Table 4 Granulomatous diseases

PGA

NOD2

AD

Uveitis, granulomatous synovitis, camptodactyly, ichthyosiform rash, fever

Increased IM during disease flares; Elevated ACE levels; Granulomatous infiltration on biopsy; Molecular analysis^#

CS, TNFi, MTX

GLILD

Usually associated with CVID genes

AR and AD

Lymphocytic interstitial lung disease and follicular bronchitis/bronchiolitis, granulomatous lung disease, lymphadenopathy

Pulmonary function with restrictive pattern with a low DLCO value; Lymphocyte infiltrate and non-caseating granulomas on lung biopsy; Molecular analysis^#

CS, RTX, AZA, HSCT

Chronic granulomatous disease

CYBB; CYBA

AR and XL

Severe and recurrent infections, McLeod phenotype, (IBD)-like colitis, cutaneous, hepatic and CNS abscess. Autoimmune features such as SLE

Increased IM during disease flares. Abnormal DHR neutrophil assay; Molecular analysis^#; Granulomatous infiltration on biopsy

Antibiotic and antifungal prophylaxis, HSCT, gamma interferon, mesalazine CS, AZA

Sarcoidosis

----*

----*

Interstitial lung disease, arthritis, lymphadenopathy, erythema nodosum, Löfgren’s syndrome, lupus pernio, uveitis, neurological and cardiac involvement, uveoparotid fever (Heerfordt’s syndrome), sarcoid dactylitis with bone lesions (Perthes Jungling syndrome)

Negative tuberculin test or negative IGRA; Elevated serum ACE or serum lysozyme, lymphopenia, increased 1,25-dihydroxyvitamin D, hypercalciuria; Elevated CD4/CD8 ratio (> 3.5) in BLF; Granulomatous infiltration on biopsy

CS, MTX, AZA, leflunomide, TNFi

Drug-induced sarcoidosis-like reactions (DISRs)

----*

----*

Systemic granulomatous lesions indistinguishable from sarcoidosis induced by immune check point inhibitors, TNF-inhibitors, antiretroviral or interferon therapies

Negative tuberculin test or negative IGRA, elevated serum ACE or serum lysozyme, lymphopenia, increased 1,25-dihydroxyvitamin D, hypercalciuria; Elevated CD4/CD8 ratio (>3.5) in BAL; Granulomatous infiltration on biopsy

Withdrawal of the offending agent, CS, switch to another TNFi

Necrotizing sarcoid granulomatosis

----*

----*

Persistent fever, night sweats, weight loss, fatigue, interstitial lung disease, peripheral lymphadenopathy, arthralgia, skin lesions

Increased IM during disease flares, necrosis (coagulative or caseous) and vasculitis with granulomas on lung biopsy, negative mycobacteria culture, negative ANCA

CS, cyclophosphamide, AZA

Lymphomatoid granulomatosis

----*

----*

Multiple bilateral pulmonary nodules with evidence of central necrosis and/or cavitation. Scattered subcutaneous or dermal nodules, CNS, lung, and kidneys involvement

Atypical EBV-positive B cells admixed with a prominent background of mononuclear cells comprised of T cells, plasma cells, and histiocytes on biopsy

CS, RTX, IFN-α, chemotherapy, HSCT

GLUS syndrome¶

----*

----*

Prolonged fever, liver, bone marrow, spleen, and lymph nodes manifestations with a benign and recurrent course

Normal ACE, normal calcium levels; Predominantly B-cells in granuloma lesions on biopsy

CS