In this prospective case series of sarcoidosis patients with refractory chronic non-infectious posterior uveitis, adalimumab treatment appeared successful. For it not only showed an improvement of the intraocular inflammatory signs in the majority of patients (85%), but also appeared to have a significantly positive effect on other sarcoidosis related features, including inflammatory parameters, diffusing capacity, and fatigue. Until the endpoint of the evaluation (December 2010), no deteriorations were reported in those successfully treated. Serious adverse effects only occurred in one patient.
The presence of posterior uveitis is a predictor of a poor visual prognosis, making treatment with immunosuppressive drugs mandatory [6
]. All patients in our case series had uncontrolled inflammation due to prednisone and methotrexate resistance or intolerance, or a flare-up during treatment, and therefore ocular inflammation after 12 months of follow-up would have been expected to be worse without attempting a different therapy like with adalimumab. Intraocular inflammatory signs at baseline were modest in some of the included patients. However, in the past they had posterior uveitis which again showed a flare-up, also with respect to the serological inflammatory signs, despite treatment. Delay in effective treatment could lead to refractory inflammation, potentially leading to further damage in the eye. Given the fact that further therapeutic options were limited in these cases, early adjunctive treatment was indicated. Furthermore, six of the included patients responded to previous therapy with immunosuppressive drugs, but demonstrated severe adverse effects. Therefore, also in these patients, the intraocular inflammatory signs were not pronounced.
If visually disabling cataract formation or glaucoma develops in patients with uveitis, it is essential that no ocular inflammatory activity is present at the time of surgery [32
]. One of our patients was successfully treated with a glaucoma surgery procedure (Baerveldt implant) during adalimumab therapy and no activation was seen postoperatively.
Disabling side-effects of steroid treatment, including cataract formation, glaucoma, osteoporosis, Cushing’s syndrome or diabetes mellitus, and the refractory character of the uveitis in some sarcoidosis patients, stress the need for alternatives. In the patients of this case series, adalimumab appeared to be a well-tolerated alternative and the dosage of both prednisone and MTX could be tapered down significantly during this treatment.
Previously, adalimumab also appeared to be an appropriate alternative for infliximab in patients with Crohn’s disease who first responded quite well, but had to stop due to antibody formation and/or the development of an allergic reaction and became intolerant to infliximab [33
]. The decision to switch to another TNF-α inhibitor has not been studied systematically in sarcoidosis. However, switching from infliximab to adalimumab has been successful for some patients in case of allergic reactions [34
]. In our institute, we successfully switched therapy in five patients (including patient 16 of the present study) whom had formed antibodies against infliximab (data not shown).
Previously, the combination of anti-TNF-α therapy and a cytotoxic drug has been shown to be superior to anti-TNF-α therapy alone [35
]. However, this was not reported in all situations [36
]. In our patients, the immunosuppressive medication as taken at the start of anti-TNF-α therapy was continued unless side effects occurred or contra-indications existed. In those cases the dosage of the MTX and prednisone was tapered off as described in the results section.
It remains unclear how long anti-TNF-α therapy in a responding patient should be continued. In sarcoidosis, longer follow-up data are needed to determine the optimal treatment period to avoid disease relapse or deterioration. In our experience, treatment should be continued for at least a year instead of a shorter period as in rheumatoid arthritis.
A recent randomized controlled trial with infliximab versus placebo in chronic pulmonary sarcoidosis patients showed a change in FVC, the primary end point of that study [12
]. Although in our studied population none of the patients had a decreased FVC (<80% of predicted), eight showed a decreased diffusing capacity (<80% of predicted) at baseline. These latter patients demonstrated a significant improvement of the DLCO after 6 months and 1 year of treatment with adalimumab. Unfortunately, the DLCO was not evaluated in the previously mentioned infliximab study [12
Several reports suggest that CRP can predict response to anti-TNF-α therapy in different inflammatory diseases [38
]. In line with this, in the present study, a decrease of the CRP was demonstrated after 6 months as well as after 1 year of treatment with adalimumab. Also, the decrease in ACE and sIL2-R and the improvement of fatigue during treatment with adalimumab is in accordance with findings of previous studies with anti-TNF-α agents, mainly infliximab, in sarcoidosis patients [11
]. Thus, although the primary reason for initiating treatment with adalimumab was refractory uveitis, the treatment also resulted in the improvement of systemic (inflammatory) manifestations of sarcoidosis.
This study has several limitations. Since during the follow-up period every sarcoidosis patient with refractory chronic non-infectious uveitis (as defined previously) in our clinic was treated with adalimumab in the absence of contra-indications, no control group could be evaluated. Also, the clinical examiner was not masked in grading response to treatment.
In conclusion, in this case series of sarcoidosis patients with refractory chronic non-infectious posterior uveitis, adalimumab appeared to be successful by showing improvement of intraocular inflammatory signs. Moreover, other relevant clinical indicators of disease activity improved as well. Future randomized studies are needed to determine optimal dosage, dose interval, and duration of therapy in refractory multisystemic sarcoidosis.