Obinutuzumab in Rheumatic Diseases: The New Kid on the Block!

Dear Editor,

We present a series of three cases in which we tried novel B-cell depleting agent obinutuzumab, where rituximab failed to respond or could not be used, with favourable outcomes.

Case No 1: IgG4-related Disease

A 39-year-old male presented with acute onset retrobulbar pain and swelling in the right eye. On examination, he had right eye proptosis. MRI of brain and orbit showed an enlargement of extraocular muscles and an enlarged lacrimal gland. His IgG4 levels were >4 g/dl (normal value <2.1 g/dl), lacrimal gland biopsy findings confirmed IgG4-related disease. He was started on high-dose oral steroids with methotrexate 15 mg/week. However, he developed persistent transaminitis and he was switched to MMF 2 g/day. In view of poor response, he was given monthly cyclophosphamide pulses followed by azathioprine. However, he continued to be symptomatic with persistently high IgG4 levels and hence started on rituximab infusion, to which he developed a severe infusion reaction. Rituximab was discontinued and in view of the refractory disease, he was started on Obinutuzumab infusions. He showed a marked clinical response with more than 50% reduction in IgG4 levels.

Case No 2: SLE with Shrinking Lung Syndrome

Twenty-eight-year males diagnosed with a case of SLE based on mucocutaneous, haematological, lupus nephritis class III+V with low compliments and high dsDNA titres. He was managed with pulse methylprednisolone followed by high-dose oral steroids and mycophenolate mofetil 2g/day along with hydroxychloroquine and ACE inhibitors. However, on follow-up, there was a worsening of proteinuria and he was started on monthly cyclophosphamide pulses. He continued to have persistent proteinuria and developed recurrent acute chest pain episodes with progressive cytopenia. He had relentless disease progression despite a combination of different immunosuppressants (Figure 1). He was diagnosed as a case of shrinking lung syndrome and started on Obinutuzumab infusions. After the initial clinical response, he succumbed to his illness due to bronchopneumonia after eight months.

Figure 1.

The Course of the Disease.

Case No 3: Mixed Connective Tissue Disorder

Thirty-year-old female with a case of mixed connective tissue disorder diagnosed on basis of high titre U1RNP positivity and severe Raynaud’s with refractory digital ulcers, diffuse cutaneous skin thickening, interstitial lung disease with moderate PAH, cutaneous ulcers, arthritis, serositis, cytopenia was started on monthly cyclophosphamide pulse for ILD. cyclophosphamide was discontinued due to tubercular arthritis left knee. She was advised mycophenolate mofetil 1g BD, but discontinued due to gastrointestinal intolerance. She continued to have refractory cutaneous ulcers and advised rituximab infusions. Rituximab had to be discontinued due to severe infusion reaction and started on Obinutuzumab infusions. On follow-up, she had marked clinical improvement (Figure 2).

Figure 2.

Healing of Treatment-refractory Cutaneous Ulcers.

A summary of three cases is given in Table 1.

Table 1.

Summary of Three Cases.

Diagnosis	IgG4-RD	SLE	MCTD
Age (years)	39	28	30
Sex	Male	Male	Female
Clinical features	Right eye proptosis with pain	Polyarthritis, cutaneous vasculitis, refractory lupus nephritis, cytopenia, shrinking lung syndrome	Diffuse cutaneous skin thickening, ILD, cytopenia, refractory digital ulcers and polyserositis
Previous immunosuppressants	Methotrexate, CYC, azathioprine, MMF, rituximab	CYC, azathioprine MMF, rituximab, IVIG, Tacrolimus	CYC, MMF, Rituximab
Indication of Obinutuzumab	Infusion reaction to rituximab	Refractory disease	Infusion reaction to rituximab
Dose	1g 2 weeks apart	1g 2 weeks apart	1g 2 weeks apart
Outcome	Improvement in ocular pain and reduction in proptosis, decrease in lacrimal gland swelling and IgG4 levels	Initial improvement in proteinuria and cytopenia. Death.	Improvement in cytopenia, skin thickening, serositis and healing of vasculitic ulcers with a significant reduction in IgG levels

Obinutuzumab is a humanised and glycoengineered type II anti-CD20 monoclonal antibody that has superior in vitro B-cell cytotoxicity compared with rituximab. ¹ Obinutuzumab showed improvement in renal response when compared to standard therapy alone in a randomised control trial done in 125 patients with lupus nephritis. ² In a retrospective study, IgG4-related ophthalmic disease rapidly reduced ocular inflammation and a mean reduction in IgG4 levels with an excellent safety profile. ³ In another case series, Obinutuzumab was also proved to be effective in SLE, anti-Jo1 syndrome and CREST syndrome in patients with no response to rituximab. ⁴ In our case series too, Obinutuzumab showed an excellent response in all cases though, one patient with refractory lupus nephritis and shrinking lung syndrome succumbed to his illness after initial response. Obinutuzumab may be promising option in rheumatic diseases in refractory disease or cases where rituximab is not a feasible option.