Tofacitinib Induced Sjogren Syndrome in a Woman Treated for PMR

Tofacitinib induced Sjogren Syndrome has not been reported in the literature before. We present here the first case of Tofacitinib induced Sjogren Syndrome in a woman who was treated for PMR.

Tofacitinib is an oral JAK-STAT inhibitor. It has been approved for treating Rheumatoid arthritis, Psoriatic arthritis, and Ulcerative Colitis.

It is available as Xeljanz in 5 mg tablet formulation. Tofacitinib is used off-label for polymyositis and PMR (polymyalgia Rheumatica).

We present here a brief discussion of one of our patients who developed transient Sjogren Syndrome after she was treated with Tofacitinib for severely symptomatic PMR.

Tofacitinib-induced Transient Sjogren Syndrome:

A 55-year-old female patient came for a follow-up in OPD. She was known to have hypertension and was on Losartan 50 mg with good control.

2 years back she had COVID pneumonia and remained hospitalized for a week. One year before this presentation, she developed severe body aches and pains with morning stiffness that lasted for more than one hour.

In addition, she had progressive weakness in her thighs and shoulders without tenderness or joint swellings.

She was investigated at that time in our OPD. Her laboratory workup, chemistry, and autoimmune profile were normal except for a very high sedimentation rate (ESR of 110 mm per hour).

She was investigated for myeloma, polymyositis, and chronic infections. All her labs were normal. 

A diagnosis of PMR (polymyalgia Rheumatica) was made and she was started on prednisolone 20 mg per day.

She noticed a dramatic improvement in her symptoms. Her prednisolone was tapered off to one tablet daily.

During the last six months before this presentation, she had about three flares in her symptoms which improved with increasing prednisolone dose for two weeks.

Because of the frequent flares in her symptoms, she was started on methotrexate about 3 months back at a dose of 10 mg weekly while continuing prednisolone at a dose of 5 mg daily.

However, her symptoms progressed and she was switched to Tofacitinib 5 mg twice daily.

After taking Tofacitinib for 2 to 4 weeks, her symptoms improved remarkably and her prednisolone was tapered to 5 mg every other day.

She reported “This is the first time in my life that I feel like a normal person. I can go jogging for more than an hour and do all my household activities without any difficulty”

 After 4 to 6 weeks, she developed symptoms of severe oral dryness and difficulty swallowing solids. She would wake up all night to take sips of water. She would drink water after every bolus of the meal.

She stated, “My tongue is like a piece of wood, although I am pain-free.”

On examination, she had dry oral mucosa, tongue, and posterior pharynx. She was taking sips of water continuously during the examination.

She had no arthritis or muscle weakness. Her systemic examination was also normal.

Her autoimmune profile (ANA and extractable nuclear antigen) was requested and she had strongly positive anti-SSA (Ro) and anti-SSB(La) antibodies.

A diagnosis of Sjogren’s syndrome was made. Because her initial autoimmune profile was normal, a drug-induced Sjogren’s was one of the differentials.

She was switched from Tofacitinib to Hydroxychloroquine and 5 mg prednisolone. Within a month, her symptoms of dry mouth resolved, almost completely.

Her sleep quality has improved and she is doing well with the pains so far. Her repeat ENA profile done a few days back came out to be normal.

A diagnosis of Tofacitinib-induced Sjogren’s syndrome was made. She is currently on our regular monthly follow-up.

Tofacitinib Induced Sjogren Syndrome: Discussion:

Tofacitinib-induced Sjogren syndrome is probably the first case in the literature associating Tofacitinib use with transient Sjogren syndrome.

Our patient was treated with Tofacitinib for PMR which is not an approved indication. However, studies have shown its effectiveness in patients with PMR [Ref].

In addition, our patient responded very well to Tofacitinib as her pain and stiffness markedly resolved.

Infections are among the dreaded complications of Tofacitinib. Immune dysregulation can result in other immune-mediated diseases.

What is Sjogren Syndrome?

Sjogren syndrome is an autoimmune disease. It affects the salivary glands and lacrimal glands. However, one-half of the patients also have systemic involvement including the joints, skin, kidneys, lungs, and brain [Ref].

Sjogren’s syndrome is further classified as:

• Primary Sjogren’s syndrome, and 
• Secondary Sjogren’s syndrome.

Primary Sjogren’s syndrome is referred to the disease when it occurs in isolation. However, patients with secondary Sjogren’s syndrome have an underlying connective tissue disease such as Rheumatoid arthritis and SLE (systemic lupus erythematosus).

Patients with Sjogren syndrome present with sicca symptoms. These include dry eyes and dry mouth.

Patients report sandy sensations in their eyes, dryness, frequent blinking, and eye pain. Oral dryness manifests as an inability to swallow solids and the need to take frequent sips of water during a meal.

Classically, the ‘cracker sign‘ is demonstrated by the patient as swallowing a cracker is much more difficult and the patient takes water while swallowing a cracker.

A long-standing disease may manifest as bad oral hygiene, oral ulcers, and dental caries.

Up to one-half of the patients have extra-glandular symptoms. These include [Ref]:

• Muscular and skeletal involvement:

Musculoskeletal involvement is the most common in patients with Sjogren’s syndrome.

Arthralgias have been observed in up to 96% [Ref] of the patients while a minority of the patients have arthritis (16%) [Ref].

Arthritis usually involves multiple joints in a symmetric pattern and may be intermittent. However, monoarthritis has been reported too.

Myalgias or muscular pains without inflammation have been reported in up to 70% of the patients [Ref]. Reports of myositis have also been reported.

• Skin manifestations:

Skin involvement is very variable. Patients may develop dry skin, purpura, redness, pigmentation, lichenification, and full-blown vasculitis.

Constant rubbing of the eyes due to dryness can lead to eyelid dermatitis. Patients may develop cutaneous amyloidosis in the late stages, which can present as nodules and purpura.

• Neurological involvement:

Neurological involvement occurs in up to 5% of the patients with primary Sjogren’s syndrome [Ref].

Here is the prevalence of main neurological manifestations according to a review article [Ref]

* Data from patients with central nervous system involvement

** Data from patients with peripheral nervous system involvement

Autonomic nervous system involvement has been reported too. These symptoms include a postural drop in blood pressure, tachycardia, bradycardia, and bladder and bowel dysfunction.

• Renal involvement:

Kidney involvement is commonly seen as chronic tubulointerstitial nephritis and Type 1 RTA (renal tubular acidosis).

Patients may develop hypokalemia and renal stones as a result of distal RTA. Membranoproliferative glomerulonephritis and cryoglobulinemic vasculitis have also been reported [Ref].

• Blood disorders in Sjogren’s Syndrome:

Hematological findings are commonly seen as leukopenia, thrombocytopenia, neutropenia, lymphopenia, hypogammaglobulinemia, or hypergammaglobulinemia and hypocomplementemia.

Monoclonal gammopathy and lymphoma (non-Hodgkins type) have been reported too.

• Lung involvement in Sjogren’s syndrome:

Lung involvement may manifest as xerotrachea, nasal crusting, rhinitis, sinusitis, epistaxis, and interstitial lung disease.

ILD may present as non-specific interstitial pneumonia, lymphocytic interstitial pneumonia, or usual interstitial pneumonia [Ref].

• GI involvement in Sjogren Syndrome:

GI involvement is very common. Patients typically report symptoms of GERD (gastroesophageal reflux disease) and dysphagia. Autonomic involvement and abdominal vasculitis have been reported too.

There have been reports of associated Celiac disease, autoimmune hepatitis, and primary biliary cirrhosis [Ref].

• Cardiac involvement:

Patients with Sjogren’s syndrome are highly at risk of developing atherosclerotic cardiovascular disease including Myocardial infarction and strokes.

Pulmonary hypertension, valvular regurgitation, and pericardial effusions have also been reported.

In addition to the above, constitutional symptoms are very common. Patients typically report fatigue, anxiety, fever, and symptoms of fibromyalgia. 

Hypothyroidism and anemia have also been reported in patients with Sjogren’s Syndrome.

• Cytokines involved in the pathogenesis of Sjogren syndrome:

Sjogren syndrome is caused by the imbalance between pro-inflammatory and anti-inflammatory cytokines [Ref].

The proinflammatory cytokines involved in Sjogren syndrome include:

• IL-6,
• IL-12,
• IL-18,
• IL-23,
• IL-1β,
• INF-α,
• INF-β,
• BAFF,
• IL-23,
• IL-17,
• IL-35

The anti-inflammatory cytokines include:

• IL-4, and 
• TGFβ

Although these cytokines have been blamed for causing Sjogren syndrome, there is still much to explore.

For example, IL-6 levels have been strongly associated with Sjogren syndrome. It has been found in the plasma and salivary glands of patients with Sjogren syndrome in an increased amount [Ref].

However, the IL-6 inhibitor (Tocilizumab, Actemra) is not effective in the treatment of patients with Sjogren Syndrome [Ref].

Tofacitinib Induced Sjogren Syndrome: Where is the link?

Tofacitinib is an inhibitor of the JAK-STAT pathway. There are four JAK enzymes, namely:

• JAK-1
• JAK-2
• JAK-3
• TYK2

There are 7 STAT transcription proteins, namely [Ref]:

• STAT1,
• STAT2,
• STAT3,
• STAT4,
• STAT5a,
• STAT5b, and
• STAT6

Activation of JAK phosphorylates STAT proteins which are responsible for gene expression and immune activation.

Tofacitinib exerts its effects on JAK-1 and JAK-3, resulting in immune suppression.

Tofacitinib suppresses the following Interleukins:

• IL-1β
• IL-2,
• IL-4
• IL-6 [Ref]
• IL-7,
• IL-9,
• IL-12
• IL-15,
• IL-17
• IL-21
• TNF-α, and
• IFN-γ

Four types of helper CD4 cells play an important role in the activation of immune and inflammatory conditions.

These are classified based on the Interleukins they release:

• Th1 secretes:
  • IFN-γ,
  • IL-2, and
  • TNF-β
• Th2 cells secrete:
  • IL-4,
  • IL-6,
  • IL-10, and
  • IL-13
• Th17 cells secrete:
  • IL-17
• Tregs:
  • IL-10
  • TGF-β
  • IL-35

IL-35 belongs to the IL-12 family that includes four different Interleukins, namely, IL-12, IL-23, IL-27, and IL-35.

Among these four Interleukins, the role of IL-35 is not fully known. It is believed to exert anti-inflammatory effects compared to IL-12 and IL-23 which are clearly pro-inflammatory.

Tofacitinib increased the levels of IL-35 [Ref]. IL-35 is mainly produced by Tregs. Decreased expression of IL-35 has been observed in patients with Sjogren syndrome [Ref].

There is no clear justification to link any specific cytokine with the development of Sjogren syndrome. However, it seems to be multifactorial and no single cytokine can be blamed.

This could be an imbalance between the pro-inflammatory and anti-inflammatory cytokines.

Take home message:

Tofacitinib acts by modulating immune and inflammatory cytokines. Likely, the balance maintained naturally between different cytokines and interleukins is disturbed by these new and very potent immune modulators.

This change could cause the development of more inflammatory conditions such as Sjogren syndrome in our patient who was treated for PMR.

In addition, early diagnosis and stopping of Tofacitinib resulted in the improvement of symptoms of Sjogren syndrome indicating reversibility.