-micronodular interstitial pattern accompanied by bilateral mediastinal and hilar lymphadenopathy.

Figure 6. Thorax CT - diffuse, roughly symmetrical distribution of micronodules throughout the lung parenchyma with a bronchocentric pattern, particularly noticeable in the mid and upper zones; in more central areas, there is dense opacification where these nodules have conglomerated around the bronchovascular structures.

Figure 6. Thorax CT - diffuse, roughly symmetrical distribution of micronodules throughout the lung parenchyma with a bronchocentric pattern, particularly noticeable in the mid and upper zones; in more central areas, there is dense opacification where these nodules have conglomerated around the bronchovascular structures.

Laboratory findings indicated an elevated inflammatory syndrome with a slightly increased ACE level. Initial bronchoscopy and bronchoalveolar lavage (LBA) were negative for malignancy and tuberculosis. Based on these findings, a diagnosis of stage II mediastino-pulmonary sarcoidosis was established. Systemic corticosteroid therapy (Medrol starting with 32mg/day) was initiated but discontinued after six months due to the development of a gastric ulcer.

In June 2022, the patient experienced a recurrence of fever, dyspnea, and polyarthralgia. HRCT imaging confirmed the return of the reticulo-micronodular pattern and mediastinal adenopathy. While transbronchial biopsy was inconclusive, a mediastinoscopy with lymph node biopsy was performed, providing histopathological confirmation of sarcoidosis (non caseating granuloma). Oral corticosteroid therapy (Medrol 32 mg) was reintroduced for a 12-month course. Symptoms improved, lung function tests remained stable but steroids tapering was associated with inflammatory arthralgias of the small joints of the hands; Methotrexate up to 20mg/week was added.

Between December 2023 and February 2024, the patient developed new clinical features, including sclerodactyly and Raynaud's phenomenon. Serological testing revealed positive antinuclear antibodies (ANA) and strongly positive anti-Scl-70 antibodies. Nailfold capillaroscopy demonstrated a "early” scleroderma pattern. HRCT revealed a change of pattern to a NSIP pattern with bilateral ground glass opacities distributed predominantly in the middle and lower lobes, primarily in the subpleural regions, thickening of the interlobular and intralobular septae, creating a net-like appearance and traction bronchiectasis.

Figure 6. Follow up CT – fibrotic NSIP pattern.

Figure 6. Follow up CT – fibrotic NSIP pattern.

A multidisciplinary review (pulmonology, rheumatology, radiology) determined the patient had diffuse cutaneous SSc with associated interstitial lung disease (SSc-ILD) exhibiting a fibrotic NSIP pattern. Due to several risk factors (male sex, age >60, diffuse cutaneous form, and Scl-70 positivity) for progression of ILD, a dual-action therapeutic regimen was initiated: Mycophenolate mofetil 2000 mg/day and Nintedanib (150 mg twice daily). Longitudinal pulmonary function tests (PFTs) showed relative stability: FVC: 2.68 L (65%) vs 2,54 l (63%), DLCO: 19.73 ml/min/mmHg (71%) vs 18,51 ml/min/mmHg (66%), 6-Minute Walk Test (6MWT) 580 m without desaturation.

Despite initial good follow-up, in the next two years the evolution was marked mostly by progressive severe visceral involvement related to systemic sclerosis. In may 2025 the capillaroscopic pattern progressed to a late one associated with multiple digital ulcers (Bosentan was added to the treatment). In september 2025 two sessions of endoscopic balloon dilation were for tight pyloro-bulbar stenosis. Despite stable fibrotic NSIP pattern on HRCT (Figure 7), lung function tests continue to decline.

Longitudinal cardiac monitoring revealed primary heart involvement: first the patient developed rthytm and conduction disturbancies (grade I atrioventricular block, premature ventricular beats ventricular and recurrent paroxistic supraventricular arrhtymias). NT-proBNP levels continue to increase in the next couple of months, echocardiography showed significant decrease of left and right ventricle systolic function, large pericardial effusion and mild pulmonary hypertension. Considering the aggressive evolution the multidisciplinary decision was to start off-label Rituximab.

4. Discussion

Sarcoidosis and systemic sclerosis are both multisystem disorders of unknown etiology. Sarcoidosis manifests as a noncaseating granulomatous disease affecting most commonly the lungs, skin and eyes, while systemic sclerosis is a connective tissue disorder characterized by cutaneous sclerosis, visceral fibrosis, and vasculopathy. The incidence of sarcoidosis is 50 to 400 per million per year [8] and the incidence of systemic sclerosis is 20 per million per year, so the likelihood of overlap disease is expected to be very low [7,8,9].

Interstitial lung disease is a common feature in both diseases and clinical, radiological, laboratory, and bronchoscopic differentiation may be difficult. Still, the thorax computed tomography can reveal distinct features [10]. Systemic sclerosis-ILD is typically a nonspecific interstitial pneumonia (NSIP) pattern with groundglass opacities, reticulation opacities, traction bronchiectasis and honeycomb cystic mainly in the lower lung zones [11]. In contrast, lung manifestations of sarcoidosis include bilateral hilar and mediastinal lymphadenopathy but may also involve beading or irregular thickening of the bronchovascular bundles, bronchial wall thickening, nodules along the bronchi, blood vessels, subpleural lesions, and mid- to upper-lobe-predominant groundglass opacities [12].

The differentiation of ILD related to each disease is important in terms of prognosis and therapy. Whereas SS-ILD may be progressive and fatal, lung involvement associated with sarcoidosis is more benign [10]. The lung involvement in sarcoidosis is treated based on the severity of symptoms. For asymptomatic patients with Stage 0 or I chest x-ray, therapy is not likely to offer benefits. Corticosteroids remain the initial drug of choice for treatment of parenchymal lung diseases. A starting dosage is 20-40 mg prednisone or its equivalent tapered at 3-6 months 10 mg of prednisone per day or less. The addition of a steroid-sparing agent, such as methotrexate, azathioprine or even anti-TNF can be individually considered based on the evolution. In more advanced involvements, use of corticosteroids (CS) and immunosuppressive (IS) drugs, antifibrotics are considered in cases of progressive phenotype [13]. However, treatment decision of SS-ILD is influenced by baseline and clinically meaningful changes in PFT values, the extent of ILD or fibrosis on HRCT, the presence of respiratory symptoms and the potential risk factors for progression. Therapeutic options include IS as Mycophenolate, Cyclophosphamide, antifibrotic therapies as Nintedanib can be used alone or in combination with Mycophenolate. Although off-label, several open-label studies and meta-analysis 20 studies support the beneficial effects of rituximab. FDA has also approved the use of Tocilizumab for SS-ILD [14]. Finally, there is a strong recommendation against the use of GC for the SS-ILD treatment [15].

The pathogenesis of sarcoidosis and systemic sclerosis is complex but some differences in immune system activation can be underlined. Sarcoidosis is a T-helper 1-(Th1)- mediated disease that results in noncaseating epithelioid cellular granuloma formation [16]. CD4+ T-lymphocytes have been identified in the tissues of patients with sarcoidosis and appear to be most concentrated within the granulomatous lesion [17]. Th1 cytokines, interferon- (IFN) λ and interleukin- (IL-) 2, are elevated in sarcoidosis, while T-helper 2 (Th2) cytokines, IL-4 and IL-5, are decreased [18]. The complex pathophysiology of systemic sclerosis varies based on the stage of the disease. The endothelial cell dysfunction is the initial event, followed by immune system activation [19]. Early and active stages of systemic sclerosis are a result of the Th2 pathway, with progression of the disease believed to result from damage of the endothelial lining in small blood vessel walls leading to impaired circulation and subsequent tissue hypoxia and collagen deposition from the activated resident fibroblasts [20]. While this foundation of systemic sclerosis and sarcoidosis pathophysiology is significantly different, both conditions have demonstrated commonalities with regard to cytokines, for example IL-6 was found to be elevated in the bronchoalveolar lavage fluid of patients with active sarcoidosis [20] and also in systemic sclerosis [21,22]. Fibrosis is also a pathologic attribute shared by both systemic sclerosis and sarcoidosis, with multiorgan involvement in systemic sclerosis and a more localized lung fibrosis in patients with sarcoidosis [22,23]. In sarcoidosis, a promoter polymorphism, −765G>C, has demonstrated an association with lung fibrosis onset [24]. Both conditions share high TGF-β1 expression. In patients with sarcoidosis levels of TGF-β1 are increased in peripheral blood lymphocytes and bronchoalveolar cells in sarcoidosis patients [25]. The cytokine TGF-β1 induces COX-2 expression through smad signaling pathways and is known to drive fibrosis in systemic sclerosis [26]. TGF-β2 and TGF-β3 gene polymorphisms have been implicated in cutaneous fibrosis of systemic sclerosis [27] with similar findings demonstrated by Kruit and colleagues in a four-year follow-up of sarcoidosis patients developing pulmonary fibrosis when bearing a genetic variation of TGF-β3 [28].

A comprehensive review of the literature, conducted through the PubMed database using the keywords “systemic sclerosis” (AND) “sarcoidosis” identified twenty-four relevant articles reporting cases of overlap syndrome between these two conditions, with a total of thirty-five patients [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. This association appeared more frequently in females, as evidenced by a female-to-male ratio of 2.57:1, and with a mean age at diagnosis of 52.25 years, based on twenty-four cases where age was available, with male patients having a mean age of 41.8 years and female patients averaging 56.5 years at diagnosis. Regarding the temporal sequence of disease onset, systemic sclerosis preceded sarcoidosis in fifteen cases (44.11%), sarcoidosis was diagnosed before systemic sclerosis in thirteen cases (38.23%), while in six patients (17.6%) both diseases were diagnosed concurrently. As for the subtype of systemic sclerosis, the limited cutaneous form was identified in twelve patients and the diffuse cutaneous form in eleven, though in some cases this information was not specified. Six patients had anti-centromere antibodies, eight had anti-Scl-70 antibodies, and six had various other autoantibodies including Ro, Ka [29], TIF-1 γ [30], U1-RNP [31], AMA-2 [32], while two patients tested negative for antinuclear antibodies [33], and two articles did not mention immunological profiles. Pulmonary involvement was present in twenty-five patients and was attributed either to sarcoidosis, systemic sclerosis, or both conditions. Sarcoidosis manifested as bilateral hilar lymphadenopathy in sixteen cases and upper-lobe interstitial lung disease in ten, while systemic sclerosis-related lung involvement appeared in fourteen patients as interstitial disease characterized by honeycombing and ground-glass opacities, and notably, no cases were reported without any pulmonary involvement.

Given the extensive time frame covered by these case reports, from 1979 to 2022, therapeutic approaches varied widely, with corticosteroids being the most commonly administered treatment, used in eleven patients either alone or in combination with immunosuppressive agents such as Azathioprine (three cases) [34,35,36], Mycophenolate mofetil (one case) [37], and Cyclophosphamide (one case) [38]; treatment data were not available in nine articles.

It is important to note that several articles lacked complete clinical data, with age being unreported in two cases [39,40], sex in another two [40,41], pulmonary involvement unspecified in two cases [39,40], systemic sclerosis subtype omitted in three reports [9,15,16], autoantibody profiles absent in two [40,41], and treatment details not provided in eight of the articles reviewed [30,32,40,41,42,43].

Each of the three cases presented has certain particularities. The first one is a young female, with the onset of scleroderma before sarcoidosis similar as most of the cases reported in the literature. Although sarcoidosis was not confirmed on biopsy of the lymph nodes, high ACE levels, the presence of mediastinal adenopathies pointed to the diagnosis of stage 1 sarcoidosis with complete remission after a short corticosteroids. Regarding systemic sclerosis evolution, we notice the late exacerbation of skin thickening, along with progression of interstitial lung disease and cardiac tamponade despite immunosuppression with mycophenolate.

The second case a male with the onset of sarcoidosis before systemic sclerosis, similar to most of the reported cases. Although the initial HRCT was highly suggestive of sarcoidosis (showing both hilar adenopathy, micronodules and interstitial changes), yet the diagnosis was initially missed because the ACE levels were normal and lymph node biopsy was not typical. The final diagnosis of sarcoidosis was revealed by the erythema nodosum lesions associated with high ACE levels after glucocorticoids were tapered. With the onset of systemic sclerosis, the pattern of lung involvement changes, associating the nodular ILD pattern with that of cellular NSIP, involving both the upper and lower lobes. The therapeutic challenge in order to choose the aproppiate immunosuppression was to decide which of the two autoimmune diseases was predominant in the lungs. We also closely monitored creatine levels and hypertension due to corticosteroids use as the patient had several risk factors for scleroderma renal crisis (male, anti topo1 antibodies). Another major particulary is the association of osteopoikilosis.

In the third case the diagnosis of sarcoidosis was confirmed by lymph node biopsy. Initially the patient had only mediastinal involvement with good response to steroids, but flared after stopping steroids due to side effects, along with the interstitial involvement. Systemic sclerosis onset was while patient was on treated with steroids and MTX and the evolution was very aggressive with diffuse skin involvement, digital ulcers, musculoarticular, gastrointestinal , lung and heart involvement. We consider that lung involvement was related to both diseases, with continuos progression despite imunosupression, corticosteroids, antifibrotics. Heart involevement was also problematic as it could have been related to scleroderma but also to sarcoidosis, albeight rare.

The three cases presented illustrate the clinical heterogeneity and the intricate temporal relationship between systemic sclerosis and sarcoidosis. While both are multisystemic diseases characterized by immune dysregulation, their coexistence creates unique diagnostic and therapeutic challenges.

4.1. Temporal Patterns of Onset

The chronological appearance of the two diseases in our series reflects the variability documented in the literature:

Case 1 followed the more frequent pattern where SSc precedes sarcoidosis. Although histological confirmation was not obtained, the clinical triad of high ACE levels, mediastinal lymphadenopathy, and a prompt response to low-dose corticosteroids strongly supports a diagnosis of Stage I sarcoidosis.

Cases 2 and 3 demonstrated the opposite sequence (sarcoidosis preceding SSc). In Case 2, the diagnosis was initially elusive due to normal ACE levels and a non-specific initial biopsy (anthracosis). The diagnosis was only unmasked by a flare—manifesting as erythema nodosum and significantly elevated ACE—following glucocorticoid tapering.

4.2. Pulmonary Involvement: A Hybrid Challenge

Determining the predominant driver of lung pathology was a central challenge.

In Case 2, the imaging evolved into a hybrid pattern, merging the bronchocentric micronodules of sarcoidosis with the cellular NSIP pattern of SSc. This necessitated a careful balance of immunosuppression to address both granulomatous and fibrotic processes.

In Case 3, the lung involvement was particularly refractory, with continuous progression despite combined treatment with immunosuppressants, corticosteroids, and antifibrotics, suggesting a synergistic detrimental effect of the two diseases.

4.3. Cardiac and Renal Risk Management

The management of systemic complications provided the most critical clinical hurdles:

Cardiac Involvement: Both case 1 and 3 were complicated by life-threatening cardiac tamponade, a rare complication for systemic sclerosis. Case 3 presented also features suggestive for SSc-related cardiomyopathy. None of the reported cases describes these visceral involvement in such overlap cases.

Renal Safety: In all cases, the use of glucocorticoids (GC) required vigilant monitoring. For Case 2, the combination of male sex, anti-Scl70 antibodies, and GC use created a high-risk profile for Scleroderma Renal Crisis (SRC), necessitating strict control of blood pressure and creatinine levels.

4.4. Unique Phenotypic Features

Case 2 is particularly noteworthy for its association with osteopoikilosis, a rare bone dysplasia. While generally benign, its presence alongside an SSc-sarcoidosis overlap adds to the rarity of this clinical triad.

Case 3 represents a highly aggressive phenotype, with the onset of SSc occurring while the patient was already receiving steroids and methotrexate. This case demonstrated rapid multisystemic deterioration (GI, digital ulcers, and cardiac involvement), suggesting that sarcoidosis might, in some instances, precede or even mask a particularly malignant form of SSc.

5. Conclusions

The coexistence of systemic sclerosis (SSc) and sarcoidosis represents a rare overlap that challenges conventional diagnostic and therapeutic paradigms. Clinicians must maintain a high index of suspicion for sarcoidosis when atypical hilar lymphadenopathy or elevated ACE levels appear in SSc patients. Conversely, an initial diagnosis of sarcoidosis should not preclude monitoring for systemic autoimmune features, as respiratory symptoms can precede skin involvement by years. Managing this overlap requires a delicate balance. While sarcoidosis often demands glucocorticoids, the inherent risk of scleroderma renal crisis—exacerbated by high-dose steroids and anti-Scl70 positivity—necessitates the use of steroid-sparing agents. Success in managing such patients depends on a coordinated effort between rheumatologists, pulmonologists, and cardiologists to navigate life-threatening complications . In summary, the SSc-sarcoidosis overlap is a high-risk phenotype. Early recognition and a personalized, aggressive therapeutic approach are essential to alter the natural history of these two converging fibrotic and granulomatous processes.