nemoci-sympt/PLICNI/sarkoidoza/terapie

Indikace k terapii

• Guided by
• Improving the patient’s symptoms
• Preventing organ damage, complications and progression [4]

Ocular sarcoidosis

• Must be treated as it may cause permanent vision loss [4]

Sarcoid hypercalciuria

• Requires treatment to prevent impaired renal function by nephrocalcinosis and renal calculi [4]

Significant neurological and cardiac disease

• Warrants treatment usually over a prolonged period in years [4]

Pulmonary hypertension

• Is rare but may help:
• Prostacyclin analogues
• Endothelin receptor antagonists
• Phosphodiesterase-5 inhibitors [4]

Atrioventricular block, dysrhythmias and heart failure

• Cardiac medication, pacemaker or implantable cardiac defibrillator may be indicated [4]

Australian therapeutic guidelines

tgldcdp.tg.org.au/etgcomplete

Kortikoidy

• Daily dose of 0.5 mg/kg/day of oral prednisolone for 4 weeks
• With subsequent tapering or increase according to clinical and radiological response in individual patients
• Not based on clinical trials
• A protracted course is needed in patients who relapse after ceasing treatment,
• If a response is observed by 3 months
• Course should continue for at least 12 months
• Pulmonary sarcoidosis
• Can be very responsive, unlike neurosarcoidosis
• Cutaneous and ocular sarcoidosis
• May respond to topical steroid-containing creams or eye drops
• Inhaled corticosteroids may be sufficient to control cough
• Meta-analysis showed no clear benefit [4]
• Regular ophthalmological review is advisable for glaucoma or cataracts as well as sarcoid eye disease

Nonsteroidal anti-inflammatory drugs and hydroxychloroquine

• May be useful in Löfgren syndrome
• For relief of arthralgia and myalgia [4]

Corticosteroids

• Cause prompt reversal of the metabolic defect - hyperkalcemie [1]
• Most patients do not require treatment;
• When indicated, corticosteroids remain the initial standard of care, despite their adverse side effect profile [4]
• Inhibition of T-lymphocytes TNF-alpha [6]

• A dosage of prednisolon under 7.5 mg/day in chronic sarcoidosis can be continued [6]

Criteria for initiating corticosteroid therapy in patients with sarcoidosis

• American Thoracic Society, European Respiratory Society and World Association of Sarcoidosis and other Granulomatous Disorders

• Progressive symptomatic pulmonary disease
• Asymptomatic pulmonary disease with persistent infiltrates
• Progressive loss of lung function
• Cardiac disease
• Neurological disease
• Eye disease not responding to topical therapy
• Symptomatic hypercalcaemia
• Other symptomatic/progressive extrapulmonary disease

• Traditionally been used in acute and chronic sarcoidosis
• There are no trials to indicate the appropriate dose or duration
• Effective in gaining disease control
• May be supplemented or replaced by drugs such as
• Methotrexate,
• Hydroxychloroquine
• Azathioprine,
• Particularly if significant steroid side effects have developed.

• Rheumatologists tend to use these drugs at an earlier stage to control systemic symptoms
• Corticosteroids remain the recommended first line therapy for pulmonary forms of the disease
• Methotrexate and azathioprine are also used
• Treatment acts only to suppress and not to cure sarcoidosis, as relapses are frequent [4] !!!
• Corticosteroids do not necessarily prevent disease progression or development of pulmonary fibrosis in all patients
• The 1999 international statement on sarcoidosis suggested a list of criteria for the initiation of corticosteroid therapy

• Absolute indications for oral corticosteroids include
• Hypercalcemia,
• Neurologic involvement,
• Cardiac involvement,
• Ocular involvement (if topical treatment for ocular problems has failed) [8]

• It is recommended to use a lower dose (e.g., 40 mg/day)
• That is tapered to every-other-day long-term therapy over several weeks [8]
• Some patients requiring long-term corticosteroids may be treated with prednisone 10 to 15 mg every other day [8]

• Often employed for symptom relief
• Remain the standard treatment
• Their efficacy in managing sarcoidosis is unclear [8]

Other drugs with fewer side effects

• May be a better long term choice
• Methotrexate, hydroxychloroquine, azathioprine, mycophenolate
• Tumour necrosis factor-a inhibitors are a treatment option for patients with refractory disease [4]

ARA290

• Two Phase II clinical trials on ARA290
• An erythropoietin derivative
• With tissue protective and healing properties
• Does not stimulate erythropoiesis
• Treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients
• Decrease in pain scores on validated questionnaires
• Significant increases in corneal nerve fibers
• Improved sensory pain thresholds
• Improved quality of life and physical functioning [17]

• Excellent safety profile while reducing neuropathy symptoms
• Prospects of ARA 290 treatment in sarcoid neuropathy seem promising
• Long-lasting beneficial effects of ARA 290 on both pain-related and non-pain-related symptoms in sarcoidosis patients prompt additional studies [17]

Adalimumab

• One small RCT in skin disease + case series pulmonary disease
• Lower rates of immunogenicity and allergy symptoms [4]
• Could be an important additional option in the treatment with biologicals [6]

Azathioprine

• Similar response rate
• Involves the risk of skin neoplasia
• Greater inhibitory effect on cell-mediated immunity than on humoral immunity
• no randomised controlled clinical trials have been performed
• Levels of thiopurine methyltransferase should be measured for dose adjustment

Chloroquine

• Drugs that should be used if
• Patient falls to respond
• Develops dangerous side effects to corticosteroid therapy (CHEST 1996; 109.535-39) [1]
• One small RCT in pulmonary disease
• May be useful as a steroid-sparing agent [4]

Cibinetide = ARA 290

• Helix B surface peptide
• Two Phase II clinical trials on ARA290
• An erythropoietin derivative
• With tissue protective and healing properties
• Does not stimulate erythropoiesis
• Treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients
• Decrease in pain scores on validated questionnaires
• Significant increases in corneal nerve fibers
• Improved sensory pain thresholds
• Improved quality of life and physical functioning [17]

• Excellent safety profile while reducing neuropathy symptoms
• Prospects of ARA 290 treatment in sarcoid neuropathy seem promising
• Long-lasting beneficial effects of ARA 290 on both pain-related and non-pain-related symptoms in sarcoidosis patients prompt additional studies [17]

• Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL)
• Can be quantified using corneal confocal microscopy (CCM)
• Innate repair receptor agonist cibinetide reverses corneal nerve loss
• Phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain
• Assessed the effect of cibinetide on corneal nerve fiber area (CNFA)
• Regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification
• Pain severity
• Functional capacity (6-minute walk test [6MWT]) [18]
• Cibinetide (1, 4, or 8 mg/day) was compared to placebo [18]
• Cibinetide significantly increased small nerve fiber abundance in the cornea and skin
• Consistent with a disease modifying effect [18]

• Cibinetide is a novel 11 amino acid peptide with high affinity and selectivity for the IRR
• Short plasma half-life
• Triggers sustained biological effects when concentrations exceed the low nanomolar affinity of the receptor
• In a mouse model of diabetic SNFL, daily administration of cibinetide reversed neuronal dystrophy [18]

• In neuropathic states
• Transient receptor potential vanilloid-1 (TRPV1) ion channel
• A key integrator of nociception and neurogenic inflammation
• Undergoes upregulation and sensitization in peripheral small nerve fibers and central pain pathways
• Cibinetide antagonizes the TRPV1 channel of small nerve fibers and relieves mechanical hypersensitivity [18]

• Three prior clinical studies have shown that cibinetide reduces neuropathic symptoms
• May promote nerve fiber repair in patients with sarcoidosis or diabetes-related SNFL
• Nerve fiber regeneration in two studies was evaluated using corneal confocal microscopy (CCM)
• In vivo ophthalmic imaging modality
• Noninvasively visualizes nerve fibers within the cornea
• Including the small fibers of the sub-basal layer
• CCM-assessed sub-basal corneal nerve status
• Correlates with sensory nerve function and lower extremity intraepidermal nerve fiber density (IENFD) [18]
• Present phase 2b clinical trial evaluated
• Safety, efficacy,
• Dose range of 28-day subcutaneous (SC) administration of cibinetide on corneal nerve fiber area (CNFA)
• Compared to placebo in subjects with sarcoidosis and painful SNFL [18]
• 1, 4, or 8 mg cibinetide or placebo daily
• 1 mg dose does not appear to be effective
• 8 mg dose group exhibited a trend for improvement similar to the 4 mg group [18]
• Major target for cibinetide could be at the level of the trigeminal ganglion where the sensory neuronal cell bodies reside.
• It currently is unknown to what extent cibinetide may be secreted into tears
• The low nanomolar peak plasma concentrations of cibinetide at the doses administered, coupled with its short circulating half-life, make this possibility unlikely [18]
• Increase in epidermal GAP-43+ nerve fiber length
• Suggesting that skin nerve fibers also possess cibinetide-induced regenerative capacity [18]
• 2 mcrom/fiber/day rate of cutaneous regrowth as estimated [18]
• Two recent longitudinal studies have shown that corneal nerve fiber loss predicts the development of DPN [18]
• More accurately than traditional measures of neuropathy, such as quantitative sensory testing and nerve conduction studies [18]
• Cibinetide in capsaicin-induced pain
• Have shown antagonism of TRPV1-mediated hyperalgesia
• Improved thermal sensory thresholds mediated by C-fibers, following 28 days of cibinetide administration in subjects with sarcoidosis and SNFL [18]

Cyclophosphamide

• Considered toxic
• Usually reserved for life-threatening sarcoidosis that has become refractory to corticosteroids and other agents
• Neurological
• Ocular [4]

Etanercept

• Reported effective in case reports
• Only trial so far resulted in detoriation of almost a third of the patients with acute pulmonary sarcoidosis [6]

Hydroxychloroqune

• Drugs that should be used if
• Patient falls to respond
• Develops dangerous side effects to corticosteroid therapy (CHEST 1996; 109.535-39) [1]
• Patients receiving hydroxychloroquine tend to have less multiorgan disease
• Associated with less fatigue
• The anti-inflammatory effects of this less toxic drug may more successfully treat fatigue [7]

Hypercalcaemia/hypercalciuria

• Severe hypercalcemia – act immediately:
• Rehydrate,
• Consider zoledronic acid,
• Give corticosteroids,
• Calcitonin
• And loop diuretics options [16]

• Moderate hypercalcemia
• Corticosteroids,
• Consider ketoconazole or hydroxychloroquine [16]

• Hypercalciuria
• More observational approach:
• Options include corticosteroids diuretics [16]

Infliximab

• Two RCTs demonstrating small effect in pulmonary disease
• Underpowered to demonstrate effect on extrapulmonary manifestations [4]
• May slightly increase vital capacity in patients with active, symptomatic stage 4 disease
• May be helpful for patients with refractory neurosarcoidosis
• However, randomised controlled trials are required [4]
• Infliximab and adalimumab propably induce apoptosis of TNF-alpha binding cells
• Contributes to the inhibition of granuloma formation
• Infliximab is the most investigated of this four
• Has shown to be effective in other inflammatory diseases [6]
• Demonstrated significant clinical benefit in large cohorts of patients with pulmonary manifestations of sarcoidosis [6]
• 12 patients were treated by infliximab
• 9 of these patients also suffered from fatigue
• All of them improved on their post-infliximab 18FDGPET/ CT scan
• Overall decrease in maximal standardised uptake rate
• Reported reduction of fatigue [7]
• In a small study, it was shown that treatment with infliximab caused improvement in patients with MRI-documented neurosarcoidosis (n = 6),
• Who had failed to respond to corticosteroids and mycophenolate mofetil [16]

Intra-abdominal disease

• Try proton-pump inhibitors and antacids if upper G-I symptoms
• Consider ursodeoxycholic acid if pruritus and fatigue discomforts [16]

Karvedilol

• Small fibre neuropathy of the hearth
• Dilated cardiomyopathy
• It was demonstrated that the cardiac sympathetic nervous system function can improve in response to carvedilol therapy [14]
• účinek
• Alpha 1- adrenergic receptors
• Decreasing the total peripheral resistance
• Cardiac nonselective beta – adrenergic receptor blocking action
• Preventing reflex tachycardia
• Has a potent antioxidant action [14]

Ketoconazole

• Drugs that should be used if
• Patient falls to respond
• Develops dangerous side effects to corticosteroid therapy (CHEST 1996; 109.535-39) [1]

Leflunomide

• Some but not all studies found leflunomide to be as effective as methotrexate in treating both pulmonary and extrapulmonary sarcoidosis
• May have less hepato- and pulmonary toxicity

Metotrexát

• Inhibitor of folic acid metabolism
• Most widely used corticosteroid-sparing agent used
• Relatively low side effect profile
• 50-70% of patients responding and about 25% weaned off corticosteroids [4]
• Side effects include
• Nausea, malaise, leukopenia, hepatotoxicity, pneumonitis and
• Increased risk of opportunistic infections [4]
• Concomitant folic acid supplement should be given
• Steroid-sparing agent
• One small RCT in pulmonary disease and several case series in extra-pulmonary disease [4]

• Methotrexate is the most-studied alternative to corticosteroids for the treatment of sarcoidosis
• Recent Delphi study of sarcoidosis methotrexate was determined to be the preferred corticosteroid-sparing agent for pulmonary sarcoidosis
• Methotrexate has been found efficacious for most forms of sarcoidosis, including
• Lung, eye, skin, and neurologic involvement [8]

Metotrexáte

• Inhibitor of folic acid metabolism
• Most widely used corticosteroid-sparing agent used
• Relatively low side effect profile
• 50-70% of patients responding and about 25% weaned off corticosteroids [4]
• Side effects include
• Nausea, malaise, leukopenia, hepatotoxicity, pneumonitis and
• Increased risk of opportunistic infections [4]
• Concomitant folic acid supplement should be given
• Steroid-sparing agent
• One small RCT in pulmonary disease and several case series in extra-pulmonary disease [4]

Mycophenolate

• Can be an effective treatment for neurosarcoidosis and cutaneous sarcoidosis
• Data on its efficacy for other forms of sarcoidosis are limited

Neurological disease

• Severe symptoms
• Methylprednisolone intravenously in pulses
• Long-term/high-dose corticosteroid regimen
• Corticosteroid-sparing agents
• Anti-TNF agents if refractory [16]

Nicotine

• Regulation of T cell-mediated inflammation
• Via a 7 nicotinic cholinergic receptor activation
• Chronic nicotine exposure (smoking) reduces the incidence of granulomatous diseases [2]
• Adults with symptomatic sarcoidosis (n 5 13) were randomly assigned
• 12 weeks of nicotine treatment plus conventional therapy
• Conventional therapy alone [2]
• Before and after nicotine treatment blood cells were evaluated for their responsiveness to
• Selected Toll-like receptor (TLR)
• Nucleotide oligomerization domain-like receptor ligands
• T cell surface marker expression [2]
• Asymptomatic patients (n 5 6) and disease-free subjects (n 5 6) served as comparative control subjects
• Symptomatic patients had
• Impaired peripheral responses to TLR2, TLR4, and TLR9 ligands (anergy)
• Reduced peripheral populations of CD4 1 FoxP3 1 regulatory T cells (Tregs) [2]
• Nicotine treatment was associated with:
• Restoration of TLR2 and TLR9 responsiveness
• Expansion of Tregs, including the CD4 1 CD25 2 FoxP3 1 phenotype [2]
• There were no serious adverse events or signs of nicotine dependency.
• Conclusions: Nicotine treatment in active pulmonary sarcoidosis
• Was well tolerated
• Restored peripheral immune responsiveness to TLR2 and TLR9 agonists and expansion of FoxP3 1 Tregs, including a specific “preactivated” (CD25 2 ) phenotype. [2]
• The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients, supporting the notion that nicotine treatment may be beneficial in this patient population. [2]

PTH

• High levels of calcitriol will suppress parathyroid hormone (PTH) levels in sarcoidosis
• Parathyroidism and sarcoidosis may coexist

PTH-related peptide (PTHrP)

• Was discovered that may be secreted in association with malignancy
• Also involved in calcium metabolism in sarcoidosis as elevated plasma levels have been shown
• Presence has been demonstrated by immunohistochemistry in lymph node biopsies from patients with sarcoidosis
• PTHrP can simulate most of the properties of PTH including
• Increase in bone resorption
• Distal tubular calcium reabsorption [16]

Pentoxyifylline

• Is suppressing the release of TNF-alpha by alveolair macrophages.
• Used dosage of pentoxifylline was causing a lot of gastrointestinal side effects [6]

Photodynamic therapy

• Two cases of cutaneous sarcoidosis successfully treated
• Represents an effective alternative therapy with fewer side effects [9]

Pulmonary hypertension

• Correct hypoxia
• Treat co-existent sleep apnoea and cardiac abnormalities
• Consider pulmonary hypertension therapies
• Transplantation [16]

Querceptin

• Which belongs to the flavanoid family, was administered to 12 of 18 patients with sarcoidosis in a small study. Querceptin supplementation showed a reduction in markers of oxidative stress (malondialdehyde) and inflammation (expressed as reduced ratios of TNF-?/IL-10 and IL-8/IL-10). These findings were more pronounced in patients with higher basal levels of suggestive markers [35¦]. In our view, these findings merit assessment in larger trials with clinical endpoints.
• www.ncbi.nlm.nih.gov/pmc/articles/PMC4134017/

Small fibre neuropathy

• Antidepressants
• Anticonvulsants
• Consider intravenous immunoglobulin, anti-TNF agents [16]

Thalidomid

• TNF-a inhibitor thalidomide
• Was effective in reducing iNOS/peroxynitriterelated pathology
• By restraining TNF-a increases
• Without harming the physiological function of iNOS [7]

• Thalidomide has been advocated as a therapeutic option in selected cases of refractory sarcoidosis
• Due to its anti-inflammatory, TNFalpha-inhibiting properties,
• Despite the well-known severe teratogenic adverse effects
• Completely reliable contraception is essential in women of child-bearing age if this approach is taken. [16]

Vasoactive intestinal peptide (VIP)

• Important immunoregulatory role in sarcoidosis
• Active sarcoid alveolitis treated with 4 weeks of nebulized VIP
• Subsequently found to have
• Significantly reduced production of TNF-alpha from BAL fluid mononuclear cells
• Increased BAL numbers of immunoregulatory CD4+ CD127- CD25+ T-cells [3]
• In vitro experiments
• VIP was able to convert naive CD4+ CD25- T-cells into CD4+ CD25+ FOXP3+ regulatory T-cells
• Suggesting generation of peripheral regulatory T-cells by VIP treatment [3]

Immunosuppressive agents

• As corticosteroidsparing agents
• For long term treatment to reduce steroidrelated side effects
• Contraindicated in
• Pregnancy,
• Breastfeeding
• Before conception
• Risks of infections and the long term risk of malignancy need to be discussed with the patient.

Inhalativ vasoaktiv intestinal Peptid

Jiná než imunosupresivní terapie

• Zatím si to jen pomalu tu a tam studuji a (snad ne uplně naivně) doufám, že se doberu někde i něčeho jiného než kortikoidů a imunosupresiv při těžkých symptomech jako první terapie v nouzi
• Jaké jsou možné vyvolavatelé
• Atpyciké mykobakterie - kdyby bylo v pozadí toto, tak se budu bát nasadit člověku anti-TNS terapii - o té se běžně ví, že její nežádoucí účinek může být aktivace skryté tuberkulozy - tedy mykobakterií !!!
• EBV také prý může vyvolat tuto reakci - ano, potlačuje efektivní imunitu a zoufalé makrofágy se pak snaží zvládnout to jinak nebo něco jiného jinak a mohou dělat i granulomy
• EBV se testovat dá, takže každý, kdo má sarkoidozu a EBV aktivaci, by podle mě měl - pokud má čas - neakutní symptomy - nejprve zkusit pomocí kde čeho a bylin potlačit EBV - tedy stimulací antivirové imunity a oxidačního vzplanutí, aby to opravdu něco ničilo a ne jen zoufale ohraničovalo a granulovalo
• Reakce na těžké kovy / jiné neživé částečky - pak by to znamenalo prozánětlivý stav a tato jediná varianta sama o sobě si zaslouží principiálně inhibici, aniž by tam bylo odložené riziko zvýšeného poškození v budoucnosti - asi
• Toto by tak nějak bylo v souladu s doporučením off-label, které jsem dostala od Dr. Claytona
• Podat betaglukany (stimulace imunity) a rybí tuk s oljem z neralých oliv (prpotizánětlivý a antifibrotický vliv)
• Dotestování potencionálních příčin hyperaktivace makrofágů - to je na tom však to nejtěžší kromě EBV
• Jestli někdo ví, kde to provádí, hned mi prosím napište

Nicotine

• An interesting study by Julian et al. [20¦¦] reported the effects of nicotine on pulmonary sarcoidosis. Thirteen patients with symptomatic sarcoidosis received conventional therapy with or without nicotine treatment. The reaction of blood cells to ligands for certain Toll-like receptors (TLRs) was assessed. TLR-2 and TLR-9 responsiveness was restored in nicotine-treated individuals. Additional research is needed to confirm these data.
• www.ncbi.nlm.nih.gov/pmc/articles/PMC4134017/

Anti-CD20 (rituximab)

• Have yet to be studied in a controlled manner
• Intervention that targets CD4 cells or the Th1 (and perhaps Th17) pathways
• Would be of potential benefit
• Problems include cost and availability [4]
• Few cases of a positive effect of anti B-lymphocyte therapy, i.e. rituximab (anti-CD20) [6]

Tumour necrosis factor-a inhibitors

• Should be beneficial
• Development of granulomas is thought to be dependent upon the cytokine [4]
• Modest, beneficial effects
• But cost, side effects and limited effect discourage their use
• Used only after other agents have failed
• Few placebo-controlled trials
• Other diseases should be excluded that could be activated with tumour necrosis factor-a suppression
• Multiple sclerosis, tuberculosis !!!

• Infliximab,
• Adalimumab
• Etanercept
• Golimumab [6]

To by mne zajímalo, jak dlouhou remisi toto může navodit a zda po vysazení terapie po přechodném zlepšení není stav lidí ještě horší. Pokud se na tom může rozvinout TBC, co asi infekce, která vyvolává podobnou imunitní reakci v těle ? Velmi bych před takovou terapií chtěla vědět, zda je to reakce na infekci nebo anorganické částice.

• Efficacy of tumour necrosis factor (TNF) antagonism
• Especially with the chimeric anti-TNF monoclonal antibody infliximab
• Has been shown relatively recently, thus providing additional therapeutic options particularly for more refractory disease [16]

Lung and other organ transplantation

• Refractory and severe end-stage pulmonary sarcoidosis is an indication for consideration of lung transplantation.
• Subsequent immunosuppression usually protects the patient from disease recurrence
• Which has nonetheless been described in the donor organ [4]