Relevance of P-glycoprotein on CXCR4+ B cells to organ manifestation in highly active rheumatoid arthritis.

INTRODUCTION: In rheumatoid arthritis (RA), P-glycoprotein (P-gp) expression on activated B cells is associated with active efflux of intracellular drugs, resulting in drug resistance. CXCR4 is associated with migration of B cells. This study was designed to elucidate the relevance of P-gp expression on CXCR4+ B cells to clinical manifestations in refractory RA. METHODS: CD19+ B cells were analyzed using flow cytometry and immunohistochemistry. RESULTS: P-gp was highly expressed especially on CXCR4+CD19+ B cells in RA. The proportion of P-gp-expressing CXCR4+ B cells correlated with disease activity, estimated by Simplified Disease Activity Index (SDAI), and showed marked expansion in RA patients with high SDAI and extra-articular involvement. In highly active RA, massive infiltration of P-gp+CXCR4+CD19+ B cells was noted in CXCL12-expressing inflammatory lesions of RA synovitis and RA-associated interstitial pneumonitis. In RA patient with active extra-articular involvement, intracellular dexamethasone level (IDL) in lymphocytes diminished with expansion of P-gp+CXCR4+ CD19+ B cells. Adalimumab reduced P-gp+CXCR4+ CD19+ B cells, increased IDL in lymphocytes, and improved the clinical manifestation and allowed tapering of concomitant medications. CONCLUSIONS: Expansion of P-gp+CXCR4+ B cells seems to be associated with drug resistance, disease activity and progressive destructive arthritis with extra-articular involvement in RA.

Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease.

Although corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) are widely used in the treatment of various systemic autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with systemic autoimmune diseases who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapy in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocytes, which are the major target in the treatment of systemic autoimmune diseases, remains unclear. Studies from our laboratories found surface expression of P-gp on peripheral lymphocytes in patients with SLE and a significant correlation between the expression level and disease activity. Such expression is induced not only by genotoxic stresses but also by various stimuli including cytokines, resulting in active efflux of drugs from the cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the use of both P-gp antagonists (e.g., cyclosporine) and inhibition of P-gp synthesis with intensive immunosuppressive therapy successfully reduces the efflux of corticosteroids from lymphocytes in vitro, suggesting that P-gp antagonists and P-gp synthesis inhibitors could be used to overcome drug-resistance in vivo and improve outcome. In conclusion, lymphocytes activated by various stimuli in patients with highly active disease apparently acquire MDR-1-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. The expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable target to combat drug resistance in patients with active systemic autoimmune diseases.

Efficacy of combination therapy of anti-TNF-α antibody infliximab and methotrexate in refractory entero-Behçet's disease.

It is often difficult to manage refractory gastrointestinal tract complications of Behçet's disease (entero-BD) by conventional therapy. In this study, we assessed the short- and long-term efficacy and safety of the combination therapy of infliximab, an anti-tumor-necrosis-factor (TNF)-α antibody, and methotrexate in ten patients with refractory entero-BD refractory to conventional therapies. The short- (weeks) and long-term (by 2 years) effects of infliximab at 3-5 mg/kg body weight every 8 weeks on the clinical course and intestinal manifestations were assessed by abdominal computed tomography (CT) and colonoscopy. The primary endpoint was the rate of disappearance of ileocecal ulceration at 12 months of therapy. All patients showed improvement of gastrointestinal symptoms and disease-associated complications within 4 weeks. Furthermore, the rate of disappearance of ileocecal ulcerations was 50% (5/10 patients) at 6 months and 90% (9/10 patients) at 12 months, and, therefore 90% of patients were satisfied with the primary endpoint. Furthermore, corticosteroid dose was significantly reduced from 22.0 to 1.8 mg/day at 24 months. No severe adverse effects were observed during the 24 months of follow-up. We provide evidence for the rapid and excellent efficacy of infliximab in patients with refractory entero-BD and that the combination of infliximab and methotrexate brings about long-term alleviation of entero-BD and excellent tolerability.

Potential of B-cell-targeting therapy in overcoming multidrug resistance and tissue invasiveness associated with P-glycoprotein expressing-B cell compartments.

Rheumatoid arthritis (RA) is a systemic autoimmune mediated inflammatory disease characterized by progressive joint damage and extra-articular organ manifestations. Among the effector pathways and cells involved in the development of RA, activated B cells play a pivotal role in the pathological process of RA. P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, is induced on the cell membrane by certain stimuli. P-gp transports various drugs from the cytoplasm to the cell exterior, resulting in the development of drug resistance. P-gp expression on B cells appears in patients with RA as the disease activity increases, and treatment of these patients' results in modification of over-expression of P-gp on activated B cells. Evidence suggests that P-gp expressing-activated B cells play important roles in the pathogenesis and treatment resistance in RA through the efflux of intracellular drugs and progression of infiltration in inflammatory lesions. Therapies designed to target activated B cells might overcome refractory RA. Identification of the subsets of peripheral activated B cells that express P-gp in RA patients might help the selection of suitable treatment strategy.

Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis.

P-glycoprotein (P-gp) on activated lymphocytes is an adenosine triphosphate (ATP)-binding cassette transporter that causes drug resistance by exclusion of intracellular drugs in patients with active rheumatoid arthritis (RA). However, infliximab with methotrexate (MTX) can overcome P-gp-mediated drug resistance. We encounter patients who cannot continue infliximab or MTX. Here we tested how etanercept affected P-gp-mediated drug resistance in such intractable RA patients. Peripheral lymphocytes of 11 RA patients (3 switched from infliximab and 8 who could not be treated with MTX) were analyzed for P-gp expression by flow cytometry and for drug exclusion using radioisotope-labeled dexamethasone. Activated lymphocytes of RA patients overexpressed P-gp and coexpressed CD69. Incubation of these lymphocytes with dexamethasone in vitro reduced intracellular dexamethasone levels. Two-week etanercept therapy significantly reduced P-gp expression and eliminated such P-gp- and CD69-high-expressing subgroup. The reduction in P-gp resulted in recovery of intracellular dexamethasone levels in lymphocytes and improvement of disease activity, thus allowing tapering of corticosteroids. None of the patients experienced any severe adverse effects. Etanercept is useful for overcoming P-gp-mediated treatment resistance in intractable RA patients who have to discontinue infliximab or are intolerant to MTX.

Treatment with Methotrexate and Intravenous Cyclophosphamide Pulse Therapy Regulates the P-gp+CD4+ Cell-related Pathogenesis in a Representative Patient with Refractory Proliferative Lupus Nephritis.

Diffuse proliferative lupus nephritis (DPLN) is a serious organ complication. Drug resistance correlates with P-glycoprotein (P-gp) expression on activated lymphocytes. We encountered a refractory DPLN patient with expansion of peripheral CD69/CXCR3-co-expressing P-gp+CD4+ cells producing IL-2 and IL-6. Treatment with high-dose corticosteroid combined with biweekly intravenous cyclophosphamide pulse therapy (IVCY) failed to reduce the population of activated P-gp+CD4+ cells or control the disease activity. Methotrexate (MTX) with monthly IVCY reduced activated P-gp+CD4+ cells and improved the clinical symptoms, resulting in long-term remission and tapering of corticosteroids. MTX-IVCY combination therapy, which down-regulates the activated P-gp+CD4+ cell-mediated disease activity, may be useful for the treatment of refractory DPLN.

Efficacy of Intravenous Cyclophosphamide Pulse Therapy for P-Glycoprotein-expressing B Cell-associated Active True Renal Lupus Vasculitis in Lupus Nephritis.

True renal lupus vasculitis (TRLV), a vascular lesion usually associated with proliferative lupus nephritis (LN), is resistant to conventional treatments. The expression of P-glycoprotein (P-gp) on activated lymphocytes causes drug resistance. We herein report a patient with TRLV, minimal change LN, overexpression of P-gp on peripheral B cells, and accumulation of P-gp+ B cells at the site of TRLV. High-dose corticosteroids combined with intravenous cyclophosphamide pulse therapy resulted in clinical remission and the long-term normal renal function.

Role of P-glycoprotein on CD69+CD4+ cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy.

INTRODUCTION: P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gp+CD4+ cells in organ manifestations in refractory SLE. METHODS: The proportion of P-gp+CD4+ cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression. RESULTS: CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4+ cells and CD69-expressing CD4+ cells in peripheral blood was higher in SLE than control. The proportion of P-gp+CD69+CD4+ cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gp+CD69+CD4+ cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gp+CD69+CD4+ cells. Marked accumulation of P-gp+CD4+ cells in renal interstitial tissue and high proportion of peripheral P-gp+CD69+CD4+ cells were noted in patients with proliferative LN. CONCLUSIONS: The results showed high proportion of P-gp+CD69+CD4+ cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4+ T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment.

[Multi-drug resistance in the treatments of autoimmune diseases].

Although corticosteroids and immunosuppressants are widely used for the treatments of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we often experience patients who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, plays a pivotal role in the acquisition of drug resistance. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE and RA express P-gp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by activation with cytokines such as IL-2, IL-4 and TNF-alpha, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, which mechanisms could lead to drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that measurement of P-gp on lymphocytes is useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE and RA patients.

Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis.

The main purpose of treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARDs) is to control activation of lymphocytes, although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, causes drug-resistance by efflux of intracellular drugs. Certain stimuli, such as tumor necrosis factor-α, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-box-binding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drug-resistance. However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists (e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P-gp-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA.

[Successful treatment of intravenous cyclophosphamide pulse therapy for systemic lupus erythematosus complicated with steroid-resistant hemolytic anemia].

(Case 1) A 13-years-old female had multiple arthralgia and butterfly rush, when she admitted in our hospital in May 2001. Nephropathy, hemolytic anemia (Hb 6.3 g/dl and direct Coombs 3+) and high titers of antinuclear antibodies and anti-ds-DNA antibody were disclosed and she was diagnosed as systemic lupus erythematosus (SLE). Although combination therapy of PSL 60 mg/day with a steroid pulse therapy, cyclosporine or an immunosorbent treatment, severe hemolytic anemia remained. However, monthly cyclophosphamide pulse therapy (IV-CY), which was started for the steroid-resistant hemolytic anemia, has gradually become effective and Hb improved up to 11.4 g/dl after 6 courses of IV-CY. (Case 2) A 53-years-old woman diagnosed as SLE in 1978 and she had PSL 5 mg for over 10 years. Severe anemia (Hb 5.9 g/dl) was disclosed with a slight fever in June 2001, and she admitted in our hospital for further examinations. Progressive hemolytic anemia was revealed with marked decrease of Hb (3.4 g/dl) and high titer of direct Coombs (3+). Neither PSL (50 mg/day) nor steroid pulse therapy were effective against hemolytic anemia. In contrast, 3 courses of monthly IV-CY (500 mg/day) resulted in the resolution of hemolysis. It is well known that the steroid-resistant hemolytic anemia is extremely hard to treat and leads to miserable prognosis, but we here propose IV-CY as an alternative and invaluable choice for the treatment of refractory hemolytic anemia complicated with SLE.

[Successful treatment of intravenous cyclophosphamide pulse therapy for lupus myelitis with urinary disturbance and acute confusional state].

A 18-year-old female had low grade fever, butterfly rush, proteinuria, leukocytopenia and hypocomplimentemia in 1988, and she was diagnosed as systemic lupus erythematosus (SLE) with lupus nephritis (WHOIIb). Treatments with prednisolone and mizoribine resulted in the remission for three years. In May 2001, she presented neurosis and polakisuria despite of the increase of prednisolone to 20 mg/day. Finally, she admitted in our hospital because of manic and repressive state and disorientaion. A brain MRI revealed high intensity lesions in bilateral basal ganglia in T2 weighted images, and cerebrospinal fluid showed elevated protein and IFN-alpha (421 IU/ml). In addition, she manifested neurogenic bladder, muscle weakness and hyperactive deep tendon reflex of bilateral lower limbs due to both supranuclear disorder and hypesthesia under the Th 10 level. Spinal MRI revealed marked atrophy and high intensity signals at the middle to lower thoracic spinal cord in T2 weighted images, indicating complication of lupus myelitis as well as cerebral involvement. Although the symptoms of CNS lupus did not respond to prednisolone, twelve monthly cyclophosphamide pulse therapy (IV-CY) has resolved urinary disturbance, muscle weakness and sensory loss, along with the improvement of both cerebral and spinal MRI images. Lupus myelitis and neurogenic bladder are the rare, but very refractory manifestation among CNS involvement of SLE. We here propose IV-CY as an invaluable choice for the treatment of not only active lupus myelitis but also neurogenic bladder resisted for steroid.

[Active arthritis due to cryoglobulinemia based on HCV infection in a patient with RA improvement of arthritis with IFN-alpha].

A 49-year-old Japanese woman was diagnosed with rheumatoid arthritis (RA) based on ACR criteria in May 1999. She developed liver injury after initiation of disease-modifying antirheumatic drugs (DMARDs) and was found to have contracted HCV infection. RA disease activity worsened following restriction of medication due to liver dysfunction. However, 3 mg/day of prednisolone (PSL) resulted in a temporary but marked improvement of RA in December 2001; but arthritis recurred along with Raynaud's phenomenon and palpable purpura. Differential diagnosis between arthritis caused by cryoglobulinemia and exacerbation of RA was important for the selection of appropriate treatment. She manifested non-erosive arthritis on medium and large joints with proteinuria, hematuria and hypocomplementemia. In addition, type III cryoglobulin was detected and chronic active hepatitis was observed on liver biopsy in March 2002. We considered that the main cause for the arthritis was HCV-related mixed cryoglobulinemia. Administration of IFN-alpha resulted in the disappearance of HCV-RNA and cryoglobulin followed by amelioration of arthritis without exacerbation of RA.

[Clinical implication of cyclosporin for rheumatoid arthritis].

Cyclosporin is a non-cytotoxic immunomodulating drug which inhibits NF-AT-dependent IL-2 transcription in lymphocytes. Cyclosporin is, therefore, beneficial as a monotherapy or as a combined therapy with methotrexate for refractory rheumatoid arthritis (RA). We also document that cyclosporin recovers the low concentration of intracellular multidrugs in lymphocytes by competitively binding to P-glycoprotein, a product of multidrug resistance gene-1, in vitro. Thus, cyclosporin could be used for the reversal of multidrug resistance, experienced in patients with longterm treated RA.

Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis.

OBJECTIVE: Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. METHODS: One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio). RESULTS: The disease activity of enrolled patients was 5.8 +/- 1.2 (mean +/- SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. CONCLUSION: Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment.

Complete resolution of dermatomyositis with refractory cutaneous vasculitis by intravenous cyclophosphamide pulse therapy.

Cutaneous ulcers associated with vasculitis are rarely reported in adult-onset dermatomyositis (DM), and are often resistant to treatment, resulting in a poor prognosis. There is no general treatment strategy and the effects of various treatments have never been confirmed histopathologically. A 43-year old man with DM developed refractory multiple cutaneous ulcers which were revealed as vasculitis by skin biopsy. Repeated intravenous cyclophosphamide pulse therapy (IV-CY) without high-dose corticosteroid therapy resulted in complete resolution of the ulcers without adverse effects or severe complications. A repeat biopsy confirmed complete remission of vasculitis. Repeated IV-CY is a useful treatment for induction of clinical remission of DM with cutaneous vasculitis.

Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system.

AIM: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious treatment-resistant phenotype of systemic lupus erythematosus. A standard treatment for NPSLE is not available. This report describes the clinical and laboratory tests of 10 patients with NPSLE before and after rituximab treatment, including changes in lymphocyte phenotypes. METHODS: Rituximab was administered at different doses in 10 patients with refractory NPSLE, despite intensive treatment. RESULTS: Treatment with rituximab resulted in rapid improvement of central nervous system-related manifestations, particularly acute confusional state. Rituximab also improved cognitive dysfunction, psychosis and seizure, and reduced the SLE Disease Activity Index Score at day 28 in all 10 patients. These effects lasted for >1 year in five patients. Flow cytometric analysis showed that rituximab down regulated CD40 and CD80 on B cells and CD40L, CD69 and inducible costimulator on CD4+ T cells. CONCLUSIONS: Rituximab rapidly improved refractory NPSLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings. The down regulation of functional molecules on B and T cells suggests that rituximab modulates the interaction of activated B and T cells through costimulatory molecules. These results warrant further analysis of rituximab as treatment for NPSLE.

Fragmented hyaluronan induces transcriptional up-regulation of the multidrug resistance-1 gene in CD4+ T cells.

P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in multidrug resistance. We found previously that interleukin-2, a lymphocyte-activation cytokine, induces P-glycoprotein expression on lymphocytes. Lymphocyte activation involves adhesion with the extracellular matrix, such as hyaluronan, through adhesion molecules on lymphocytes. We investigated the transcriptional regulation of MDR-1 in lymphocytes by fragmented hyaluronan. Fragmented hyaluronan (especially the 6.9-kDa form), not native high molecular hyaluronan, induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into the nucleus and resulted in the transcription of MDR-1 and the expression of P-glycoprotein on lymphocytes in a dose-dependent manner. Transfection of YB-1 antisense oligonucleotides inhibited P-glycoprotein expression induced by fragmented hyaluronan. The fragmented hyaluronan induced significant P-glycoprotein expression on only activated CD4+ T cells, which highly expressed CD69, and resulted in excretion of intracellular dexamethasone added in vitro. Cyclosporin A, a competitive P-glycoprotein inhibitor, restored intracellular dexamethasone levels in CD4+ T cells. Anti-CD44 monoclonal antibody (Hermes-1) inhibited fragmented hyaluronan-induced YB-1 activation and P-glycoprotein expression in CD4+ T cells. We provide the first evidence that binding of fragmented hyaluronan to CD44 induces YB-1 activation followed by P-glycoprotein expression in accordance with activation of CD4+ T cells. Our findings imply that CD4+ T cell activation by fragmented hyaluronan, induced by characteristic extracellular matrix changes in inflammation, tumors, and other conditions, results in P-glycoprotein-mediated multidrug resistance.

Human urinary trypsin inhibitor bolus infusion improved severe interstitial pneumonia in mixed connective tissue disease.

Interstitial pneumonia (IP) with mixed connective tissue disease (MCTD) often progresses despite immunosuppressive therapies that caused serious infections. Human urinary trypsin inhibitor (UT) inhibits inflammatory factors associated with IP, without immunosuppression. UT bolus infusion rescued a female MCTD patient with refractory IP and severe opportunistic fungal pneumonia. Her IP diminished with monthly UT bolus infusion despite tapering of prednisolone, without UT-related side effects. UT pulse therapy could prove beneficial for refractory IP in MTCD even with opportunistic infections.