Granulomas are compact inflammatory aggregates composed of immune and structural cells. They typically contain mature macrophages at the center, surrounded by scattered T cells, with fibroblasts encasing the whole structure. Evolutionary, granulomas serve to contain pathogens locally, preventing their dissemination and allowing efficient immune elimination, as seen in tuberculosis or schistosomiasis. In contrast, in non-infectious granulomas like sarcoidosis, no external or internal trigger has been identified, and the continuous inflammation causes tissue destruction and organ dysfunction [11].

Although the initiating factors remain unknown, several environmental exposures, such as mold, insecticides, building materials, mycobacteria, especially insoluble mycobacterial antigens, or the skin commensal Propionibacterium acnes, have been linked to disease onset [12]. Further, genetic susceptibility also plays a role, with variants in immune-related genes predisposing individuals to disease. Interestingly, interactions between genetic variants and environmental exposures suggest a multifactorial pathogenesis [13, 14]. Therefore, it is believed that the disease is triggered by a combination of environmental factors, genetic factors, and an imbalance in the immune system [Figure 1]. It is thought that impaired antigen clearance by macrophages may lead to their activation, recruitment of other immune cells, and, consequently, persistent granulomatous inflammation [15].

The initiating cellular events triggering granuloma formation remain unknown. However, pro-inflammatory macrophages are considered central (Figure 1). Activated by cytokines such as INF-gamma, TNF-alpha, GM-CSF, IL-12 and IL-23, they upregulate adhesion molecules, aggregate, and form epithelioid cells with interlocking cell membranes, which form the compact center of the granulomas. Ultimately, epithelioid cells can fuse to form multinucleated giant cells – a histological hallmark of sarcoidosis [16, 17]. While the function of giant cells in sarcoidosis remains unclear, they may have an enhanced phagocytic capacity [18]. Evidence from a sex-mismatched lung transplantation of one patient with refractory lung sarcoidosis suggests that granulomas consist largely of recipient-derived cells, highlighting the importance of peripheral immune cell recruitment for granuloma formation [19].

In chronic disease, macrophages may shift towards an M2-like phenotype under IL-13 influence, supporting tissue remodeling and later fibrotic processes [16, 20]. A growing body of literature implicates hyperactivation of the proteinkinase mammalian target of rapamycin [mTOR] in sarcoidosis. Activation of its complex mTORC1, one of the two main complexes of the enzyme mTOR and a potent repressor of autophagy, drives and maintains granuloma formation [21]. In murine models, myeloid-specific activation of mTOR induces sarcoidosis-like granuloma formation in multiple organs [22], and in human sarcoidosis high mTOR activity is observed in granulomas and granuloma-associated macrophages [20, 21]. This likely drives macrophage proliferation, reduced apoptosis and metabolic reprogramming promoting persistent granulomatous inflammation [22, 25, 26]. Sarcoid macrophages exhibit a certain hypermetabolic state, simultaneously upregulating oxidative phosphorylation, glycolysis, cholesterol metabolism and fatty acid oxidation – involved in energy generation, inflammation and cell survival – and the pentose phosphate pathway, which may support giant cell formation [15, 22, 23, 24].

Alongside macrophages, T cells play a pivotal role. Th17.1 cells accumulate in granulomas, producing INF-gamma, GM-CSF, TNF-alpha and IL-17 (Figure 1). They express Th1 receptors (CXCR3, CCR5, IL-12R, and IL-18R) and transcription factors (STAT1, STAT3, RORγt and TBX21), driving interferon production and macrophage activation. Interestingly, these granuloma-associated Th17.1 cells secrete lymphotoxin-beta (LTB) [17, 28], a cytokine that induces tertiary lymphoid structures in inflammatory or neoplastic conditions by activating fibroblasts and promoting angiogenesis, thereby recruiting additional immune cells from blood [29]. Granulomas thus share structural and functional similarities with tertiary lymphoid organs – organized aggregates of immune cells that arise in non-lymphoid tissues in response to chronic inflammation or cancer. However, in sarcoidosis, they fail to resolve the inflammatory process and instead perpetuate disease progression [17].

Structural cells also contribute significantly to chronic inflammation by supporting innate and adaptive immunity [30]. This is also reflected in the newest molecular analyses from sarcoidosis tissue [17, 28]. Fibroblasts encapsulate granulomas and serve dual roles: i) producing extracellular matrix components such as collagen and fibronectin, which can lead to tissue fibrosis in cases of persistent inflammation, and ii) acting as immune modulators by secreting cytokines and chemokines like CCL19, the ligand of CCR7 on T cells and activated macrophages (Figure 1). Thereby, fibroblasts organize the spatial distribution of immune cells in the granuloma. This cytokine-driven architecture reinforces the resemblance of sarcoid granuloma structures to aberrant tertiary lymphoid organs [17].

Although cutaneous sarcoidosis lesions can persist for years, granulomatous inflammation can also resolve spontaneously as a self-limiting form. This resolution is thought to result from a local shift in the balance between regulatory T cells (Treg) and Th17.1 cells toward Tregs, thereby restoring immune homeostasis [16].

Papules (Figure 2a) and nodules (Figure 2b, o) are the most frequent forms of cutaneous sarcoidosis. They manifest as firm, livid, brownish-red, skin-colored or hypopigmented, either grouped or disseminated, and typically non-scaly. These skin lesions may be limited to certain regions or affect the entire body surface. Larger indurated nodules may appear, often on the elbows [31, 32].

This variant manifests as firm, round to oval, movable nodules or hardened nodules with granulomas located in the subcutis. Lesions are typically located on the trunk and extremities and may appear hyperpigmented, erythematous, livid, or skin-colored [31, 32].

Plaques (Figure 2d–f) appear as livid to reddish-brown or skin-colored, sharply demarcated, round to oval lesions that are compact to indurated, with variable degrees of elevation and scaling. They most often occur on the trunk, back, face, shoulders, and arms [31, 32].

Lupus pernio (Figure 2g) is a disfiguring subtype of plaque sarcoidosis and manifests as shiny, scaly, livid-to-erythematous plaques on the nose or central area of the face. It is more common in women with darker skin types and is often associated with therapy-resistant systemic disease, requiring systemic immunosupression, for example with glucocorticoids and TNF-alpha inhibitors. Pulmonary and sinonasal involvement should be carefully monitored [31–33]. Angiolupid sarcoidosis (Figure 2n) is a clinical variant of lupus pernio with prominent telangiectasia formation that overlies the inflammatory lesions of the central face.

Ichthyosiform sarcoidosis is a much rarer form of cutaneous sarcoidosis and manifests as polygonal, brownish-white, scaly lesions with fissures, typically on the lower extremities [34]. Atrophic plaques with ulcerations can occur as another rare manifestation [35].

Papules, plaques, nodules, local edema, or lichenification can affect oral and genital mucous membranes [36, 37].

On the scalp, sarcoidosis can manifest as scarring (Figure 2l) or non-scarring alopecia [38], while nail destruction may occur as dystrophy or dactylitis [39, 40]. However, nail changes can be so diverse, presenting as onychodystrophies, atrophy or nail loss, that a clinical diagnosis is nearly impossible without histology showing sarcoid granulomas of the nail matrix [41].

Erythrodermic manifestations are characterized by large, indurated, brownish, reddish, or livid confluent plaques. These often exhibit fine superficial to coarse scaling [42].

Cutaneous sarcoidosis lesions may arise at sites of tattoos (Figure 2h, j), scars (Figure 2i), or trauma as painful, itchy, discolored papules or nodules. These changes sometimes appear years after the inciting event and can subsequently spread to other areas of the skin and even other organs. Scar sarcoidosis can mimic hypertrophic scars, keloid formation, or foreign body reactions. Biopsy and histopathological confirmation remain critical for distinguishing these entities [43, 44].

Löfgren syndrome, also referred to as acute sarcoidosis, is defined by the triad of erythema nodosum, bilateral lymphadenopathy, and polyarthralgia, often accompanied by fever. Erythema nodosum typically manifests as tender, livid to brownish subcutaneous nodules on the shins and is frequently associated with fever, joint pain, swelling, and leg edema. Histologically, it usually shows septal panniculitis without sarcoid granulomas. Thus, erythema nodosum represents a non-specific cutaneous lesion in sarcoidosis, occurring in up to 25% of patients. It reflects a reactive panniculitis rather than true granulomatous sarcoid lesions. In contrast, a variant called erythema nodosum-like sarcoid has been described in a Japanese cohort, which – by contrast – is a specific cutaneous sarcoidosis manifestation [47]. Although the histology of erythema nodosum itself is not diagnostic for sarcoidosis, sarcoid granulomas are typically detected in the bilateral hilar lymph nodes, supporting the diagnosis. Nevertheless, the diagnosis is often made clinically without the need for lymph node biopsies. Löfgren syndrome generally follows a self-limiting course with spontaneous resolution.

Heerfordt syndrome is a rare condition defined by the classic triad of parotid gland swelling, facial nerve paralysis, and uveitis (inflammation of the eye), often accompanied by low-grade fever.

Another rare sarcoidosis syndrome manifesting in early childhood is Blau syndrome, an autosomal dominant genetic inflammatory disorder caused by a mutation in the NOD2 (CARD15) gene. It is characterized by the triad of granulomatous arthritis, uveitis, and dermatitis and classified as an inborn error of immunity. If left untreated, this condition may lead to joint deformation and blindness [5, 31].

Typical laboratory abnormalities include elevated calcium, decreased vitamin D, and elevated ACE, which is produced by activated macrophages. In patients taking ACE inhibitors, this value may be falsely low. Other serum markers include neopterin, which is produced by activated immune cells after exposure to interferon-gamma, and soluble IL2R (sIL2R/sCD25). These two markers may be falsely elevated due to a viral infection. To investigate additional organ involvement, a complete blood count, blood chemistry, liver, and kidney function parameters should be obtained. To exclude infectious mimics, diagnostic tests such as a interferon-gamma release assay (IGRA) (e.g., QuantiFERON-TB test for Mycobacterium tuberculosis) and a broad-range bacterial PCR from biopsy tissue are recommended.

Beyond dermatological examination, further diagnostics should clarify systemic organ involvement. In patients with cutaneous sarcoidosis, pulmonary function testing and a chest X-ray are recommended as first-line investigations, as they may reveal restrictive lung changes or bilateral hilar lymphadenopathy. In early stages of lung involvement, chest CT provides greater sensitivity in detecting sarcoidosis-specific changes. Furthermore, a cranial CT, cardiac MRI, and an ophthalmological evaluation are recommended. Additional diagnostic steps may be initiated based on clinical suspicion.

The definitive diagnosis requires histological confirmation. Classic findings include non-caseating granulomas in affected tissue (Figure 3), composed of epithelioid cells, absence or only a sparse ring of lymphocytic infiltrates around granulomas, so called “naked” granulomas, and some multinucleated giant cells of either Langhans-type or foreign body-type [32]. Asteroid and Schaumann bodies may occasionally be found. Recent data highlight line-field confocal optical coherence tomography (LC-OCT) as a promising non-invasive diagnostic tool to identify granulomas in areas where a biopsy is challenging, such as in the face [51].

For cutaneous sarcoidosis without organ involvement requiring treatment, topical therapy with high-potent corticosteroids is the first option and can be applied twice daily. Alternatively, in locally limited forms of the disease, steroids can be applied intracutaneously at a dose of 5–40 mg/ml [32]. As a steroid-sparing alternative, topical tacrolimus twice daily over several weeks has shown efficacy [53].

Alternatively, there are reports on the use of 5-fluorouracil, topical retinoids, phototherapy, topical allopurinol, photodynamic therapy, and laser therapy. A recent case report describes efficient treatment of nodular sarcoidosis with intralesional TNF-alpha inhibitor administration or application of the topical JAK inhibitor ruxolitinib. However, these are off-label and based on limited evidence (Table 2) [54–56].

Systemic therapy is indicated in severe forms of cutaneous sarcoidosis or in cases with other organ involvement requiring treatment. Available systemic options include immunomodulatory drugs such as tetracyclines, hydroxychloroquine, or phosphodiesterase inhibitors, and immunosuppressive agents such as glucocorticoids, methotrexate, and TNF-alpha inhibitors [57].

Systemic glucocorticoids remain the first-line therapy for pulmonary sarcoidosis and have a good and rapid effect on cutaneous involvement. They act rapidly but are limited by their broad side effect profile. Relapses commonly occur after tapering or discontinuation. Combination therapy with other immunomodulatory or immunosuppressive drugs may help to achieve sustained disease control and allow glucocorticoid dose reduction [52].

Antibiotics of the tetracycline group can be used as immunomodulatory systemic therapy in cutaneous sarcoidosis. The use of doxycycline at a dosage of 200 mg daily is recommended, as minocycline can cause hyperpigmentation and an increased risk of hypersensitivity reactions [58].

Hydroxychloroquine is effective as monotherapy or in combination with doxycycline for cutaneous sarcoidosis. Clinical trials support doses of 2–3 mg/kg daily [59]. Because of the risk of retinopathy, patients require regular ophthalmological monitoring [60]. If feasible, hydroxychloroquine can be combined with UVA1 phototherapy [61]

The PDE4 inhibitor apremilast has demonstrated benefit in isolated cases of chronic treatment-resistant cutaneous sarcoidosis [62].

Methotrexate is an established option for treatment-refractory forms of sarcoidosis, particularly in lupus pernio or extensive plaque disease. Typical dosing ranges from 7.5 mg to 25 mg weekly, with subcutaneous administration preferred to reduce systemic toxicity. Close monitoring is necessary due to the risk of hepatotoxicity. Methotrexate also shows efficacy in sarcoidosis-related uveitis [63].

TNF-alpha inhibitors are indicated in therapy-refractory sarcoidosis, especially in lupus pernio or pronounced ulcerative forms. Recommended dosing includes adalimumab 40 mg weekly or infliximab 5 mg/kg body weight at variable intervals [64]. In addition, immunomodulatory or immunosuppressive agents can be combined with TNF-alpha inhibitors.

Paradoxically, TNF-alpha inhibitors may induce sarcoidosis-like granulomatous reactions, the mechanism of which remains unclear. Therefore, patients must be closely monitored during therapy [57].

A recent clinical trial has shown therapeutic success with JAK/STAT inhibition. Tofacitinib 5mg twice daily was effective in 10 patients with steroid-refractory cutaneous sarcoidosis. Similar results in patients with granuloma annulare suggest broader applicability in non-infectious granulomatous skin diseases [23, 28, 65].

Another promising new treatment represents mTOR inhibitors. Sirolimus, a selective mTORC1 inhibitor, restores autophagy and macrophage function, offering a targeted therapeutic approach. mTOR has been linked to sarcoidosis-associated myeloid cells [17, 22], and a clinical trial showed that 4 months of systemic treatment with the mTOR inhibitor sirolimus results in a long-lasting resolution of cutaneous sarcoidosis in 7 of 10 patients. The treatment effect lasted for at least 2 years after the end of the therapy [66]. These therapies represent promising steroid-sparing alternatives, but larger trials are needed to confirm their efficacy and safety.

Tofacitinib and sirolimus have also been used recently in the systemic treatment of sarcoidosis with involvement of different organs, such as the heart, larynx, and lungs [28, 67–72]. Both agents have shown efficacy. However, a recent case report described a patient who relapsed while receiving tofacitinib but went into complete remission after twelve months on sirolimus [73]. This raises the possibility that distinct subtypes of the disease exist: some more JAK/STAT-driven, and thus responsive to JAK inhibition, and others more mTOR-driven, responding better to mTOR inhibition. To clarify this, further studies are needed that combine clinical outcomes with molecular analyses.