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Neurosarcoidosis in a Patient with Rheumatoid Arthritis During Treatment with Infliximab

To the Editor:

We describe a 41-year-old woman with erosive rheumatoid arthritis (RA) that was positive for rheumatoid factor (RF) and anti-cyclic citrullinated peptide; she was given successful treatment with infliximab combined with methotrexate (MTX), without side effects. During treatment she developed sarcoidosis, mainly involving the eyes and the central nervous system (CNS).

Case report. The patient, born in 1965, had undergone a splenectomy due to thrombocytopenia at age 16 years. At the age of 23 she was diagnosed with RA based on widespread polyarthritis, rheumatoid nodules, erosions of small joints in her feet, and RF positivity. During the following years several courses of antirheumatic treatment were given, including injectable gold, sulfasalazine, MTX, and cyclosporin A. Due to erosiveness and increased disease activity, infliximab infusions were started in March 2000 at a dosage of 3 mg/kg body weight at 6–8 week intervals together with MTX, and she responded well to this treatment. During October 2005 the patient and her husband spent 17 days in China adopting a child, during which time she remained healthy, and she received an infliximab infusion on November 18. However, during the first days of December she felt tired and had low-grade fever (38°C) and headache. At examination 2 weeks later she presented no neurological symptoms besides headache. Routine laboratory variables showed erythrocyte sedimentation rate 22 mm/h, C-reactive protein 5.3 mg/l, hemoglobin 138 g/l, white blood cell count 7.2, S-creatinine 53 µmol/l, and a slightly increased S-ALT of 1.2 µkat/l (reference value < 0.7 µkat/l). She was hospitalized at the Infectious Diseases Clinic 1 week later. At admission, physical examination was unremarkable and there was no nuchal rigidity. However, cerebrospinal fluid (CSF) analysis revealed slight pleocytosis with mononuclear leukocytes of 49 ´ 10⁶/l and polynuclear leukocytes 4 ´ 10⁶/l, normal CSF/blood glucose ratio, and slightly increased CSF protein concentration of 0.78 g/l. A tentative diagnosis of meningoencephalitis in an immunosuppressed patient with a recent history of travel in China prompted an extensive investigation for infectious etiology. However, all analyses for bacterial, viral, fungal, or protozooan infection were negative (Table 1), and no specific antimicrobial therapy was given. On repeat CSF analyses 1 and 3 weeks after admission, pleocytosis and protein level remained unchanged. Neuroradiologic investigation by computed tomography of the brain, magnetic resonance imaging (MRI) of the brain and spinal cord, and MR angiography was normal, and an electroencephalogram showed no abnormalities. Chest radiograph was unremarkable, and there was no hilar lymphadenopathy. However, the headache remained unchanged and 4 weeks after admission she developed diplopia. At neuro-ophthalmological examination 1 week later nerve palsy of the left eye and a severe papilledema in both eyes were discovered. Transcranial Doppler analysis confirmed a high intracranial pressure. Further, bilateral granulomatous iridocyclitis and retinal periphlebitis, typical for sarcoidosis, were noted. The sarcoidosis diagnosis was supported by the increased activity in the mediastinal lymph nodes bilaterally and in the parotid glands observed with ¹¹¹In-DTPA-octreotide scintigraphy. Serum angiotensin-converting enzyme (ACE) was normal, but CSF ACE showed an increased value of 5.75 kE/l (reference value < 3.0 kE/l). High-dose (4 mg bid) betamethasone was instituted, but notably without effect on high intracranial pressure. Therefore she received a ventriculoperitoneal shunt 5 weeks after admission. Following surgery she became free of headache and the pathologic ophthalmologic changes slowly subsided. She was treated with high-dose glucocorticoids (prednisolone 1 mg/kg), and MTX was started and gradually increased to 25 mg/week (injectable). There was low activity of the arthritis symptoms during summer 2006, and ophthalmologic examination revealed no papilledema and her eye muscle function was normal. She was able to return to work full-time during autumn 2006.

Table 1. Microbiological analyses of CSF and/or serum with negative results.

Tumor necrosis factor-a (TNF-a) is a proinflammatory cytokine that together with interleukin 1ß plays a major role in the pathogenesis of both RA and sarcoidosis¹. Anti-TNF therapy is recommended for treatment of active RA that is nonresponsive to disease modifying antirheumatic drugs (DMARD) such as MTX and sulfasalazine³. TNF-blocking agents are usually given in combination with other DMARD, often MTX, but are sometimes used as monotherapy⁴.

Etanercept and infliximab have been reported to improve skin and joint involvement of sarcoidosis^5,6. However, the effect of anti-TNF treatment in ocular sarcoidosis has been questioned⁷. Baughman, et al⁸ performed a placebo-controlled trial in sarcoidosis showing that infliximab improved lung function but was not efficacious in several other outcome variables. Recently, there have been 2 reports of pulmonary sarcoidosis developing during infliximab treatment in patients with ankylosing spondylitis^9,10. Further, there are reports of sarcoidosis development during treatment of RA with etanercept^11-13. Thus the efficacy and safety of TNF antagonists in sarcoidosis remain unclear. The time course of development of sarcoidosis from start of TNF inhibitor varies from 6 months up to 5 years in these reports.

The diagnosis of RA in our patient was considered definite, with erosive polyarthritis, presence of rheumatoid nodules, and RF, thus fulfilling American College of Rheumatology classification criteria. A key question is the validity of the diagnosis of sarcoidosis. This was based on typical eye findings, i.e., granulomatous iridocyclitis (mutton-fat keratic precipitate) and retinal periphlebitis ("candle wax drippings"), positive ¹¹¹In-DPTA-octreotide scintigraphy, high CSF ACE level, and clinical response to therapy. Unfortunately, no histological confirmation of the diagnosis was possible.

In our experience coexistence of RA and sarcoidosis occasionally occurs and has been reported¹⁴. Prior to the institution of infliximab therapy in our patient there were no clinical or radiological (repeated chest radiographs) signs of sarcoidosis. However, it cannot be entirely excluded that sarcoidosis occurred concomitantly with RA and it is possible that infliximab, not crossing the blood-brain barrier, in fact contributed to some control of sarcoidosis outside the CNS. Another possibility is that immunomodulation caused by anti-TNF treatment facilitated, or at least did not protect from, development of sarcoidosis. This is supported by the increased uptake outside the CNS in lymph nodes and parotid glands found with the octreotide scintigraphy. Aseptic meningitis has been reported during infliximab treatment, but without signs of sarcoidosis¹⁵.

The etiology of sarcoidosis remains unknown, although some observations suggest interactions between genetic inheritance and environmental or infectious agents. Several microorganisms have been implicated as potential causes of sarcoidosis, i.e., mycobacteria, Borrelia burgdorferi, Propionibacterium acnes, and Rickettsia helvetica^16-19. However, their role in the pathogenesis of sarcoidosis remains obscure, although it cannot be excluded that immunomodulating therapy such as TNF antagonists may trigger a disease related to a dormant microorganism.

Our case, together with previous reports on sarcoidosis manifestations developing during treatment with TNF antagonists for RA and spondyloarthropathies, stresses the importance of careful vigilance in monitoring patients treated with these drugs. These observations may contribute to understanding of the pathogenesis of autoimmune inflammatory diseases, especially sarcoidosis.

GUNNAR STURFELT, MD, PhD, Rheumatology Section; BERTIL CHRISTENSSON, MD, PhD, Clinical and Experimental Infection Medicine Section; GUNNEL BYNKE, MD, PhD, Ophthalmology Section; TORE SAXNE, MD, PhD, Rheumatology Section, Department of Clinical Sciences, University Hospital of Lund, 22185 Lund, Sweden. Address reprint requests to Dr. Sturfelt. E-mail: gunnar.sturfelt@reum.lu.se

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