Treating OSA and small fibre neuropathy and reconsidering drug therapies can make life better, experts say.
Quality of life is the most important priority for people with sarcoidosis, even ahead of survival and pulmonary function.
Elements affecting that are often overlooked even though they are modifiable, and practitioners can really make a difference, delegates at the European Respiratory Congress in Vienna heard last month.
“It is included in the recent treatment guidelines, and it was suggested as an endpoint in clinical trials again last year in the Delphi survey,” said Dr Katharina Buschulte, an internal medicine and pneumology specialist from the Thoraxklinik Heidelberg, Germany.
“Quality of life is a complex concept in sarcoidosis, and it’s influenced by various factors.”
Sarcoidosis can affect every organ and have many symptoms, including impaired vision and severe shortness of breath.
Fatigue affects up to 90% of patients, and seems not to be related to disease severity, persisting even without signs of active inflammation and worsening anxiety and depression. In addition, sarcoidosis drugs have side effects that affect people differently.
“We would think that, of course, disease severity is related to quality of life, but this is less clear in sarcoidosis,” said Dr Buschulte.
In order to know how a patient is really doing, she said, it’s important to measure their quality of life, and there are good tools for that: the Medical Outcome Study 36-Item Short Form Health Survey (SF-36) the WHO Quality of Life 100 (WHOQOL-100), the Sarcoidosis Health Questionnaire (SHQ), the King’s Sarcoidosis Questionnaire (KSQ) (best for pulmonary sarcoidosis), and the Fatigue Assessment Scale (FAS).
Making life better with pharmaceuticals
One way to make improvements is through disease-modifying pharmacology, treating inflammation where it exists. But drugs themselves can have a negative impact on quality of life.
For instance, research has shown that low dose-dexamethasone (1mg per day for six months) increased quality of life for study participants. But another showed that higher doses of prednisone (more than 500mg a day versus under 200mg for a year) increased fatigue and reduced quality of life.
“We can conclude there is a tendency for lower initial dose of corticosteroids and rapid taper,” Dr Buschulte said.
The main second-line drug, methotrexate, has been shown to improve quality of life and there was a significant decrease in corticosteroid doses for participants.
Third-line therapy with infliximab in patients with chronic symptomatic pulmonary sarcoidosis showed no change in quality of life or dyspnoea but significant improvement in lung function. In patients with cutaneous sarcoidosis there was no change in quality of life. But a 2016 prospective study did show improved quality of life in patients with severe pulmonary sarcoidosis.
“So maybe patients with more chronic disease, worse baseline dyspnoea and worse quality of life may benefit more from infliximab,” said Dr Busschulte.
There is also evidence showing improved quality of life from treating symptoms with drug therapy. Dexmethylphenidate hydrochloride (d-MPH) has been shown to reduce fatigue and improve quality of life and Armodafinil has also reduced fatigue. Azithromycin has improved quality of life, cough severity and frequency. And while there are no large studies on therapy for small fibre neuropathy, cibinetide has been shown to make life better for patients.
Going down the non-drug route
Physical training and pulmonary rehabilitation are considered very important for patients with sarcoidosis and can improve fatigue, said Dr B, but “the long-term effect is unclear”.
Psychological interventions, such as online mindfulness based cognitive therapy have been demonstrated to improve fatigue.
“Patient education and self-support groups are very important for disease education, for awareness, for peer support, and all these factors which are beneficial in patients with sarcoidosis.
“And of course, we have other therapies as supplemental oxygen, which showed an improvement in quality of life,” said Dr B.
Is obstructive sleep apnoea making things worse?
“In any patient that describes fatigue with sarcoid we should be thinking about sleep disordered breathing, and particularly obstructive sleep apnoea,” Professor Elisabetta Renzoni, respiratory medicine specialist at the Imperial College, London, told delegates.
Obstructive sleep apnoea is an underestimated comorbidity, said Professor Renzoni. Studies show a high prevalence, with the largest of them finding that 45% of patients with sarcoidosis had OSA, compared with 31% in the control group.
The two conditions have “quite a lot of overlap”, she said, including fatigue, excessive day-time sleepiness, pulmonary hypertension and cognitive deficits.
“Fatigue is one of the most devastating symptoms of patients with sarcoidosis, it can have a truly life changing impact,” she said.
Patients with both conditions are feeling fatigued from disrupted sleep due to hypoxia, as well as because of inflammation, small fibre neuropathy, depression and medication side effects.
Corticosteroid-induced weight gain/obesity is one of the modifiable OSA risk factors for patients with sarcoidosis, said Professor Renzoni.
“In all patients with sarcoidosis and particularly those with, or at risk of OSA, a key priority is to minimise corticosteroid use, with early consideration of corticosteroid-sparing therapy,” she said.
Obesity is the strongest risk factor for OSA in the general population, with 44% of men and 14% of women aged 30-49 with a BMI 30 or higher having OSA, compared with 7% of men and 1% of women with a BMI under 25. An increase of 10% in body weight is associated with an increase of 30% in the Apnoea Hypopnoea Index.
Obesity accounts for 58% of OSA cases in people with sarcoidosis, said Professor Renzoni.
Corticosteroid use plays a large part in this. It’s also been shown that the time taken to develop toxicities associated with steroid use – diabetes, hyperlipidaemia, systemic hypertension, increasing BMI, osteoporosis and cataract/glaucoma – is related to increased dose and duration of treatment.
Treating sleep apnoea in patients with sarcoidosis really does help, said Professor Renzoni. A study looking at CPAP treatment showed that Apnoea Hypopnoea Index score was weakly correlated with fatigue and sleepiness scores, but there was a significant reduction in both for those treated with CPAP.
OSA can also be a contributor to hypertension in people with sarcoidosis and is worth treating, said Professor Renzoni. It has been suggested that in all patients with pulmonary hypertension, once elevated wedge pressure has been ruled out, a sleep study should be done unless the likelihood is very low, and any sleep disorder should be treated.
CPAP is associated with a decrease in pulmonary artery pressure. While studies are small and mostly observational, a meta-analysis found an overall mild but significant reduction in the mean primary arterial pressure, with the authors concluding that “OSA patients with PH might need to be treated more actively with CPAP to decrease pulmonary artery pressure and achieve a better prognosis.”
Consider small fibre neuropathy
Clinicians are used to being vigilant for small fibre neuropathy in patients with diabetes, where defects in the thin C fibres of the peripheral nervous system affect heat and pain sensation. But sarcoidosis can also induce small fibre neuropathy.
Between 40 and 86% of sarcoidosis patients have symptoms that could indicate small fibre neuropathy, pulmonologist and medical biologist Dr Marcel Veltkamp told delegates.
The symptom list is broad. In addition to the pain (pins and needles, shooting pains, cold or burning sensation, tingling) and other sensory symptoms, there are also dysautonomia symptoms, like dry eyes, gastrointestinal problems, urinary incontinence or retention, and – for almost 70% of both male and female patients – sexual dysfunction.
“So it’s really good for us as clinicians to know that these things occur in our patient with sarcoid,” said Dr Veltkamp.
He recommends using the Small Fiber Neuropathy Screening list to assess how often patients experience pain and how serious it is. Patients with small fibre neuropathy tend to score 11 or higher.
“Beware, this is not a diagnostic test, but you can use it to screen and if you have a patient who scores high… then you have a reason to discuss further,” Dr Veltkamp said.
“When I was in training, I thought the gold standard was if you see a patient with suspicion of small fibre neuropathy, you do skin biopsy and you measure the intra epidermal nerve density, and if it’s decreased, you have a diagnosis. Unfortunately, this is not exactly how the how it works.”
A diagnosis could be considered if the patient has symptoms and two or more clinical signs. Thick fibre neuropathy has to be excluded using an EMG, and diagnosis made when there is decrease in intraepidermal nerve density, or an abnormal result in threshold thermal testing or quantitative sensory testing, Dr Veltkamp explained.
“Unfortunately, the clinical presentation [in sarcoidosis] is not textbook case,” he said.
“We know the length dependent from a lot of work in diabetes, but you also have non-length dependent or atypical or focal presentation. Also, symptoms can be either continuous or intermittent.”
Unpublished data presented at the conference showed that most patients with sarcoidosis had symptoms that were non-length dependent, and some were atypical, “for example, just having a little bit of chest pain, that’s all”. That meant it wouldn’t show up in some of the tests, he said.
Autonomic symptoms, like heart dysfunction where cardiac sarcoidosis is not present, are often overlooked, said Dr Veltkamp. But they can be treated.
Treatment of small fibre neuropathy is symptomatic. First line treatment includes TCAs (amitriptyline, nortriptyline), duloxetine, venlafaxine, and gabapentin; second-line treatments tramadol and tapentadol, and third-line treatment is strong opioids.
Autonomic heart dysfunction has been successfully treated with carvedilol and inflammation symptoms can also be treated.
