Castleman disease and lymphocytic interstitial pneumonia: a complex diagnostic and management challenge

Rheumatology key message Combined proteasome inhibitor and anti-CD20 therapy is effective in treatment-resistant multicentric Castleman disease. Sir, Castleman disease (CD) is a rare lymphoproliferative disorder, which in its multicentric form results in systemic inflammatory symptoms, lymphadenopathy and multi-organ involvement. IL-6 is implicated in CD pathogenesis, inducing B cell proliferation, hypergammaglobulinaemia and acute phase responses [1]. Mediastinal lymphadenopathy is common, but other pulmonary manifestations are infrequent [2, 3]. Multiple treatments have been reported1; unsurprisingly, an evolving role of biological therapies is emerging. We present the clinical course of a 33-year-old female of Chinese descent with systemic upset and cystic lung disease due to lymphoid interstitial pneumonia (LIP), subsequently diagnosed as manifestations of idiopathic HIV-negative HHV-8-negative multicentric plasma cell type of CD. We describe her clinical course as influenced by the advent of a variety of immunomodulatory therapies. Radiological, pathological and immunological manifestations in a case of multicentric Castleman disease (A) High-resolution CT scan demonstrating multiple thin-walled cysts. (B) Bone marrow trephine stained for CD138. (C) Mediastinal lymph node biopsy stained with haematoxylin and eosin. (D) Serum immunoglobulin concentrations during the course of treatment (IgG normal range: 6–16 g/l; IgM normal range: 0.4–2.4 g/l; IgA normal range: 0.8–4.0 g/l). (E) ESR during course of treatment (normal range: 1–12 mm/h). (F) CRP during course of treatment (normal range: <10 mg/l). (D–F) Boxes relate to treatment periods with toculizumab, bortezomib and rituximab (with corresponding key shown to the right of the figure). Given the lack of treatment response, alternative diagnoses were explored. Hypergammaglobulinaemia was notably persisting and rising [IgG being 60 g/l (normal range: 6–16 g/l) in 2010, increasing to 68.2 g/l by March 2011, with additional IgA and M increases]. Bone marrow aspirate demonstrated excess plasma cells (up to 50% of the cellularity; Fig. 1B), but no clonal lymphocyte population or lymphoma evident. Whole-body CT demonstrated persistent thoracic lymphadenopathy and worsening lung involvement, but no solid organ abnormality or non-thoracic adenopathy. Repeat autoantibody and infection screen was negative. Literature review highlighted an association of CD with LIP in patients of Asian ancestry, a feature not readily evident in the Western literature [4]. Lymph node biopsy via mediastinoscopy demonstrated substantial plasmacytic infiltrate (Fig. 1C) consistent with the plasma cell variant of CD. Both HIV and HHV-8 infection are associated with CD, but serum and lymph node tissue demonstrated no HHV-8 infection. Serum free IL-6 concentrations were not elevated. Her condition deteriorated, with requirement for home oxygen, ongoing weight-loss and IgG rising to 72.9 g/l. With IL-6 implicated in CD pathogenesis, the anti-human IL-6 receptor mAb tocilizumab (350 mg i.v. monthly infusion) was commenced. Mixed treatment response was seen, with only transient symptomatic improvement, mixed immunoglobulin response with partial improvement in IgG, only transient reduction in IgA and no improvement in IgM levels (Fig. 1D), no effect on ESR (Fig. 1E) and limited CRP reduction (Fig. 1F). Dosage was increased to twice monthly infusions, with no additional benefit. Respiratory disease continued to worsen. Given the lack of elevation in free IL-6 and response to IL-6 blockade in our patient, we elected to focus on the hyperglobulinaemia, and accordingly used the proteasome inhibitor bortezomib (six cycles of 2-weekly s.c. injections with dexamethasone; commenced April 2014) to target plasma cell immunoglobulin synthesis directly. Initial improvements were evident, with reduction in all immunoglobulins, normalization of CRP and reduction in ESR (Fig. 1D–F), improved respiratory function and nutritional status, with normalization of weight and albumin. Inflammatory indices began to increase during the treatment course, and disease activity recurred shortly after bortezomib cessation. B cell targeting was re-attempted via anti-human CD20 mAb rituximab (two 1000 mg i.v. infusions; June 2015), in combination with further bortezomib (six cycles with dexamethasone). Combination therapy resulted in sustained symptomatic improvement, lung disease stabilization and marked improvement in all inflammatory indices (Fig. 1D–F). However, recent rising inflammatory indices off therapy suggest that further courses will be required. Aside from the complex diagnostic challenge presented by this case and the importance of considering clinical disease in the setting of ethnicity, her management highlights evolving therapies against CD-mediated immune dysregulation. Despite a small prospective study reporting sustained efficacy (median treatment duration of 65 weeks) of tocilizumab in multicentric HIV-negative CD [5], we achieved only transient response; perhaps commensurate with the low circulating IL-6 levels. Neutralizing antibodies to tocilizumab have been implicated in lack of efficacy, although typically occur infrequently with this agent. Reports of bortezimib inducing sustained remission in CD exist [6]. Small prospective studies in HIV-positive CD demonstrate that rituximab maintains a sustained response either alone or following chemotherapy [7]. We are unaware of any previous reports of bortezomib with rituximab in HIV-negative CD, a therapeutic combination that we have found to result in effective sustained amelioration of resistant systemic CD manifestations. Although we have focused on therapeutic targeting of B cell dysregulation and hyperglobulinaemia, we are open to consideration of alternative immune pathways [8], with comprehensive studies potentially elucidating a complex immunopathogenesis in our patient. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: I.B.M. has received grants or honoraria from AbbVie, Roche, Novartis Janssen, Union Chimique Belge, Celgene, Pfizer and Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

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