How PI affects other body systems

Your thyroid is a small gland in the lower neck that makes hormones that are important for controlling how fast the body uses energy, along with growth and development. People that make too little thyroid hormone (hypothyroidism) usually gain weight, have a slow heartbeat, feel cold and tired, have trouble with bowel movements, and have rough hair and dry skin. On the other hand, people that make too much thyroid hormone (hyperthyroidism) usually lose weight, have a fast heartbeat, feel hot and anxious, and may have hair loss.

Sometimes, the body makes autoantibodies that attack the thyroid, causing inflammation (thyroiditis) that leads to either hypothyroidism or hyperthyroidism. Autoimmune thyroiditis, such as Hashimoto’s disease, is the most common autoimmune disease among the general population. In certain types of PI, including CVID and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, autoimmune thyroiditis is even more common.

High blood sugar levels over a long period of time is a condition known as diabetes. Diabetes can happen when the body doesn't make enough of the hormone insulin (type 1) or when the body's cells don't respond to insulin (type 2). Autoantibodies cause type 1 diabetes by attacking the islet cells in the pancreas that make insulin. Once these special cells are destroyed, they don’t grow back. When a person loses too many of these insulin-making cells, they develop diabetes.

Type 1 diabetes is very common in some PIs, like IPEX syndrome, where it affects up to 80% of individuals [9].

The parathyroid gland controls calcium levels in the body. Autoimmunity against this gland is rare, but does happen in people with APECED syndrome. The parathyroid gland can also be underdeveloped in some PIs such as 22q11.2 deletion (DiGeorge) syndrome or CHARGE syndrome. The main symptoms of hypoparathyroidism stem from dangerously low calcium levels and can include muscle spasms, cramps, twitching, numbness or tingling of the hands or feet, and irregular heartbeat. If untreated, low calcium levels can lead to seizures.

As with other types of infections, people with PI can develop infections of the musculoskeletal system, such as septic arthritis and osteomyelitis. Septic arthritis is when there’s an infection of the joint space. It causes joint pain and swelling, and may also cause fever. Osteomyelitis is when there is an infection in a bone. Symptoms of osteomyelitis include bone pain, tenderness or a feeling of heat near the infected bone, as well as general infection symptoms like fever and chills.

To diagnose septic arthritis, healthcare providers use a needle to collect a sample of the joint fluid. They look for high numbers of white blood cells, as well as germs, in the sample. Sometimes, providers do blood tests such as CBC, blood cultures, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) as well. Diagnosis of osteomyelitis includes similar blood tests but may also require imaging such as MRI. In some cases, a bone biopsy may be needed to make a diagnosis.

Both septic arthritis and osteomyelitis require antimicrobial treatment. Oftentimes, osteomyelitis requires several months of treatment. To help clear the infection, osteomyelitis may also require surgery in some cases.

People with particular types of PI develop septic arthritis or osteomyelitis more often than others. Antibody deficiencies, particularly X-linked agammaglobulinemia (XLA) and common variable immune deficiency (CVID), are linked to septic arthritis caused by several different types of bacteria [12]. In some cases, Mycoplasma spp. or Ureaplasma spp. bacteria cause the infection and can be difficult to diagnose because they are difficult to culture from patient samples.

Osteomyelitis can spread to the bone from the blood or develop from any deep infection that reaches the bone in a person with PI. However, those with chronic granulomatous disease (CGD) are at even higher risk of developing osteomyelitis [13]. In those with CGD, osteomyelitis is usually caused by bacteria like Serratia marcescens or fungi like Aspergillus spp.

Arthritis, or joint inflammation, is common both in people with PI and in people who don’t have PI. Different types of arthritis are named based on their root cause. Osteoarthritis is inflammation caused by joint ‘wear-and-tear.’ Rheumatoid, psoriatic, and juvenile idiopathic arthritis (RA, PA, and JIA, respectively) are conditions caused by autoantibodies attacking the joints.

People with PI don’t seem to have higher risk of osteoarthritis but some types of PI are linked to a higher chance of developing autoimmune arthritis. Unlike arthritis, myositis, which is muscle inflammation, is not very common in PI.

Many different antibody deficiencies have been connected to a greater risk of autoimmune arthritis [14]. One study found that about 15% of people with X-linked agammaglobulinemia (XLA) develop arthritis at some point [15]. People with CVID can develop rheumatoid arthritis or psoriatic arthritis, which also causes the skin condition psoriasis. These conditions can cause a lot of pain, limit daily activities, and potentially lead to lasting joint damage.

Common signs and symptoms of arthritis include joint pain and stiffness, swelling, and sometimes warmth or redness around the affected joints. Stiffness is often worse after not moving the joint, like in the morning or after resting, and it usually gets better with activity. When the arthritis is active, people may also have fevers, feel tired, and have a reduced appetite.

A physical exam by an experienced healthcare provider is extremely helpful in diagnosing arthritis. Your provider may refer you to a specialist called a rheumatologist for diagnosis and treatment.

Blood tests can help determine whether there is ongoing inflammation and look for specific autoantibodies, which may help determine what kind of arthritis someone has. X-rays, ultrasounds, CT scans, and MRIs of affected joints can show if there is active inflammation and if the joint has been damaged by arthritis. Sometimes, taking a sample of the fluid from inside the joint to test it can help determine the type of arthritis and make sure there is no infection in the joint. This is usually done by taking fluid out of the joint with a needle and syringe.

Treating arthritis often involves using medicines that weaken the immune system (immunosuppressants). Healthcare providers frequently first use steroids, like prednisone. These can be taken as pills, through an IV, or injected directly into the affected joints. They often work well for a while but can have serious side effects and do not prevent the arthritis itself from getting worse.

To better manage autoimmune arthritis, healthcare providers may use other immunosuppressants that aren't steroids. Because immunosuppressants weaken a person’s immune system further, they can make people with PI even more likely to get infections. To balance treating arthritis with preventing infections, your immunologist and rheumatologist need to coordinate these treatments together, and they may need to select therapies that don’t suppress your immune system as broadly.

People with many types of PI can get skin infections caused by viruses, bacteria, fungi, or even parasites [17,18]. Common viruses that can cause skin infections include varicella-zoster virus (chickenpox and shingles), human papillomavirus (HPV; warts), herpes simplex virus (HSV; cold sores and genital herpes) and molluscum contagiosum virus. Bacteria like Staphylococcus aureus can cause pus-filled bumps under the skin (abscesses) and bacteria or fungi like Pseudomonas spp. can cause an infection of deep skin layers called cellulitis.

Particular skin infections are linked to specific types of PI in some cases. For example, chronic skin and mucous membrane infections from Candida spp. fungi (mucocutaneous candidiasis) are common in people with STAT1 GOF or APECED. Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is part of a group of PIs that make people particularly vulnerable to warts and skin cancer from human papilloma virus (HPV). People with chronic granulomatous disease (CGD) can develop skin abscesses or cellulitis from several species of bacteria or fungi, including Serratia marcescens, S. aureus, Aspergillus spp. [19].

Eczema, also called atopic dermatitis, is a type of chronic inflammation of the skin. It is usually mild and is the most common skin problem in people with PI. It often starts as patches of dry, itchy skin that waxes and wanes in severity. People with PI who have other autoimmune or inflammatory conditions may also have eczema.

However, some types of PI cause more severe eczema. These include Wiskott-Aldrich syndrome (WAS), DOCK8 deficiency, IPEX syndrome, and some kinds of severe combined immunodeficiency (SCID). In these cases, the eczema may not respond to standard treatments such as topical steroid creams.

Psoriasis is an autoimmune skin problem that can be mistaken for eczema. The usual rash in psoriasis is called plaques. These plaques may be red, raised, itchy, and painful. These patches have a silvery scale on top. If the scale is removed, the plaque often bleeds. Psoriasis plaques are most common on the scalp, elbows, or knees. People with several types of PI, such as CVID, can develop psoriasis [20].

Several types of PI can cause the body to attack a person’s hair follicles, causing alopecia areata. People with alopecia areata develop bald spots because their body produces autoantibodies that target the cells, called hair follicles, responsible for hair growth. Alopecia areata specifically refers to circular areas of hair loss.

Additionally, some people develop vitiligo, a condition where the skin loses its coloring because the body produces autoantibodies that target the skin cells that make a pigment called melanin. The affected skin areas appear white, and how noticeable the change is depends on the contrast with the surrounding skin. The affected areas may change slightly over time.

Vitiligo and alopecia are most often linked to conditions like autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), CVID, IPEX, and 22q11.2 deletion (DiGeorge) syndrome, but they can also occur in other types of PI.