Management Challenges in Sarcoidosis

In summary, based on the findings of the aforementioned trials and case series, anti-TNF therapy may be considered as a treatment option in carefully selected patients after discussion of the potential adverse effects, followed by close monitoring at a specialist center for the management of sarcoidosis. Furthermore, anti-TNF therapy should not delay referral for lung transplant assessment, particularly when disease progression is relatively rapid. Duration of treatment and timing of thoracic imaging after anti-TNF therapy is subject to debate and should be individualized in close collaboration with a specialist center.

Case Continued

• What is the role of newer biologics in the treatment of sarcoidosis? And what other therapies are on the horizon?

Although sarcoidosis is a T cell–mediated disease, humoral immunity has been implicated in sarcoidosis [40] and B cell depletion by rituximab (anti-CD 20⁺chimeric monoclonal antibody) has been successfully utilized in T cell–mediated diseases such as rheumatoid arthritis. Rituximab has been studied in phase I/II trial [41] in patients with refractory pulmonary sarcoidosis. The response to rituximab was inconsistent in these patients, with only a small group demonstrating > 5% improvement in FVC or walking distance. Hence, further studies are required to demonstrate a significant clinical benefit of this treatment in refractory sarcoidosis and potentially identify the characteristics of patients that may respond to B-cell depletion.

Adalimumab is another biologic agent that may be a potential option in refractory sarcoidosis as demonstrated in an open-label study of 11 patients [42]. This small trial of 52 weeks’ duration showed that adalimumab is well tolerated and may be considered in refractory pulmonary sarcoidosis when other treatment options have been exhausted.

Acthar had been used to treat pulmonary sarcoidosis in 1950s and there has been recent interest in evaluating the value of acthar gel therapy in the management of sarcoidosis. Baughman and colleagues [43] carried out a retrospective analysis of 47 patients with advanced sarcoidosis treated with acthar gel. The results showed that there was an objective improvement in approximately a third of patients receiving at least 3 months of treatment. Thirty-six percent of patients (n = 17) managed to reduce their oral corticosteroid dosage by more than 50% while on this therapy. However, a significant proportion of patients were unable to take ≥ 3 months of treatment, suggesting poor tolerance/adherence. The utility of acthar gel therapy would need to be examined in larger prospective randomized trial before it can be recommended for a treatment option in advanced disease.

• Should pneumocystis pneumonia (PCP) prophylaxis be considered in sarcoidosis?

We do not routinely consider PCP prophylaxis in all sarcoidosis patients. However, it should be considered in the following clinical situations:

• Failure to reduce oral corticosteroid dose to less than 20 mg of prednisolone daily
• Concomitant use of anti-TNF agents with relatively high maintenance dose of oral corticosteroids (≥ 20 mg per day)
• Significant comorbid condition in association with sarcoidosis resulting in significant level of immunosuppression

As our patient did not fall in any of the above categories, we did not offer him PCP prophylaxis. However, clinicians treating patients with sarcoidosis with strong immunosuppressants should be aware of this potential complication and be vigilant about discussing prophylaxis with trimethoprim-sulphamethoxazole, which is the first-line agent for this purpose.

• Is there a role of anti-tuberculous treatment in sarcoidosis?

Both mycobacterium tuberculosis (MTB) and non-mycobateria (NTM) have been implicated in sarcoidosis [44] and it is challenging to differentiate tuberculosis (TB) from sarcoidosis in certain clinical situations, such as when dealing with patients from countries with a high incidence of TB. The association of mycobacterium with sarcoidosis was explored in 2 recent trials of concomitant use of levofloxacin, ethambutol, azithromycin, and rifampin in cutaneous [45] and pulmonary sarcoidosis [46]. Drake and colleagues evaluated 15 chronic pulmonary sarcoidosis patients in an open-label trial to investigate if the combination of these drugs was associated with improvement in pulmonary sarcoidosis. The patients who completed 8 weeks of treatment had improvement in FVC at both 4 and 8 weeks of treatment. However, only 8 patients could complete 8 weeks of therapy, with significant adverse events. The small sample size limits our ability to draw meaningful conclusions and larger randomized trials are warranted to investigate this approach in sarcoidosis management.

• Are there any valid serum biomarkers for sarcoidosis?

A biomarker is defined as a compound easily measurable in serum, urine, or other body fluids that can be used as indicator of presence and/or severity of particular disease state. Moreover, it helps in evaluation of effectiveness of drug therapy and useful to monitor the disease longitudinally. Unfortunately, there is no ideal serum biomarker in sarcoidosis. The most widely evaluated marker is serum angiotensin-converting enzyme (ACE). It has been found to be elevated in three quarters of patients with sarcoidosis [47]. However, it has poor diagnostic utility due to limited sensitivity and specificity. Furthermore, levels of serum ACE are reduced in patients taking ACE inhibitors and hence measurement of ACE levels in patients taking ACE inhibitors may lead to inaccurate interpretations [48].

A number of other serum biomarkers have been evaluated in sarcoidosis. Gungor and colleagues [49] evaluated 48 patients with sarcoidosis and 20 healthy controls. The biomarkers measured were ACE, adenosine deaminase (ADA), total IgE, serum amyloid-A (SAA), soluble interleukin-2 receptor (sIL2R), and C-reactive protein (CRP). This study showed that SAA was significantly elevated in sarcoidosis as compared to controls (P < 0.001). Furthermore, sIL2R levels were raised in extra-pulmonary sarcoidosis (P < 0.014). In another study, Grutters and co-workers [50] demonstrated elevated levels of sIL2R in 47 patients with active sarcoidosis. However, the levels did not correlate with radiolographic or physiological outcomes or response to treatment. Hence, the utility of these biomarkers in clinical practice is questionable and larger longitudinal studies are required to demonstrate the actual benefit of these biomarkers in everyday clinical practice.

There is a complex relationship between vitamin D and calcium metabolism and risk of osteoporosis in sarcoidosis. The value of active vitamin D metabolite 1, 25-dihydroxy vitamin D in relation to the degree of sarcoidosis disease chronicity was evaluated in a study of 59 patients with sarcoidosis [51]. It was noted that increased levels of 1,25 vitamin D were associated with increased risk of chronic phenotype and the need to require repeated treatments with immunosuppressive agents. Hence, serum levels of 1,25 vitamin D may have a prognostic value in sarcoidosis. It is important to note that both vitamin D deficiency as well as vitamin D excess can result in osteoporosis [52], and there is a risk of bone fragility and fractures in patients who may need long-term oral corticosteroid therapy. Hence, an optimal level of vitamin D is crucial; we recommend a value of serum 25(OH) vitamin D between 10 and 20 ng/mL as evidenced by a cross-sectional analysis of 142 consecutive patients with biopsy-proven sarcoidosis [53]. The above range of 25(OH) vitamin D was associated with higher bone mineral density and values above 20 ng/mL resulted in increased risk of fractures, demonstrating the need to keep vitamin D levels of these patients to be lower than those recommended for general population.

• When should a patient with sarcoidosis be referred for lung transplantation?

Lung transplantation is a treatment option in advanced/end-stage disease after pharmacologic treatments have been exhausted and there is no evidence of progressive or severe extrapulmonary disease. The most critical decision regarding transplantation in pulmonary sarcoidosis is the timing of the referral and close liaison with the transplant center to ensure the maximal chance of success with lung transplantation. We recommend considering transplant referral when % predicted FVC approaches a value of 50% or less with or without significant pulmonary hypertension. Single lung transplant is appropriate for the majority of patients with sarcoidosis. However, bilateral transplant should be considered in bilateral mycetomas and bilateral bronchiectasis. Arcasoy and colleagues [54] analysed 43 patients listed for transplantation and found the following factors associated with increased risk of mortality:

• pulmonary hypertension
• hypoxia
• low cardiac output
• elevated right atrial pressure

It is important to note that pulmonary function parameters have not been found to be predictive of mortality in sarcoidosis [54,55]. Although granuloma recurrence in transplanted lung has been observed, it is a rare to have organ failure secondary to recurrence, and lung transplant should be considered in refractory cases of pulmonary sarcoidosis in the absence of contraindications and close liaison with the transplant center at the earliest opportunity is recommended.

• What is the optimal duration of clinical follow-up in sarcoidosis?

There is no consensus on appropriate follow-up duration once a diagnosis of sarcoidosis is confirmed, and it is dependent on physician preference, vital organ involvement, disease progression, need for pharmacological treatment, and availability of resources. The American Thoracic Society statement on sarcoidosis suggested at least 3 years of follow-up after corticosteroid treatment is completed irrespective of radiographic stage [56]. Patients with serious extrapulmonary symptoms would require longer-term follow-up and a recent single-center Japanese study of corticosteroid-naive patients showed that the number of organs involved at the outset dictates the cumulative risk of subsequent progression of sarcoidosis [57]. This study of 150 patients with sarcoidosis with a median follow-up of 7.7 years demonstrated significantly increased risk of progression when there were > 3 organ systems involved as compared to ≤ 3 involved. These corticosteroid-naive patients may require longer follow-up (up to 10 years) than previously thought. However, the findings of this study would require confirmation in multi-center and multi-ethnic cohort of sarcoidosis patients.

Summary

Sarcoidosis presents as a fascinating and challenging disease with myriad clinical, radiological, and pathological manifestations. Despite extensive research in the last decade to increase our understanding of the mechanisms of disease evolution and progression, the underlying etiology remains unidentified. The treatment paradigm has changed over the last 10 years with the introduction of biological agents such as infliximab and adalimumab [42]; these anti-TNF drugs offer a treatment option in refractory cases of sarcoidosis with or without corticosteroids and other anti-metabolites. Methotrexate is the preferred first-line immunosuppressive agent after corticosteroids and has a safer adverse effect profile in comparison to azathioprine. Larger randomized studies to evaluate the efficacy of antimycobacterial agents and newer biologics are warranted before making strong recommendations for the use of these drugs, as there are significant potential toxic effects associated with their use.

Corresponding author: Dr. Ahmed Fahim, Dept. of Respiratory Medicine, McHale Centre New Cross Hospital, Wolverhampton, UK WV10 0QP, ahmedfahim@doctors.org.uk.

Financial disclosures: None.