Atypical Chronic Sarcoidosis with Multiorgan Manifestations and Therapeutic Refractoriness: A Case Report
About the Author
Dino-Josip Ključarić, mag. theol., is the president of the Croatian Sarcoidosis Patients’ Association. For more than two decades, he has been living with a chronic form of atypical sarcoidosis, linking his personal experiences with academic knowledge and social engagement. He is the author of numerous educational texts and projects dedicated to raising awareness about sarcoidosis, supporting patients, and developing a multidisciplinary approach to treatment.
Abstract
We present a male patient from Zagreb, aged 45, formerly an active athlete and later a recreational swimmer, whose first symptoms appeared in early adulthood as dyspnea, profuse night sweats, and skin rashes.
Sarcoidosis is a chronic granulomatous disease of unknown etiology that can affect almost all organ systems. The classic presentation includes pulmonary and lymphatic manifestations, but atypical forms often lead to diagnostic delays and misinterpretations.
Over the course of 20 years, the patient developed progressive pain in the ankles, heels, and tendons, episodes of sepsis (later linked to a granulomatous lesion in the spleen), severe tendon pain, paresthesia, and transient cerebrovascular episodes. The final diagnosis of sarcoidosis (D86.9) was made after 12 years of extensive testing, including BAL, bone marrow biopsy, nodular erythema biopsy, spirometry, DLCO, and laboratory markers (ACE).
Despite initial corticosteroid and methotrexate therapy, the disease proved refractory, with long-term corticosteroid therapy leading to retinopathy and vision loss in the left eye. Later, small fiber neuropathy (QST positive), chronic radiculopathy, and significant synovial hypertrophy with polytenosynovitis were confirmed, resulting in severe functional limitations requiring walking aids. Therapy with leflunomide (Arava) was introduced without effect. The patient also developed episodes of resting tachycardia with transiently elevated CK and troponins, raising suspicion of cardiac sarcoidosis.
Conclusion: This case illustrates the importance of recognizing nonspecific sarcoidosis symptoms, as well as the role of the patient in actively seeking medical care and diverse specialist opinions. In this refractory form, with pronounced musculoskeletal and neurological manifestations, biological therapy is indicated.
Neurological Component
Confirmed by:
Tilt test (vasovagal syncope),
QST test (positive for small fiber neuropathy),
MRI of brain and spinal cord (described demyelinating lesions),
Lumbar puncture (without specific biomarkers for MS).
Musculoskeletal Component
Confirmed by ultrasound of joints: marked synovial hypertrophy causing tendinitis and polytenosynovitis in multiple joints, particularly ankles and wrists. Pain intensity reached 8–9/10, with functional limitation and dependence on crutches.
Therapeutic trials:
Leflunomide (Arava) introduced, but after 5 months showed no clinical efficacy.
Corticosteroids gradually tapered, but musculoskeletal symptoms persisted as dominant.
Cardiac Manifestations
Episodes of resting tachycardia,
Mildly elevated CK and troponin on emergency admission,
Syncope with CK up to 550 a few days later, interpreted as possible transient myocardial injury (suspected myocardial sarcoidosis, not confirmed on MRI).
Current Status and Therapeutic Options
At age 45, the patient presented with severe musculoskeletal symptoms (synovial hypertrophy, polytenosynovitis, strong pain, functional dependence on crutches) along with neurological episodes and cardiac events. Due to poor response to Arava and methotrexate with complications from corticosteroid therapy, adalimumab was proposed as a second-line biologic therapy, aiming to reduce inflammatory activity, preserve joint function, and prevent further neurological and cardiac deterioration.
Metabolic Manifestations of Sarcoidosis
One of the important but often overlooked manifestations is hypercalcemia and hypercalciuria, resulting from increased production of active vitamin D (1,25-dihydroxyvitamin D₃) in macrophage granulomas. Consequences include increased intestinal calcium absorption and reduced renal excretion. Clinically, hypercalcemia manifests as fatigue, polyuria, polydipsia, nephrolithiasis, and renal failure, while hypercalciuria increases the risk of nephrolithiasis and nephrocalcinosis.
Immunomodulatory Effect of Corticosteroids, Methotrexate, and Leflunomide in Sarcoidosis
Corticosteroids: first-line therapy, acting via glucocorticoid receptors to suppress proinflammatory cytokines (TNF-α, IL-1β, IL-6). Effective in acute pulmonary forms, but long-term therapy leads to glucocorticoid resistance and severe side effects (Barnes, Nat Rev Immunol 2016).
Methotrexate (MTX): cytotoxic and immunomodulatory, inhibits dihydrofolate reductase, suppresses proliferation of activated T-lymphocytes, increases adenosine concentrations, and reduces synovial fibroblast proliferation. Beneficial in acute disease but limited efficacy in low-vascularized, high-stress tissues (tendons, synovia).
Leflunomide (Arava): inhibits dihydroorotate dehydrogenase, blocking pyrimidine synthesis and proliferation of activated lymphocytes. However, clinical efficacy in chronic sarcoidosis is limited (Lower et al., Sarcoidosis Vasc Diffuse Lung Dis 2004).
Conclusion of conventional therapy: While these agents suppress acute granulomatous inflammation, they do not sufficiently control chronic synovial and neurological progression, justifying the introduction of anti-TNF biological therapy.
Biological Therapy in Sarcoidosis: Adalimumab and the Anti-TNF Approach
Mechanism of action:
Adalimumab is a fully human monoclonal IgG1 antibody binding TNF-α, preventing receptor interaction and thereby reducing granulomatous inflammation, macrophage and lymphocyte recruitment, and synovial proliferation (Keane, Clin Chest Med 2015).
Clinical experience:
Sweiss et al.: clinical improvement in 77% of patients with refractory sarcoidosis.
Baughman et al.: stabilization or improvement of neurosarcoidosis and musculoskeletal involvement in over 70% of cases.
van Laar et al.: remission rates up to 80% in ocular sarcoidosis.
Risks: include latent infection reactivation (TB), opportunistic infections, and possible increased malignancy risk with long-term use.
Prognosis with Adalimumab Therapy
Scenario 1: Successful response
Reduction of synovial hypertrophy and tendon pain, improved mobility, reduced dependence on crutches.
Stabilization of restrictive ventilatory disorder and improved DLCO/FEV1.
Stabilization of small fiber neuropathy and reduced syncopal episodes.
Improved cardiac safety by lowering risk of arrhythmias.
Improved quality of life and life expectancy (additional 15–20 years under stable disease control).
Scenario 2: Unsuccessful response
Worsening tenosynovitis and synovial hypertrophy with functional dependence within 5–7 years.
Progressive lung function decline (~150–200 ml FEV1 per year), leading to respiratory failure within 5–10 years.
Increased neurological deficits and disability.
Progressive cardiac sarcoidosis with risk of sudden death.
Reduced life expectancy to 8–10 years, with significant loss of independence and quality of life.
Discussion
This case demonstrates an atypical, long-standing sarcoidosis, initially affecting soft tissues and lymph nodes, misinterpreted for decades until systemic disease was recognized. Neurological symptoms (paresthesia, balance loss, transient strokes) appeared in the third decade of life, suggesting neurosarcoidosis, though never formally diagnosed. Later testing confirmed small fiber neuropathy and demyelinating lesions.
Musculoskeletal manifestations with pronounced synovial hypertrophy and polytenosynovitis became dominant, accompanied by corticosteroid-induced retinopathy and cardiac episodes. Conventional therapy (corticosteroids, methotrexate, leflunomide) failed to halt disease progression, highlighting the need for biological therapy.
Multisystemic Inflammation and Damage Cascade
Chronic T-cell and macrophage activation with TNF-α and IL-6 production led to:
Musculoskeletal: fibrotic remodeling, progressive bone loss (Kobak, Curr Opin Pulm Med 2013).
Neurological: small fiber neuropathy, autonomic dysfunction, irreversible damage (Zajicek et al., Brain 1999).
Cardiac: granulomas in myocardium, arrhythmia risk, sudden death (Birnie et al., Circulation 2016).
Immunological: sepsis episode linked to splenic granuloma.
Conclusion
This case illustrates the complexity of atypical, chronic, multiorgan sarcoidosis with refractory progression over nearly 25 years. Standard immunomodulatory therapy failed to control synovial and neurological inflammation, leading to severe complications.
Given the central role of TNF-α in maintaining granulomas and synovial hypertrophy, the introduction of biological therapy (adalimumab) appears justified. The therapeutic goal is not only symptom control but also the prevention of further organ damage, preservation of functional capacity, and improvement of quality of life.
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