Primary Sjögren’s syndrome-associated interstitial lung disease: a case report with favourable response to tocilizumab

Abstract

Severe pulmonary involvement in primary Sjögren’s syndrome presents a therapeutic challenge, particularly when conventional immunosuppression is insufficient. We report on the case of a 50-year-old woman with interstitial lung disease and profound gas exchange impairment (DLCO 17%). Despite initial treatment with azathioprine, clinical response was inadequate. Early escalation to tocilizumab was followed by marked clinical and radiological improvement. This case highlights the potential importance of timely biologic intervention in severe disease and suggests that advanced functional impairment may still be reversible. Limitations include a single-case design and concomitant therapy.

PLAIN LANGUAGE SUMMARY

What was studied and why?

Sjögren’s syndrome a condition where the immune system attacks the body’s own tissues. While it often causes dry eyes and mouth, it can also affect the lungs. In some patients, this leads to serious lung disease that makes breathing difficult and reduces oxygen transfer. Treating lung involvement can be challenging, especially when standard medications do not work well.

What were the findings?

We describe a 50-year-old woman who first developed breathing problems and was later diagnosed with Sjögren’s syndrome-related lung disease. Her lung function was severely reduced. Initial treatment with commonly used medications did not lead to improvement. A different type of treatment, tocilizumab, which targets a specific part of the immune system, was started relatively early. After this, her symptoms improved, and her lung scans and test results showed clear recovery.

Why does this matter?

This case suggests that some patients with severe lung involvement may benefit from earlier use of targeted treatments rather than relying only on standard therapies. It also shows that even serious lung problems may improve if treated appropriately. Although this is only a single case and more research is needed, it highlights a possible approach for managing difficult cases of Sjögren’s syndrome-related lung disease.

Introduction

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, yet its clinical burden is often driven by extraglandular manifestations.1 Amongst these, pulmonary involvement is particularly significant, encompassing a wide spectrum, from airway disease to interstitial lung disease (ILD) and is associated with substantial morbidity and functional decline.2 Management of pSS-associated ILD remains challenging, particularly in patients with severe or progressive disease, as response to conventional immunosuppressive therapies is often variable and may be inadequate.3 In this context, there is growing interest in targeted biologic therapies that address specific inflammatory pathways.

IL-6 has been implicated in the pathogenesis of Sjögren’s syndrome,4 and tocilizumab, an IL-6 receptor antagonist, has demonstrated efficacy in several autoimmune conditions;5,6 however, its role in pSS-associated pulmonary disease remains poorly defined, with limited clinical evidence available. Here, we present a case of severe pSS-associated ILD in which early consideration of IL-6 inhibition was pursued following inadequate response to conventional therapy.

Methods

This case report was prepared in following CARE guidelines. All patient information has been fully de-identified; therefore, institutional review board approval and patient consent were not required.

Case presentation

A 50-year-old Iranian woman presented with progressive respiratory symptoms in September 2025. The patient was referred to Shahid Rahnemoon Hospital on September 16, 2025, with a 2-month history of persistent cough accompanied by haemoptysis. She had previously received empirical antibiotic therapy without clinical improvement.

She reported exertional dyspnoea, experiencing shortness of breath after walking approximately 100 m. She denied any associated chest pain. Additionally, she had a history of chronic ocular dryness with redness, along with xerostomia. She also reported episodic epistaxis. There was no history of fever, myalgia, arthralgia or recent significant respiratory infection.

The patient presented with a significant past medical history, including hypertension for 10 years, ischaemic heart disease for which a coronary angiography was performed 7 years prior and a history of infertility. At the time of initial assessment, her medication regimen comprised amlodipine/valsartan 5/80 mg (Valzomix*1), taken twice daily and rosuvastatin 40 mg daily. She reported denial of tobacco use or second-hand smoke exposure, of alcohol or substance abuse, and of specific occupational exposures such as farming or baking. No known allergies were reported, and her family history was unremarkable.

The baseline physical examination found the patient to be alert, oriented and co-operative and she had obesity with a weight of 108 kg and a height of 165 cm, yielding a body mass index of approximately 39.7 kg/m². Oral examination revealed no ulcers, and no palpable lymphadenopathy was detected. Pulmonary examination showed decreased breath sounds and the presence of rales in both lungs. Neurological and musculoskeletal examinations were also within normal limits, demonstrating a full range of motion without joint swelling or tenderness.

The patient’s complete blood count revealed high red blood cells and low lymphocyte counts. Biochemical analysis (Table 1) was unremarkable except for elevated levels of aspartate aminotransferase and alanine aminotransferase. Urinalysis results were largely unremarkable with a normal yellow appearance, specific gravity of 1020 and a normal pH range. Autoimmune markers were largely negative, including double-stranded DNA, anti-SSA (Ro60) and anti-SSB (La). However, a positive result for anti-SSA (Ro52) was noted at 24.31 U/mL (normal <12 U/mL). The Schirmer test, conducted by an ophthalmologist, revealed reduced tear production of 4 mm.

Table 1.

Summary of laboratory test results.

	Test	Result	Unit	Reference interval	Interpretation
Complete blood count	White blood cells	8.5	103/μL	4.0–11.0	Normal
	Red blood cells	5.34	106/μL	4.5–5.1	High
	Neutrophils	61.9%	–		Normal
	Lymphocytes	26.1%	–		Low
	Haemoglobin	14.0	g/dL	13.5–17.5	Normal
	Platelets	223	K/μL	150–450	Normal
	MCV	80.9	fL	80–100	Normal
	MCH	26.22	pg	27–33	Low
	MCHC	32.41	g/dL	33.4–35.5	Low
	RDW	15.1%	–	<15%	Borderline high
Biochemistry panel	Fasting blood sugar	95	mg/dL	70–100	Normal
	Creatinine	0.9	mg/dL	0/6–1.3	Normal
	Blood urea nitrogen	15	mg/dL	7–20	Normal
	Aspartate aminotransferase	45	U/L	10–40	High
	Alanine aminotransferase	55	U/L	7–56	High
	Alkaline phosphatase	110	U/L	40–130	Normal
	Total bilirubin	0.8	mg/dL	0.2–1.2	Normal
	Triglycerides	160	mg/dL	45–160	Borderline high
	Cholesterol	190	mg/dL	<200	Normal
	HDL	35	mg/dL	>40	Low
	LDL	130	mg/dL	<130	Borderline high
Blood gas	PH	7.362	–	7.36–7.41	Normal
	PCO2	38.6	mmHg	35–45	Normal
	PO2	60.0	mmHg	95–100	Low
	HCO3−	21.4	mEq/L	21–28	Low
	SO2c	89.9	%	95–100	Low
	BE ecf	−4.0	Mmol/l	−2 to +2	Low
	BE(B)	−3.6	Mmol/l	−2 to +2	Low

HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; RDW, red cell distribution width.

Chest X-ray demonstrated opacities in the lower right lung zone, accompanied by atelectasis in the same region. High-resolution computed tomography (HRCT) was recommended for further evaluation (Figure 1). HRCT of the chest demonstrated bilateral reticulation with residual ground-glass opacities (Figure 2). Additional findings included plate-like atelectasis, bronchiectasis and interlobular septal thickening in both lungs, along with cardiomegaly. No pleural effusion was identified. In light of these imaging findings, PCR testing for COVID-19 and influenza viruses was performed, with both yielding negative results. Sputum culture and Mycobacterium tuberculosis (BK) testing were also conducteded, and both results were negative.

Figure 1.

Chest X-ray demonstrating opacities and associated atelectasis within the lower right lung zone.

Figure 2.

(A) Chest computed tomography (CT) at the beginning of follow-up showing multi-lobar ground-glass opacities (blue arrow) and interlobular septal thickening. (B) Chest CT after 6 months of tocilizumab therapy demonstrating marked reduction of ground-glass opacities and septal thickening with residual fibrotic ground-glass (blue arrow) and evidence of bronchiectasis (orange arrow).

Spirometry and body plethysmography data indicated a mild to moderate obstructive lung pattern, characterized by reduced forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁), despite a relatively preserved FEV₁-to-FVC ratio. There were also clear signs of air trapping with elevated residual volume (RV) and functional residual capacity, resulting in a significantly increased RV-to-total lung capacity (TLC) ratio (Table 2). Diffusion lung capacity for carbon monoxide (DLCO) results indicated significantly impaired lung function. DLCO was markedly reduced at 17% of predicted, suggesting poor gas exchange efficiency. This was corroborated by a low KCO (transfer coefficient) of 68% predicted. Lung volumes were also diminished with RV, functional residual capacity, inspiratory vital capacity and TLC all below 33% of predicted, indicating severe restrictive lung disease. The RV-to-TLC ratio of 69% predicted further supports a restrictive pattern (Table 3).

Table 2.

Spirometry and body plethysmography parameters.

Parameter	Unit	Pred	Best (Pre)	%Pred
FVCex	L	3.15	1.61	51
FEV1	L	2.69	1.49	55
PEF	L/s	6.50	5.80	89
FEV1/FVC	%	80	92	115
MEF25–75	L/s	3.32	3.08	93
RV	L	1.77	1.95	110
TLC	L	5.10	3.56	70
RV/TLC	%	34	55	161
VC	L	3.14	1.61	51
FRC	L	2.75	2.58	94
FRC/TLC	%	53	73	138
VTG	L	2.75	2.20	80

FEV₁, forced expiratory volume in 1 second; FEV₁/FVC, forced expiratory volume in 1 second to forced vital capacity ratio; FRC, functional residual capacity; FRC/TLC, functional residual capacity to total lung capacity ratio; FVCex, forced vital capacity (expiratory); MEF25–75, maximal expiratory flow at 25–75% of FVC; PEF, peak expiratory flow; RV, residual volume; TLC, total lung capacity; VC, vital capacity; VTG, volume of thoracic gas.

Table 3.

DLCO manoeuvre results.

Parameter	Pred	Best (Pre)	%Pred	Pre #1(B)	%Pred
DLCO (mL/min/mmHg)	24.92	4.26	17	4.26	17
KCO (mL/min/mmHg/l)	4.89	3.31	68	3.31	68
RV (I)	1.77	0.32	18	0.32	18
FRCdiff (1)	2.75	0.73	27	0.73	27
IVC (1)	3.14	1.03	33	1.03	33
TLC (1)	5.10	1.34	26	1.34	26
RV/TLC (%)	34	24	69	24	69

DLCO, diffusing capacity of the lung for carbon monoxide; FRCdiff, functional residual capacity; IVC, inspiratory vital capacity; KCO, transfer coefficient for carbon monoxide; RV, residual volume; TLC, total lung capacity.

Based on the presence of sicca symptoms, positive anti-SSA antibodies, and an abnormal Schirmer test, the patient met the EULAR/ACR classification criteria for Sjögren’s disease.7 Given pulmonary involvement, spirometry and DLCO, the patient was diagnosed with pSS with associated ILD. She was initiated on immunosuppressive therapy, including low-dose corticosteroids and azathioprine. Due to the patient’s reduced pulmonary function, significant xerostomia (dry mouth) and ocular dryness, which caused considerable discomfort and showed slow efficacy with oral medications, treatment was further augmented with the IL-6 receptor inhibitor, tocilizumab (Actemra‡2). This decision was informed, in part, by limited published experience describing the potential benefit of tocilizumab in connective tissue disease-associated ILD though direct evidence in pSS-associated ILS remains scarce.8

Follow-up

Over the course of 6 months, the treatment regimen evolved. In the first month, the patient was prescribed prednisolone 10 mg daily and azathioprine (Izatip§3) 50 mg daily. By the second month, the prednisolone dose was tapered to 5 mg daily, whilst azathioprine was prescribed at 150 mg daily. In the third month, prednisolone was discontinued. Tocilizumab (400 mg monthly) and azathioprine (150 mg daily) were continued throughout the sixth month.

At the follow-up evaluation, at 6 months following initiation of tocilizumab therapy, the patient reported substantial clinical improvement. She denied experiencing cough, sputum production, exertional dyspnoea, fever, chills, night sweats, myalgia, arthralgia, ocular redness, xerostomia or vaginal dryness. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) follow-up data are presented in Figure 3. Her current medications consisted of amlodipine/valsartan (80/5 mg daily), rosuvastatin (20 mg daily), aspirin (81 mg daily), supracal K2 daily, azathioprine (maintenance dose: 150 mg daily) and tocilizumab (maintenance dose: 400 mg monthly). The physical examination at this follow-up revealed a weight of 112 kg. The patient remained withobesity but clinically stable. No oral ulcers or lymphadenopathy were observed. Chest examination remained symmetric without respiratory distress, and cardiac examination was normal. Abdominal examination indicated a soft, non-tender abdomen with an umbilical hernia noted which had been present for 1 year. Neurological and musculoskeletal examinations were also normal, with a full range of motion documented.

Figure 3.

Time-course of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).

Discussion

pSS is a systemic autoimmune disorder with well-recognized extraglandular manifestations, amongst which ILD is a severe complication associated with increased morbidity and mortality, significantly impacting patient prognosis.2 The reported prevalence of ILD in pSS varies widely (approximately 9–75%), reflecting differences in study populations and diagnostic criteria; however, clinically significant pulmonary involvement represents an important and potentially progressive disease subset.9,10 This case highlights an atypical presentation, complex functional impairment, and a favourable response to combined immunosuppressive and biologic therapy.

A key feature of this case is the predominance of respiratory symptoms at presentation, including chronic cough, haemoptysis and exertional dyspnoea with relatively subtle sicca manifestations. Although glandular symptoms are classically central to pSS, pulmonary involvement may precede or overshadow them, contributing to delayed diagnosis. The diagnosis in this patient was supported by an abnormal Schirmer test and anti-SSA (Ro52) positivity. Whilst isolated anti-Ro52 antibodies have been associated with an increased risk of ILD and more severe pulmonary involvement in pSS and other autoimmune diseases, this relationship remains incompletely defined and should be interpreted cautiously.11,12

Radiologically, HRCT demonstrated bilateral ground-glass opacities, reticulation, bronchiectasis and interlobular septal thickening — findings consistent with patterns such as non-specific interstitial pneumonia and lymphoid interstitial pneumonia, which are commonly reported in pSS-associated ILD. The coexistence of interstitial and airway abnormalities underscores the heterogeneous nature of pulmonary involvement, encompassing both parenchymal and small airway pathology.

Pulmonary function testing revealed severe impairment, particularly a markedly reduced diffusing capacity (DLCO 17% predicted), indicative of significant gas exchange dysfunction. Reduced DLCO is a sensitive but non-specific marker of gas exchange impairment in connective tissue disease-associated ILD and has been associated with greater disease extent and poorer clinical outcomes, including increased mortality risk.13 Notably, the patient exhibited a mixed ventilatory defect with both restrictive features and evidence of air trapping. This pattern is consistent with combined interstitial fibrosis and small airway disease, the latter increasingly recognized in pSS and supported in this case by the presence of bronchiectasis.

In this patient, trends in NLR and PLR appeared to parallel clinical improvement following treatment, suggesting a potential role as adjunctive markers of disease activity and therapeutic response. Elevated values of NLR and PLR have been associated with increased disease activity and poorer outcomes in autoimmune diseases and ILD, reflecting an imbalance between innate and adaptive immune responses.14

The differential diagnosis of ILD in this patient included infectious aetiologies, overlap connective tissue diseases and other forms of interstitial pneumonia. Extensive microbiological evaluation was negative, and the absence of additional autoimmune features supported the diagnosis of pSS-associated ILD. Although histopathological confirmation was not obtained, current clinical practice and EULAR-aligned approaches do not mandate lung biopsy in cases where clinical, serological and radiological findings are concordant, as in this patient.15

Management of pSS-associated ILD is not standardized and is based largely on empirical use of corticosteroids and immunosuppressive agents, including azathioprine and mycophenolate mofetil, owing to the limited availability of randomized controlled trial data.3,16 Current American College of Rheumatology recommendations do not support the routine use of tocilizumab in pSS-associated ILD progression, reflecting the limited and low-certainty evidence currently available.17 However, therapeutic decision making in connective tissue disease-associated ILD is often influenced not only by the underlying diagnostic classification but also by disease severity, progression, radiological phenotype and treatment responsiveness. In the present case, despite initial immunosuppressive therapy, the patient continued to demonstrate severe functional impairment with markedly reduced DLCO and progressive respiratory symptoms. In addition, glucocorticoid escalation was limited by comorbidity-related risk considerations. Following multidisciplinary discussion and individualized risk–benefit assessment, treatment was escalated to tocilizumab. IL-6 is elevated in pSS and contributes to B cell activation, autoantibody production and systemic inflammation.4 It has also been implicated in fibrotic pathways through its effects on fibroblast activation and tissue remodelling, supporting a possible role in disease progression and pulmonary involvement.18 Figure 4 presents a proposed conceptual framework based on current literature regarding IL-6 signalling in connective tissue disease-associated ILD.

Figure 4.

Proposed immunopathogenic mechanisms in Sjögren’s syndrome-associated interstitial lung disease and the potential relevance of tocilizumab. Progression from initial epithelial injury to end-stage fibrosis is characterized by three distinct phases. In the initial trigger phase, the Sjögren’s syndrome environment, marked by activated B cells and auto-antibodies, induces alveolar epithelial injury, releasing IL-1 and damage-associated molecular patterns (DAMPs) that establish a pro-inflammatory positive feedback loop. During macrophage polarization and T cell interaction, recruited monocytes differentiate into M1 (pro-inflammatory) or M2 (pro-fibrotic) macrophages; M1 cells drive T helper 17 (T_H17)-mediated chronic inflammation via IL-6, whilst M2 cells promote TGFβ release. This cytokine imbalance suppresses regulatory T (T_reg) cells, further destabilizing immune homeostasis. In the final epithelial–mesenchymal transition (EMT) and fibrosis phase, chronic IL-6 and TGFβ signalling synergistically trigger EMT and activate the JAK–STAT3 pathway, facilitating fibroblast–myofibroblast transition (FMT). This cascade results in pathological extracellular matrix (ECM) and collagen production, leading to lung fibrosis. Tocilizumab intervenes by blocking IL-6, thereby inhibiting T_H17 activation, restoring T_reg cell-mediated immune suppression, and halting JAK–STAT3-driven fibrotic signalling. This figure was created by the authors.

Following the introduction of tocilizumab, the patient demonstrated marked clinical and radiological improvement, including resolution of symptoms and reduction of ground-glass opacities. Given the markedly reduced DLCO and progressive clinical presentation, spontaneous improvement would be unlikely. Although concomitant azathioprine therapy may have contributed to the observed response, the temporal association with tocilizumab initiation suggests a potential therapeutic effect. Notably, despite profound baseline impairment, the observed improvement indicates that a significant component of the pulmonary involvement may have reflected potentially reversible inflammatory activity rather than irreversible fibrosis. Nevertheless, conclusions regarding efficacy should be interpreted cautiously, given the single-case nature of this report.

From a novelty standpoint, this case contributes to the limited literature on biologic therapy in pSS-associated ILD, particularly in the context of severe gas exchange impairment and mixed ventilatory defects. It also emphasizes the importance of recognizing atypical presentations and the potential for meaningful clinical improvement even in advanced disease. However, larger prospective studies are required before definitive conclusions regarding the role of IL-6 inhibition in pSS-associated ILD can be established.

Conclusion

This case illustrates an atypical and severe presentation of pSS-associated ILD with significant functional impairment, highlights the complexity of diagnosis and management, and supports a possible therapeutic role for IL-6-targeted therapy in selected severe cases, warranting further investigations.